Research Annual Report 2005

Transcription

1 Research Annual Report 2005 Molecular Medicine (MM) [ 1/4 ] Clinical and expiremental neuroendocrinology Regulation of calcium and bone metabolism Regulation of bioactivity of thyroid hormone Signalling in reproduction and ageing Inherited metabolic disease and disorders of intermediary metabolism 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 Regulation of the differentiation and functional activity of leukocytes 28408, B&T Ontwerp en advies (

2 Research Annual Report 2005 Molecular Medicine (MM) [ 2/4 ] Interactions between the immune and neuroendocrine system under physical conditions and during endocrine or organ-specific autoimmune diseases ('immuno-neuroendocrinology') Diagnosis and classification of leukemias and malignant lymphomas and detection of 'minimal residual disease' Solid tumors between bench and bed Improving accuracy and therapeutic ratio in radiation oncology Hyperthermia for the treatment of 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 28408, B&T Ontwerp en advies (

3 Research Annual Report 2005 Molecular Medicine (MM) [ 3/4 ] 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 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 28408, B&T Ontwerp en advies (

4 Research Annual Report 2005 Molecular Medicine (MM) [ 4/4 ] 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 28408, B&T Ontwerp en advies (

5 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 2, , reproduction and development 0, ,2 surgery 0, ,1 Total 2,45 3,95 0,15 0 6, Theses Pivonello, R. (2005, november 09). Dopamine receptor expression and function in the normal and pathological hypothalamus-pituitary-adrenal axis. EUR. Prom./coprom.: Prof.Dr. S.W.J. Lamberts & Dr. L.J. Hofland. Rossum, E.F.C. van (2005, oktober 19). Variation of the glucocorticoid receptor gene: Consequences for body and brain. EUR. Prom./coprom.: Prof.Dr. S.W.J. Lamberts & Dr. F.J.W. Koper. Article/Letter to the editor Aken, M.O. van, Pereira, AM, Biermasz, NR, Thiel, SW van, Hoftijzer, HC, Smit, J.W.A., Roelfsema, F, Lamberts, S.W.J. & Romijn, J.A. (2005). Quality of life in patients after long-term biochemical cure of Cushing's disease. Journal of Clinical Endocrinology and Metabolism, 90(6), Barkan, A.L., Burman, P, Clemmons, D.R., Drake, W.M., Gagel, RF, Harris, PE, Trainer, P.J., Lely, A.J. van der & Vance, M.L. (2005). Glucose homeostasis and safety in patients with acromegaly converted from long-acting octreotide to pegvisomant. Journal of Clinical Endocrinology and Metabolism, 90(10), Beld, A.W. van den, Visser, T.J., Feelders, R.A., Grobbee, D.E. & Lamberts, S.W.J. (2005). Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. Journal of Clinical Endocrinology and Metabolism, 90(12), Bleumink, G.S., Schut, A.F.C., Sturkenboom, M.C.J.M., Janssen, J.A.M.J.L., Witteman, J.C.M., Duijn, C.M. van, Hofman, A. & Stricker, B.H.C. (2005). A promoter polymorphism of the insulin-like growth factor-i gene is associated with left ventricular hypertrophy. Heart, 91(2), Bonapart, IE, Domburg, R.T. van, Have, S.M.T.H. ten, Herder, W.W. de, Erdman, R.A.M., Janssen, J.A.M.J.L. & Lely, A.J. van der (2005). The 'bio-assay' quality of life might be a better marker of disease activity in acromegalic patients than serum total IGF-I concentrations. European Journal of Endocrinology, 152(2), Brinker, M. den, Joosten, K.F.M., Liem, O, Jong, F.H. de, Hop, W.C.J., Hazelzet, J.A., Dijk, M. van & Koelega, A.C.S. (2005). Adrenal insufficiency in meningococcal sepsis: Bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality. Journal of Clinical Endocrinology and Metabolism, 90(9), Bruijne, E.L.E. de, Burgmans, J.P.J., Krestin, G.P., Pols, H.A.P., Meiracker, A.H. van den & Herder, W.W. de (2005). Het incidentaloom van de bijnier: een klinisch probleem van beeldvorming. Nederlands Tijdschrift voor Geneeskunde, 149, Eijken, M, Hewison, M., Cooper, MS, Jong, F.H. de, Chiba, H., Stewart, P.M., Uitterlinden, A.G., Pols, H.A.P. & Leeuwen, J.P.T.M. van (2005). 11 beta-hydroxysteroid dehydrogenase expression and glucocorticoid synthesis are directed by a molecular switch during osteoblast differentiation. Molecular Endocrinology, 19(3), Feelders, R.A., Bidlingmaier, M., Strasburger, C.J., Janssen, J.A.M.J.L., Uitterlinden, P., Hofland, L.J., Lamberts, S.W.J., Lely, A.J. van der & Herder, W.W. de (2005). Postoperative evaluation of patients with acromegaly: Clinical significance and timing of oral glucose tolerance testing and measurement of (free) insulin-like growth factor I, acid-

6 labile subunit, and growth hormone-binding protein levels. Journal of Clinical Endocrinology and Metabolism, 90(12), Feenstra, J., Herder, W.W. de, Have, S.M.T.H. ten, Beld, A.W. van den, Feelders, R.A., Janssen, J.A.M.J.L. & Lely, A.J. van der (2005). Combined therapy with somatostatin analogues and weekly pegvisomant in active acromegaly. Lancet (UK), 365(9471), Franco Duran, O.H., Burger, H., Lebrun, C.E.I., Peeters, P.H.M., Lamberts, S.W.J., Grobbee, D.E. & Schouw, Y.T. van der (2005). Higher dietary intake of lignans is associated with better cognitive performance in postmenopausal women. Journal of Nutrition, 135(5), Freda, P.U., Katznelson, L., Lely, A.J. van der, Reyes, CM, Zhao, SH & Rabinowitz, D (2005). Long-acting somatostatin analog therapy of acromegaly: A meta- analysis. Journal of Clinical Endocrinology and Metabolism, 90(8), Gauna, C., Delhanty, P.J.D., Hofland, L.J., Janssen, J.A.M.J.L., Broglio, F., Ross, R.J., Ghigo, E. & Lely, A.J. van der (2005). Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes. Journal of Clinical Endocrinology and Metabolism, 90, Hagendorf, A., Koper, F.J.W., Jong, F.H. de, Brinkmann, A.O., Lamberts, S.W.J. & Feelders, R.A. (2005). Expression of the human glucocorticoid receptor splice variants alpha, beta, and P in peripheral blood mononuclear leukocytes in healthy controls and in patients with hyper- and hypocortisolism. Journal of Clinical Endocrinology and Metabolism, 90(11), Hendriks, D.J., Broekmans, F.J.M., Bancsi, L.F.J.M.M., Jong, F.H. de, Looman, C.W.N. & Velde, E.R. te (2005). Repeated clomiphene citrate challenge testing in the prediction of outcome in IVF: a comparison with basal markers for ovarian reserve. Human Reproduction, 20(1), Hendriks, D.J., Broekmans, F.J.M., Bancsi, L.F.J.M.M., Looman, C.W.N., Jong, F.H. de & Velde, E.R. te (2005). Single and repeated GnRH agonist stimulation tests compared with basal markers of ovarian reserve in the prediction of outcome in IVF. Journal of Assisted Reproduction and Genetics, 22(2), Herder, W.W. de (2005). A bronze statue of the tallest acromegalic giant. Journal of Endocrinological Investigation, 28(7), Herder, W.W. de (2005). A postcard of a giant and his physician (collection W.W. de Herder). Journal of Endocrinological Investigation, 28(4), Herder, W.W. de, Taal, HR, Uitterlinden, P., Feelders, R.A., Janssen, J.A.M.J.L. & Lely, A.J. van der (2005). Limited predictive value of an acute test with subcutaneous octreotide for long-term IGF-I normalization with Sandostatin LAR in acromegaly. European Journal of Endocrinology, 153(1), Herder, W.W. de (2005). Tumours of the midgut (jejunum, ileum and ascending colon, including carcinoid syndrome). Best Practice & Research in Clinical Gastroenterology, 19(5), Hoek, J., Waaijers, A.M., Koetsveld, P.M. van, Sprij-Mooij, D, Feelders, R.A., Schmid, HA, Schoeffter, P, Hoyer, D, Cervia, D, Taylor, JE, Culler, MD, Lamberts, S.W.J. & Hofland, L.J. (2005). Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by corticotroph tumor cells. American Journal of Physiology, Endocrinology and Metabolism, 289(2), E278-E287. Hoek, J., Hofland, L.J. & Lamberts, S.W.J. (2005). Novel subtype specific and universal somatostatin analogues: Clinical potential and pitfalls. Current Pharmaceutical Design, 11(12), Hoek, J. van der, Lely, A.J. van der, Feelders, R.A., Herder, W.W. de, Uitterlinden, P., Poon, K.W., Boerlin, V., Lewis, I., Krahnke, T., Hofland, L.J. & Lamberts, S.W.J. (2005). The somatostatin analogue SOM230, compared with octreotide, induces differential effects in several metabolic pathways in acromegalic patients. Clinical Endocrinology, 63, Hofland, L.J., Capello, A., Krenning, E.P., Jong, M. de & Hagen, P.M. van (2005). Induction of apoptosis with hybrids of Arg-Gly-Asp molecules and peptides and antimitotic effects of hybrids of cytostatic drugs and peptides. Journal of Nuclear Medicine, 46, 191S-198S. Hofland, L.J., Hoek, J., Feelders, R.A., Aken, M.O. van, Koetsveld, P.M. van, Waaijers, A.M., Sprij-Mooij, D, Bruns, C., Weckbecker, G., Herder, W.W. de, Beckers, A. & Lamberts, S.W.J. (2005). The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. European Journal of Endocrinology, 152(4), Hohmann, F.P., Laven, J.S.E., Jong, F.H. de & Fauser, B.C.J.M. (2005). Relationship between inhibin A and B, estradiol and follicle growth dynamics during ovarian stimulation in normo-ovulatory women. European Journal of Endocrinology, 152(3), Jonkers, YMH, Claessen, SMH, Perren, A, Schmid, S, Komminoth, P., Verhofstad, AA, Hofland, L.J., Krijger, R.R. de, Slootweg, P.J., Ramaekers, F.C.S. & Speel, E.J.M. (2005). Chromosomal instability predicts metastatic disease in patients with insulinomas. Endocrine-Related Cancer, 12(2),

7 Kate, M. ten, Sluiter, W., Hofland, L.J., Jeekel, J. & Eijck, C.H. van (2005). The role of surgical derived reactive oxygen species on the development of distant tumor recurrence: An in vitro model. Cancer Epidemiology Biomarkers & Prevention, 14(11), 2735S-2735S. Kranse, R., Dagnelie, P.C., Kemenade, M.C. van, Jong, F.H. de, Blom, J.H.M., Tijburg, LBM, Weststrate, JA & Schroder, F.H. (2005). Dietary intervention in prostate cancer patients: PSA response in a randomized double-blind placebo-controlled study. International Journal of Cancer, 113(5), Krenning, E.P., Valkema, R., Kwekkeboom, D.J., Herder, W.W. de, Eijck, C.H.J. van, Jong, M. de, Pauwels, S. & Reubi, J.C. (2005). Molecular imaging as in vivo molecular pathology for gastroenteropancreatic neuroendocrine tumors: Implications for follow-up after therapy. Journal of Nuclear Medicine, 46, 76S-82S. Kwekkeboom, D.J., Teunissen, J.J.M., Bakker, W.H., Kooij, P.P.M., Herder, W.W. de, Feelders, R.A., Eijck, C.H.J. van, Esser, J-P., Kam, B.L.R. & Krenning, E.P. (2005). Radiolabeled somatostatin analog [Lu-177-DOTA(0),Tyr(3)] octreotate in patients with endocrine gastroenteropancreatic tumors. Journal of Clinical Oncology, 23(12), Lanting, L.C., Joung, I.M.A., Mackenbach, J.P., Lamberts, S.W.J. & Bootsma, A.H. (2005). Ethnic differences in mortality, end-stage complications, and quality of care among diabetic patients - A review. Diabetes Care, 28(9), Lebrun, C.E.I., Schouw, Y.T. van der, Jong, F.H. de, Pols, H.A.P., Grobbee, D.E. & Lamberts, S.W.J. (2005). Endogenous oestrogens are related to cognition in healthy elderly women. Clinical Endocrinology, 63(1), Ma, PM, Wang, YF, Hoek, J., Nedelman, J, Schran, H., Tran, LL & Lamberts, S.W.J. (2005). Pharmacokineticpharmacodynamic comparison of a novel multiligand somatostatin analog, SOM230, with octreotide in patients with acromegaly. Clinical Pharmacology & Therapeutics, 78(1), Melmed, S., Casanueva, F.F., Cavagnini, F., Chanson, P., Frohman, L.A., Gaillard, R., Ghigo, E., Ho, K.K., Jaquet, P, Kleinberg, D.L., Lamberts, S.W.J., Laws, E, Lombardi, G., Sheppard, M.C., Thorner, M.O., Vance, M.L., Wass, J.A. & Giustina, A (2005). Consensus statement: medical management of acromegaly. European Journal of Endocrinology, 153, Moore, SB, Hoek, J., Capua, A de, Koetsveld, P.M. van, Hofland, L.J., Lamberts, S.W.J. & Goodman, M (2005). Discovery of iodinated somatostatin analogues selective for hsst2 and hsst5 with excellent inhibition of growth hormone and prolactin release from rat pituitary cells. Journal of Medicinal Chemistry, 48(21), Muller, M., Grobbee, D.E., Tonkelaar, I. den, Lamberts, S.W.J. & Schouw, Y.T. van der (2005). Endogenous sex hormones and metabolic syndrome in aging men. Journal of Clinical Endocrinology and Metabolism, 90(5), Peeters, R.P., Beld, A.W. van den, Attalki, H, Toor, H. van, Rijke, Y.B. de, Kuiper, G.G.J.M., Lamberts, S.W.J., Janssen, J.A.M.J.L., Uitterlinden, A.G. & Visser, T.J. (2005). A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters. American Journal of Physiology, Endocrinology and Metabolism, 289(1), E75-E81. Peeters, R.P., Beld, A.W. van den, Toor, H. van, Uitterlinden, A.G., Janssen, J.A.M.J.L., Lamberts, S.W.J. & Visser, T.J. (2005). A polymorphism in type I deiodinase is associated with circulating free insulin-like growth factor I levels and body composition in humans. Journal of Clinical Endocrinology and Metabolism, 90(1), Pivonello, R., Ferone, D., Lamberts, S.W.J. & Colao, A. (2005). Cabergoline plus lanreotide for ectopic Cushing's syndrome. New England Journal of Medicine, 352(23), Plockinger, U, Rindi, G., Arnold, R., Eriksson, B., Krenning, E.P., Herder, W.W. de, Goede, A, Caplin, M., Oberg, K, Reubi, J.C., Nilsson, O., Delle Fave, G., Ruszieuski, P, Ahlman, H & Wiedenmann, B. (2004). Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology, 80(394), 424. Pozo, E del, Popp, AWE, MacKenzie, A, Perrelet, R, Lamberts, S.W.J. & Lippuner, K (2005). Graded doses of recombinant interleukin-1 beta induce generalized osteopenia in rats without altering skeletal growth and joint integrity. Hormone Research, 64(2), Ronde, W. de, Hofman, A., Pols, H.A.P. & Jong, F.H. de (2005). A direct approach to the estimation of the origin of oestrogens and androgens in elderly men by comparison with hormone levels in postmenopausal women. European Journal of Endocrinology, 152(2), Ronde, W. de, Schouw, Y.T. van der, Muller, M., Grobbee, D.E., Gooren, L.J.G., Pols, H.A.P. & Jong, F.H. de (2005). Associations of sex-hormone-binding globulin (SHBG) with non-shbg-bound levels of testosterone and estradiol in independently living men. Journal of Clinical Endocrinology and Metabolism, 90(1), Ronde, W. de, Schouw, Y.T. van der, Pierik, F.H., Pols, H.A.P., Muller, M., Grobbee, D.E., Gooren, L.J.G., Weber, R.F.A. & Jong, F.H. de (2005). Serum levels of sex hormone-binding globulin (SHBG) are not associated with lower levels of non-shbg-bound testosterone in male newborns and healthy adult men. Clinical Endocrinology, 62(4),

8 Rooij, I.A.J. van, Broekmans, F.J.M., Scheffer, G.J., Looman, C.W.N., Habbema, J.D.F., Jong, F.H. de, Fauser, B.C.J.M., Themmen, A.P.N. & Velde, E.R. te (2005). Serum antimullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study. Fertility & Sterility, 83(4), Rossum, E.F.C. van, Russcher, H. & Lamberts, S.W.J. (2005). Genetic polymorphisms and multifactorial diseases: facts and fallacies revealed by the glucocorticoid receptor gene. Trends in Endocrinology and Metabolism, 16, Russcher, H., Rossum, E.F.C. van, Jong, F.H. de, Brinkmann, A.O., Lamberts, S.W.J. & Koper, F.J.W. (2005). Increased expression of the glucocorticoid receptor-a translational isoform as a result of the ER22/23EK polymorphism. Molecular Endocrinology, 19(7), Russcher, H., Smit, P., Akker, E.L.T. van den, Rossum, E.F.C. van, Brinkmann, A.O., Jong, F.H. de, Lamberts, S.W.J. & Koper, F.J.W. (2005). Two Polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoidregulated gene expression. Journal of Clinical Endocrinology and Metabolism, 90(10), Schuit, S.C.E., Jong, F.H. de, Stolk, L., Kock, WNH, Meurs, J.B.J. van, Schoofs, M.W.C.J., Zillikens, M.C., Hofman, A., Leeuwen, J.P.T.M. van, Pols, H.A.P. & Uitterlinden, A.G. (2005). Estrogen receptor alpha gene polymorphisms are associated with estradiol levels in postmenopausal women. European Journal of Endocrinology, 153(2), Smit, P., Schaik, R.H.N. van, Werf, M. van der, Beld, A.W. van den, Koper, F.J.W., Lindemans, J., Pols, H.A.P., Brinkmann, A.O., Jong, F.H. de & Lamberts, S.W.J. (2005). A common polymorphism in the CYP3A7 gene is associated with a nearly 50% reduction in serum dehydroepiandrosterone sulfate levels. Journal of Clinical Endocrinology and Metabolism, 90(9), Smit, P., Russcher, H., Jong, F.H. de, Brinkmann, A.O., Lamberts, S.W.J. & Koper, F.J.W. (2005). Differential regulation of synthetic glucocorticoids on gene expression levels of glucocorticoid-induced leucine zipper and interleukin-2. Journal of Clinical Endocrinology and Metabolism, 90(5), Tissing, W.J.E., Lauten, A, Meijerink, J.P.P., Boer, M.L. den, Koper, F.J.W., Sonneveld, P. & Pieters, R. (2005). Expression of the glucocorticold receptor and its isoforms in relation to glucocorticold resistance in childhood acute lymphocytic leukemia. Haematologica, 90(9), Tissing, W.J.E., Meijerink, J.P.P., Boer, M.L. den, Brinkhof, B., Rossum, E.F.C. van, Wering, E.R. van, Koper, F.J.W., Sonneveld, P. & Pieters, R. (2005). Genetic variations in the glucocorticoid receptor gene are not related to glucocorticoid resistance in childhood acute lymphoblastic leukemia. Clinical Cancer Research, 11(16), Velde, S.J. te, Rossum, E.F.C. van, Voorhoeve, P.G., Twisk, J.W.R., Delemarre van de Waal, HA, Stehouwer, C.D.A., Mechelen, W. van, Lamberts, S.W.J. & Kemper, H.C.G. (2005). An IGF-I promoter polymorphism modifies the relationships between birth weight and risk factors for cardiovascular disease and diabetes at age 36. BMC Endocrine Disorders, 5, Winsen, LLM van, Veen, T., Rossum, E.F.C. van, Polman, C.H., Berg, TK van den, Koper, F.J.W. & Uitdehaag, B.M.J. (2005). The impact of glucocorticoid receptor gene polymorphisms on glucocorticoid sensitivity is outweighted in patients with multiple sclerosis. Journal of Neuroimmunology, 167(1-2), Wust, S, Federenko, I.S., Rossum, E.F.C. van, Koper, F.J.W. & Hellhammer, D.H. (2005). Habituation of cortisol responses to repeated psychosocial stress-further characterization and impact of genetic factors. Psychoneuroendocrinology, 30, Zomerhuis, M.T., Hussain, S.M., Feelders, R.A., Lely, A.J. van der & Herder, W.W. de (2005). Octreotide exerts only acute, but no sustained, effects on MRI enhancement of liver metastases in carcinoid syndrome. Neuroendocrinology, 82, Book editorship Lely, A.J. van der, Beckers, A., Daly, AF, Lamberts, S.W.J. & Clemmons, D.R. (Eds.). (2005). Acromegaly: pathology, diagnosis and treatment. Baton Rouge USA: Taylor & Francis.

9 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 epidemiology & biostatics 0, ,05 internal medicine 3,6 4,4 0 0,25 8,25 Total 3,65 4,4 0 0,25 8, Theses Fang, Y. (2005, december 21). Vitamin D receptor gene polymorphisms and bone. EUR. Prom./coprom.: Prof.Dr. H.A.P. Pols & Dr. A.G. Uitterlinden. Schoofs, M. (2005, juni 15). The effects of cardiovascular drugs on bone. EUR. Prom./coprom.: Prof.Dr. H.A.P. Pols, Prof.Dr. B.H.C. Stricker & Dr. M.C.J.M. Sturkenboom. Article/Letter to the editor Abel, M. van, Hoenderop, J.G.J., Kemp, A.W.C.M., Friedlaender, MM, Leeuwen, J.P.T.M. van & Bindels, R.J.M. (2005). Coordinated control of renal Ca2+ transport proteins by parathyroid hormone. Kidney International, 68(4), Alizadeh, B.Z., Njajou Tchikamgoua, O., Bijkerk, C., Meulenbelt, I., Wildt, SC De, Hofman, A., Pols, H.A.P., Slagboom, P.E. & Duijn, C.M. van (2005). Evidence for a role of the genomic region of the gene encoding for the alpha 1 chain of type IX collagen (COL9A1) in hip osteoarthritis - A population-based study. Arthritis & Rheumatism, 52(5), Bergink, A.P., Uitterlinden, A.G., Leeuwen, J.P.T.M. van, Hofman, A., Verhaar, J.A.N. & Pols, H.A.P. (2005). Bone mineral density and vertebral fracture history are associated with incident and progressive radiographic knee osteoarthritis in elderly men and women: The Rotterdam Study. Bone, 37(4), Bongers, T.N., Maat, M.P.M. de, Dippel, D.W.J., Uitterlinden, A.G. & Leebeek, F.W.G. (2005). Absence of Pro475Ser polymorphism in ADAMTS-13 in Caucasians. Journal of Thrombosis and Haemostasis, 3(4), Bruijne, E.L.E. de, Burgmans, J.P.J., Krestin, G.P., Pols, H.A.P., Meiracker, A.H. van den & Herder, W.W. de (2005). Het incidentaloom van de bijnier: een klinisch probleem van beeldvorming. Nederlands Tijdschrift voor Geneeskunde, 149, Claassen, M.A.A., Nouwen, J.L., Fang, Y., Ott, A., Verbrugh, H.A., Hofman, A., Belkum, A. van & Uitterlinden, A.G. (2005). Staphylococcus aureus nasal carriage is not associated with polymorphism in the Vitamin D receptor gene. Fems Immunology & Medical Microbiology, 43(2), Dahaghin, S., Zeinstra, S.M.A., Reijman, M., Pols, H.A.P., Hazes, J.M.W. & Koes, B.W. (2005). Does hand osteoarthritis predict future hip or knee osteoarthritis? Arthritis & Rheumatism, 52(11), Dahaghin, S., Zeinstra, S.M.A., Ginai-Karamat, A.Z., Pols, H.A.P., Hazes, J.M.W. & Koes, B.W. (2005). Prevalence and pattern of radiographic hand osteoarthritis and association with pain and disability (the Rotterdam study). Annals of the Rheumatic Diseases, 64(8),

10 Duijnhoven, FJB van, Bezemer, ID, Peeters, P.H.M., Roest, M., Uitterlinden, A.G., Grobbee, D.E. & Gils, CH van (2005). Polymorphisms in the estrogen receptor alpha gene and mammographic density. Cancer Epidemiology Biomarkers & Prevention, 14(11), Eerden, B.C.J. van der, Hoenderop, J.G.J., Vries, T.J. de, Schoenmaker, T, Buurman, C.J., Uitterlinden, A.G., Pols, H.A.P., Bindels, R.J.M. & Leeuwen, J.P.T.M. van (2005). The epithelial Ca2+ channel TRPV5 is essential for proper osteoclastic bone resorption. Proceedings of the National Academy of Sciences of the United States of Ame, 102(48), Eijken, M, Hewison, M., Cooper, MS, Jong, F.H. de, Chiba, H., Stewart, P.M., Uitterlinden, A.G., Pols, H.A.P. & Leeuwen, J.P.T.M. van (2005). 11 beta-hydroxysteroid dehydrogenase expression and glucocorticoid synthesis are directed by a molecular switch during osteoblast differentiation. Molecular Endocrinology, 19(3), Fang, Y., Meurs, J.B.J. van, d'alesio, A, Jhamai, P., Zhao, HY, Rivadeneira Ramirez, F., Hofman, A., Leeuwen, J.P.T.M. van, Jehan, F, Pols, H.A.P. & Uitterlinden, A.G. (2005). Promoter and 3 '-untranslated-region haplotypes in the vitamin D receptor gene predispose to osteoporotic fracture: The Rotterdam study. American Journal of Human Genetics, 77(5), Hart, L.M. 't, Hansen, T, Rietveld, I., Dekker, J.M., Nijpels, G., Janssen, GMC, Arp, P.P., Uitterlinden, A.G., Jorgensen, T, Borch-Johnsen, K, Pols, H.A.P., Pedersen, O, Duijn, C.M. van, Heine, R.J. & Maassen, J.A. (2005). Evidence that the mitochondrial leucyl trna synthetase (LARS2) gene represents a novel type 2 diabetes susceptibility gene. Diabetes, 54(6), Holweg, C., Balk, A.H.M.M., Uitterlinden, A.G., Niesters, H.G.M., Maat, LPWM, Weimar, W. & Baan, C.C. (2005). Functional heme oxygenase-1 promoter polymorphism in relation to heart failure and cardiac transplantation. Journal of Heart and Lung Transplantation, 24(4), Ioannidis, JPA, Bernstein, J, Boffetta, P., Danesh, J, Dolan, S, Hartge, P, Hunter, D, Inskip, P, Jarvelin, MR, Little, J, Maraganore, D.M., Bishop, JAN, O'Brien, TR, Petersen, G., Riboli, E, Seminara, D, Taioli, E, Uitterlinden, A.G., Vineis, P, Winn, DM, Salanti, G, Higgins, JPT & Khoury, MJ (2005). A network of investigator networks in human genome epidemiology. American Journal of Epidemiology, 162(4), Jahr, H., Driel, M.J.J.E. van, Osch, G.J.V.M. van, Weinans, H.H. & Leeuwen, J.P.T.M. van (2005). Identification of acid-sensing ion channels in bone. Biochemical & Biophysical Research Communications, 337(1), Karnauskas, AJ, Leeuwen, J.P.T.M. van, Bemd, G.J.C.M., Kathpalia, PP, Deluca, H.F., Bushinsky, DA & Favus, MJ (2005). Mechanism and function of high vitamin D receptor levels in genetic hypercalciuric stone-forming rats. Journal of Bone and Mineral Research, 20(3), Klift, M. van der, Laet, C.E.D.H. de & Pols, H.A.P. (2005). Assessment of fracture risk: Who should be treated for osteoporosis? Best Practice & Research in Clinical Rheumatology, 19(6), Lau, L.M.L. de, Koudstaal, P.J., Meurs, J.B.J. van, Uitterlinden, A.G., Hofman, A. & Breteler, M.M.B. (2005). Methylenetetrahydrofolate reductase C677T genotype and PD. Annals of Neurology, 57(6), Lebrun, C.E.I., Schouw, Y.T. van der, Jong, F.H. de, Pols, H.A.P., Grobbee, D.E. & Lamberts, S.W.J. (2005). Endogenous oestrogens are related to cognition in healthy elderly women. Clinical Endocrinology, 63(1), Lemos, F., Mol, W.M., Roodnat, J.I., Uitterlinden, A.G., IJzermans, J.N.M., Weimar, W. & Baan, C.C. (2005). The beneficial effects of recipient-derived vascular endothelial growth factor on graft survival after kidney transplantation. Transplantation, 79(9), Liefde, I.I. de, Klift, M. van der, Laet, C.E.D.H. de, Daele, P.L.A. van, Hofman, A. & Pols, H.A.P. (2005). Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study. Osteoporosis International, 16(12), Meurs, J.B.J. van & Uitterlinden, A.G. (2005). Homocysteine and fracture prevention. Jama - Journal of the American Medical Association, 293(9), Min, JL, Meulenbelt, I., Riyazi, N, Kloppenburg, M, Duistermaat, J.J., Seymour, A.B., Pols, H.A.P., Duijn, C.M. van & Slagboom, P.E. (2005). Association of the Frizzled-related protein gene with symptomatic osteoarthritis at multiple sites. Arthritis & Rheumatism, 52(4), Peeters, R.P., Beld, A.W. van den, Attalki, H, Toor, H. van, Rijke, Y.B. de, Kuiper, G.G.J.M., Lamberts, S.W.J., Janssen, J.A.M.J.L., Uitterlinden, A.G. & Visser, T.J. (2005). A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters. American Journal of Physiology, Endocrinology and Metabolism, 289(1), E75-E81. Peeters, R.P., Beld, A.W. van den, Toor, H. van, Uitterlinden, A.G., Janssen, J.A.M.J.L., Lamberts, S.W.J. & Visser, T.J. (2005). A polymorphism in type I deiodinase is associated with circulating free insulin-like growth factor I levels and body composition in humans. Journal of Clinical Endocrinology and Metabolism, 90(1), Ralston, S.H., Galwey, N, McKay, I, Albagha, O.M., Cardon, L., Compston, J.E., Cooper, C., Duncan, E.L., Keen, R., Langdahl, B., McLellan, A, O'Riordan, J, Pols, H.A.P., Reid, D.M., Uitterlinden, A.G., Wass, J.A. & Bennett, S.T.

11 (2005). Loci for regulation of bone mineral density in men and women identified by. Human Molecular Genetics, 14(7), Reijman, M., Hazes, J.M.W., Pols, H.A.P., Koes, B.W. & Zeinstra, S.M.A. (2005). Acetabular dysplasia predicts incident osteoarthritis of the hip: the Rotterdam study. Arthritis & Rheumatism, 52(3), Reijman, M., Zeinstra, S.M.A., Pols, H.A.P., Koes, B.W., Stricker, B.H.C. & Hazes, J.M.W. (2005). Is there an association between the use of different types of nonsteroidal antiinflammatory drugs and radiologic progression of osteoarthritis? The Rotterdam study. Arthritis & Rheumatism, 52(10), Reijman, M., Hazes, J.M.W., Pols, H.A.P., Bernsen, R.M.D., Koes, B.W. & Zeinstra, S.M.A. (2005). Role of radiography in predicting progression of osteoarthritis of the hip: prospective cohort study. British Medical Journal (International Edition), 330(7501), Renkema, KY, Nijenhuis, T, Eerden, B.C.J. van der, Kemp, A.W.C.M., Weinans, H.H., Leeuwen, J.P.T.M. van, Bindels, R.J.M. & Hoenderop, J.G.J. (2005). Hypervitaminosis D mediates compensatory Ca2+ hyperabsorption in TRPV5 knockout mice. Journal of the American Society of Nephrology, 16(11), Ronde, W. de, Hofman, A., Pols, H.A.P. & Jong, F.H. de (2005). A direct approach to the estimation of the origin of oestrogens and androgens in elderly men by comparison with hormone levels in postmenopausal women. European Journal of Endocrinology, 152(2), Ronde, W. de, Schouw, Y.T. van der, Pierik, F.H., Pols, H.A.P., Muller, M., Grobbee, D.E., Gooren, L.J.G., Weber, R.F.A. & Jong, F.H. de (2005). Serum levels of sex hormone-binding globulin (SHBG) are not associated with lower levels of non-shbg-bound testosterone in male newborns and healthy adult men. Clinical Endocrinology, 62(4), Sayed-Tabatabaei, F.A., Rijn, M.J.E. van, Schut, A.F.C., Aulchenko, Y.S., Croes, E.A., Zillikens, M.C., Pols, H.A.P., Witteman, J.C.M., Oostra, B.A. & Duijn, C.M. van (2005). Heritability of the function and structure of the arterial wall - Findings of the erasmus rucphen family (ERF) study. Stroke, 36(11), Schuit, S.C.E., Jong, F.H. de, Stolk, L., Kock, WNH, Meurs, J.B.J. van, Schoofs, M.W.C.J., Zillikens, M.C., Hofman, A., Leeuwen, J.P.T.M. van, Pols, H.A.P. & Uitterlinden, A.G. (2005). Estrogen receptor alpha gene polymorphisms are associated with estradiol levels in postmenopausal women. European Journal of Endocrinology, 153(2), Smit, P., Schaik, R.H.N. van, Werf, M. van der, Beld, A.W. van den, Koper, F.J.W., Lindemans, J., Pols, H.A.P., Brinkmann, A.O., Jong, F.H. de & Lamberts, S.W.J. (2005). A common polymorphism in the CYP3A7 gene is associated with a nearly 50% reduction in serum dehydroepiandrosterone sulfate levels. Journal of Clinical Endocrinology and Metabolism, 90(9), Staa, T.P. van, Geusens, P., Pols, H.A.P., Laet, C.E.D.H. de, Leufkens, H.G.M. & Cooper, C. (2005). A simple score for estimating the long-term risk of fracture in patients using oral glucocorticoids. QJM. Quarterly Journal of Medecine (Association of Physicians), 98(3), Tiemeier, H.W., Schuit, S.C.E., Heijer, T. den, Meurs, J.B.J. van, Tuijl, H.R. van, Hofman, A., Breteler, M.M.B., Pols, H.A.P. & Uitterlinden, A.G. (2005). Estrogen receptor alpha gene polymorphisms and anxiety disorder in an elderly population. Molecular Psychiatry, 10(9), Verhaak, R.G.W., Goudswaard, C.S., Putten, W.L.J. van, Bijl, M.A., Sanders, M.A., Hugens, W., Uitterlinden, A.G., Erpelinck-Verschuren, C.A.J., Delwel, H.R., Lowenberg, B. & Valk, P.J.M. (2005). Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood, 106(12), Zhao, HY, Liu, JM, Ning, G., Zhao, YJ, Zhang, LZ, Sun, LH, Xu, MY, Uitterlinden, A.G. & Chen, JL (2005). The influence of Lys3Asn polymorphism in the osteoprotegerin gene on bone mineral density in Chinese postmenopausal women. Osteoporosis International, 16(12), Part of book - abstract Leeuwen, J.P.T.M. van & Pols, H.A.P. (2005). Vitamin D: cancer and differentiation. In - Feldman, - Pike & - Glorieux (Eds.), Vitamin D (pp ). San Diego: Academic Press. Uitterlinden, A.G., Fang, Y., Meurs, J.B.J. van & Pols, H.A.P. (2005). Genetic vitamin D receptor polymorphisms and risk of disease. In Feldman, Pike & Glorieux (Eds.), Vitamin D (pp ). San Diego: Academic Press.

12 EMC MM Regulation of 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 0,83 4, ,33 nuclear medicine 0, ,2 Total 1,03 4, , Theses Peeters, R.P. (2005, december 07). Regulation of thyroid hormone bioactivity in health and disease. EUR (320 pag.). Prom./coprom.: Prof.Dr.Ir. T.J. Visser. Wassen, F.W.J.S. (2005, september 28). Iodothyronine deiodinases: structure-function analysis and their role in the regulation of thyroid hormone levels. EUR (233 pag.). Prom./coprom.: Prof.Dr.Ir. T.J. Visser. Article/Letter to the editor Alkemade, A, Friesema, E.C.H., Unmehopa, UA, Fabriek, BO, Kuiper, GG, Leonard, J.L., Wiersinga, W.M., Swaab, DF, Visser, T.J. & Fliers, E. (2005). Neuroanatomical pathways for thyroid hormone feedback in the human hypothalamus. Journal of Clinical Endocrinology and Metabolism, 90(7), Appelhof, BC, Peeters, R.P., Wiersinga, W.M., Visser, T.J., Wekking, EM, Huyser, J., Schene, AH, Tijssen, J.G.P., Hoogendijk, WJG & Fliers, E. (2005). Polymorphisms in type 2 deiodinase are not associated with well-being, neurocognitive functioning, and preference for combined thyroxine/3,5,3 '-triiodothyronine therapy. Journal of Clinical Endocrinology and Metabolism, 90(11), Beld, A.W. van den, Visser, T.J., Feelders, R.A., Grobbee, D.E. & Lamberts, S.W.J. (2005). Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. Journal of Clinical Endocrinology and Metabolism, 90(12), Boelen, A., Kwakkel, J., Alkemade, A, Renckens, R, Kaptein, E., Kuiper, G, Wiersinga, W.M. & Visser, T.J. (2005). Induction of type 3 deiodinase activity in inflammatory cells of mice with chronic local inflammation. Endocrinology, 146(12), Brinker, M. den, Joosten, K.F.M., Visser, T.J., Hop, W.C.J., Rijke, Y.B. de, Hazelzet, J.A., Boonstra, V.H. & Koelega, A.C.S. (2005). Euthyroid sick syndrome in meningococcal sepsis: The impact of peripheral thyroid hormone metabolism and binding proteins. Journal of Clinical Endocrinology and Metabolism, 90(10), Brinker, M. den, Dumas, B, Visser, T.J., Hop, W.C.J., Hazelzet, J.A., Festen, D.A.M., Koelega, A.C.S. & Joosten, K.F.M. (2005). Thyroid function and outcome in children who survived meningococcal septic shock. Intensive Care Medicine, 31(7), Cettour-Rose, P., Theander-Carrillo, C, Asensio, C, Klein, M., Visser, T.J., Burger, A.G., Meier, C.A. & Rohner- Jeanrenaud, F. (2005). Hypothyroidism in rats decreases peripheral glucose utilisation, a defect partially corrected by central leptin infusion. Diabetologia, 48(4), Cettour-Rose, P., Visser, T.J., Burger, A.G. & Rohner-Jeanrenaud, F. (2005). Inhibition of pituitary type 2 deiodinase by reverse triiodothyronine does not alter thyroxine-induced inhibition of thyrotropin secretion in hypothyroid rats. European Journal of Endocrinology, 153(3), Friesema, E.C.H., Jansen, J. & Visser, T.J. (2005). Membrane transporters for thyroid hormone. Current Opinion in Endocrinology & Diabetes, 12, Friesema, E.C.H., Jansen, J., Milici, C & Visser, T.J. (2005). Thyroid hormone transporters. Vitamins and Hormones. Advances in Research and Applications, 70,

13 Heuer, H., Maier, MK, Iden, S, Mittag, J., Friesema, E.C.H., Visser, T.J. & Bauer, K. (2005). The monocarboxylate transporter 8 linked to human psychomotor retardation is highly expressed in thyroid hormone-sensitive neuron populations. Endocrinology, 146(4), Hume, R., Williams, F.L.R. & Visser, T.J. (2005). Transient hypothyroxinaemia and preterm infant brain development. Thyroid International, 2, Jansen, J., Friesema, E.C.H., Milici, C & Visser, T.J. (2005). Thyroid hormone transporters in health and disease. Thyroid, 15(8), Jong, M. de, Barone, R., Krenning, E.P., Bernard, H.F., Melis, M., Visser, T.J., Gekle, M, Willnow, TE, Walrand, S., Jamar, F. & Pauwels, S. (2005). Megalin is essential for renal proximal tubule reabsorption of iii in-dtpa-octreotide. Journal of Nuclear Medicine, 46(10), Jong, M. de & Krenning, E.P. (2005). Molecular imaging and therapy of cancer using radiolabelled peptides. European Journal of Hospital Pharmacy Practice, 11(1), Kalsbeek, A, Buijs, R.M., Schaik, R van, Kaptein, E., Visser, T.J., Doulabi, BZ & Fliers, E. (2005). Daily variations in type II iodothyronine deiodinase activity in the rat brain as controlled by the biological clock. Endocrinology, 146(3), Kuiper, G.G.J.M., Kester, M.H.A., Peeters, R.P. & Visser, T.J. (2005). Biochemical mechanisms of thyroid hormone deiodination. Thyroid, 15(8), Kuiper, G.G.J.M., Klootwijk, W. & Visser, T.J. (2005). Expression of recombinant membrane-bound type I iodothyronine deiodinase in yeast. Journal of Molecular Endocrinology, 34(3), Lipzig, MMH van, Commandeur, JN, Kanter, FJJ de, Damsten, MC, Vermeulen, NPE, Maat, E, Groot, EJ, Brouwer, A., Kester, M.H.A., Visser, T.J. & Meerman, JHN (2005). Bioactivation of dibrominated biphenyls by cytochrome P450 activity to metabolites with estrogenic activity and estrogen sulfotransferase inhibition capacity. Chemical Research in Toxicology, 18(11), Melis, M., Krenning, E.P., Bernard, BG, Barone, R., Visser, T.J. & Jong, M. de (2005). Localisation and mechanism of renal retention of radiolabelled somatostatin analogues. European Journal of Nuclear Medicine and Molecular Imaging, 32(10), Mittag, J., Friedrichsen, S., Heuer, H., Polsfuss, S, Visser, T.J. & Bauer, K. (2005). Athyroid Pax8(-/-) mice cannot be rescued by the inactivation of thyroid hormone receptor alpha 1. Endocrinology, 146(7), Peeters, R.P., Beld, A.W. van den, Attalki, H, Toor, H. van, Rijke, Y.B. de, Kuiper, G.G.J.M., Lamberts, S.W.J., Janssen, J.A.M.J.L., Uitterlinden, A.G. & Visser, T.J. (2005). A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters. American Journal of Physiology, Endocrinology and Metabolism, 289(1), E75-E81. Peeters, R.P., Beld, A.W. van den, Toor, H. van, Uitterlinden, A.G., Janssen, J.A.M.J.L., Lamberts, S.W.J. & Visser, T.J. (2005). A polymorphism in type I deiodinase is associated with circulating free insulin-like growth factor I levels and body composition in humans. Journal of Clinical Endocrinology and Metabolism, 90(1), Peeters, R.P., Kester, M.H.A., Wouters, PJ, Kaptein, E., Toor, H. van, Visser, T.J. & Berghe, G. van den (2005). Increased thyroxine sulfate levels in critically ill patients as a result of a decreased hepatic type I deiodinase activity. Journal of Clinical Endocrinology and Metabolism, 90(12), Peeters, R.P., Wouters, PJ, Toor, H. van, Kaptein, E., Visser, T.J. & Berghe, G. van den (2005). Serum 3,3 ',5 '- triiodothyronine (rt(3)) and 3,5,3 '-triiodothyronine/rt(3) are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. Journal of Clinical Endocrinology and Metabolism, 90(8), Peeters, R.P., Geyten, S. v.d., Wouters, PJ, Darras, V.M., Toor, H. van, Kaptein, E., Visser, T.J. & Berghe, G. van den (2005). Tissue thyroid hormone levels in critical illness. Journal of Clinical Endocrinology and Metabolism, 90(12), Rajatapiti, P., Kester, M.H.A., Krijger, R.R. de, Rottier, R.J., Visser, T.J. & Tibboel, D. (2005). Expression of glucocorticoid, retinoid, and thyroid hormone receptors during human lung development. Journal of Clinical Endocrinology and Metabolism, 90(7), Simpson, J, Williams, F.L.R., Delahunty, C., Toor, H. van, Wu, S.Y., Ogston, S.A., Visser, T.J. & Hume, R. (2005). Serum thyroid hormones in preterm infants and relationships to indices of severity of intercurrent illness. Journal of Clinical Endocrinology and Metabolism, 90(3), Williams, F.L.R., Ogston, S.A., Toor, H. van, Visser, T.J. & Hume, R. (2005). Serum thyroid hormones in preterm infants: Associations with postnatal illnesses and drug usage. Journal of Clinical Endocrinology and Metabolism, 90(11),

14 Williams, F.L.R., Mires, GJ, Barnett, C, Ogston, S.A., Toor, H. van, Visser, T.J. & Hume, R. (2005). Transient hypothyroxinemia in preterm infants: The role of cord sera thyroid hormone levels adjusted for prenatal and intrapartum factors. Journal of Clinical Endocrinology and Metabolism, 90(8), Part of book - abstract Kester, M.H.A., Coughtrie, M.W.H. & Visser, T.J. (2005). Sulfation of thyroid hormones. In G.M. Pacifici & M.W.H. Coughtrie (Eds.), Human cytosolic sulfotransferases (pp ). Boca Raton: Taylor & Francis.

15 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 2, ,01 Total 2, , Article/Letter to the editor Al-Qahtani, A, Muttukrishna, S, Appasamy, M, Johns, J, Cranfield, M., Visser, J.A., Themmen, A.P.N. & Groome, N.P. (2005). Development of a sensitive enzyme immunoassay for anti-mullerian hormone and the evaluation of potential clinical applications in males and females. Clinical Endocrinology, 63(3), Bremer, S, Balduzzi, D, Cortvrindt, R, Daston, G, Eletti, B, Galli, A, Huhtaniemi, P, Laws, S, Lazzari, G, Liminga, U, Smitz, J, Spano, M, Themmen, A.P.N., Tilloy, A & Waalkens-Behrends, I (2005). The effects of chemicals on mammalian fertility - The report and recommendations of ECVAM workshop 53 - the first strategic workshop of the EU ReProTect project. Atla-Alternatives to Laboratory Animals, 33(4), Brinker, M. den, Joosten, K.F.M., Liem, O, Jong, F.H. de, Hop, W.C.J., Hazelzet, J.A., Dijk, M. van & Koelega, A.C.S. (2005). Adrenal insufficiency in meningococcal sepsis: Bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality. Journal of Clinical Endocrinology and Metabolism, 90(9), Eijken, M, Hewison, M., Cooper, MS, Jong, F.H. de, Chiba, H., Stewart, P.M., Uitterlinden, A.G., Pols, H.A.P. & Leeuwen, J.P.T.M. van (2005). 11 beta-hydroxysteroid dehydrogenase expression and glucocorticoid synthesis are directed by a molecular switch during osteoblast differentiation. Molecular Endocrinology, 19(3), Hagendorf, A., Koper, F.J.W., Jong, F.H. de, Brinkmann, A.O., Lamberts, S.W.J. & Feelders, R.A. (2005). Expression of the human glucocorticoid receptor splice variants alpha, beta, and P in peripheral blood mononuclear leukocytes in healthy controls and in patients with hyper- and hypocortisolism. Journal of Clinical Endocrinology and Metabolism, 90(11), Hendriks, D.J., Broekmans, F.J.M., Bancsi, L.F.J.M.M., Jong, F.H. de, Looman, C.W.N. & Velde, E.R. te (2005). Repeated clomiphene citrate challenge testing in the prediction of outcome in IVF: a comparison with basal markers for ovarian reserve. Human Reproduction, 20(1), Hendriks, D.J., Broekmans, F.J.M., Bancsi, L.F.J.M.M., Looman, C.W.N., Jong, F.H. de & Velde, E.R. te (2005). Single and repeated GnRH agonist stimulation tests compared with basal markers of ovarian reserve in the prediction of outcome in IVF. Journal of Assisted Reproduction and Genetics, 22(2), Hohmann, F.P., Laven, J.S.E., Mulders, A.G.M.G.J., Oberye, JJL, Mannaerts, B.M.J.L., Jong, F.H. de & Fauser, B.C.J.M. (2005). LH suppression following different low doses of the GnRH antagonist ganirelix in polycystic ovary syndrome. Journal of Endocrinological Investigation, 28, Hohmann, F.P., Laven, J.S.E., Jong, F.H. de & Fauser, B.C.J.M. (2005). Relationship between inhibin A and B, estradiol and follicle growth dynamics during ovarian stimulation in normo-ovulatory women. European Journal of Endocrinology, 152(3), Huhtaniemi, I.T. & Themmen, A.P.N. (2005). Mutations in human gonadotropin and gonadotropin-receptor genes. Endocrine, 26(3),