Research Annual Report 2007

Transcription

1 Research Annual Report 2007 MolecularMedicine (MM) Clinical and expiremental neuroendocrinology Regulation of calcium and bone metabolism Regulation of the bioactivity of thyroid hormone Signalling in reproduction and ageing Localisation, detection and radionuclide therapy of various diseases Regulation of follicle development, oocyte and endometrial embryo quality Pathophysiology of pediatric endocrine, metabolic and renal diseases Malignant transformation of hematopoietic stem cells: pathophysiology and development of therapy Hematopoiesis: regulation of the proliferation and differentiation of hematopoietic progenitor cells Molecular determinants of therapy response and outcome in childhood cancer Lymphoid differentiation and immunodeficiencies Immune regulation and autoimmunity Diagnosis, classification and treatment evaluation of leukemias and malignant lymphomas Solid tumors between bench and bed 28760, B&T Ontwerp en advies (

2 Research Annual Report 2007 MolecularMedicine (MM) Improving accuracy and therapeutic ratio in radiation oncology Hyperthermia: a treatment for cancer Photodynamic therapy Neuro-oncology and pain Pathophysiological aspects and treatment of gastro-intestinal diseases Surgical trauma and the development of tumour recurrence Innovative tumor model development/tumor vasculature/tumor targeting/locoregional control Clinical and experimental aspects of urological tumors Gynaecological oncology; basics, epidemiology and clinical aspects Developmental biology; pathophysiology of the newborn Experimental therapeutical approaches in inflammatory dermatoses and cutaneous oncology Tumour endocrinology, genetics, prognostic factors and experimental therapy of cancer Biological and clinical aspects of drug-resistance and -sensitivity of malignancies Clinical and experimental immuno(-gene) therapy 28760, B&T Ontwerp en advies (

3 Research Annual Report 2007 MolecularMedicine (MM) Neoplastic lesions and chronic inflammatation of the gastrointestinal tract Liverspecific immunopathology; mechanism and therapeutic modulation Human virus infections: immunity, therapy and epidemiology Infections due to bacteria, fungi and parasites: diagnosis, molecular mechanisms, epidemiology, therapy and prevention Clinical research in infectious diseases in adults Renal insufficiency and organ transplantation Cell biological and pathophysiological investigations on pulmonary diseases Neuromuscular and degenerative diseases of the nervous system Organ transplantation Genitourinary tract disorders in children Disorders of the gastrointestinal tract in childhood Clinical, epidemiological and basic research of infectious diseases and immunological diseases in children Sexually transmitted diseases 28760, B&T Ontwerp en advies (

4 EMC MM Clinical and expiremental neuroendocrinology Programme design in brief A. Studies on the regulation of hormone secretion by the normal pituitary gland as well as by human pituitary tumours in vivo and in vitro. B. An integrative approach to the endocrinology of ageing. Hormonal factors related to the ageing process are investigated in population studies. Intervention studies with hormones (growth hormone, dehydroepiandrosterone) are carried out. C. An integrative approach to factors determining glucocorticoid sensitivity in man. Molecular studies of mutations in the glucocorticoid receptor and in the translational regulation of glucocorticoid action are carried out in cells obtained from patients with glucocorticoid resistance and from patients with transient changes in glucocorticoid sensitivity. D. Studies on the expression of peptide receptors in cancer, and in immune cells. The regulation of the growth and activity of immunological and of tumour cells in vitro by manipulation of the expression of peptide receptors is studied in relation with the potential endocrine manipulation of immune diseases and cancer growth in vivo. E. An integrative approach of clinical and surgical endocrinology is used in studies aimed at improving patient care. F. Evaluation of the (metabolic) role of natural and synthetic growth hormone secretatogues in peripheral tissues in vitro and in vivo. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot internal medicine 1,7 2 1,15 1 5,85 reproduction and development 0, ,1 surgery 0, ,1 Total 1,9 2 1,15 1 6, Theses Lanting, L.C. (2007, februari 09). Ethnic differences in utilization of an outpatient clinic in The Netherlands - a study of diabetes patients and patients with gastrointestinal symptoms. EUR (138 pag.). Prom./coprom.: Prof.Dr. J.P. Mackenbach, Prof.Dr. S.W.J. Lamberts, Dr. I.M.A. Joung & Dr. A.H. Bootsma. Zandbergen, A.A.M. (2007, april 11). Inhibition of the renin-angiotensin system in normotensive type 2 diabetes. Effects and mechanisms of action. EUR. Prom./coprom.: Prof.Dr. S.W.J. Lamberts & Dr. A.H. Bootsma. Article/Letter to the editor Aken, M.O. van, Feelders, R.A. & Herder, W.W. de (2007). Cushing's syndrome in children (author's reply). Nederlands Tijdschrift voor Geneeskunde, 151, Daly, AF, Vanbellinghen, JF, Khoo, SK, Jaffrain-Rea, ML, Naves, LA, Guitelman, MA, Murat, A, Emy, P, Gimenez- Roqueplo, AP, Tamburrano, G, Raverot, G, Barlier, A, Herder, W. de, Penfornis, A, Ciccarelli, E, Estour, B, Lecomte, P, Gatta, B, Chabre, O, Sabate, MI, Bertagna, X, Basavilbaso, NG, Stalldecker, G, Colao, A., Ferolla, P, Wemeau, JL, Caron, P, Sadoul, JL, Oneto, A, Archambeaud, F, Calender, A, Sinilnikova, O, Montanana, CF, Cavagnini, F., Hana, V, Solano, A, Delettieres, D, Luccio-Camelo, DC, Basso, A, Rohmer, V, Brue, T, Bours, V, Teh, BT & Beckers, A. (2007). Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: Analysis in 73 families. Journal of Clinical Endocrinology and Metabolism, 92(5), Delhanty, P.J.D., Koetsveld, P.M. van, Gauna, C., Zande, B. van de, Vitale, G., Hofland, L.J. & Lely, A.J. van der (2007). Ghrelin and its unacylated isoform stimulate the growth of adrenocortical tumor cells via an anti-apoptotic pathway. American Journal of Physiology, Endocrinology and Metabolism, 293(1), E302-E309. Essen, M. van, Krenning, E.P., Bakker, W.H., Herder, W.W. de, Aken, M.O. van & Kwekkeboom, D.J. (2007). Peptide receptor radionuclide therapy with Lu-177-octreotate in patients with foregut carcinoid tumours of bronchial, gastric and thymic origin. European Journal of Nuclear Medicine and Molecular Imaging, 34(8), Fedele, M, Martino, I De, Pivonello, R., Ciarmiello, A, Caro, MLD De, Visone, R, Palmieri, D, Pierantoni, GM, Arra, C, Schmid, HA, Hofland, L., Lombardi, G., Colao, A. & Fusco, A (2007). SOM230, a new somatostatin analogue, is highly effective in the therapy of growth hormone/prolactin-secreting pituitary adenomas. Clinical Cancer Research, 13(9), Felder-Puig, R, Scherzer, C, Baumgartner, M., Ortner, M, Aschenbrenner, C, Bieglmayer, C, Voigtlander, T, Panzer- Grumayer, ER, Tissing, W.J.E., Koper, J.W., Steinberger, K, Nasel, C, Gadner, H., Topf, R. & Dworzak, M (2007). Glucocorticoids in the treatment of children with acute lymphoblastic leukemia and Hodgkin's disease: A pilot study on the adverse psychological reactions and possible associations with neurobiological, endocrine, and genetic markers. Clinical Cancer Research, 13(23),

5 Gauna, C., Uitterlinden, P., Kramer, P., Kiewiet, R.M., Janssen, J.A.M.J.L., Delhanty, P.J.D., Aken, M.O. van, Ghigo, E., Hofland, L.J., Themmen, A.P.N. & Lely, A.J. van der (2007). Intravenous glucose administration in fasting rats has differential effects on acylated and unacylated ghrelin in the portal and systemic circulation: A comparison between portal and peripheral concentrations in anesthetized rats. Endocrinology, 148(11), Gauna, C., Kiewiet, R.M., Janssen, J.A.M.J.L., Zande, BV De, Delhanty, P.J.D., Ghigo, E., Hofland, L.J., Themmen, A.P.N. & Lely, A.J. van der (2007). Unacylated ghrelin acts as a potent insulin secretagogue in glucose-stimulated conditions. American Journal of Physiology, Endocrinology and Metabolism, 293(3), E697-E704. Gonzalez Zuloeta Ladd, A.M., Liu, F., Houben, M.P.W.A., Arias Vasquez, A., Siemes, C., Janssens, A.C.J.W., Coebergh, J.W.W., Hofman, A., Janssen, J.A.M.J.L., Stricker, B.H.C. & Duijn, C.M. van (2007). IGF-1 CA repeat variant and breast cancer risk in postmenopausal women. European Journal of Cancer, 43(11), Grevenstein, W.M.U. van, Hofland, L.J., Rossen, M.E.E. van, Koetsveld, P.M. van, Jeekel, J. & Eijck, C.H.J. van (2007). Inflammatory Cytokines stimulate the adhesion of colon carcinoma cells to mesothelial monolayers. Digestive Diseases & Sciences, 52(10), Grevenstein, W.M.U. van, Aalbers, A.G.J., Raa, S. ten, Sluiter, W., Hofland, L.J., Jeekel, J. & Eijck, C.H.J. van (2007). Surgery-derived reactive oxygen species produced by polymorphonuclear leukocytes promote tumor recurrence: Studies in an in vitro model. Journal of Surgical Research, 140(1), Herder, W.W. de (2007). Biochemistry of neuroendocrine tumours. Best Practice & Research Clinical Endocrinology & Metabolism, 21(1), Herder, W.W. de, Reijs, A.E.M., Feelders, R.A., Aken, M.O. van, Krenning, E.P., Lely, A.J. van der & Kwekkeboom, D.J. (2007). Diagnostic imaging of dopamine receptors in pituitary adenomas. European Journal of Endocrinology, 156, S53- S56. Hoek, J. van der, Lamberts, S.W.J. & Hofland, L.J. (2007). Preclinical and clinical experiences with the role of somatostatin receptors in the treatment of pituitary adenomas. European Journal of Endocrinology, 156, S45-S51. Hofland, J., Nederveen, F.H. van, Timmerman, M.A., Korpershoek, E., Herder, W.W. de, Lenders, JW, Verhofstad, AA, Krijger, R.R. de & Jong, F.H. de (2007). Expression of activin and inhibin subunits, receptors and binding proteins in human pheochromocytomas: a study based on mrna analysis and immunohistochemistry. Clinical Endocrinology, 66(3), Hovind, P, Lamberts, S., Hop, W., Deinum, J., Tarnow, L., Parving, HH & Janssen, J.A.M.J.L. (2007). An IGF-I gene polymorphism modifies the risk of developing persistent microalbuminuria in type 1 diabetes. European Journal of Endocrinology, 156(1), Jonkers, YMH, Claessen, SMH, Perren, A, Schmitt, AM, Hofland, L.J., Herder, W. de, Krijger, R.R. de, Verhofstad, AAJ, Hermus, A.R., Kummer, JA, Skogseid, B, Volante, M., Voogd, A.C., Ramaekers, F.C.S. & Speel, E.J.M. (2007). DNA copy number status is a powerful predictor of poor survival in endocrine pancreatic tumor patients. Endocrine-Related Cancer, 14(3), Kate, M. ten, Aalbers, A.G.J., Sluiter, W., Hofland, L.J., Sonneveld, P., Jeekel, J. & Eijck, C.H.J. van (2007). Polymorphonuclear leukocytes increase the adhesion of circulating tumor cells to microvascular endothelium. Anticancer Research, 27(1A), Korpershoek, E., Petri, B.J., Nederveen, F.H. van, Dinjens, W.N.M., Verhofstad, AA, Herder, W.W. de, Schmid, S, Perren, A, Komminoth, P. & Krijger, R.R. de (2007). Candidate gene mutation analysis in bilateral adrenal pheochromocytoma and sympathetic paraganglioma. Endocrine-Related Cancer, 14(2), Kumsta, R., Entringer, S, Koper, J.W., Rossum, E.F.C. van, Hellhammer, D.H. & Wust, S (2007). Sex specific associations between common glucocorticoid receptor gene variants and hypothalamus-pituitary-adrenal axis responses to psychosocial stress. Biological Psychiatry, 62(8), Kwekkeboom, D.J., Teunissen, J.J.M., Kam, B.L.R., Valkema, R., Herder, W.W. de & Krenning, E.P. (2007). Treatment of patients who have endocrine gastroenteropancreatic tumors with radiolabeled somatostatin analogues. Hematology- Oncology Clinics of North America, 21(3), Neggers, S.J.C.M.M., Aken, M.O. van, Janssen, J.A.M.J.L., Feelders, R.A., Herder, W.W. de & Lely, A.J. van der (2007). Long-term efficacy and safety of combined treatment of somatostatin analogs and Pegvisomant in acromegaly. Journal of Clinical Endocrinology and Metabolism, 92(12), Peeters, R.P., Deure, W.M. van der, Beld, A.W. van den, Toor, H. van, Lamberts, S.W.J., Janssen, J.A.M.J.L., Uitterlinden, A.G. & Visser, T.J. (2007). The Asp727Glu polymorphism in the TSH receptor is associated with insulin resistance in healthy elderly men. Clinical Endocrinology, 66(6),

6 Pivonello, R., Ferone, D., Herder, W.W. de, Faggiano, A, Bodei, L., Krijger, R.R. de, Lombardi, G., Colao, A., Lamberts, S.W.J. & Hofland, L.J. (2007). Dopamine receptor expression and function in corticotroph ectopic tumors. Journal of Clinical Endocrinology and Metabolism, 92(1), Pivonello, R., Ferone, D., Lombardi, G., Colao, A., Lamberts, S.W.J. & Hofland, L.J. (2007). Novel insights in dopamine receptor physiology. European Journal of Endocrinology, 156, S13-S21. Rolleman, E.J., Kooij, P.P.M., Herder, W.W. de, Valkema, R., Krenning, E.P. & Jong, M. de (2007). Somatostatin receptor subtype 2-mediated uptake of radiolabelled somatostatin analogues in the human kidney. European Journal of Nuclear Medicine and Molecular Imaging, 34(11), Russcher, H., Dalm, V.A.S.H., Jong, F.H. de, Brinkmann, A.O., Hofland, L.J., Lamberts, S.W.J. & Koper, J.W. (2007). Associations between promoter usage and alternative splicing of the glucocorticoid receptor gene. Journal of Molecular Endocrinology, 38(1-2), Sant, HP van't, Bouvy, N.D., Kazemier, G., Bonjer, H.J., Hop, W.C.J., Feelders, R.A., Herder, W.W. de & Krijger, R.R. de (2007). The prognostic value of two different histopathological scoring systems for adrenocortical carcinomas. Histopathology, 51(2), Smit, P., Dekker, M.J.H.J., Jong, F.J. de, Beld, A.W. van den, Koper, J.W., Pols, H.A.P., Brinkmann, A.O., Jong, F.H. de, Breteler, M.M.B. & Lamberts, S.W.J. (2007). Lack of association of the 11 beta-hydroxysteroid dehydrogenase type 1 gene 83,557insA and hexose-6-phosphate dehydrogenase gene R453Q polymorphisms with body composition, adrenal androgen production, blood pressure, glucose metabolism, and dementia. Journal of Clinical Endocrinology and Metabolism, 92(1), Vitale, G., Eijck, C.H.J. van, Koetsveld, P.M. van, Erdmann, JI, Speel, E.J.M., Wansem, K. van der, Mooij, D.M., Colao, A., Lombardi, G., Croze, E, Lamberts, S.W.J. & Hofland, L.J. (2007). Type I Interferons in the treatment of pancreatic cancer - Mechanisms of action and role of related receptors. Annals of Surgery, 246(2), Winsen, LML van, Veen, T., Rossum, E.F.C. van, Koper, J.W., Barkhof, F., Polman, C.H. & Ultdehaag, BMJ (2007). Glucocorticoid receptor gene polymorphisms associated with more aggressive disease phenotype in MS. Journal of Neuroimmunology, 186(1-2), Yazdan Panah, M., Aulchenko, Y.S., Hofman, A., Janssen, J.A., Sayed-Tabatabaei, F.A., Schaik, R.H.N. van, Klungel, O.H., Stricker, B.H.C., Pols, H.A.P., Witteman, J.C.M., Lamberts, S.W.J., Oostra, B.A. & Duijn, C.M. van (2007). Effects of the renin-angiotensin system genes and salt sensitivity genes on blood pressure and atherosclerosis in the total population and patients with type 2 diabetes. Diabetes, 56, Zandbergen, A.A.M., Vogt, L, Zeeuw, D. de, Lamberts, S.W.J., Ouwendijk, R.J.Th., Baggen, M.G.A. & Bootsma, A.H. (2007). Change in albuminuria is predictive of cardiovascular outcome in normotensive patients with type 2 diabetes and microalbuminuria. Diabetes Care, 30(12), Part of book - abstract Herder, W.W. de, Kwekkeboom, D.J. & Lips, C.J.M. (2007). Neuroendocriene tumoren. In E.P. Krenning, W.M. Wiersinga, S.W.J. Lamberts, F. Nobels & R. Bouillon (Eds.), Endocrinologie (pp ). Maarssen: Elsevier Gezondheidszorg. Janssen, J.A.M.J.L. & Lips, C.J.M. (2007). Pathogenese van endocrine ziekten. In E.P. Krenning, W.M. Wiersinga, S.W.J. Lamberts, F. Nobels & R. Bouillon (Eds.), Endocrinologie (pp ). Maarssen: Elsevier Gezondheidszorg. Koper, F.J.W. (2007). Glucocorticoid receptor mutations and polymorphisms. In G. Flink (Ed.), Encyclopedia of stress (2e edition) (pp ). Oxford: Academic Press. Lelij, A.J. van der, Abs, R. & Velkeniers, B. (2007). Hypothalamus en hypofyse. In E.P. Krenning, W.M. Wiersinga, S.W.J. Lamberts, F. Nobels & R. Bouillon (Eds.), Endocrinologie (pp ). Maarssen: Elsevier Gezondheidszorg. Romijn, J.A., Gaal, L. van & Lelij, A.J. van der (2007). Energiehuishouding en obesitas. In E.P. Krenning, W.M. Wiersinga, S.W.J. Lamberts, F. Nobels & R. Bouillon (Eds.), Endocrinologie (pp ). Maarssen: Elsevier Gezondheidszorg. Visser, T.J., Hofland, L.J., Themmen, A.P.N. & Verhoeven, G. (2007). Werkingsmechanisme van hormonen. In E.P. Krenning, W.M. Wiersinga, S.W.J. Lamberts, F. Nobels & R. Bouillon (Eds.), Endocrinologie (pp ). Maarssen: Elsevier Gezondheidszorg.

7 EMC MM Regulation of calcium and bone metabolism Programme design in brief Research focus is skeletal and calcium homeostasis and development and progression of related disorders with particular emphasis on ageing. Increasing life span is accompanied by an increase in age-related diseases such as osteoporosis. osteoporosis is an important common disease with a large impact on quality of life as well as health care budget. Development of pharmaceutical and life style interventions as prevention or as treatment is important and requires an optimal knowledge in aetiology and mechanisms of development of osteoporosis. Current therapies for osteoporosis are directed to inhibit bone loss and thereby its progression. There is, however, a major need for anabolic therapies which stimulate bone formation because bone loss has already occurred when the consequences of osteoporosis have become overt. Directly coupled to this improvement in early diagnostics. The overall aim of this research line is to develop better diagnostics and therapies for skeletal disorders and disturbances in calcium homeostatis by a combination of molecular, cellular, animal, epidemiological and eventually clinical studies. Four integrated lines of research can be identified 1) Characterisation of molecular mechanisms of bone cell differentation and bone formation and degradation uging human bone cell models by bioinformatic and systems biological analyses of gene, protein and enzyme activity profiles 2) Identification of risk determinants for osteoporosis and osteoarthritis on basis of genetic epidemiological and serum proteomic studies within a.o. the Rotterdam Study 3) Calcium homeostasis and skeletal metabolism in relation to ageing by analyses of experimental animal models, e.g. premature ageing mice, as well as human population research. 4) Development of medium/high throughtput screenings procedures to quickly screen therapeutic targets and to evaluate novel therapeutic compounds Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot internal medicine 4,1 7, ,22 Total 4,1 7, , Theses Eijken, H.J.M. (2007, september 05). Human osteoblast differentiation and bone formation: growth factors, hormones and regulatory networks. EUR. Prom./coprom.: Prof.dr. J.P.T.M. van Leeuwen. Koeijvoets, K.C.M.C. (2007, september 12). Complex genetics of monogenic familial hypercholesterolemia. EUR. Prom./coprom.: Prof.Dr. H.A.P. Pols. Piersma, D. (2007, januari 27). The role of the hupothalamus-pituitary-gonadal axis in breast cancer; a candidate gene approach. EUR (157 pag.). Prom./coprom.: Prof.Dr. H.A.P. Pols, Dr.Ir. A.P.N. Themmen & Dr. P.M.J.J. Berns. Siemes, C. (2007, mei 09). New insights into genetic variation and cancer. EUR. Prom./coprom.: Prof.Dr. H.A.P. Pols. Velde, N. van der (2007, mei 23). Falls in old age: pills, the heart and beyond; Withdrawal of drugs and screening for cardiovascular causes in older fallers. EUR. Prom./coprom.: Prof.Dr. B.H.C. Stricker, Prof.Dr. H.A.P. Pols & T.J.M. van der Cammen. Yazdan Panah, M. (2007, december 05). Genetic determinants of homocysteine in relation to bone health. EUR. Prom./coprom.: Prof.Dr. H.A.P. Pols. Article/Letter to the editor Aarnoudse, A.L.H.J., Newton-Cheh, C, Bakker, PIW de, Straus, S.M.J.M., Kors, J.A., Hofman, A., Uitterlinden, A.G., Witteman, J.C.M. & Stricker, B.H.C. (2007). Common NOS1AP variants are associated with a prolonged QTc interval in the Rotterdam study. Circulation, 116(1), Alizadeh, B.Z., Njajou, OT, Hazes, J.M.W., Hofman, A., Slagboom, P.E., Pols, H.A.P. & Duijn, C.M. van (2007). The H63D variant in the HFE gene predisposes to arthralgia, chondrocalcinosis and osteoarthritis. Annals of the Rheumatic Diseases, 66(11), Aulchenko, Y.S., Pullen, J., Kloosterman, WP, Yazdan Panah, M., Hofman, A., Vaessen, N., Snijders, P.J.L.M., Zubakov, D., Mackay, I, Olavesen, M, Sidhu, B, Smith, VE, Carey, A, Berezikov, E, Uitterlinden, A.G., Plasterk, R.H.A., Oostra, B.A. & Duijn, C.M. van (2007). LPIN2 is associated with type 2 diabetes, glucose metabolism, and body composition. Diabetes, 56(12), Boekhoorn, S.S., Vingerling, J.R., Uitterlinden, A.G., Meurs, J.B.J. van, Duijn, C.M. van, Pols, H.A.P., Hofman, A. & Jong, P.T.V.M. de (2007). Estrogen receptor alpha gene polymorphisms associated with incident aging macula disorder. Investigative Ophthalmology & Visual Science, 48(3),

8 Born, BJH van den, Montfrans, GA van, Uitterlinden, A.G., Zwinderman, A.H. & Koopmans, RP (2007). The M235T polymorphism in theangiotensinogen gene is associated with the risk of malignant hypertension in white patients. Journal of Hypertension, 25(11), Brouwer, GM, Tol, AW van, Bergink, A.P., Belo, J.N., Bernsen, R.M.D., Reijman, M., Pols, H.A.P. & Bierma-Zeinstra, S.M.A. (2007). Association between valgus and varus alignment and the development and progression of radiographic osteoarthritis of the knee. Arthritis & Rheumatism, 56(4), Dahaghin, S., Bierma-Zeinstra, S.M.A., Koes, B.W., Hazes, J.M.W. & Pols, H.A.P. (2007). Do metabolic factors add to the effect of overweight on hand osteoarthritis? The Rotterdam Study. Annals of the Rheumatic Diseases, 66(7), Dehghan, A., Kardys, I., Maat, M.P.M. de, Uitterlinden, A.G., Sijbrands, E.J.G., Bootsma, A.H., Stijnen, T., Hofman, A., Schram, M.T. & Witteman, J.C.M. (2007). Genetic variation, C-reactive protein levels, and incidence of diabetes. Diabetes, 56(3), Delmas, P.D., Vrijens, B, Eastell, R., Roux, C, Pols, H.A.P., Ringe, JD, Grauer, A, Cahall, D & Watts, NB (2007). Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis. Journal of Clinical Endocrinology and Metabolism, 92(4), Easton, D.F., Pooley, KA, Dunning, A.M., Pharoah, PDP, Thompson, D., Ballinger, DG, Struewing, J.P., Morrison, J, Field, H, Luben, R, Wareham, N, Ahmed, S., Healey, CS, Bowman, R, Meyer, KB, Haiman, CA, Kolonel, LK, Henderson, BE, Marchand, L Le, Brennan, P, Sangrajrang, S, Gaborieau, V, Odefrey, F., Shen, CY, Wu, PE, Wang, HC, Eccles, D., Evans, D.G., Peto, J., Fletcher, O, Johnson, N, Seal, S., Stratton, M.R., Rahman, N., Chenevix-Trench, G., Bojesen, SE, Nordestgaard, BG, Axelsson, CK, Garcia-Closas, M, Brinton, L, Chanock, S, Lissowska, J, Peplonska, B, Nevanlinna, H., Fagerholm, R, Eerola, H., Kang, D, Yoo, KY, Noh, DY, Ahn, SH, Hunter, DJ, Hankinson, SE, Cox, DG, Hall, P., Wedren, S, Liu, JJ, Low, YL, Bogdanova, N, Schurmann, P, Dork, T., Tollenaar, R.A.E.M., Jacobi, C.E., Devilee, P., Klijn, J.G.M., Sigurdson, AJ, Doody, MM, Alexander, BH, Zhang, JH, Cox, A., Brock, IW, MacPherson, G, Reed, MWR, Couch, F.J., Goode, EL, Olson, JE, Meijers-Heijboer, H, Ouweland, A. van den, Uitterlinden, A., Rivadeneira Ramirez, F., Milne, RL, Ribas, G, Gonzalez-Neira, A, Benitez, J., Hopper, J.L., McCredie, M, Southey, M, Giles, G.G., Schroen, C, Justenhoven, C, Brauch, H, Hamann, U., Ko, YD, Spurdle, A.B., Beesley, J, Chen, XQ, Mannermaa, A., Kosma, VM, Kataja, V. & Hartikainen, J (2007). Genome-wide association study identifies novel breast cancer susceptibility loci. Nature, 447(7148), 1087-U7. Eijken, M, Swagemakers, S., Koedam, M., Steenbergen, C, Derkx, P., Uitterlinden, A.G., Spek, P.J. van der, Visser, J.A., Jong, F.H. de, Pols, H.A.P. & Leeuwen, J.P.T.M. van (2007). The activin A-follistatin system: potent regulator of human extracellular matrix mineralization. Faseb Journal, 21(11), Fang, Y., Meurs, J.B.J. van, Rivadeneira Ramirez, F., Schoor, N.M., Leeuwen, JPT van, Lips, P., Pols, H.A.P. & Uitterlinden, A.G. (2007). Vitamin D receptor gene haplotype is associated with body height and bone size. Journal of Clinical Endocrinology and Metabolism, 92(4), Gonzalez Zuloeta Ladd, A.M., Arias Vasquez, A., Siemes, C., Coebergh, J.W.W., Hofman, A., Witteman, J.C.M., Uitterlinden, A., Stricker, B.H.C. & Duijn, C.M. van (2007). Transforming-growth factor beta(1) Leu10Pro polymorphism and breast cancer morbidity. European Journal of Cancer, 43(2), Gregory, JS, Waarsing, J.H., Day, J., Pols, H.A., Reijman, M., Weinans, H. & Aspden, RM (2007). Early identification of radiographic osteoarthritis of the hip using an active shape model to quantify changes in bone morphometric features - Can hip shape tell us anything about the progression of osteoarthritis? Arthritis & Rheumatism, 56(11), Hak, A.E., Westendorp, I.C.D., Pols, H.A.P., Hofman, A. & Witteman, J.C.M. (2007). High dose testosterone is associated with atherosclerosis in postmenopausal women. Maturitas, 56(2), Ioannidis, JPA, Ng, M.Y., Sham, P.C., Zintzaras, E, Lewis, C.M., Deng, H.W., Econs, M.J., karasik, D., Devoto, M., Kammerer, CM, Spector, T., Andrew, T., Cupples, L.A., Duncan, E.L., Foroud, T., Kiel, DP, Koller, D., Langdahl, B., Mitchell, B.D., Peacock, M., Recker, R, Shen, H., Sol-Church, K., Spotila, LD, Uitterlinden, A.G., Wilson, S.G., Kung, A.W.C. & Ralston, S.H. (2007). Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. Journal of Bone and Mineral Research, 22(2), Isaacs, A.J., Sayed-Tabatabaei, F.A., Aulchenko, Y.S., Zillikens, M.C., Sijbrands, E.J.G., Schut, A.F.C., Rutten, W.P.F., Pols, H.A.P., Witteman, J.C.M., Oostra, B.A. & Duijn, C.M. van (2007). Heritabilities, apolipoprotein E, and effects of inbreeding on plasma lipids in a genetically isolated population: The Erasmus Rucphen Family Study. European Journal of Epidemiology, 22(2), Jaddoe, V.W.V.K., Bakker, R., Duijn, C.M. van, Heijden, A.J. van der, Lindemans, J., Mackenbach, J.P., Moll, H.A., Steegers, E.A.P., Tiemeier, H.W., Uitterlinden, A.G., Verhulst, F.C. & Hofman, A. (2007). The Generation R Study Biobank: a resource for epidemiological studies in children and their parents. European Journal of Epidemiology, 22(1),

9 Jong, F.J. de, Ikram, M.K., Despriet, D.D.G., Uitterlinden, A.G., Hofman, A., Breteler, M.M.B. & Jong, P.T.V.M. de (2007). Complement factor H polymorphism, inflammatory mediators, and retinal vessel diameters: the Rotterdam study. Investigative Ophthalmology & Visual Science, 48, Jong, F.J. de, Peeters, R.P., Heijer, T. den, Deure, W.M. van der, Hofman, A., Uitterlinden, A.G., Visser, T.J. & Breteler, M.M.B. (2007). The association of polymorphisms in the type 1 and 2 deiodinase genes with circulating thyroid hormone parameters and atrophy of the medial temporal lobe. Journal of Clinical Endocrinology and Metabolism, 92(2), Kaptoge, S, Reid, D.M., Scheidt-Nave, C., Poor, G., Pols, H.A.P., Khaw, KT, Felsenberg, D., Benevolenskaya, LI, Diaz, M.N., Stepan, J.J., Eastell, R., Boonen, S, Cannata, J.B., Glueer, CC, Crabtree, N.J., Kaufman, J.M. & Reeve, J. (2007). Geographic and other determinants of BMD change in European men and women at the hip and spine. A populationbased study from the Network in Europe for Male Osteoporosis (NEMO). Bone, 40(3), Kardys, I., Uitterlinden, A.G., Hofman, A., Witteman, J.C.M. & Maat, M.P.M. de (2007). Fibrinogen gene haplotypes in relation to risk of coronary events and coronary and extracoronary atherosclerosis: The Rotterdam Study. Thrombosis and Haemostasis, 97(2), Kardys, I., Maat, M.P.M. de, Klaver, C.C.W., Despriet, D.D.G., Uitterlinden, A.G., Hofman, A., Jong, P.T.V.M. de & Witteman, J.C.M. (2007). Usefulness of combining complement factor H and C-reactive protein genetic profiles for predicting myocardial infarction (from the Rotterdam study). American Journal of Cardiology, 100(4), Kevenaar, M.E., Themmen, A.P.N., Rivadeneira Ramirez, F., Uitterlinden, A.G., Laven, J.S.E., Schoor, N.M., Lips, P., Pols, H.A.P. & Visser, J.A. (2007). A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity. Human Reproduction, 22(9), Kevenaar, M.E., Themmen, A.P.N., Laven, J.S.E., Sonntag, B, Fong, SL, Uitterlinden, A.G., Jong, F.H. de, Pols, H.A.P., Simoni, M. & Visser, J.A. (2007). Anti-Mullerian hormone and anti-mullerian hormone type II receptor polymorphisms are associated with follicular phase estradiol levels in normo-ovulatory women. Human Reproduction, 22(6), Mos, M. de, Koevoet, WJLM, Jahr, H., Verstegen, M.M.A., Heijboer, M.P., Kops, N., Leeuwen, J.P.T.M. van, Weinans, H., Verhaar, J.A.N. & Osch, G.J.V.M. van (2007). Intrinsic differentiation potential of adolescent human tendon tissue: an invitro cell differentiation study. BioMed Central, 8. Peeters, R.P., Deure, W.M. van der, Beld, A.W. van den, Toor, H. van, Lamberts, S.W.J., Janssen, J.A.M.J.L., Uitterlinden, A.G. & Visser, T.J. (2007). The Asp727Glu polymorphism in the TSH receptor is associated with insulin resistance in healthy elderly men. Clinical Endocrinology, 66(6), Piersma, D., Verhoef-Post, M., Look, M.P., Uitterlinden, A.G., Pols, H.A.P., Berns, E.M.J.J. & Themmen, A.P.N. (2007). Polymorphic variations in exon 10 of the luteinizing hormone receptor: Functional consequences and associations with breast cancer. Molecular and Cellular Endocrinology, 276(1-2), Rijn, M.J.E. van, Schut, A.F.C., Aulchenko, Y.S., Deinum, J., Sayed-Tabatabaei, F.A., Yazdan Panah, M., Isaacs, A.J., Axenovich, T.I., Zorkoltseva, IV, Zillikens, M.C., Pols, H.A.P., Witteman, J.C.M., Oostra, B.A. & Duijn, C.M. van (2007). Heritability of blood pressure traits and the genetic contribution to blood pressure variance explained by four bloodpressure-related genes. Journal of Hypertension, 25(3), Rivadeneira Ramirez, F., Zillikens, M.C., Laet, CE De, Hofman, A., Uitterlinden, A.G., Beck, T.J. & Pols, H.A.P. (2007). Femoral neck BMD is a strong predictor of hip fracture susceptibility in elderly men and women because it detects cortical bone instability: The Rotterdam study. Journal of Bone and Mineral Research, 22(11), Schoor, N.M., Dennison, E, Lips, P., Uitterlinden, A.G. & Cooper, C. (2007). Serum fasting cortisol in relation to bone, and the role of genetic variations in the glucocorticoid receptor. Clinical Endocrinology, 67(6), Seminara, D, Khoury, MJ, O'Brien, TR, Manolio, T, Gwinn, ML, Little, J, Higgins, JP T, Bernstein, JL, Boffetta, P., Bondy, M, Bray, MS, Brenchley, PE, Buffler, PA, Casas, JP, Chokkalingam, AP, Danesh, J, Smith, G.D., Dolan, S, Duncan, R, Gruis, NA, Hashibe, M, Hunter, D, Jarvelin, MR, Malmer, B, Maraganore, D.M., Newton-Bishop, JA, Riboli, E, Salanti, G, Taioli, E, Timpson, N, Uitterlinden, A.G., Vineis, P, Wareham, N, Winn, DM, Zimmern, R & Ioannidis, JPA (2007). The emergence of networks in human genome epidemiology - Challenges and opportunities. Epidemiology, 18(1), 1-8. Sie, M.P.S., Mattace Raso, F.U.S., Uitterlinden, A.G., Arp, P.P., Hofman, A., Hoeks, A.P.G., Reneman, R.S., Asmar, R., Duijn, C.M. van & Witteman, J.C.M. (2007). TGF-beta 1 polymorphisms and arterial stiffness; the Rotterdam Study. Journal of Human Hypertension, 21(6), Smit, P., Dekker, M.J.H.J., Jong, F.J. de, Beld, A.W. van den, Koper, J.W., Pols, H.A.P., Brinkmann, A.O., Jong, F.H. de, Breteler, M.M.B. & Lamberts, S.W.J. (2007). Lack of association of the 11 beta-hydroxysteroid dehydrogenase type 1 gene 83,557insA and hexose-6-phosphate dehydrogenase gene R453Q polymorphisms with body composition, adrenal androgen production, blood pressure, glucose metabolism, and dementia. Journal of Clinical Endocrinology and Metabolism, 92(1),

10 Stolk, L., Meurs, J.B.J. van, Jhamai, M, Arp, P.P., Leeuwen, J.P.T.M. van, Hofman, A., Jong, F.H. de, Pols, H.A.P. & Uitterlinden, A.G. (2007). The catechol-o-methyltransferase Met(158) low-activity allele and association with nonvertebral fracture risk in elderly men. Journal of Clinical Endocrinology and Metabolism, 92(8), Tas, U., Verhagen, A.P., Bierma-Zeinstra, S.M.A., Hofman, A., Odding, E., Pols, H.A.P. & Koes, B.W. (2007). Incidence and risk factors of disability in the elderly: The Rotterdam Study. Preventive Medicine, 44(3), Velde, N. van der, Stricker, B.H.C., Pols, H.A.P. & Cammen, T.J.M. van der (2007). Risk of falls after withdrawal of fallrisk-increasing drugs: a prospective cohort study. British Journal of Clinical Pharmacology, 63(2), Velde, N. van der, Stricker, B.H.C., Pols, H.A.P. & Cammen, T.J.M. van der (2007). Withdrawal of fall-risk-increasing drugs in older persons - Effect on mobility test outcomes. Drugs & Aging, 24(8), Velde, N. van der, Meiracker, A.H. van den, Pols, H.A.P., Stricker, B.H.C. & Cammen, T.J.M. van der (2007). Withdrawal of fall-risk-increasing drugs in older persons: Effect on tilt-table test outcomes. Journal of American Geriatrics Society, 55(5), Vilarino-Guell, C, Miles, L.J., Duncan, E.L., Ralston, S.H., Compston, J.E., Cooper, C., Langdahl, BL, MacLelland, A., Pols, H.A., Reid, D.M., Uitterlinden, A.G., Steer, CD, Tobias, JH, Wass, J.A. & Brown, M.A. (2007). PTHR1 polymorphisms influence BMD variation through effects on the growing skeleton. Calcified Tissue International, 81(4), Visser, L.E., Schaik, R.H.N. van, Danser, A.H.J., Hofman, A., Witteman, J.C.M., Duijn, C.M. van, Uitterlinden, A.G., Pols, H.A.P. & Stricker, B.H.C. (2007). The risk of myocardial infarction in patients with reduced activity of cytochrome P4502C9. Pharmacogenetics Genomics, 17(7), Westbroek, I., Waarsing, J.H., Leeuwen, J.P.T.M. van, Waldum, H, Reseland, JE, Weinans, H., Syversen, U & Gustafsson, BI (2007). Long-term fluoxetine administration does not result in major changes in bone architecture and strength in growing rats. Journal of Cellular Biochemistry, 101(2), Yazdan Panah, M., Zillikens, M.C., Rivadeneira Ramirez, F., Jong, R. de, Lindemans, J., Uitterlinden, A.G., Pols, H.A.P. & Meurs, J.B.J. van (2007). Effect of dietary B vitamins on BMD and risk of fracture in elderly men and women: The Rotterdam Study. Bone, 41(6), Yazdan Panah, M., Aulchenko, Y.S., Hofman, A., Janssen, J.A., Sayed-Tabatabaei, F.A., Schaik, R.H.N. van, Klungel, O.H., Stricker, B.H.C., Pols, H.A.P., Witteman, J.C.M., Lamberts, S.W.J., Oostra, B.A. & Duijn, C.M. van (2007). Effects of the renin-angiotensin system genes and salt sensitivity genes on blood pressure and atherosclerosis in the total population and patients with type 2 diabetes. Diabetes, 56, Yazdan Panah, M., Rivadeneira Ramirez, F., Meurs, J.B.J. van, Zillikens, M.C., Arp, P., Hofman, A., Duijn, C.M. van, Pols, H.A.P. & Uitterlinden, A.G. (2007). The-1997 G/T and sp1 polymorphisms in the collagen type I alpha1 (COLIA1) gene in relation to changes in femoral neck bone mineral density and the risk of fracture in the elderly: The Rotterdam study. Calcified Tissue International, 81(1), Patent Leeuwen, J.P.T.M. van & Eijken, H.J.M. (). Controlled bone mineralization. no PCT/NL/2007/

11 EMC MM Regulation of the bioactivity of thyroid hormone Programme design in brief The prohormone T4 is converted by outer ring deiodination to the active hormone T3 and by inner ring deiodination to the inactive metabolite rt3. The three deiodinases (D1-3) involved are expressed in different tissues, where they play different roles in systemic and local control of T3 levels. The deiodinases are located in cell membranes with their active site exposed to the cytoplasm, while the T3 receptors reside in the nucleus. Uptake of thyroid hormone across the plasma membrane is thus required for thyroid hormone action and metabolism, and is mediated by specific transporters. Recently, our group identified an important T3 transporter (MCT8) which was shown to be mutated in patients with severe psychomotor retardation and grossly elevated serum T3 levels. This project concerns the characterization of the deiodinases and transporters in human tissues as well as their importance in the regulation of the bioactivity of thyroid hormone in health and disease Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot internal medicine 0,5 5, ,13 nuclear medicine 0, ,2 Total 0,7 5, , Article/Letter to the editor Barrett, P, Ebling, FJP, Schuhler, S, Wilson, D, Ross, AW, Warner, A, Jethwa, P, Boelen, A., Visser, T.J., Ozanne, DM, Archer, ZA, Mercer, JG & Morgan, PJ (2007). Hypothalamic thyroid hormone catabolism acts as a gatekeeper for the seasonal control of body weight and reproduction. Endocrinology, 148(8), Bolk, N., Visser, T.J., Kalsbeek, A, Domburg, R.T. van & Berghout, A. (2007). Effects of evening vs morning thyroxine ingestion on serum thyroid hormone profiles in hypothyroid patients. Clinical Endocrinology, 66(1), Breeman, W.A.P., Kwekkeboom, D.J., Blois, E. de, Jong, M. de, Visser, T.J. & Krenning, E.P. (2007). Radiolabelled regulatory peptides for imaging and therapy. Anti-Cancer Agents in Medical Chemistry, 7, Cederroth, CR, Vinciguerra, M, Kuhne, F, Madani, R, Doerge, DR, Visser, T.J., Foti, M, Rohner-Jeanrenaud, F., Vassalli, JD & Nef, S (2007). A phytoestrogen-rich diet increases energy expenditure and decreases adiposity in mice. Environmental Health Perspectives, 115(10), Deure, W.M. van der, Peeters, R.P. & Visser, T.J. (2007). Genetic variation in thyroid hormone transporters. Best Practice & Research Clinical Endocrinology & Metabolism, 21(2), Festen, D.A.M., Visser, T.J., Otten, B.J., Wit, J.M., Duivenvoorden, H.J. & Hokken-Koelega, A.C.S. (2007). Thyroid hormone levels in children with Prader-Willi syndrome before and during growth hormone treatment. Clinical Endocrinology, 67(3), Forhead, AJ, Jellyman, JK, Gardner, DS, Giussani, DA, Kaptein, E., Visser, T.J. & Fowden, AL (2007). Differential effects of maternal dexamethasone treatment on circulating thyroid hormone concentrations and tissue deiodinase activity in the pregnant ewe and fetus. Endocrinology, 148(2), Hansen, PS, Deure, W.M. van der, Peeters, R.P., Iachine, I, Fenger, M, Sorensen, T.I.A., Kyvik, KO, Visser, T.J. & Hegedus, L (2007). The impact of a TSH receptor gene polymorphism on thyroid-related phenotypes in a healthy Danish twin population. Clinical Endocrinology, 66(6), Jansen, J., Friesema, E.C.H., Kester, M.H.A., Milici, C, Reeser, M., Gruters, A, Barrett, T.G., Mancilla, E.E., Svensson, J., Wemeau, JL, Canalli, MHBD, Lundgren, J, McEntagart, ME, Hopper, N, Arts, W.F. & Visser, T.J. (2007). Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine. Journal of Clinical Endocrinology and Metabolism, 92(6), Jong, F.J. de, Peeters, R.P., Heijer, T. den, Deure, W.M. van der, Hofman, A., Uitterlinden, A.G., Visser, T.J. & Breteler, M.M.B. (2007). The association of polymorphisms in the type 1 and 2 deiodinase genes with circulating thyroid hormone parameters and atrophy of the medial temporal lobe. Journal of Clinical Endocrinology and Metabolism, 92(2), Mani, AR, Ippolito, S, Moreno, JC, Visser, T.J. & Moore, KP (2007). The metabolism and dechlorination of chlorotyrosine in vivo. Journal of Biological Chemistry, 282(40), Mebis, L., Langouche, L, Visser, T.J. & Berghe, G. van den (2007). The type II iodothyronine deiodinase is up-regulated in skeletal muscle during prolonged critical illness. Journal of Clinical Endocrinology and Metabolism, 92(8), Moreno, JC & Visser, T.J. (2007). New phenotypes in thyroid dyshormonogenesis: hypothyroidism due to DUOX2 mutations. Endocrine Development, 10,

12 Peeters, R.P., Deure, W.M. van der, Beld, A.W. van den, Toor, H. van, Lamberts, S.W.J., Janssen, J.A.M.J.L., Uitterlinden, A.G. & Visser, T.J. (2007). The Asp727Glu polymorphism in the TSH receptor is associated with insulin resistance in healthy elderly men. Clinical Endocrinology, 66(6), Rolleman, E.J., Krenning, E.P., Bernard, H.F., Visser, M., Bijster, M., Visser, T.J., Vermeij, M., Lindemans, J. & Jong, M. de (2007). Long-term toxicity of [Lu-177-DOTA(0),Tyr(3)]octreotate in rats. European Journal of Nuclear Medicine and Molecular Imaging, 34(2), Smit, J.W.A., Stokkel, MPM, Pereira, AM, Romijn, J.A. & Visser, T.J. (2007). Bexarotene-induced hypothyroidism: Bexarotene stimulates the peripheral metabolism of thyroid hormones. Journal of Clinical Endocrinology and Metabolism, 92(7), Thijssen-Timmer, DC, Peeters, R.P., Wouters, P., Weekers, F., Visser, T.J., Fliers, E., Wiersinga, W.M., Bakker, O. & Berghe, G. van den (2007). Thyroid hormone receptor isoform expression in livers of critically ill patients. Thyroid, 17(2), Trajkovic, M, Visser, T.J., Mittag, J., Horn, S, Lukas, J, Darras, V.M., Raivich, G, Bauer, K. & Heuer, H. (2007). Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8. Journal of Clinical Investigation, 117(3), Visser, T.J. (2007). Thyroid hormone transporters in health and disease - Preface. Best Practice & Research Clinical Endocrinology & Metabolism, 21(2), VII-VIII. Visser, W., Friesema, E.C.H., Jansen, J. & Visser, T.J. (2007). Thyroid hormone transport by monocarboxylate transporters. Best Practice & Research Clinical Endocrinology & Metabolism, 21(2),

13 EMC MM Signalling in reproduction and ageing Programme design in brief Glycoprotein hormones and members of the TGFß/activin family of growth and differentiation factors play a central role in development and functioning of the organism throughout life. This program focuses on the effect of variations in signal transduction of glycoprotein hormones (including LH, hcg, FSH and TSH) and TGFb family members (including anti- Mullerian hormone, BMPs, inhibins and activins) during foetal and postnatal development and subsequent ageing of the organism. Furthermore, effects of mutations or single nucleotide polymorphisms in enzymes involved in biosynthesis or catabolism of steroid hormones are investigated. Variations in signalling through these pathways affect the early make-up of physiological response systems that can have effects during adult life and in the ageing process. Signal transduction variations of ligand-receptor interaction, signal transduction, gene expression, proliferation and apoptosis are studied not only at the molecular and cellular level, bbut also at the level of the whole body in animal models of ageing and in populations of ageing men and women. Specific areas are: 1. The role of TGFß family members in female ageing, oestrogen effects and age at menopause 2. The role of LH and LH receptor variations in female ageing 3. The influence of polymorphic gene variants in female and male physiology 4. Development of animal models for the study of the role of genetic variations in the pathophysiology of ageing. 5. Causes and effects of changes in steroid biosynthetic pathways 6. Evaluation of the (metabolic) role of natural and synthetic growth hormone secretatogues in peripheral tissues in vitro and in vivo Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot internal medicine 3,78 1, ,11 Total 3,78 1, , Article/Letter to the editor Andreescu, C.E., Milojkovic, B., Haasdijk, E.D., Kramer, P., Jong, F.H. de, Krust, A., Zeeuw, C.I. de & Jeu, M.T.G. de (2007). Estradiol improves cerebellar memory formation by activating ER? Journal of Neuroscience, 27(40), Beek, R.D. van, Heuvel-Eibrink, M.M. van den, Laven, J.S.E., Jong, F.H. de, Themmen, A.P.N., Hakvoort-Cammel, F.G.A.J., Bos, C van den, Berg, H., Pieters, R. & Muinck Keizer-Schrama, S.M.P.F. (2007). Anti-mullerian hormone is a sensitive serum marker for gonadal function in women treated for Hodgkin's lymphoma during childhood. Journal of Clinical Endocrinology and Metabolism, 92(10), Beek, R.D. van, Smit, M., Heuvel-Eibrink, M.M. van den, Jong, F.H. de, Hakvoort-Cammel, F.G.A.J., Bos, C. van den, Berg, H. van den, Weber, R.F.A., Pieters, R. & Muinck Keizer-Schrama, S.M.P.F. (2007). Inhibin B is superior to FSH as a serum marker for spermatogenesis in men treated for Hodgkin's lymphoma with chemotherapy during childhood. Human Reproduction, 22(12), Delhanty, P.J.D., Koetsveld, P.M. van, Gauna, C., Zande, B. van de, Vitale, G., Hofland, L.J. & Lely, A.J. van der (2007). Ghrelin and its unacylated isoform stimulate the growth of adrenocortical tumor cells via an anti-apoptotic pathway. American Journal of Physiology, Endocrinology and Metabolism, 293(1), E302-E309. Eijken, M, Swagemakers, S., Koedam, M., Steenbergen, C, Derkx, P., Uitterlinden, A.G., Spek, P.J. van der, Visser, J.A., Jong, F.H. de, Pols, H.A.P. & Leeuwen, J.P.T.M. van (2007). The activin A-follistatin system: potent regulator of human extracellular matrix mineralization. Faseb Journal, 21(11), Elburg, AA van, Eijkemans, M.J.C., Kas, MJH, Themmen, A.P.N., Jong, F.H. de, Engeland, H. van & Fauser, B.C.J.M. (2007). Predictors of recovery of ovarian function during weight gain in anorexia nervosa. Fertility & Sterility, 87(4), Gauna, C., Uitterlinden, P., Kramer, P., Kiewiet, R.M., Janssen, J.A.M.J.L., Delhanty, P.J.D., Aken, M.O. van, Ghigo, E., Hofland, L.J., Themmen, A.P.N. & Lely, A.J. van der (2007). Intravenous glucose administration in fasting rats has differential effects on acylated and unacylated ghrelin in the portal and systemic circulation: A comparison between portal and peripheral concentrations in anesthetized rats. Endocrinology, 148(11), Gauna, C., Kiewiet, R.M., Janssen, J.A.M.J.L., Zande, BV De, Delhanty, P.J.D., Ghigo, E., Hofland, L.J., Themmen, A.P.N. & Lely, A.J. van der (2007). Unacylated ghrelin acts as a potent insulin secretagogue in glucose-stimulated conditions. American Journal of Physiology, Endocrinology and Metabolism, 293(3), E697-E704. Hehenkamp, WJK, Volkers, NA, Broekmans, F.J.M., Jong, F.H. de, Themmen, A.P.N., Birnie, E., Reekers, J.A. & Ankum, W.M. (2007). Loss of ovarian reserve after uterine artery embolization: a randomized comparison with hysterectomy. Human Reproduction, 22(7),

14 Hofland, J., Nederveen, F.H. van, Timmerman, M.A., Korpershoek, E., Herder, W.W. de, Lenders, JW, Verhofstad, AA, Krijger, R.R. de & Jong, F.H. de (2007). Expression of activin and inhibin subunits, receptors and binding proteins in human pheochromocytomas: a study based on mrna analysis and immunohistochemistry. Clinical Endocrinology, 66(3), Jong, F.H. de, Themmen, A.P.N. & Visser, J.A. (2007). Anti Mller-hormoon in serum als marker voor testiculaire en ovariële functies. Nederlands Tijdschrift voor Klinische Chemie en Laboratoriumgeneeskunde, Kevenaar, M.E., Themmen, A.P.N., Rivadeneira Ramirez, F., Uitterlinden, A.G., Laven, J.S.E., Schoor, N.M., Lips, P., Pols, H.A.P. & Visser, J.A. (2007). A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity. Human Reproduction, 22(9), Kevenaar, M.E., Themmen, A.P.N., Laven, J.S.E., Sonntag, B, Fong, SL, Uitterlinden, A.G., Jong, F.H. de, Pols, H.A.P., Simoni, M. & Visser, J.A. (2007). Anti-Mullerian hormone and anti-mullerian hormone type II receptor polymorphisms are associated with follicular phase estradiol levels in normo-ovulatory women. Human Reproduction, 22(6), Knauff, E.A.H., Richardus, R, Eijkemans, M.J., Broekinans, FJ, Jong, F.J. de, Fauser, B.C.J.M. & Bosch, A.M. van den (2007). Heterozygosity for the classical galactosemia mutation does not affect ovarian reserve and menopausal age. Reproductive Sciences, 14(8), McTavish, KJ, Jimenez, M, Walters, KA, Spaliviero, J, Groome, N.P., Themmen, A.P., Visser, J.A., Handelsman, DJ & Allan, CM (2007). Rising follicle-stimulating hormone levels with age accelerate female reproductive failure. Endocrinology, 148(9), Piersma, D., Themmen, A.P., Look, M.P., Klijn, J.G., Foekens, J.A., Uitterlinden, A.G., Pols, H. & Berns, EM (2007). GnRH and LHR gene variants predict adverse outcome in premenopausal breast cancer patients. Breast Cancer Research, 9(4). Piersma, D., Verhoef-Post, M., Berns, E.M.J.J. & Themmen, A.P.N. (2007). LH receptor gene mutations and polymorphisms: An overview. Molecular and Cellular Endocrinology, 260, Piersma, D., Verhoef-Post, M., Look, M.P., Uitterlinden, A.G., Pols, H.A.P., Berns, E.M.J.J. & Themmen, A.P.N. (2007). Polymorphic variations in exon 10 of the luteinizing hormone receptor: Functional consequences and associations with breast cancer. Molecular and Cellular Endocrinology, 276(1-2), Russcher, H., Dalm, V.A.S.H., Jong, F.H. de, Brinkmann, A.O., Hofland, L.J., Lamberts, S.W.J. & Koper, J.W. (2007). Associations between promoter usage and alternative splicing of the glucocorticoid receptor gene. Journal of Molecular Endocrinology, 38(1-2), Smit, P., Dekker, M.J.H.J., Jong, F.J. de, Beld, A.W. van den, Koper, J.W., Pols, H.A.P., Brinkmann, A.O., Jong, F.H. de, Breteler, M.M.B. & Lamberts, S.W.J. (2007). Lack of association of the 11 beta-hydroxysteroid dehydrogenase type 1 gene 83,557insA and hexose-6-phosphate dehydrogenase gene R453Q polymorphisms with body composition, adrenal androgen production, blood pressure, glucose metabolism, and dementia. Journal of Clinical Endocrinology and Metabolism, 92(1), Stolk, L., Meurs, J.B.J. van, Jhamai, M, Arp, P.P., Leeuwen, J.P.T.M. van, Hofman, A., Jong, F.H. de, Pols, H.A.P. & Uitterlinden, A.G. (2007). The catechol-o-methyltransferase Met(158) low-activity allele and association with nonvertebral fracture risk in elderly men. Journal of Clinical Endocrinology and Metabolism, 92(8), Visser, J.A., Durlinger, A.L.L., Peters, IJJ, Heuvel, ER van den, Rose, U.M., Kramer, P., Jong, F.H. de & Themmen, A.P.N. (2007). Increased oocyte degeneration and follicular atresia during the estrous cycle in anti-mullerian hormone null mice. Endocrinology, 148(5), Part of book - abstract Brinkmann, A.O. & Themmen, A.P.N. (2007). Hormonen werken meestal goed, maar soms ook niet. Hoe komt dat? In R. Abs, M.A. Bex, A.O. Brinkmann, R.A. Feelders, A.J. van der Lely & F. Nobels (Eds.), 33e Erasmus Endocrinologie Cursus (pp ). Rotterdam: Erasmusmc. Jong, F.H. de (2007). Steroid hydroxylases. In G. Fink (Ed.), Encyclopedia of stress (pp ). Oxford: Academic Press. Jong, F.H. de & Ronde, W. de (2007). Zijn geslachtshormonen seksegebonden? In R. Abs, M.A. Bex, A.O. Brinkmann, R.A. Feelders, A.J. van der Lely & F.R.E. Nobels (Eds.), 33e Erasmus Endocrinologie Cursus (pp ). Rotterdam: Erasmusmc. Visser, T.J., Hofland, L.J., Themmen, A.P.N. & Verhoeven, G. (2007). Werkingsmechanisme van hormonen. In E.P. Krenning, W.M. Wiersinga, S.W.J. Lamberts, F. Nobels & R. Bouillon (Eds.), Endocrinologie (pp ). Maarssen: Elsevier Gezondheidszorg.

15 EMC MM Localisation, detection and radionuclide therapy of various diseases Programme design in brief Detection of disease: (Pre)clinical development and use of radiolabeled pharmaceuticals (e.g. peptides, anti-sense molecules, 18F-deoxyglucose (FGD)) to localize and detect various diseases (e.g. tumour and heart imaging). Comparison of results with those of conventional imaging modalities (e.g. MRI, CT, US) and cost-benefit analyses. Investigation of predictive value of scintigraphy for success of various treatment modalities, e.g. unlabelled peptides versus cytostatic drugs. New radiolabelled peptide-analogues, such as of Bombesine, CCK, Substance P, neurotensin and adhesion molecules have been introduced for lesion visualization. As tumour cells have receptors on their surface for different peptides, many receptor-positive tumours may then be localized, possibly followed by therapy with unlabelled compound or by radionuclide therapy. Treatment of disease: As a new modality of cancer treatment, we introduced radionuclide therapy of somatostatin receptor-positive lesions by repeated administration of chelated somatostatin analogues (octreotide, [Tyr3]octreotide, [Tyr3]octreotate) radiolabelled with high doses of therapeutic radionuclides, like the auger electron emitter 111In, the high energy beta particle emitter 90Y and the low energy beta particle emitter 177Lu. Different phase1 studies have been started on radionuclide therapy of human tumours using these radiolabelled peptide analogues. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot nuclear medicine 3, ,94 5,24 surgery 0, ,1 Total 3, ,94 5, Theses Forrer, F. (2007, december 12). Targeted radionuclide therapy: current status and potentials for future improvements. EUR (123 pag.). Prom./coprom.: Prof.Dr.Ir. M. de Jong & HR Maecke. Rolleman, E.J. (2007, juni 14). Kidney protection during peptide receptor radionuclide therapy. EUR. Prom./coprom.: Prof.Dr. E.P. Krenning & Prof.Dr.Ir. M. de Jong. Verwijnen, S.M. (2007, december 12). Improvement of malignant glioma treatment: preclinical evaluation of adenoviral gene therapy and PRRT. EUR (244 pag.). Prom./coprom.: Prof.Dr.Ir. M. de Jong & Prof.Dr. P.A.E. Sillevis Smitt. Visser, M. de (2007, december 12). Bombesin and neurotensin receptor targeting using radiolabeled peptide analogs. EUR (176 pag.). Prom./coprom.: Prof.Dr.Ir. M. de Jong & Prof.Dr. E.P. Krenning. Article/Letter to the editor Breeman, W.A.P., Kwekkeboom, D.J., Blois, E. de, Jong, M. de, Visser, T.J. & Krenning, E.P. (2007). Radiolabelled regulatory peptides for imaging and therapy. Anti-Cancer Agents in Medical Chemistry, 7, Breeman, W.A.P. & Verbruggen, AM (2007). The Ge-68/Ga-68 generator has high potential, but when can we use Ga-68- labelled tracers in clinical routine? European Journal of Nuclear Medicine and Molecular Imaging, 34(7), Essen, M. van, Krenning, E.P., Bakker, W.H., Herder, W.W. de, Aken, M.O. van & Kwekkeboom, D.J. (2007). Peptide receptor radionuclide therapy with Lu-177-octreotate in patients with foregut carcinoid tumours of bronchial, gastric and thymic origin. European Journal of Nuclear Medicine and Molecular Imaging, 34(8), Essen, M. van, Krenning, E.P., Jong, M. de, Valkema, R. & Kwekkeboom, D.J. (2007). Peptide Receptor Radionuclide Therapy with radiolabelled somatostatin analogues in patients with somatostatin receptor positive tumours. Acta Oncologica, 46(6), Forrer, F., Rolleman, E.J., Schramm, N, Krenning, E.P. & Jong, M. de (2007). Bone and marrow imaging: do we know what we see and do we see what we want to know? Reply. European Journal of Nuclear Medicine and Molecular Imaging, 34(7), Forrer, F., Rolleman, E.J., Bijster, M., Melis, M., Bernard, H.F., Krenning, E.P. & Jong, M. de (2007). From outside to inside? Dose-dependent renal tubular damage after high-dose peptide receptor radionuclide therapy in rats measured with in vivo Tc-99m-DMSA-SPECT and molecular imaging. Cancer Biotherapy & Radiopharmaceuticals, 22(1), Forrer, F., Valkema, R., Kwekkeboom, D.J., Jong, M. de & Krenning, E.P. (2007). Peptide receptor radionuclide therapy. Best Practice & Research Clinical Endocrinology & Metabolism, 21(1), Gotthardt, M, Eerd-Vismale, J van, Oyen, W.J.G., Jong, M. de, Zhang, H., Maecke, HR, Behe, M., Boerman, O & Rolleman, E.J. (2007). Indication for different mechanisms of kidney uptake of radiolabeled peptides. Journal of Nuclear Medicine, 48(4),

16 Hennemann, G. & Krenning, E.P. (2007). The kinetics of thyroid hormone transporters and their role in non-thyroidal illness and starvation. Best Practice & Research Clinical Endocrinology & Metabolism, 21(2), Herder, W.W. de, Reijs, A.E.M., Feelders, R.A., Aken, M.O. van, Krenning, E.P., Lely, A.J. van der & Kwekkeboom, D.J. (2007). Diagnostic imaging of dopamine receptors in pituitary adenomas. European Journal of Endocrinology, 156, S53- S56. Herder, W.W. de, Kwekkeboom, D.J., Feelders, R.A., Aken, M.O. van, Lamberts, S.W.J., Lely, A.J. van der & Krenning, E.P. (2007). Afbeelding van somatostatinereceptoren bij endocriene tumoren. Somatoselectief, 1. Horst, M. ter, Brouwer, E., Verwijnen, S., Rodijk, M., Jong, M. de, Hoeben, R, Leeuw, B. de & Sillevis Smitt, P.A.E. (2007). Targeting malignant gliomas with a glial fibrillary acidic protein (GFAP)-selective oncolytic adenovirus. Journal of Gene Medicine, 9(12), Janssen, P.J.J.M., Visser, M., Verwijnen, S.M., Bernard, H.F., Srinivasan, A., Erion, J.L., Breeman, W.A.P., Vulto, A.G., Krenning, E.P. & Jong, M. de (2007). Five stabilized (111)in-labeled neurotensin analogs in nude mice bearing HT29 tumors. Cancer Biotherapy & Radiopharmaceuticals, 22(3), Konijnenberg, M, Melis, M., Valkema, R., Krenning, E.P. & Jong, M. de (2007). Radiation dose distribution in human kidneys by octreotides in peptide receptor radionuclide therapy. Journal of Nuclear Medicine, 48(1), Kwekkeboom, D.J., Teunissen, J.J.M., Kam, B.L.R., Valkema, R., Herder, W.W. de & Krenning, E.P. (2007). Treatment of patients who have endocrine gastroenteropancreatic tumors with radiolabeled somatostatin analogues. Hematology- Oncology Clinics of North America, 21(3), Melis, M., Krenning, E.P., Bernard, H.F., Visser, M., Rolleman, E.J. & Jong, M. de (2007). Renal uptake and retention of radiolabeled somatostatin, bombesin, neurotensin, minigastrin and CCK analogues: species and gender differences. Nuclear Medicine and Biology, 34(6), Melis, M.L., Forrer, F., Capello, A., Bijster, M., Bernard, H.F., Reubi, J.C., Krenning, E.P. & Jong, M. de (2007). Upregulation of somatostatin receptor density on rat CA20948 tumors escaped from low dose [(177)Lu-DOTA(0), Tyr(3)octreotate therapy. Quarterly Journal of Nuclear Medicine and Molecular Imaging, 51, Muller, C.M., Forrer, F., Bernard, H.F., Melis, M., Konijnenberg, M, Krenning, E.P. & Jong, M. de (2007). Diagnostic versus therapeutic doses of [Lu-177-DOTA-Tyr(3)]-octreotate: Uptake and dosimetry in somatostatin receptor-positive tumors and normal organs. Cancer Biotherapy & Radiopharmaceuticals, 22(1), Muller, C.M., Schibli, R, Forrer, F., Krenning, E.P. & Jong, M. de (2007). Dose-dependent effects of (anti)folate preinjection on Tc-99m-radiofolate uptake in tumors and kidneys. Nuclear Medicine and Biology, 34(6), Rodriguez Hernandez, S.A., Lafeber, A., Esser, J-P., Coo, R.F.M. de, Verhaegen, M.J.A. & Kwekkeboom, D.J. (2007). Verdelingspatroon in-111-dtpa in liquor bij meningitis. Tijdschrift voor Nucleaire Geneeskunde, 2, 89. Rolleman, E.J., Forrer, F., Bernard, H.F., Bijster, M., Vermeij, M., Valkema, R., Krenning, E.P. & Jong, M. de (2007). Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [Lu-177-DOTA(0),Tyr(3)]octreotate. European Journal of Nuclear Medicine and Molecular Imaging, 34(5), Rolleman, E.J., Forrer, F., Deckers, J., Groot, H. de, Valkema, R., Jong, M. de & Krenning, E.P. (2007). Anaphylactoid reaction from amifostine. Radiotherapy and Oncology, 82(1), Rolleman, E.J., Krenning, E.P., Bernard, H.F., Visser, M., Bijster, M., Visser, T.J., Vermeij, M., Lindemans, J. & Jong, M. de (2007). Long-term toxicity of [Lu-177-DOTA(0),Tyr(3)]octreotate in rats. European Journal of Nuclear Medicine and Molecular Imaging, 34(2), Rolleman, E.J., Kooij, P.P.M., Herder, W.W. de, Valkema, R., Krenning, E.P. & Jong, M. de (2007). Somatostatin receptor subtype 2-mediated uptake of radiolabelled somatostatin analogues in the human kidney. European Journal of Nuclear Medicine and Molecular Imaging, 34(11), Visser, M., Weerden, W.M. van, Ridder, C.M.A. de, Reneman, S., Melis, M., Krenning, E.P. & Jong, M. de (2007). Androgen-dependent expression of the gastrin-releasing peptide receptor in human prostate tumor xenografts. Journal of Nuclear Medicine, 48(1), Visser, M., Bernard, H.F., Erion, J.L., Schmidt, M.A., Srinivasan, A., Waser, B., Reubi, J.C., Krenning, E.P. & Jong, M. de (2007). Novel In-111-labelled bombesin analogues for molecular imaging of prostate tumours. European Journal of Nuclear Medicine and Molecular Imaging, 34(8), Part of book - abstract Endert, E., Wiersinga, W.M. & Krenning, E.P. (2007). Referentiewaarden functietests. In E.P. Krenning, W.M. Siersinga, S.W.J. Lamberts, F. Nobels & R. Bouillon (Eds.), Endocrinologie (pp ). Maarssen: Elsevier.

17 Herder, W.W. de, Kwekkeboom, D.J. & Lips, C.J.M. (2007). Neuro-endocrine tumoren. In E.P. Krenning, W.M. Wiersinga, S.W.J. Lamberts, F. Nobels & R. Bouillon (Eds.), Endocrinologie (pp ). Maarssen: Elsevier. Krenning, E.P., Wiersinga, W.M. & Glinoer, D (2007). Schildklier. Embryologie en fysiologie. In E.P. Krenning, W.M. Wiersinga, S.W.J. Lamberts, R. Nobels & R. Bouillon (Eds.), Endocrinologie (pp ). Maarssen: Elsevier. Krenning, E.P. & Glinoer, D (2007). Zwangerschap en endocrinologie. In E.P. Krenning, W.M. Wiersinga, S.W.J. Lamberts, F. Nobels & R. Bouillon (Eds.), Endocrinologie (pp ). Maarssen: Elsevier Gezondheidszorg. Kwekkeboom, D.J., Krenning, E.P., Hermans, R.M., Pauwels, S. & Jamar, F. (2007). Beeldvorming in de endocrinologie. In E.P. Krenning, W.M. Wiersinga, S.W.J. Lamberts, F. Nobels & R. Bouillon (Eds.), Endocrinologie (pp ). Maarssen: Elsevier.

18 EMC MM Regulation of follicle development, oocyte and endometrial embryo quality Programme design in brief General objectives: The ability of a primordial follicle to undergo folliculogenesis constitutes the very foundation of the expression of the menstrual cycle. During its growth important changes occur within the oöcyte, as well as in its granulose- and theca-cells. These changes include proliferation, differentiation and as well as growth and apoptosis. Hormones (steroid as well proteins) and growth factors control the early (gonadotropin-independent) and late (gonadotropin-dependent) follicle development. Regulation of follicle recruitment and dominant follicle selection as well as ovarian dysfunction is studied in the human model both in-vivo and in-vitro using morphometric, molecular and genetic techniques. Clinical studies involve a) Genetic (genotype - phenotype association) and environmental determinants of anovulatory infertility, especially polycystic ovary syndrome (PCOS) and premature ovarian failure (POF). b) Development of new ovulation induction strategies and optimization of fertility treatment and outcome in patients with ovarian dysfunction. c) Prevention of long-term health implications of reproductive, metabolic and cardiovascular components of ovarian dysfunction especially PCOS and POF. d) Gamete and embryo quality using genetic (preimplantation genetic aneuploidy screening) and molecular techniques in subfertile patients as well as in patients with anovulatory dysfunction Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot gynaecology/obstetrics 1, ,04 6,27 Total 1, ,04 6, Theses Baart, E.B. (2007, februari 07). Aneuploidy screening of human IVF embryos: Cytogenetic aspects and clinical implications. EUR. Prom./coprom.: Prof.Dr. B.C.J.M. Fauser. Article/Letter to the editor Baart, E.B., Martini, E., Eijkemans, M.J., Opstal, D. van, Beckers, N.G.M., Verhoeff, A., Macklon, N.S. & Fauser, B.C.J.M. (2007). Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Human Reproduction, 22(4), Beek, R.D. van, Heuvel-Eibrink, M.M. van den, Laven, J.S.E., Jong, F.H. de, Themmen, A.P.N., Hakvoort-Cammel, F.G.A.J., Bos, C van den, Berg, H., Pieters, R. & Muinck Keizer-Schrama, S.M.P.F. (2007). Anti-mullerian hormone is a sensitive serum marker for gonadal function in women treated for Hodgkin's lymphoma during childhood. Journal of Clinical Endocrinology and Metabolism, 92(10), Berg, I.M. van den, Baart, E.B., Martini, E., Eussen, HJ, Fauser, B.C.J.M. & Opstal, D. van (2007). FISH analysis of 15 chromosomes in human day 4 and 5 preimplantation embryos: the added value of extended aneuploidy detection. Prenatal Diagnosis, 27(1), Bos Eyssen, M.E., Deelen, J.A. van, Casteren, N.J. van, Weber, R.F.A. & Dohle, G.R. (2007). Hormonale behandeling van idiopatische oligoastenoteratozoospermie. Nederlands Tijdschrift voor Urologie, 5, Boxmeer, J.C., Smit, M., Weber, R.F.A., Lindemans, J., Romijn, J.C., Eijkemans, M.J., Macklon, N.S. & Steegers- Theunissen, R.P. (2007). Seminal plasma cobalamin significantly correlates with sperm concentration in men undergoing IVF or ICSI procedures. Journal of Andrology, 28(4), Dohle, G.R. (2007). Re: The age related decrease in testosterone is significantly exacerbated in obese men with the metabolic syndrome. What are the implications for the relatively high incidence of erectile dysfunction observed in these men? Kaplan SA, Meehan AG, Shah A. European Urology, 51(5), Dohle, G.R. (2007). Sperm retrieval rates in subgroups of primary azoospermic males, Editorial comment. European Urology, 51(2), 540. Dohle, G.R., Giwercman, A., Lenzi, A., Weidner, W., Forti, G. & Mirone, V. (2007). Training in andrology: the level 1 programme of the European Academy of Andrology (EAA) and of the European Society for Andrological Urology (ESAU). International Journal of Andrology, 30(1). Dohle, G.R. (2007). Implementatie van de herziene richtlijn vasectomie, commentaar. Nederlands Tijdschrift voor Urologie, 5, Dohle, G.R. & Hoek, J. van den (2007). Urethraplastiek met wangslijmvlies: de nieuwe standaard? Nederlands Tijdschrift voor Urologie, 2, Gan, M, Smit, M., Dohle, G.R., Bosch, J.L.H.R. & Bohnen, A. (2007). Determinants of ejaculatory dysfunction in a community-based longitudinal study. Bju International, 99(6),

19 Heijnen, E.M.E.W., Eijkemans, M.J.C., Klerk, C. de, Polinder, S., Beckers, N.G.M., Klinkert, E.R., Broekmans, F.J.M., Passchier, J., Velde, E.R. te & Fauser, B.C.J.M. (2007). A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial. Lancet (UK), 369(9563), Kevenaar, M.E., Themmen, A.P.N., Rivadeneira Ramirez, F., Uitterlinden, A.G., Laven, J.S.E., Schoor, N.M., Lips, P., Pols, H.A.P. & Visser, J.A. (2007). A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity. Human Reproduction, 22(9), Kevenaar, M.E., Themmen, A.P.N., Laven, J.S.E., Sonntag, B, Fong, SL, Uitterlinden, A.G., Jong, F.H. de, Pols, H.A.P., Simoni, M. & Visser, J.A. (2007). Anti-Mullerian hormone and anti-mullerian hormone type II receptor polymorphisms are associated with follicular phase estradiol levels in normo-ovulatory women. Human Reproduction, 22(6), Klerk, C. de, Macklon, N.S., Heijnen, E.M.E.W., Eijkemans, M.J.C., Fauser, B.C.J.M., Passchier, J. & Hunfeld, J.A.M. (2007). The psychological impact of IVF failure after two or more cycles of IVF with a mild versus standard treatment strategy. Human Reproduction, 22(9), Passchier, J. (2007). Medische dilemma's IVF. Monitor. Pastoor, H. (2007). Eros op de divan; congresverslag Utrecht, 1 december Tijdschrift voor Seksuologie, 31, Smit, M., Dohle, G.R., Wildhagen, M.F. & Weber, R.F.A. (2007). Can inhibin-b predict the outcome of microsurgical epididymal sperm aspiration in patients with suspected primary obstructive azoospermia? Asian Journal of Andrology, 9(3), Smit, M., Dohle, G.R., Hop, W.C.J., Wildhagen, M.F., Weber, R.F.A. & Romijn, J.C. (2007). Clinical correlates of the biological variation of sperm DNA fragmentation in infertile men attending an andrology outpatient clinic. International Journal of Andrology, 30(1), Visser, J. (2007). Eitjesvoorraad: meet je 'anti-mllers' houdbaarheidsdatum. Monitor. Part of book - abstract Dohle, G.R., Jungwirth, A., Zsolt, K. & Hargreave, TB (2007). Guidelines for the investigation and treatment of male infertility. In G.R. Dohle, A. Jungwirth, G. Colpi, A. Giwercman, T. Diemer & T.B. Hargreave (Eds.), Guidelines on male infertility (pp ). European Association of Urology. Dohle, G.R. (2007). Klinische probleemstellingen, urologie bijdrage. In Compendium klinische diagnostiek deel 1. Houten: Prelum uitgevers. Fauser, B.C.J.M., Broekmans, F.J.M., Laven, J.S.E., Macklon, N.S. & Tarlatzis, B. (2007). Polycystic ovary syndrome. In E. Diamanti-Kandarakis, J.E. Nestler, D. Panidis & R. Pasquali (Eds.), Insulin resistance and polycystic ovary syndrome (pp. 1). Totowa NJ: Humana press. Laven, J.S.E., Verhaeghe, J. & Fauser, B.C.J.M. (2007). Het ovarium. In E.P. Krenning, W.M. Wiersinga, S.W.J. Lamberts, F. Nobels & R. Bouillon (Eds.), Leerboek encodrinologie. Maarssen: Elsevier gezondheiszorg. Book editorship Dohle, G.R., Jungwirth, A., Colpi, G., Giwercman, A., Diemer, T. & Hargreave, TB (Eds.). (2007). European association of urology guidelines on male infertility. --: --. Dohle, G.R., Jungwirth, A., Colpi, G., Giwercman, A., Diemer, T. & Hargreave, TB (Eds.). (2007). Guidelines on male infertility. --: European Association of Urology. Kaandorp, C.J.E., Brand, A., Broek, P.J.. van den, Dekhuijzen, P.N.R., Dohle, G.R., Floor, S.E., Groot, C.J.M. de, Hengeveld, M.W., Hooymans, J.M.M., Kleibeuker, JH, Kneepkens, C.M.F., Kooy, A., Laven, J.S.E., Man, R.A. de, Roumen, R.M.H., Tak, P.P., Trines, S.A.I.P., Vries, N. de, Waal, R.I.F. van der, Wee, P.M. ter & Westerink, M. (Eds.). (2007). Compendium klinische diagnostiek- Klinische probleemstellingen. Houten: Prelum Publishers. Book review Pastoor, H. (2007). Book reviewen [Bespreking van de boeken Haar penisboek & Het Vaginaboek]. Tijdschrift voor Seksuologie, 30, 236. Pastoor, H. (2007). Literatuurbulletin [Bespreking van het boek De liefde bedrijven]. Tijdschrift voor Seksuologie, 31,

20 EMC MM Pathophysiology of pediatric endocrine, metabolic and renal diseases Programme design in brief Human growth and development including sexual differentiation and puberty and individual organ systems such as the kidney and bone are regulated by the concerted action of a large number of endocrine, paracrine and autocrine factors. This programme aims at: a. Studying normal growth and development and the role of growth hormone and growth factors in congenital and acquired growth disorders by means of epidemiological investigations and clinical trials as well as laboratory studies using various in vitro techniques. b. Long term goals are to unravel in molecular detail the factors involved in the etiology of type 1 diabetes. We want to develop techniques to predict and prevent this disease, eventually applicable in the general population. Immunological, genetic and beta-cell factors are studied. These aims and goals should allow to develop concomitant strategies to cure or improve the current treatment of those who have already developed the disease. The search for the pathogenesis of type 1 diabetes mellitus the optimal treatment and ultimately its prevention is highly relevant for longterm morbidity, prognosis and socioeconomic consequences at adulthood. c. Studying normal and abnormal renal development as well as therapeutic options by means of multicenter clinical trials. d. Studying intermediary metabolism of patients with inborn errors of aminoacids, organic acids, lipids and defects of cellular organelles, some of them by newborn screening. Development of therapeutic options by dietary intervention or enzyme replacement therapy in nationwide and international collaboration. Special attention is focused on congenital defects of glycosylation, a recently detected group of inborn errors. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot pediatrics 0,3 0,25 3,73 6,22 10,5 Total 0,3 0,25 3,73 6,22 10, Theses Dijk, M. van (2007, maart 23). Children and young adults born small for gestational age (SGA). EUR (168 pag.) (Enschede: PrintPartners IPSKAMP). Prom./coprom.: prof.dr. A.C.S. Hokken-Koelega. Festen, D.A.M. (2007, november 16). Prader Willi syndrome: clinical aspects and effects of growth hormone treatment. EUR (219 pag.). Prom./coprom.: prof.dr. A.C.S. Hokken-Koelega. Vorst, M.M.J. van der (2007, juni 07). Optimal furosemide therapy in critically ill infants. EUR. Prom./coprom.: Prof.dr. A.J. van der Heijden & Prof.Dr. D. Tibboel Article/Letter to the editor Akker, E.L.T. van den, Puiman, P.J., Groen, M., Timman, R., Jongejan, M.T. & Trijsburg, R.W. (2007). A cognitive behavioral therapy program for overweight children. Journal of Pediatrics, 151(3), Bannink, E.M.N., Doorn, J. van, Mulder, P.G.H. & Hokken-Koelega, A.C.S. (2007). Free/dissociable insulin-like growth factor (IGF)-I, not total IGF-I, correlates with growth response during growth hormone treatment in children born small for gestational age. Journal of Clinical Endocrinology and Metabolism, 92(8), Beek, R.D. van, Heuvel-Eibrink, M.M. van den, Laven, J.S.E., Jong, F.H. de, Themmen, A.P.N., Hakvoort-Cammel, F.G.A.J., Bos, C van den, Berg, H., Pieters, R. & Muinck Keizer-Schrama, S.M.P.F. (2007). Anti-mullerian hormone is a sensitive serum marker for gonadal function in women treated for Hodgkin's lymphoma during childhood. Journal of Clinical Endocrinology and Metabolism, 92(10), Beek, R.D. van, Smit, M., Heuvel-Eibrink, M.M. van den, Jong, F.H. de, Hakvoort-Cammel, F.G.A.J., Bos, C. van den, Berg, H. van den, Weber, R.F.A., Pieters, R. & Muinck Keizer-Schrama, S.M.P.F. (2007). Inhibin B is superior to FSH as a serum marker for spermatogenesis in men treated for Hodgkin's lymphoma with chemotherapy during childhood. Human Reproduction, 22(12), Cools, M., Boter, M., Gurp, R.J.H.L. van, Stoop, H., Poddighe, P, Lau, YFC, Drop, S.L.S., Wolffenbuttel, K.P. & Looijenga, L.H.J. (2007). Impact of the Y-containing cell line on histological differentiation patterns in dysgenetic gonads. Clinical Endocrinology, 67(2), Cox-Brinkman, J., Timmermans, R.G.M., Wijburg, F.A., Donker, W.E., Ploeg, A.T. van der, Aerts, J.M.F.G. & Hollak, C.E.M. (2007). Home treatment with enzyme replacement therapy for mucopolysaccharidosis type I is feasible and safe. Journal of Inherited Metabolic Disease, 30, 984. Cransberg, K., Comelissen, M, Liliell, M, Hoeck, K Van, Davill, JC & Nauta, J. (2007). Long term immunosuppression with mycophenolate mofetil and corticosteroids in pediatric kidney transplantation: Temporary improvement but not without risk. Pediatric Transplantation, 11,