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1. Establishing Patient-Centered Outcomes for MCT8 Deficiency: Stakeholder Engagement and Systematic Literature Review

Author

Wilpert NM, Tonduti D, Vaia Y, Krude H, Sarret C, and Schuelke M

Subjects
mct8 deficiency, slc16a2, ultra-rare disease, movement disorders, triac, stakeholder engagement, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Nina-Maria Wilpert,1,2 Davide Tonduti,3 Ylenia Vaia,3 Heiko Krude,4 Catherine Sarret,5 Markus Schuelke1,2,6 1Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Pediatric Neurology, Berlin, Germany; 2Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health (BIH), Center for Chronically Sick Children, Berlin, Germany; 3Unit of Pediatric Neurology, C.O.A.L.A. (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children’s Hospital, Università Degli Studi Di Milano, Milan, Italy; 4Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Experimental Pediatric Endocrinology, Berlin, Germany; 5Centre de Compétence des Leucodystrophies et Leucoencéphalopathies de Cause Rare, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France; 6Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), NeuroCure Clinical Research Center, Berlin, GermanyCorrespondence: Markus Schuelke, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin, 13353, Germany, Tel +49 30 450566468, Email markus.schuelke@charite.deIntroduction: The SCL16A2 gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations. Patients suffer from severe neurodevelopmental delay and require multidisciplinary care. Since a first compassionate use study in 2008, the development of therapies has recently gained momentum. Treatment strategies range from symptom-based approaches, supplementation with TH or TH-analogs, to gene therapy. All these studies have mainly used surrogate endpoints and clinical outcomes. However, the EMA and FDA strongly encourage researchers to involve patients and their advocacy groups in the design of clinical trials. This should strengthen the patients’ perspective and identify clinical endpoints that are clinically relevant to their daily life.Methods: We involved patient families to define patient-relevant outcomes for MCT8 deficiency. In close collaboration with patient families, we designed a questionnaire asking for their five most preferred therapeutic goals, which, if achieved at least, make a difference in their lives. In addition, we performed a systematic review according to Cochrane recommendations of the published treatment trials.Results: We obtained results from 15 families with completed questionnaires from 14 mothers and 8 fathers. Improvement in development, especially in gross motor skills, was most important to the parents. 59% wished for head control and 50% for sitting ability. Another 36% wished for weight gain, 32% for improvement of expressive language skills, and 18% for a reduction of dystonia/spasticity, less dysphagia, and reflux. Paraclinical aspects were least important (5– 9%). In a treatment trial (n=46) and compassionate use cases (n=83), the results were mainly inconclusive, partly due to a lack of predefined patient-centered clinical endpoints.Discussion: We recommend that future trials should define a relevant improvement in “development” and/or other patient-relevant outcomes compared to natural history as treatment goals.Keywords: MCT8 deficiency, SLC16A2, ultra-rare disease, movement disorders, Triac, stakeholder engagement

Published
2023

3. Aktualisierung der S2k-Leitlinie: Operative Therapie benigner Schilddrüsenerkrankungen

Author

Musholt, T. J., Bockisch, A., Clerici, T., Dotzenrath, C., Dralle, H., Goretzki, P. E., Hermann, M., Holzer, K., Karges, W., Krude, H., Kussmann, J., Lorenz, K., Luster, M., Niederle, B., Nies, C., Riss, P., Schabram, J., Schabram, P., Schmid, K. W., Simon, D., Spitzweg, Ch., Steinmüller, Th., Trupka, A., Vorländer, C., Weber, T., Bartsch, D. K., and Leitliniengruppe der CAEK

Published
2018
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4. Development of a pediatric differentiated thyroid carcinoma registry within the EuRRECa project: rationale and protocol

Author

Clement, S C, primary, Visser, W E, additional, Lebbink, C A, additional, Albano, D, additional, Claahsen-van der Grinten, H L, additional, Czarniecka, A, additional, Dias, R P, additional, Dierselhuis, M P, additional, Dzivite-Krisane, I, additional, Elisei, R, additional, Garcia-Burillo, A, additional, Izatt, L, additional, Kanaka-Gantenbein, C, additional, Krude, H, additional, Lamartina, L, additional, Lorenz, K, additional, Luster, M, additional, Navardauskaitė, R, additional, Negre Busó, M, additional, Newbold, K, additional, Peeters, R P, additional, Pellegriti, G, additional, Piccardo, A, additional, Priego, A L, additional, Redlich, A, additional, de Sanctis, L, additional, Sobrinho-Simões, M, additional, van Trotsenburg, A S P, additional, Verburg, F A, additional, Vriens, M, additional, Links, T P, additional, Ahmed, S F, additional, and van Santen, H M, additional

Published
2023
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5. Development of a pediatric differentiated thyroid carcinoma registry within the EuRRECa project:rationale and protocol

Author

Clement, S. C., Visser, W. E., Lebbink, C. A., Albano, D., Claahsen-Van der Grinten, H. L., Czarniecka, A., Dias, R. P., Dierselhuis, M. P., Dzivite-Krisane, I., Elisei, R., Garcia-Burillo, A., Izatt, L., Kanaka-Gantenbein, C., Krude, H., Lamartina, L., Lorenz, K., Luster, M., Navardauskaitė, R., Negre Busó, M., Newbold, K., Peeters, R. P., Pellegriti, G., Piccardo, A., Priego, A. L., Redlich, A., de Sanctis, L., Sobrinho-Simões, M., van Trotsenburg, A. S.P., Verburg, F. A., Vriens, M., Links, T. P., Ahmed, S. F., van Santen, H. M., Clement, S. C., Visser, W. E., Lebbink, C. A., Albano, D., Claahsen-Van der Grinten, H. L., Czarniecka, A., Dias, R. P., Dierselhuis, M. P., Dzivite-Krisane, I., Elisei, R., Garcia-Burillo, A., Izatt, L., Kanaka-Gantenbein, C., Krude, H., Lamartina, L., Lorenz, K., Luster, M., Navardauskaitė, R., Negre Busó, M., Newbold, K., Peeters, R. P., Pellegriti, G., Piccardo, A., Priego, A. L., Redlich, A., de Sanctis, L., Sobrinho-Simões, M., van Trotsenburg, A. S.P., Verburg, F. A., Vriens, M., Links, T. P., Ahmed, S. F., and van Santen, H. M.

Abstract

Background: Although differentiated thyroid carcinoma (DTC) is the most frequent endocrine pediatric cancer, it is rare in childhood and adolescence. While tumor persistence and recurrence are not uncommon, mortality remains extremely low. Complications of treatment are however reported in up to 48% of the survivors. Due to the rarity of the disease, current treatment guidelines are predominantly based on the results of small observational retrospective studies and extrapolations from results in adult patients. In order to develop more personalized treatment and follow-up strategies (aiming to reduce complication rates), there is an unmet need for uniform international prospective data collection and clinical trials. Methods and analysis: The European pediatric thyroid carcinoma registry aims to collect clinical data for all patients ≤18 years of age with a confirmed diagnosis of DTC who have been diagnosed, assessed, or treated at a participating site. This registry will be a component of the wider European Registries for Rare Endocrine Conditions project which has close links to Endo-ERN, the European Reference Network for Rare Endocrine Conditions. A multidisciplinary expert working group was formed to develop a minimal dataset comprising information regarding demographic data, diagnosis, treatment, and outcome. We constructed an umbrella-type registry, with a detailed basic dataset. In the future, this may provide the opportunity for research teams to integrate clinical research questions. Ethics and dissemination: Written informed consent will be obtained from all participants and/or their parents/guardians. Summaries and descriptive analyses of the registry will be disseminated via conference presentations and peer-reviewed publications.

Published
2023

6. Development of a pediatric differentiated thyroid carcinoma registry within the EuRRECa project: rationale and protocol

Author

Endocrinologie onderzoek, Arts-assistenten Kinderen, CTI Van der Vlist, Cancer, Heelkunde Opleiding, MS CGO, Endocrinologie patientenzorg, Brain, Child Health, Clement, S. C., Visser, W. E., Lebbink, C. A., Albano, D., Claahsen-Van der Grinten, H. L., Czarniecka, A., Dias, R. P., Dierselhuis, M. P., Dzivite-Krisane, I., Elisei, R., Garcia-Burillo, A., Izatt, L., Kanaka-Gantenbein, C., Krude, H., Lamartina, L., Lorenz, K., Luster, M., Navardauskaitė, R., Negre Busó, M., Newbold, K., Peeters, R. P., Pellegriti, G., Piccardo, A., Priego, A. L., Redlich, A., de Sanctis, L., Sobrinho-Simões, M., van Trotsenburg, A. S.P., Verburg, F. A., Vriens, M., Links, T. P., Ahmed, S. F., van Santen, H. M., Endocrinologie onderzoek, Arts-assistenten Kinderen, CTI Van der Vlist, Cancer, Heelkunde Opleiding, MS CGO, Endocrinologie patientenzorg, Brain, Child Health, Clement, S. C., Visser, W. E., Lebbink, C. A., Albano, D., Claahsen-Van der Grinten, H. L., Czarniecka, A., Dias, R. P., Dierselhuis, M. P., Dzivite-Krisane, I., Elisei, R., Garcia-Burillo, A., Izatt, L., Kanaka-Gantenbein, C., Krude, H., Lamartina, L., Lorenz, K., Luster, M., Navardauskaitė, R., Negre Busó, M., Newbold, K., Peeters, R. P., Pellegriti, G., Piccardo, A., Priego, A. L., Redlich, A., de Sanctis, L., Sobrinho-Simões, M., van Trotsenburg, A. S.P., Verburg, F. A., Vriens, M., Links, T. P., Ahmed, S. F., and van Santen, H. M.

Published
2023

14. Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study

Author

Groeneweg, S., Geest, F.S. van, Abaci, A., Alcantud, A., Ambegaonkar, G.P., Armour, C.M., Bakhtiani, P., Barca, D., Bertini, E.S., Beijnum, I.M. van, Brunetti-Pierri, N., Bugiani, M., Cappa, M., Cappuccio, G., Castellotti, B., Castiglioni, C., Chatterjee, K., Coo, I.F.M. de, Coutant, R., Craiu, D., Crock, P., DeGoede, C., Demir, K., Dica, A., Dimitri, P., Dolcetta-Capuzzo, A., Dremmen, M.H.G., Dubey, R., Enderli, A., Fairchild, J., Gallichan, J., George, B., Gevers, E.F., Hackenberg, A., Halasz, Z., Heinrich, B., Huynh, T., Klosowska, A., Knaap, M.S. van der, Knoop, M.M. van der, Konrad, D., Koolen, D.A., Krude, H., Lawson-Yuen, A., Lebl, J., Linder-Lucht, M., Lorea, C.F., Lourenco, C.M., Lunsing, R.J., Lyons, G., Malikova, J., Mancilla, E.E., McGowan, A., Mericq, V., Lora, F.M., Moran, C., Muller, K.E., Oliver-Petit, I., Paone, L., Paul, P.G., Polak, M, Porta, F., Poswar, F.O., Reinauer, C., Rozenkova, K., Menevse, T.S., Simm, P., Simon, A., Singh, Y., Spada, M., Spek, J. van der, Stals, M.A.M., Stoupa, A., Subramanian, G.M., Tonduti, D., Turan, S., Uil, C.A. den, Vanderniet, J., Walt, A. van der, Wemeau, J.L., Wierzba, J., Wit, M.Y. de, Wolf, N.I., Wurm, M., Zibordi, F., Zung, A., Zwaveling-Soonawala, N., Visser, Wesley J., Groeneweg, S., Geest, F.S. van, Abaci, A., Alcantud, A., Ambegaonkar, G.P., Armour, C.M., Bakhtiani, P., Barca, D., Bertini, E.S., Beijnum, I.M. van, Brunetti-Pierri, N., Bugiani, M., Cappa, M., Cappuccio, G., Castellotti, B., Castiglioni, C., Chatterjee, K., Coo, I.F.M. de, Coutant, R., Craiu, D., Crock, P., DeGoede, C., Demir, K., Dica, A., Dimitri, P., Dolcetta-Capuzzo, A., Dremmen, M.H.G., Dubey, R., Enderli, A., Fairchild, J., Gallichan, J., George, B., Gevers, E.F., Hackenberg, A., Halasz, Z., Heinrich, B., Huynh, T., Klosowska, A., Knaap, M.S. van der, Knoop, M.M. van der, Konrad, D., Koolen, D.A., Krude, H., Lawson-Yuen, A., Lebl, J., Linder-Lucht, M., Lorea, C.F., Lourenco, C.M., Lunsing, R.J., Lyons, G., Malikova, J., Mancilla, E.E., McGowan, A., Mericq, V., Lora, F.M., Moran, C., Muller, K.E., Oliver-Petit, I., Paone, L., Paul, P.G., Polak, M, Porta, F., Poswar, F.O., Reinauer, C., Rozenkova, K., Menevse, T.S., Simm, P., Simon, A., Singh, Y., Spada, M., Spek, J. van der, Stals, M.A.M., Stoupa, A., Subramanian, G.M., Tonduti, D., Turan, S., Uil, C.A. den, Vanderniet, J., Walt, A. van der, Wemeau, J.L., Wierzba, J., Wit, M.Y. de, Wolf, N.I., Wurm, M., Zibordi, F., Zung, A., Zwaveling-Soonawala, N., and Visser, Wesley J.

Abstract

Contains fulltext : 220431.pdf (Publisher’s version ) (Closed access), BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1.5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. FINDINGS: Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24.0 months (IQR 12.0-60.0, range 0.0-744.0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35.0 years (95% CI 8.3-61.7). Individuals who did not attain head control by age 1.5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3.46, 95% CI 1.76-8.34; log-rank test p=0.0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who

Published
2020

15. Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study

Author

Groeneweg, S, van Geest, FS, Abaci, A, Alcantud, A, Ambegaonkar, GP, Armour, CM, Bakhtiani, P, Barca, D, Bertini, ES, van Beynum, IM, Brunetti-Pierri, N, Bugiani, M, Cappa, M, Cappuccio, G, Castellotti, B, Castiglioni, C, Chatterjee, K, de Coo, IFM, Coutant, R, Craiu, D, Crock, P, DeGoede, C, Demir, K, Dica, A, Dimitri, P, Dolcetta-Capuzzo, A, Dremmen, MHG, Dubey, R, Enderli, A, Fairchild, J, Gallichan, J, George, B, Gevers, EF, Hackenberg, A, Halasz, Z, Heinrich, B, Huynh, T, Klosowska, A, van der Knaap, MS, van der Knoop, MM, Konrad, D, Koolen, DA, Krude, H, Lawson-Yuen, A, Lebl, J, Linder-Lucht, M, Lorea, CF, Lourenco, CM, Lunsing, RJ, Lyons, G, Malikova, J, Mancilla, EE, McGowan, A, Mericq, V, Lora, FM, Moran, C, Mueller, KE, Oliver-Petit, I, Paone, L, Paul, PG, Polak, M, Porta, F, Poswar, FO, Reinauer, C, Rozenkova, K, Menevse, TS, Simm, P, Simon, A, Singh, Y, Spada, M, van der Spek, J, Stals, MAM, Stoupa, A, Subramanian, GM, Tonduti, D, Turan, S, den Uil, CA, Vanderniet, J, van der Walt, A, Wemeau, J-L, Wierzba, J, de Wit, M-CY, Wolf, N, Wurm, M, Zibordi, F, Zung, A, Zwaveling-Soonawala, N, Visser, WE, Groeneweg, S, van Geest, FS, Abaci, A, Alcantud, A, Ambegaonkar, GP, Armour, CM, Bakhtiani, P, Barca, D, Bertini, ES, van Beynum, IM, Brunetti-Pierri, N, Bugiani, M, Cappa, M, Cappuccio, G, Castellotti, B, Castiglioni, C, Chatterjee, K, de Coo, IFM, Coutant, R, Craiu, D, Crock, P, DeGoede, C, Demir, K, Dica, A, Dimitri, P, Dolcetta-Capuzzo, A, Dremmen, MHG, Dubey, R, Enderli, A, Fairchild, J, Gallichan, J, George, B, Gevers, EF, Hackenberg, A, Halasz, Z, Heinrich, B, Huynh, T, Klosowska, A, van der Knaap, MS, van der Knoop, MM, Konrad, D, Koolen, DA, Krude, H, Lawson-Yuen, A, Lebl, J, Linder-Lucht, M, Lorea, CF, Lourenco, CM, Lunsing, RJ, Lyons, G, Malikova, J, Mancilla, EE, McGowan, A, Mericq, V, Lora, FM, Moran, C, Mueller, KE, Oliver-Petit, I, Paone, L, Paul, PG, Polak, M, Porta, F, Poswar, FO, Reinauer, C, Rozenkova, K, Menevse, TS, Simm, P, Simon, A, Singh, Y, Spada, M, van der Spek, J, Stals, MAM, Stoupa, A, Subramanian, GM, Tonduti, D, Turan, S, den Uil, CA, Vanderniet, J, van der Walt, A, Wemeau, J-L, Wierzba, J, de Wit, M-CY, Wolf, N, Wurm, M, Zibordi, F, Zung, A, Zwaveling-Soonawala, N, and Visser, WE

Abstract

BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. FINDINGS: Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3-61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who

Published
2020

28. Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial

Author

Groeneweg, S., Peeters, R.P., Moran, C., Stoupa, A., Auriol, F., Tonduti, D., Dica, A., Paone, L., Rozenkova, K., Malikova, J., Walt, A. van der, Coo, I.F.M. de, McGowan, A., Lyons, G., Aarsen, F.K., Barca, D., Beynum, I.M. van, Knoop, M.M. van der, Jansen, J, Manshande, M., Lunsing, R.J., Nowak, S., Uil, C.A. den, Zillikens, M.C., Visser, F.E., Vrijmoeth, P., Wit, M.C. de, Wolf, N.I., Zandstra, A., Ambegaonkar, G., Singh, Y., Rijke, Y.B. de, Medici, M., Bertini, E.S., Depoorter, S., Lebl, J., Cappa, M., Meirleir, L. de, Krude, H., Craiu, D., Zibordi, F., Petit, I., Polak, M, Chatterjee, K., Visser, T.J., Visser, W.E., Groeneweg, S., Peeters, R.P., Moran, C., Stoupa, A., Auriol, F., Tonduti, D., Dica, A., Paone, L., Rozenkova, K., Malikova, J., Walt, A. van der, Coo, I.F.M. de, McGowan, A., Lyons, G., Aarsen, F.K., Barca, D., Beynum, I.M. van, Knoop, M.M. van der, Jansen, J, Manshande, M., Lunsing, R.J., Nowak, S., Uil, C.A. den, Zillikens, M.C., Visser, F.E., Vrijmoeth, P., Wit, M.C. de, Wolf, N.I., Zandstra, A., Ambegaonkar, G., Singh, Y., Rijke, Y.B. de, Medici, M., Bertini, E.S., Depoorter, S., Lebl, J., Cappa, M., Meirleir, L. de, Krude, H., Craiu, D., Zibordi, F., Petit, I., Polak, M, Chatterjee, K., Visser, T.J., and Visser, W.E.

Abstract

Contains fulltext : 215609.pdf (publisher's version ) (Closed access), BACKGROUND: Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T3) concentrations (Allan-Herndon-Dudley syndrome). This chronic thyrotoxicosis leads to progressive deterioration in bodyweight, tachycardia, and muscle wasting, predisposing affected individuals to substantial morbidity and mortality. Treatment that safely alleviates peripheral thyrotoxicosis and reverses cerebral hypothyroidism is not yet available. We aimed to investigate the effects of treatment with the T3 analogue Triac (3,3',5-tri-iodothyroacetic acid, or tiratricol), in patients with MCT8 deficiency. METHODS: In this investigator-initiated, multicentre, open-label, single-arm, phase 2, pragmatic trial, we investigated the effectiveness and safety of oral Triac in male paediatric and adult patients with MCT8 deficiency in eight countries in Europe and one site in South Africa. Triac was administered in a predefined escalating dose schedule-after the initial dose of once-daily 350 mug Triac, the daily dose was increased progressively in 350 mug increments, with the goal of attaining serum total T3 concentrations within the target range of 1.4-2.5 nmol/L. We assessed changes in several clinical and biochemical signs of hyperthyroidism between baseline and 12 months of treatment. The prespecified primary endpoint was the change in serum T3 concentrations from baseline to month 12. The co-primary endpoints were changes in concentrations of serum thyroid-stimulating hormone (TSH), free and total thyroxine (T4), and total reverse T3 from baseline to month 12. These analyses were done in patients who received at least one dose of Triac and had at least one post-baseline evaluation of serum throid function. This trial is registered with ClinicalTrials.gov, number NCT02060474. FINDINGS: Between Oct 15, 2014, and June 1, 2017, we screened 50 patients, all of whom were eligible. Of these patient

Published
2019

34. European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism

Author

Léger J, Olivieri A, Donaldson M, Torresani T, Krude H, van Vliet G, Polak M, Butler G, Alexander P, Alvarez M, Blankenstein O, CASSIO, ALESSANDRA, Castanet M, Cesaretti G, Cheetham T, Chiesa A, Corbetta C, Craig ME, Foley TP, Grosse S, Kempers M, de Labriolle Vaylet C, LaFranchi S, Luton D, Minagawa M, Raghupathy P, Rapaport R, Rovet J, Rustama DS, Salerno M, Simon A, Szinnai G, Tajima T, van Trotsenburg P., Léger, Juliane, Olivieri, Antonella, Donaldson, Malcolm, Torresani, Toni, Krude, Heiko, van Vliet, Guy, Polak, Michel, Butler, Gary, Salerno, Mariacarolina, Léger J, Olivieri A, Donaldson M, Torresani T, Krude H, van Vliet G, Polak M, Butler G, Alexander P, Alvarez M, Blankenstein O, Cassio A, Castanet M, Cesaretti G, Cheetham T, Chiesa A, Corbetta C, Craig ME, Foley TP, Grosse S, Kempers M, de Labriolle-Vaylet C, LaFranchi S, Luton D, Minagawa M, Raghupathy P, Rapaport R, Rovet J, Rustama DS, Salerno M, Simon A, Szinnai G, Tajima T, van Trotsenburg P., and University of Zurich

Subjects
1303 Biochemistry, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Thyrotropin, 1308 Clinical Biochemistry, Biochemistry, Pediatrics, Severity of Illness Index, 0302 clinical medicine, Endocrinology, Epidemiology, Mass Screening, Early childhood, Grading (education), Societies, Medical, Congenital Hypothyroidism, Consensus Guidelines, Screening, Special Features, Congenital hypothyroidism, 1310 Endocrinology, 3. Good health, Europe, 2712 Endocrinology, Diabetes and Metabolism, medicine.medical_specialty, Thyroid Hormones, Consensus, Pediatric endocrinology, MEDLINE, 610 Medicine & health, 030209 endocrinology & metabolism, 2704 Biochemistry (medical), 03 medical and health sciences, Neonatal Screening, Patient Education as Topic, Internal medicine, 030225 pediatrics, Severity of illness, medicine, Congenital Hypothyroidism, Humans, 2735 Pediatrics, Perinatology and Child Health, Mass screening, Dose-Response Relationship, Drug, business.industry, Biochemistry (medical), Infant, Newborn, medicine.disease, Newborn, Thyroxine, 10036 Medical Clinic, Pediatrics, Perinatology and Child Health, business
Abstract

OBJECTIVE: The aim was to formulate practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). EVIDENCE: A systematic literature search was conducted to identify key articles relating to the screening, diagnosis, and management of CH. The evidence-based guidelines were developed with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. CONSENSUS PROCESS: Thirty-two participants drawn from the European Society for Paediatric Endocrinology and five other major scientific societies in the field of pediatric endocrinology were allocated to working groups with assigned topics and specific questions. Each group searched the literature, evaluated the evidence, and developed a draft document. These papers were debated and finalized by each group before presentation to the full assembly for further discussion and agreement. RECOMMENDATIONS: The recommendations include: worldwide neonatal screening, approaches to assess the cause (including genotyping) and the severity of the disorder, the immediate initiation of appropriate L-T4 supplementation and frequent monitoring to ensure dose adjustments to keep thyroid hormone levels in the target ranges, a trial of treatment in patients suspected of transient CH, regular assessments of developmental and neurosensory functions, consulting health professionals as appropriate, and education about CH. The harmonization of diagnosis, management, and routine health surveillance would not only optimize patient outcomes, but should also facilitate epidemiological studies of the disorder. Individuals with CH require monitoring throughout their lives, particularly during early childhood and pregnancy Objective: The aim was to formulate practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). Evidence: A systematic literature search was conducted to identify key articles relating to the screening, diagnosis, andmanagementof CH. The evidence-based guidelines were developed with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. Consensus Process: Thirty-two participants drawn from the European Society for Paediatric Endocrinology and five other major scientific societies in the field of pediatric endocrinology were allocated to working groups with assigned topics and specific questions. Each group searched the literature, evaluated the evidence, and developed a draft document. These papers were debated and finalized by each group before presentation to the full assembly for further discussion and agreement. Recommendations: The recommendations include: worldwide neonatal screening, approaches to assess the cause (including genotyping) and the severity of the disorder, the immediate initiation of appropriate L-T4 supplementation and frequent monitoring to ensure dose adjustments to keep thyroid hormone levels in the target ranges, a trial of treatment in patients suspected of transient CH, regular assessments of developmental and neurosensory functions, consulting health professionals as appropriate, and education about CH. The harmonization of diagnosis, management, and routine health surveillance would not only optimize patient outcomes, but should also facilitate epidemiological studies of the disorder. Individuals with CH require monitoring throughout their lives, particularly during early childhood and pregnancy.

Published
2014

35. Surfactant proteins in pediatric interstitial lung disease

Author

Griese M, Lorenz E, Hengst M, Schams A, Wesselak T, Rauch D, Wittmann T, Kirchberger V, Escribano A, Schaible T, Baden W, Schulze J, Krude H, Aslanidis C, Schwerk N, Kappler M, Hartl D, Lohse P, and Zarbock R

Published
2016

36. Detection of novel gene variants associated with congenital hypothyroidism in a Finnish patient cohort

Author

Löf, C. (Christoffer), Patyra, K. (Konrad), Kuulasmaa, T. (Teemu), Vangipurapu, J. (Jagadish), Undeutsch, H. (Henriette), Jaeschke, H. (Holger), Pajunen, T. (Tuulia), Kero, A. (Andreina), Krude, H. (Heiko), Biebermann, H. (Heike), Kleinau, G. (Gunnar), Kühnen, P. (Peter), Rantakari, K. (Krista), Miettinen, P. (Päivi), Kirjavainen, T. (Turkka), Pursiheimo, J.-P. (Juha-Pekka), Mustila, T. (Taina), Jääskeläinen, J. (Jarmo), Ojaniemi, M. (Marja), Toppari, J. (Jorma), Ignatius, J. (Jaakko), Laakso, M. (Markku), Kero, J. (Jukka), Löf, C. (Christoffer), Patyra, K. (Konrad), Kuulasmaa, T. (Teemu), Vangipurapu, J. (Jagadish), Undeutsch, H. (Henriette), Jaeschke, H. (Holger), Pajunen, T. (Tuulia), Kero, A. (Andreina), Krude, H. (Heiko), Biebermann, H. (Heike), Kleinau, G. (Gunnar), Kühnen, P. (Peter), Rantakari, K. (Krista), Miettinen, P. (Päivi), Kirjavainen, T. (Turkka), Pursiheimo, J.-P. (Juha-Pekka), Mustila, T. (Taina), Jääskeläinen, J. (Jarmo), Ojaniemi, M. (Marja), Toppari, J. (Jorma), Ignatius, J. (Jaakko), Laakso, M. (Markku), and Kero, J. (Jukka)

Abstract

Background: Congenital hypothyroidism (CH) is defined as the lack of thyroid hormones at birth. Mutations in at least 15 different genes have been associated with this disease. While up to 20% of CH cases are hereditary, the majority of cases are sporadic with unknown etiology. Apart from a monogenic pattern of inheritance, multigenic mechanisms have been suggested to play a role in CH. The genetics of CH has not been studied in Finland so far. Therefore, multigenic sequencing of CH candidate genes was performed in a Finnish patient cohort with both familial and sporadic CH. Methods: A targeted next-generation sequencing (NGS) panel, covering all exons of the major CH genes, was applied for 15 patients with sporadic and 11 index cases with familial CH. Results: Among the familial cases, six pathogenic mutations were found in the TPO, PAX8, and TSHR genes. Furthermore, pathogenic NKX2.1 and TG mutations were identified from sporadic cases, together with likely pathogenic variants in the TG, NKX2.5, SLC26A4, and DUOX2 genes. All identified novel pathogenic mutations were confirmed by Sanger-sequencing and characterized in silico and/or in vitro. Conclusion: In summary, the CH panel provides an efficient, cost-effective, and multigenic screening tool for both known and novel CH gene mutations. Hence, it may be a useful method to identify accurately the genetic etiology for dyshormogenic, familial, or syndromic forms of CH.

Published
2016

37. Aktualisierung der S2k-Leitlinie.

Author

Leitliniengruppe der CAEK, Musholt, T. J., Krude, H., Kussmann, J., Lorenz, K., Luster, M., Niederle, B., Nies, C., Riss, P., Schabram, J., Schabram, P., Schmid, K. W., Bockisch, A., Simon, D., Spitzweg, Ch., Steinmüller, Th., Trupka, A., Vorländer, C., Weber, T., and Bartsch, D. K.

Abstract

Copyright of Der Chirurg is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2018
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38. Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency

Author

Krude H, Schutz B, Biebermann H, von Moers A, Schnabel D, Neitzel H, Tonnies H, Weise D, Lafferty A, Schwarz S, von Deimling A, van Landeghem F, Gruters A., DE FELICE, MARIO, DI LAURO, ROBERTO, Krude, H, Schutz, B, Biebermann, H, von Moers, A, Schnabel, D, Neitzel, H, Tonnies, H, Weise, D, Lafferty, A, Schwarz, S, DE FELICE, Mario, von Deimling, A, van Landeghem, F, DI LAURO, Roberto, and Gruters, A.

Published
2002

41. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, R.J. Dupuis, J. Prokopenko, I. Barker, A. Ahlqvist, E. Rybin, D. Petrie, J.R. Travers, M.E. Bouatia-Naji, N. Dimas, A.S. Nica, A.C. Wheeler, E. Chen, H. Voight, B.F. Taneera, J. Kanoni, S. Peden, J.F. Turrini, F. Gustafsson, S. Zabena, C. Almgren, P. Barker, D.J.P. Barnes, D. Dennison, E.M. Eriksson, J.G. Eriksson, P. Eury, E. Folkersen, L. Fox, C.S. Frayling, T.M. Goel, A. Gu, H.F. Horikoshi, M. Isomaa, B. Jackson, A.U. Jameson, K.A. Kajantie, E. Kerr-Conte, J. Kuulasmaa, T. Kuusisto, J. Loos, R.J.F. Luan, J. Makrilakis, K. Manning, A.K. Martínez-Larrad, M.T. Narisu, N. Mannila, M.N. Öhrvik, J. Osmond, C. Pascoe, L. Payne, F. Sayer, A.A. Sennblad, B. Silveira, A. Stančcáková, A. Stirrups, K. Swift, A.J. Syvänen, A.-C. Tuomi, T. Van't Hooft, F.M. Walker, M. Weedon, M.N. Xie, W. Zethelius, B. Scott, L.J. Steinthorsdottir, V. Morris, A.P. Dina, C. Welch, R.P. Zeggini, E. Huth, C. Aulchenko, Y.S. Thorleifsson, G. Mcculloch, L.J. Ferreira, T. Grallert, H. Amin, N. Wu, G. Willer, C.J. Raychaudhuri, S. McCarroll, S.A. Hofmann, O.M. Qi, L. Segre, A.V. Van Hoek, M. Navarro, P. Ardlie, K. Balkau, B. Benediktsson, R. Bennett, A.J. Blagieva, R. Boerwinkle, E. Bonnycastle, L.L. Bostrom, K.B. Bravenboer, B. Bumpstead, S. Burtt, N.P. Charpentier, G. Chines, P.S. Cornelis, M. Couper, D.J. Crawford, G. Doney, A.S.F. Elliott, K.S. Elliott, A.L. Erdos, M.R. Franklin, C.S. Ganser, M. Gieger, C. Grarup, N. Green, T. Griffin, S. Groves, C.J. Guiducci, C. Hadjadj, S. Hassanali, N. Herder, C. Johnson, P.R.V. Jorgensen, T. Kao, W.H.L. Klopp, N. Kong, A. Kraft, P. Lauritzen, T. Li, M. Lieverse, A. Lindgren, C.M. Lyssenko, V. Marre, M. Meitinger, T. Midthjell, K. Morken, M.A. Nilsson, P. Owen, K.R. Perry, J.R.B. Petersen, A.-K. Platou, C. Proenca, C. Rathmann, W. Rayner, N.W. Robertson, N.R. Rocheleau, G. Roden, M. Sampson, M.J. Saxena, R. Shields, B.M. Shrader, P. Sigurdsson, G. Sparso, T. Strassburger, K. Stringham, H.M. Sun, Q. Thorand, B. Tichet, J. Van Dam, R.M. Van Haeften, T.W. Van Herpt, T. Van Vliet-Ostaptchouk, J.V. Walters, G.B. Wijmenga, C. Witteman, J.C.M. Bergman, R.N. Cauchi, S. Collins, F.S. Gloyn, A.L. Gyllensten, U. Hansen, T. Hide, W.A. Hitman, G.A. Hofman, A. Hunter, D.J. Hveem, K. Laakso, M. Mohlke, K.L. Morris, A.D. Palmer, C.N.A. Pramstaller, P.P. Rudan, I. Sijbrands, E. Stein, L.D. Tuomilehto, J. Uitterlinden, A.G. Wareham, N.J. Watanabe, R.M. Abecasis, G.R. Boehm, B.O. Campbell, H. Daly, M.J. Hattersley, A.T. Hu, F.B. Meigs, J.B. Pankow, J.S. Pedersen, O. Wichmann, H.-E. Barroso, I. Groop, L. Sladek, R. Thorsteinsdottir, U. Wilson, J.F. Illig, T. Froguel, P. Van Duijn, C.M. Stefansson, K. Altshuler, D. Boehnke, M. McCarthy, M.I. Speliotes, E.K. Berndt, S.I. Monda, K.L. Allen, H.L. Magi, R. Randall, J.C. Vedantam, S. Winkler, T.W. Workalemahu, T. Heid, I.M. Wood, A.R. Weyant, R.J. Estrada, K. Liang, L. Nemesh, J. Park, J.-H. Kilpelainen, T.O. Yang, J. Esko, T. Feitosa, M.F. Kutalik, Z. Mangino, M. Scherag, A. Smith, A.V. Zhao, J.H. Aben, K.K. Absher, D.M. Dixon, A.L. Fisher, E. Glazer, N.L. Goddard, M.E. Heard-Costa, N.L. Hoesel, V. Hottenga, J.-J. Johansson, A. Johnson, T. Ketkar, S. Lamina, C. Li, S. Moffatt, M.F. Myers, R.H. Peters, M.J. Preuss, M. Ripatti, S. Rivadeneira, F. Sandholt, C. Timpson, N.J. Tyrer, J.P. Van Wingerden, S. White, C.C. Wiklund, F. Barlassina, C. Chasman, D.I. Cooper, M.N. Jansson, J.-O. Lawrence, R.W. Pellikka, N. Shi, J. Thiering, E. Alavere, H. Alibrandi, M.T.S. Arnold, A.M. Aspelund, T. Atwood, L.D. Balmforth, A.J. Ben-Shlomo, Y. Bergmann, S. Biebermann, H. Blakemore, A.I.F. Boes, T. Bornstein, S.R. Brown, M.J. Buchanan, T.A. Busonero, F. Cappuccio, F.P. Cavalcanti-Proenca, C. Chen, Y.-D.I. Chen, C.-M. Clarke, R. Coin, L. Connell, J. Day, I.N.M. Den Heijer, M. Duan, J. Ebrahim, S. Elliott, P. Elosua, R. Eiriksdottir, G. Facheris, M.F. Felix, S.B. Fischer-Posovszky, P. Folsom, A.R. Friedrich, N. Freimer, N.B. Fu, M. Gaget, S. Gejman, P.V. Geus, E.J.C. Gjesing, A.P. Goyette, P. Grasler, J. Greenawalt, D.M. Gudnason, V. Hartikainen, A.-L. Hall, A.S. Havulinna, A.S. Hayward, C. Heath, A.C. Hengstenberg, C. Hicks, A.A. Hinney, A. Homuth, G. Hui, J. Igl, W. Iribarren, C. Jacobs, K.B. Jarick, I. Jewell, E. John, U. Jousilahti, P. Jula, A. Kaakinen, M. Kaplan, L.M. Kathiresan, S. Kettunen, J. Kinnunen, L. Knowles, J.W. Kolcic, I. König, I.R. Koskinen, S. Kovacs, P. Kvaloy, K. Laitinen, J. Lantieri, O. Lanzani, C. Launer, L.J. Lecoeur, C. Lehtimaki, T. Lettre, G. Liu, J. Lokki, M.-L. Lorentzon, M. Luben, R.N. Ludwig, B. Manunta, P. Marek, D. Martin, N.G. McArdle, W.L. McCarthy, A. McKnight, B. Melander, O. Meyre, D. Montgomery, G.W. Mulic, R. Ngwa, J.S. Nelis, M. Neville, M.J. Nyholt, D.R. O'Donnell, C.J. O'Rahilly, S. Ong, K.K. Oostra, B. Pare, G. Parker, A.N. Perola, M. Pichler, I. Pietilainen, K.H. Platou, C.G.P. Polasek, O. Pouta, A. Rafelt, S. Raitakari, O. Rayner, N.W. Ridderstrale, M. Rief, W. Ruokonen, A. Rzehak, P. Salomaa, V. Sanders, A.R. Sandhu, M.S. Sanna, S. Saramies, J. Savolainen, M.J. Scherag, S. Schipf, S. Schreiber, S. Schunkert, H. Silander, K. Sinisalo, J. Siscovick, D.S. Smit, J.H. Soranzo, N. Sovio, U. Stephens, J. Surakka, I. Tammesoo, M.-L. Tardif, J.-C. Teder-Laving, M. Teslovich, T.M. Thompson, J.R. Thomson, B. Tonjes, A. Van Meurs, J.B.J. Van Ommen, G.-J. Vatin, V. Viikari, J. Visvikis-Siest, S. Vitart, V. Vogel, C.I.G. Waite, L.L. Wallaschofski, H. Widen, E. Wiegand, S. Wild, S.H. Willemsen, G. Witte, D.R. Xu, J. Zhang, Q. Zgaga, L. Ziegler, A. Zitting, P. Beilby, J.P. Farooqi, I.S. Hebebrand, J. Huikuri, H.V. James, A.L. Kahonen, M. Levinson, D.F. Macciardi, F. Nieminen, M.S. Ohlsson, C. Palmer, L.J. Ridker, P.M. Stumvoll, M. Beckmann, J.S. Boeing, H. Boomsma, D.I. Caulfield, M.J. Chanock, S.J. Cupples, L.A. Smith, G.D. Erdmann, J. Gronberg, H. Hall, P. Harris, T.B. Hayes, R.B. Heinrich, J. Jarvelin, M.-R. Kaprio, J. Karpe, F. Khaw, K.-T. Kiemeney, L.A. Krude, H. Lawlor, D.A. Metspalu, A. Munroe, P.B. Ouwehand, W.H. Penninx, B.W. Peters, A. Quertermous, T. Reinehr, T. Rissanen, A. Samani, N.J. Schwarz, P.E.H. Shuldiner, A.R. Spector, T.D. Uda, M. Valle, T.T. Wabitsch, M. Waeber, G. Watkins, H. Wright, A.F. Zillikens, M.C. Chatterjee, N. Purcell, S. Schadt, E.E. Visscher, P.M. Assimes, T.L. Borecki, I.B. Deloukas, P. Haritunians, T. Kaplan, R.C. O'Connell, J.R. Peltonen, L. Schlessinger, D. Strachan, D.P. North, K.E. Hirschhorn, J.N. Ingelsson, E. Parts, L. Glass, D. Nisbet, J. Barrett, A. Sekowska, M. Potter, S. Grundberg, E. Small, K. Hedman, A.K. Bataille, V. Bell, J.T. Surdulescu, G. Ingle, C. Nestle, F.O. Di Meglio, P. Min, J.L. Wilk, A. Hammond, C.J. Yang, T.-P. Montgomery, S.B. Zondervan, K.T. Durbin, R. Ahmadi, K. Dermitzakis, E.T. Reilly, M.P. Holm, H. Stewart, A.F.R. Barbalic, M. Aherrahrou, Z. Allayee, H. Anand, S.S. Andersen, K. Anderson, J.L. Ardissino, D. Ball, S.G. Barnes, T.A. Becker, D.M. Becker, L.C. Berger, K. Bis, J.C. Boekholdt, S.M. Braund, P.S. Burnett, M.S. Buysschaert, I. Carlquist, J.F. Chen, L. Codd, V. Davies, R.W. Cichon, S. Dedoussis, G.V. Demissie, S. Dehghan, A. Devaney, J.M. Diemert, P. Do, R. Doering, A. Eifert, S. El Mokhtari, N.E. Ellis, S.G. Engert, J.C. Epstein, S.E. De Faire, U. Fischer, M. Freyer, J. Gigante, B. Girelli, D. Gretarsdottir, S. Gulcher, J.R. Halperin, E. Hammond, N. Hazen, S.L. Horne, B.D. Jones, G.T. Jukema, J.W. Kaiser, M.A. Kastelein, J.J.P. Kolovou, G. Laaksonen, R. Lambrechts, D. Leander, K. Li, M. Lieb, W. Loley, C. Lotery, A.J. Mannucci, P.M. Maouche, S. Martinelli, N. McKeown, P.P. Meisinger, C. Merlini, P.A. Mooser, V. Morgan, T. Mühleisen, T.W. Muhlestein, J.B. Münzel, T. Musunuru, K. Nahrstaedt, J. Nelson, C.P. Nöthen, M.M. Olivieri, O. Patel, R.S. Patterson, C.C. Peyvandi, F. Qu, L. Quyyumi, A.A. Rader, D.J. Rallidis, L.S. Rice, C. Rosendaal, F.R. Rubin, D. Sampietro, M.L. Sandhu, M.S. Schadt, E. Schäfer, A. Schillert, A. Schrezenmeir, J. Schwartz, S.M. Sivananthan, M. Sivapalaratnam, S. Smith, T.B. Snoep, J.D. Spertus, J.A. Stark, K. Stoll, M. Wilson Tang, W.H. Tennstedt, S. Thorgeirsson, G. Tomaszewski, M. Van Rij, A.M. Wells, G.A. Wild, P.S. Willenborg, C. Wright, B.J. Ye, S. Zeller, T. Cambien, F. Goodall, A.H. Marz, W. Blankenberg, S. Roberts, R. McPherson, R. Hopewell, J.C. Parish, S. Offer, A. Bowman, L. Sleight, P. Armitage, J. Peto, R. Collins, R. Chambers, J.C. Ahmed, N. Donnelly, P. Kooner, A.S. Scott, J. Sehmi, J. Zhang, W. Kooner, J. Sabater-Lleal, M. Mälarstig, A. Hellénius, M.-L. Olsson, G. Rust, S. Assmann, G. Seedorf, U. Barlera, S. Tognoni, G. Franzosi, M.G. Linksted, P. Ongen, H. Kyriakou, T. Green, F. Farrall, M. Saleheen, D. Rasheed, A. Zaidi, M. Shah, N. Samuel, M. Mallick, N. Azhar, M. Zaman, K. Samad, A. Ishaq, M. Gardezi, A. Memon, F.-U.-R. Frossard, P. Danesh, J. Östenson, C.-G. Lind, L. Cooper, C.C. Serrano-Ríos, M. Ferrannini, E. Forsen, T.J. Pattou, F. Langenberg, C. Hamsten, A. Florez, J.C.

Subjects
endocrine system, endocrine system diseases, nutritional and metabolic diseases
Abstract

OBJECTIVE - Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS - We have conducted a meta-analysis of genome-wide association tests of ;2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS - Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10-8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/ C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 3 10-4), improved b-cell function (P = 1.1 × 10-5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10-6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS - We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. © 2011 by the American Diabetes Association.

Published
2011

42. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, Rj, Dupuis, J, Prokopenko, I, Barker, A, Ahlqvist, E, Rybin, D, Petrie, Jr, Travers, Me, Bouatia Naji, N, Dimas, As, Nica, A, Wheeler, E, Chen, H, Voight, Bf, Taneera, J, Kanoni, S, Peden, Jf, Turrini, F, Gustafsson, S, Zabena, C, Almgren, P, Barker, Dj, Barnes, D, Dennison, Em, Eriksson, Jg, Eriksson, P, Eury, E, Folkersen, L, Fox, Cs, Frayling, Tm, Goel, A, Gu, Hf, Horikoshi, M, Isomaa, B, Jackson, Au, Jameson, Ka, Kajantie, E, Kerr Conte, J, Kuulasmaa, T, Kuusisto, J, Loos, Rj, Luan, J, Makrilakis, K, Manning, Ak, Martínez Larrad MT, Narisu, N, Nastase Mannila, M, Ohrvik, J, Osmond, C, Pascoe, L, Payne, F, Sayer, Aa, Sennblad, B, Silveira, A, Stancáková, A, Stirrups, K, Swift, Aj, Syvänen, Ac, Tuomi, T, van 't Hooft FM, Walker, M, Weedon, Mn, Xie, W, Zethelius, B, Diagram, Consortium, Giant, Consortium, Muther, Consortium, Cardiogram, Consortium, C4d, Consortium, Ongen, H, Mälarstig, A, Hopewell, Jc, Saleheen, D, Chambers, J, Parish, S, Danesh, J, Kooner, J, Ostenson, Cg, Lind, L, Cooper, Cc, Serrano Ríos, M, Ferrannini, E, Forsen, Tj, Clarke, R, Franzosi, Mg, Seedorf, U, Watkins, H, Froguel, P, Johnson, P, Deloukas, P, Collins, Fs, Laakso, M, Dermitzakis, Et, Boehnke, M, Mccarthy, Mi, Wareham, Nj, Groop, L, Pattou, F, Gloyn, Al, Dedoussis, Gv, Lyssenko, V, Meigs, Jb, Barroso, I, Watanabe, Rm, Ingelsson, E, Langenberg, C, Hamsten, A, Voight BF, Florez J. C., Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Ys, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Hofmann, Om, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Bengtsson Boström, K, Bravenboer, B, Bumpstead, S, Burtt, P, Charpentier, G, Chines, Ps, Cornelis, M, Couper, Dj, Crawford, G, Doney, As, Elliott, Ks, Elliott, Al, Erdos, Mr, Franklin, Cs, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Nilsson, P, Owen, Kr, Perry, Jr, Petersen, K, Platou, C, Proença, C, Rathmann, W, William Rayner, N, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Thorand, B, Tichet, J, van Dam RM, van Haeften TW, van Herpt, T, van Vliet JV, Bragi Walters, G, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Pankow, Js, Pedersen, O, Wichmann, E, Florez, Jc, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Stefansson, K, Altshuler, D, Speliotes, Ek, Berndt, Si, Monda, Kl, Allen, Hl, Mägi, R, Randall, Jc, Vedantam, S, Winkler, Tw, Workalemahu, T, Heid, Im, Wood, Ar, Weyant, Rj, Estrada, K, Liang, L, Nemesh, J, Park, Jh, Kilpeläinen, To, Yang, J, Esko, T, Feitosa, Mf, Kutalik, Z, Mangino, M, Scherag, A, Smith, Av, Welch, R, Zhao, Jh, Aben, Kk, Absher, Dm, Dixon, Al, Fisher, E, Glazer, Nl, Goddard, Me, Heard Costa NL, Hoesel, V, Hottenga, Jj, Johansson, Å, Johnson, T, Ketkar, S, Lamina, C, Li, S, Moffatt, Mf, Myers, Rh, Peters, Mj, Preuss, M, Ripatti, S, Rivadeneira, F, Sandholt, C, Timpson, Nj, Tyrer, Jp, van Wingerden, S, White, Cc, Wiklund, F, Barlassina, C, Chasman, Di, Cooper, Mn, Jansson, Jo, Lawrence, Rw, Pellikka, N, Shi, J, Thiering, E, Alavere, H, Alibrandi, Mt, Arnold, Am, Aspelund, T, Atwood, Ld, Balmforth, Aj, Ben Shlomo, Y, Bergmann, S, Biebermann, H, Blakemore, Ai, Boes, T, Bornstein, Sr, Brown, Mj, Buchanan, Ta, Busonero, F, Cappuccio, Fp, Cavalcanti Proença, C, Ida Chen YD, Chen, Cm, Coin, L, Connell, J, Day, In, den Heijer, M, Duan, J, Ebrahim, S, Elliott, P, Elosua, R, Eiriksdottir, G, Facheris, Mf, Felix, Sb, Fischer Posovszky, P, Folsom, Ar, Friedrich, N, Freimer, Nb, Fu, M, Gaget, S, Gejman, Pv, Geus, Ej, Gjesing, Ap, Goyette, P, Grässler, J, Greenawalt, Dm, Gudnason, V, Hartikainen, Al, Hall, As, Havulinna, As, Hayward, C, Heath, Ac, Hengstenberg, C, Hicks, Aa, Hinney, A, Homuth, G, Hui, J, Igl, W, Iribarren, C, Jacobs, Kb, Jarick, I, Jewell, E, John, U, Jousilahti, P, Jula, A, Kaakinen, M, Kaplan, Lm, Kathiresan, S, Kettunen, J, Kinnunen, L, Knowles, Jw, Kolcic, I, König, Ir, Koskinen, S, Kovacs, P, Kvaløy, K, Laitinen, J, Lantieri, O, Lanzani, C, Launer, Lj, Lecoeur, C, Terho, L, Lettre, G, Liu, J, Lokki, Ml, Lorentzon, M, Luben, Rn, Ludwig, B, Magic, Manunta, P, Marek, D, Martin, Ng, Mcardle, Wl, Mccarthy, A, Mcknight, B, Melander, O, Meyre, D, Montgomery, Gw, Mulic, R, Ngwa, Js, Nelis, M, Neville, Mj, Nyholt, Dr, O'Donnell, Cj, O'Rahilly, S, Ong, Kk, Oostra, B, Paré, G, Parker, An, Perola, M, Pichler, I, Pietiläinen, Kh, Platou, Cg, Polasek, O, Pouta, A, Rafelt, S, Raitakari, O, Rayner, Nw, Ridderstråle, M, Rief, W, Ruokonen, A, Rzehak, P, Salomaa, V, Sanders, Ar, Sandhu, Ms, Sanna, S, Saramies, J, Savolainen, Mj, Scherag, S, Schipf, S, Schreiber, S, Schunkert, H, Silander, K, Sinisalo, J, Siscovick, Ds, Smit, Jh, Soranzo, N, Sovio, U, Stephens, J, Surakka, I, Tammesoo, Ml, Tardif, Jc, Teder Laving, M, Teslovich, Tm, Thompson, Jr, Thomson, B, Tönjes, A, van Meurs JB, van Ommen GJ, Vatin, V, Viikari, J, Visvikis Siest, S, Vitart, V, Vogel, Ci, Waite, Ll, Wallaschofski, H, Walters, Gb, Widen, E, Wiegand, S, Wild, Sh, Willemsen, G, Witte, Dr, Witteman, Jc, Xu, J, Zhang, Q, Zgaga, L, Ziegler, A, Zitting, P, Beilby, Jp, Farooqi, Is, Hebebrand, J, Huikuri, Hv, James, Al, Kähönen, M, Levinson, Df, Macciardi, F, Nieminen, Ms, Ohlsson, C, Palmer, Lj, Ridker, Pm, Stumvoll, M, Beckmann, Js, Boeing, H, Dorret, I. B., Caulfield, Mj, Chanock, Sj, Cupples, La, Smith, Gd, Erdmann, J, Grönberg, H, Hall, P, Harris, Tb, Hayes, Rb, Heinrich, J, Jarvelin, Mr, Kaprio, J, Karpe, F, Khaw, Kt, Kiemeney, La, Krude, H, Lawlor, Da, Metspalu, A, Munroe, Pb, Ouwehand, Wh, Penninx, Bw, Peters, A, Quertermous, T, Reinehr, T, Rissanen, A, Samani, Nj, Schwarz, Pe, Shuldiner, Ar, Spector, Td, Uda, M, Valle, Tt, Wabitsch, M, Waeber, G, Shaun, P, Eric, E. S., Peter, M. V., Assimes, Tl, Borecki, Ib, Groop, Lc, Haritunians, T, Kaplan, Rc, O'Connell, Jr, Peltonen, L, Schlessinger, D, Strachan, Dp, van Duijn CM, Barroso, H, North, Ke, Hirschhorn, Jn, Nica, Ac, Parts, L, Glass, D, Nisbet, J, Barrett, A, Sekowska, M, Travers, M, Potter, S, Grundberg, E, Small, K, Hedman, Åk, Bataille, V, Bell, Jt, Surdulescu, G, Ingle, C, Nestle, Fo, di Meglio, P, Min, Jl, Wilk, A, Hammond, Cj, Yang, Tp, Montgomery, Sb, Zondervan, Kt, Durbin, R, Ahmadi, K, Reilly, Mp, Holm, H, Stewart, Af, Barbalic, M, Absher, D, Aherrahrou, Z, Allayee, H, Anand, Ss, Andersen, K, Anderson, Jl, Ardissino, D, Ball, Sg, Barnes, Ta, Becker, Dm, Becker, Lc, Berger, K, Bis, Jc, Boekholdt, Sm, Braund, Ps, Burnett, Ms, Buysschaert, I, Cardiogenics, Carlquist, Jf, Chen, L, Cichon, S, Codd, V, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, Jm, Diemert, P, Do, R, Doering, A, Eifert, S, El Mokhtari NE, Ellis, Sg, Engert, Jc, Epstein, Se, de Faire, U, Fischer, M, Freyer, J, Gigante, B, Girelli, Domenico, Gretarsdottir, S, Gulcher, Jr, Halperin, E, Hammond, N, Hazen, Sl, Horne, Bd, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kastelein, Jj, Kolovou, G, Laaksonen, R, Lambrechts, D, Leander, K, Lieb, W, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meisinger, C, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Münzel, T, Musunuru, K, Nahrstaedt, J, Nelson, Cp, Nöthen, Mm, Olivieri, Oliviero, Patel, Rs, Patterson, Cc, Peyvandi, F, Qu, L, Quyyumi, Aa, Rader, Dj, Rallidis, Ls, Rice, C, Rosendaal, Fr, Rubin, D, Sampietro, Ml, Schadt, E, Schäfer, A, Schillert, A, Schrezenmeir, J, Schwartz, Sm, Sivananthan, M, Sivapalaratnam, S, Smith, A, Smith, Tb, Snoep, Jd, Spertus, Ja, Stark, K, Stoll, M, Tang, Wh, Tennstedt, S, Thorgeirsson, G, Tomaszewski, M, Uitterlinden, Ag, van Rij AM, Wells, Ga, Wichmann, He, Wild, Ps, Willenborg, C, Wright, Bj, Ye, S, Zeller, T, Cambien, F, Goodall, Ah, März, W, Blankenberg, S, Roberts, R, Mcpherson, R, Nilesh, J. S., Medical Research Council (MRC), Nica, Alexandra, Ongen, Halit, Dermitzakis, Emmanouil, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Vascular Medicine, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Scherag, Andre (Beitragende*r), Hinney, Anke (Beitragende*r), Scherag, S. (Beitragende*r), Vogel, C (Beitragende*r), Hebebrand, Johannes (Beitragende*r), University of Groningen, Wheeler, Eleanor [0000-0002-8616-6444], Barnes, Daniel [0000-0002-3781-7570], Luan, Jian'an [0000-0003-3137-6337], Johnson, Kathleen [0000-0002-6823-3252], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository

Subjects
Male, Netherlands Twin Register (NTR), endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Medizin, Genome-wide association study, Type 2 diabetes, CORONARY HEART-DISEASE, Fasting/blood, 0302 clinical medicine, Insulin, Glucose homeostasis, ddc:576.5, Genome-wide, Diabetes Mellitus, Type 2/blood/genetics/metabolism, CARDIoGRAM Consortium, POPULATION, Proinsulin, RISK, Genetics, 0303 health sciences, INSULIN SENSITIVITY, 11 Medical And Health Sciences, Fasting, Polymorphism, Single Nucleotide/genetics, OBESITY, Female, type 2 diabetes, Life Sciences & Biomedicine, hormones, hormone substitutes, and hormone antagonists, Insulin processing, Adult, medicine.medical_specialty, endocrine system, ENDOCRINOLOGY & METABOLISM, SUSCEPTIBILITY LOCI, Genotype, 030209 endocrinology & metabolism, DIAGRAM Consortium, Biology, C4D Consortium, Polymorphism, Single Nucleotide, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Insulin resistance, BETA-CELL FUNCTION, SDG 3 - Good Health and Well-being, Internal medicine, GIANT Consortium, Internal Medicine, medicine, Humans, METAANALYSIS, 030304 developmental biology, Science & Technology, Genome, Human, Hormonal regulation [IGMD 6], Genetic Variation, nutritional and metabolic diseases, proinsulin, medicine.disease, Proinsulin/blood, TCF7L2, Endocrinology, Diabetes Mellitus, Type 2, MuTHER Consortium, GLUCOSE-HOMEOSTASIS, Insulin/blood
Abstract

OBJECTIVE Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Published
2011

43. New G protein coupled receptor targets for 3-iodotyronamine

Author

Dinter, J, primary, Mühlhaus, J, additional, Jacobi, S, additional, Wienchol, CL, additional, Cöster, M, additional, Meister, J, additional, Höfig, C, additional, Müller, A, additional, Köhrle, J, additional, Grüters, A, additional, Krude, H, additional, Mittag, J, additional, Schöneberg, T, additional, Kleinau, G, additional, and Biebermann, H, additional

Published
2015
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44. PAX8 mutations associated with congenital hypothyroidism caused by thyroid

Author

MACCHIA, PAOLO EMIDIO, MISSERO, Caterina, FENZI, GIANFRANCO, DI LAURO, ROBERTO, Lapi P, Krude H, Pirro MT, Chiovato L, Souabni A, Baserga M, Tassi V, Pinchera A, Grüters A, Busslinger M, Macchia, PAOLO EMIDIO, Lapi, P, Krude, H, Pirro, Mt, Missero, Caterina, Chiovato, L, Souabni, A, Baserga, M, Tassi, V, Pinchera, A, Fenzi, Gianfranco, Grüters, A, Busslinger, M, and DI LAURO, Roberto

Published
1998

46. ein Blended-Learning Szenario

Author

Sostmann, K, Müller, S, Krude, H, Gross, M, Liermann, C, Fix, T, and Gaedicke, G

Subjects
ddc: 610
Published
2006

48. Consensus statement: Childhood obesity

Author

Speiser, Pw, Rudolf, Mcj, Anhalt, H, Camacho Hubner, C, Chiarelli, F, Eliakim, A, Freemark, M, Gruters, A, Hershkovitz, E, Iughetti, Lorenzo, Krude, H, Latzer, Y, Lustig, Rh, Pescovitz, Oh, Hamiel, Op, Rogol, Ad, Shalitin, S, Sultan, C, Stein, D, Vardi, P, Werther, Ga, Zadik, Z., Zuckerman Levin, N, and Hochberg, Z.

Subjects
consensus statement, childhood obesity
Published
2005

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