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  • 1.
    Abrahamsson, Annelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Morad, Vivian
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Saarinen, Niina M
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Estradiol, Tamoxifen, and Flaxseed Alter IL-1 beta and IL-1Ra Levels in Normal Human Breast Tissue in Vivo2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 11, E2044-E2054 p.Article in journal (Refereed)
    Abstract [en]

    Introduction: Sex steroid exposure increases the risk of breast cancer by unclear mechanisms. Diet modifications may be one breast cancer prevention strategy. The proinflammatory cytokine family of IL-1 is implicated in cancer progression. IL-1Ra is an endogenous inhibitor of the proinflammatory IL-1 alpha and IL-1 beta. less thanbrgreater than less thanbrgreater thanObjective: The objective of this study was to elucidate whether estrogen, tamoxifen, and/or diet modification altered IL-1 levels in normal human breast tissue. less thanbrgreater than less thanbrgreater thanDesign and Methods: Microdialysis was performed in healthy women under various hormone exposures, tamoxifen therapy, and diet modifications and in breast cancers of women before surgery. Breast tissue biopsies from reduction mammoplasties were cultured. less thanbrgreater than less thanbrgreater thanResults: We show a significant positive correlation between estradiol and in vivo levels of IL-1 beta in breast tissue and abdominal sc fat, whereas IL-1Ra exhibited a significant negative correlation with estradiol in breast tissue. Tamoxifen or a dietary addition of 25 g flaxseed per day resulted in significantly increased levels of IL-1Ra in the breast. These results were confirmed in ex vivo culture of breast biopsies. Immunohistochemistry of the biopsies did not reveal any changes in cellular content of the IL-1s, suggesting that mainly the secreted levels were affected. In breast cancer patients, intratumoral levels of IL-1 beta were significantly higher compared with normal adjacent breast tissue. less thanbrgreater than less thanbrgreater thanConclusion: IL-1 may be under the control of estrogen in vivo and may be attenuated by antiestrogen therapy and diet modifications. The increased IL-1 beta in breast cancers of women strongly suggests IL-1 as a potential therapeutic target in breast cancer treatment and prevention.

  • 2.
    Albertsson-Wikland, Kerstin
    et al.
    University of Gothenburg, Sweden.
    Mårtensson, Anton
    University of Gothenburg, Sweden; Stat Konsultgrp, Sweden.
    Savendahl, Lars
    Karolinska University Hospital, Sweden; Karolinska University Hospital, Sweden.
    Niklasson, Aimon
    University of Gothenburg, Sweden.
    Bang, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Dahlgren, Jovanna
    University of Gothenburg, Sweden.
    Gustafsson, Jan
    Uppsala University, Sweden.
    Kriström, Berit
    Umeå University, Sweden.
    Norgren, Svante
    Karolinska University Hospital, Sweden; Karolinska University Hospital, Sweden.
    Pehrsson, Nils-Gunnar
    Stat Konsultgrp, Sweden.
    Oden, Anders
    Stat Konsultgrp, Sweden; Chalmers, Sweden.
    Mortality Is Not Increased in Recombinant Human Growth Hormone-treated Patients When Adjusting for Birth Characteristics2016In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, no 5, 2149-2159 p.Article in journal (Refereed)
    Abstract [en]

    Objective: This study aimed to investigate whether reported high mortality in childhood recombinant human GH (rhGH)-treated patients was related to birth-characteristics and/or rhGH treatment. Design and Setting: We sought to develop a mortality model of the Swedish general population born between 1973 and 2010, using continuous-hazard functions adjusting for birth characteristics, sex, age intervals, and calendar year to estimate standardized mortality ratio (SMR) and to apply this model to assess expected deaths in Swedish rhGH-treated patients with idiopathic isolated GH deficiency (IGHD), idiopathic short stature (155) or born small for gestational age (SGA). Participants:The general population: Swedish Medical Birth Register (1973-2010: 1 880 668 males; 1 781 131 females) and Cause of Death Register (1985-2010). Intervention Population: Three thousand eight hundred forty-seven patients starting rhGH treatment between 1985 and 2010 and followed in the National GH Register and/or in rhGH trials diagnosed with IGHD (n = 1890), ISS (n = 975), or SGA (n=982). Main Outcome Measures: Death. Results: Using conventional models adjusting for age, sex, and calendar-year, the SMR was 1.43 (95% confidence interval, 0.89-2.19), P = .14, observed/expected deaths 21/14.68. The rhGH population differed (P amp;lt; .001) from the general population regarding birth weight, birth length, and congenital malformations. Application of an Advanced Model: When applying the developed mortality model of the general population, the ratio of observed/expected deaths in rhGH-treated patients was 21/21.99; SMR = 0.955 (0.591-1.456)P = .95. Model Comparison: Expected number of deaths were 14.68 (14.35-14.96) using the conventional model, and 21.99 (21.24-22.81) using the advanced model, P amp;lt; .001, which had at all ages a higher gradient of risk per SD of the model, 24% (range, 18-42%; P amp;lt; .001). Conclusions: Compared with the general Swedish population, the ratio of observed/expected deaths (21/21.99) was not increased in childhood rhGH-treated IGHD, ISS, and SGA patients when applying an advanced sex-specific mortality model adjusting for birth characteristics.

  • 3.
    Arner, Peter
    et al.
    Karolinska Institute, Huddinge Hospital, Stockholm, Sweden.
    Andersson, Daniel Peter
    Karolinska Institute, Huddinge Hospital, Stockholm, Sweden.
    Thörne, Anders
    Södertälje Hospital, Sweden.
    Wirén, Mikael
    Karolinska Institute, Huddinge Hospital, Stockholm, Sweden.
    Hoffstedt, Johan
    Karolinska Institute, Huddinge Hospital, Stockholm, Sweden.
    Näslund, Erik
    Karolinska Institute, Danderyd Hospital, Stockholm, Sweden.
    Thorell, Anders
    Karolinska Institute, Ersta Hospital, Stockholm, Sweden.
    Rydén, Mikael
    Karolinska Institute, Huddinge Hospital, Stockholm, Sweden.
    Variations in the size of the major omentum are primarily determined by fat cell number2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 5, E897-E901 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Accumulation of visceral adipose tissue (VAT) is strongly linked to insulin resistance. Variations in the size of any adipose depot are determined by alterations in adipocyte volume and/or number. The individual contribution of each of the latter factors was determined in the major omentum, a fully resectable VAT depot.

    SUBJECTS: Total removal of the major omentum (omentectomy) was performed in conjunction with bariatric surgery in 55 obese patients. Tissue weight as well as mean adipocyte size and number in the omentum were determined. In subgroups, total VAT was estimated by computerized tomography (n = 17) or dual-energy x-ray absorptiometry (n = 34).

    RESULTS: The weight of the major omentum (on average 0.6 kg) correlated significantly with total VAT mass estimated by computerized tomography or dual-energy x-ray absorptiometry (r = 0.48-0.7; P < .01). Omental weight in relation to total body fat correlated with several features of the metabolic syndrome and inversely with serum-leptin (P < .001). Mean adipocyte size and total adipocyte number correlated strongly with omental weight (r = 0.6-0.8; P < .0001), irrespective of body mass index and total body fat mass, and accounted almost in total for interindividual variations in omental size. However, stepwise regression analysis demonstrated that adipocyte number was significantly (P < .0001) more important (62%) than adipocyte size (35%).

    CONCLUSION: The size of the major omentum is representative for VAT mass and correlates with a pernicious metabolic profile. Variations in omental weight are primarily determined by adipocyte number and to a lesser degree by adipocyte size, suggesting that increased VAT mass in obesity is predominantly dependent on adipocyte proliferation.

  • 4.
    Bausch, Birke
    et al.
    Department of Nephrology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
    Borozdin, Wiktor
    Institute for Human Genetics and Anthropology, University of Freiburg, Freiburg, Germany / Center of Human Genetics, Freiburg, Germany.
    Mautner, Victor F
    Department of Maxillofacial Surgery, University Hospital Eppendorf, Hamburg, Germany.
    Hoffmann, Michael M
    Department of Laboratory Medicine, University Medical Center Freiburg, D-79106 Freiburg, Germany.
    Boehm, Detlef
    Department of Nephrology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
    Robledo, Mercedes
    Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain.
    Cascon, Alberto
    Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain.
    Harenberg, Tomas
    Department of Nephrology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
    Schiavi, Francesca
    Istituto Oncologico Veneto Instituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy.
    Pawlu, Christian
    Department of Nephrology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
    Peczkowska, Mariola
    Department of Hypertension, Institute of Cardiology, Warsaw, Poland.
    Letizia, Claudio
    Department of Clinical Sciences, University of Rome La Sapienza, Rome, Italy.
    Calvieri, Stefano
    Department of Dermatology, University of Rome La Sapienza, Rome, Italy.
    Arnaldi, Giorgio
    Department of Endocrinology, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy.
    Klingenberg-Noftz, Rolf D
    Medical Clinic I, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
    Reisch, Nicole
    Department of Endocrinology, Ludwig-Maximilians-University of Munich, Munich, Germany.
    Fassina, Ambrogio
    Department of Pathology, University of Padova, Padova, Italy.
    Brunaud, Laurent
    Department of Digestive and Endocrine Surgery, University Hospital Nancy, University of Nancy, Nancy, France.
    Walter, Martin A
    Institute of Nuclear Medicine, Division of Endocrinology, University of Basel, Basel, Switzerland.
    Mannelli, Massimo
    Department of Clinical Pathophysiology, Endocrine Unit, University of Florence, Florence, Italy.
    MacGregor, Graham
    Blood Pressure Unit, Department of Cardiovascular Sciences, St. George’s University, London, United Kingdom.
    Palazzo, F Fausto
    Endocrine Surgery Unit, Hammersmith Hospital, London, United Kingdom.
    Barontini, Marta
    Centro de Investigaciones Endocrinologicas-Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
    Walz, Martin K
    Department of Surgery, Kliniken Essen-Mitte, Essen, Germany.
    Kremens, Bernhard
    Department of Pediatrics, University of Essen, Essen, Germany.
    Brabant, Georg
    Department of Endocrinology, Medizinische Hochschule, Hannover, Germany.
    Pfäffle, Roland
    Department of Pediatrics, University of Leipzig, Leipzig, Germany.
    Koschker, Ann-Cathrin
    Department of Internal Medicine I-Endocrine and Diabetes, University of Wuerzburg, Wuerzburg, Germany.
    Lohoefner, Felix
    Department of Surgery, Hospital of the German Red Cross, Berlin, Germany.
    Mohaupt, Markus
    Department of Nephrology and Hypertension, University of Berne, Berne, Switzerland.
    Gimm, Oliver
    Department of Visceral Surgery, University of Halle, Halle, Germany.
    Jarzab, Barbara
    Department of Nuclear Medicine and Endocrine Oncology, M. Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Gliwice, Poland.
    McWhinney, Sarah R
    Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA / Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
    Opocher, Giuseppe
    Istituto Oncologico Veneto Instituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy.
    Januszewicz, Andrzej
    Department of Hypertension, Institute of Cardiology, Warsaw, Poland.
    Kohlhase, Jürgen
    Institute for Human Genetics and Anthropology, University of Freiburg, Freiburg, Germany / Center of Human Genetics, Freiburg, Germany.
    Eng, Charis
    Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA / Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
    Neumann, Hartmut P H
    Department of Nephrology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
    Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1.2007In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, no 7, 2784-92 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma that also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma.

    MATERIALS AND METHODS: An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing HPLC for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity analysis using markers in and around NF1 was performed.

    RESULTS: There were 37 eligible subjects (ages 14-70 yr). Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus vs. 0 of 12 sporadic tumors (P = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35% but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype.

    CONCLUSIONS: The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RAS-GAP domain, suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. Loss-of-heterozygosity of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1.

  • 5.
    Benn, Diana E
    et al.
    Department of Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney 2006, Australia.
    Gimenez-Roqueplo, Anne-Paule
    Department of Genetics, Hôpital Européen Georges Pompidou, Assistance Publique des Hôpitaux de Paris, L’Institut National de la Santé et de la Recherche Médicale (INSERM) U36, Collège de France, University Paris 5, Paris 75015, France.
    Reilly, Jennifer R
    Department of Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney 2006, Australia.
    Bertherat, Jérôme
    Department of Endocrinology, INSERM U567, Hôpital Cochin Assistance Publique des Hôpitaux de Paris, University Paris 5, Paris 75014, France.
    Burgess, John
    Department of Endocrinology, Royal Hobart Hospital, Tasmania 7001, Australia.
    Byth, Karen
    National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney 2006, Australia.
    Croxson, Michael
    Department of Endocrinology, Greenlane Clinical Centre, Auckland, New Zealand.
    Dahia, Patricia L M
    Departments of Medicine and Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
    Elston, Marianne
    Department of Endocrinology, Waikato Hospital, Hamilton, New Zealand.
    Gimm, Oliver
    Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Halle 06097, Germany.
    Henley, David
    Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia.
    Herman, Philippe
    Department of Otorhinolaryngology and Head and Neck Surgery, Hôpital Lariboisière, Assistance Publique des Hopitaux de Paris, Paris 75010, France.
    Murday, Victoria
    West of Scotland, Regional Genetics Services, Yorkhill G3 8SJ, Scotland.
    Niccoli-Sire, Patricia
    Department of Endocrinology, Hôpital de la Timone, Assistance Publique des Hôpitaux de Marseille, Marseille 13385, France.
    Pasieka, Janice L
    Department of Surgery, Faculty of Medicine, University of Calgary, Calgary, Canada T2N 1N4.
    Rohmer, Vincent
    Department of Endocrinology, Hôpital d’Angers, Angers 49033, France.
    Tucker, Kathy
    Hereditary Cancer Clinic, Prince of Wales Hospital and School of Medicine, University of New South Wales, Sydney, New South Wales 2052, Australia.
    Jeunemaitre, Xavier
    Department of Genetics, Hôpital Européen Georges Pompidou, Assistance Publique des Hôpitaux de Paris, L’Institut National de la Santé et de la Recherche Médicale (INSERM) U36, Collège de France, University Paris 5, Paris 75015, France.
    Marsh, Deborah J
    Department of Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney 2006, Australia.
    Plouin, Pierre-François
    Department Hypertension, Hôpital Européen Georges Pompidou, Assistance Publique des Hôpitaux de Paris, L’Institut National de la Santé et de la Recherche Médicale (INSERM) U36, Collège de France, University Paris 5, Paris 75015, France.
    Robinson, Bruce G
    Department of Endocrinology, Royal North Shore Hospital, Sydney 2065, Australia.
    Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes.2006In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 91, no 3, 827-36 p.Article in journal (Refereed)
    Abstract [en]

    CONTEXT: The identification of mutations in genes encoding peptides of succinate dehydrogenase (SDH) in pheochromocytoma/paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations.

    OBJECTIVE: Our objective was to determine genotype-phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and succinate dehydrogenase subunit B (SDHB) or subunit D (SDHD) mutations.

    DESIGN, SETTING, AND PARTICIPANTS: The International SDH Consortium studied 116 individuals (83 affected and 33 clinically unaffected) from 62 families with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. Clinical data were collected between August 2003 and September 2004 from tertiary referral centers in Australia, France, New Zealand, Germany, United States, Canada, and Scotland.

    MAIN OUTCOME MEASURES: Data were collected on patients with pheochromocytomas and/or paragangliomas with respect to onset of disease, diagnosis, genetic testing, surgery, pathology, and disease progression. Clinical features were evaluated for evidence of genotype-phenotype associations, and penetrance was determined.

    RESULTS: SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs. 28 yr, respectively; P = 0.3). However, when all mutation carriers were included (n = 112), the estimated age-related penetrance was different for SDHB vs. SDHD mutation carriers (P = 0.008).

    CONCLUSIONS: For clinical follow-up, features of SDHB mutation-associated disease include a later age of onset, extraadrenal (abdominal or thoracic) tumors, and a higher rate of malignancy. In contrast, SDHD mutation carriers, in addition to head and neck paragangliomas, should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal pheochromocytoma.

  • 6.
    Burman, P
    et al.
    Skånes University Hospital Malmö Lund, Sweden .
    Mattsson, A F
    Pfizer Health AB, Sweden .
    Johannsson, G
    University of Gothenburg, Sweden .
    Hoybye, C
    Karolinska University Hospital, Sweden .
    Holmer, H
    Central Hospital Kristianstad, Sweden .
    Dahlqvist, P
    Umeå University, Sweden .
    Berinder, K
    Karolinska University Hospital, Sweden .
    Engstrom, B E
    Uppsala University, Sweden .
    Ekman, Bertil
    Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Erfurth, E M.
    Skånes University Hospital Malmö Lund, Sweden .
    Svensson, J
    University of Gothenburg, Sweden .
    Wahlberg, J
    Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Karlsson, F A
    Uppsala University, Sweden .
    Deaths Among Adult Patients With Hypopituitarism: Hypocortisolism During Acute Stress, and De Novo Malignant Brain Tumors Contribute to an Increased Mortality2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 4, 1466-1475 p.Article in journal (Refereed)
    Abstract [en]

    Context: Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified. less thanbrgreater than less thanbrgreater thanObjective: To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up. less thanbrgreater than less thanbrgreater thanDesign and Methods: All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed. less thanbrgreater than less thanbrgreater thanMain Outcome Measures: Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up. less thanbrgreater than less thanbrgreater thanResults: An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy. less thanbrgreater than less thanbrgreater thanConclusion: Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease. (J Clin Endocrinol Metab 98: 1466-1475, 2013)

  • 7.
    Dabrosin, Charlotta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Variability of vascular endothelial growth factor in normal human breast tissue in vivo during the menstrual cycle2003In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, Vol. 88, no 6, 2695-2698 p.Article in journal (Refereed)
    Abstract [en]

    Exposure to sex steroids increases the risk of breast cancer, but the mechanisms are poorly understood. Angiogenesis is crucial in tumor development and progression. Very little is known about the regulation of angiogenesis in the normal breast. Vascular endothelial growth factor ( VEGF) has a key stimulatory role in angiogenesis. Interferon-inducible protein 10 (IP-10) is a potent inhibitor of angiogenesis in vivo. These factors function in autocrine/paracrine pathways, therefore, direct measurements in the target tissue are needed. I measured VEGF and IP-10 in normal human breast tissue in situ in healthy women, using microdialysis, in the follicular and luteal phase of the menstrual cycle. In breast tissue, VEGF levels increased in the luteal phase, compared with the follicular phase (17.8+/-4 pg/ml to 34+/-9 pg/ml, P<0.05). Plasma VEGF did not show a cyclic variation (10.6&PLUSMN,2.8 pg/ml vs. 14.6&PLUSMN,3.5 pg/liter, P=0.3). IP-10 levels did not vary during the menstrual cycle either in breast tissue (65&PLUSMN,17 pg/ml vs. 75&PLUSMN,21 pg/ml, P=0.6) or in plasma (64&PLUSMN,7 pg/ml vs. 81&PLUSMN,10 pg/ml, P=0.06). The data suggests that, in the luteal phase, VEGF and IP-10, in the normal human breast, exhibit a proangiogenic profile. This may be one mechanism by which sex steroids contribute to breast cancer development.

  • 8.
    Dalin, Frida
    et al.
    Karolinska Institutet, Stockholm, Sweden, Uppsala University, Uppsala, Sweden.
    Nordling Eriksson, Gabriel
    Karolinska Institutet, Stockholm, Sweden.
    Dahlqvist, Per
    Umeå University, Umeå, Sweden.
    Hallgren, Åsa
    Karolinska Institutet, Stockholm, Sweden.
    Wahlberg, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences.
    Ekwall, Olov
    The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Söderberg, Stefan
    Umeå University, Umeå, Sweden.
    Rönnelid, Johan
    The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Olcén, Per
    Örebro University, Örebro, Sweden.
    Winqvist, Ola
    Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Catrina, Sergiu-Bogdan
    Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Kriström, Berit
    Umeå University, Umeå, Sweden.
    Laudius, Maria
    Umeå University, Umeå, Sweden.
    Isaksson, Magnus
    Uppsala University, Uppsala, Sweden.
    Halldin Stenlid, Maria
    Uppsala University, Uppsala, Sweden.
    Gustafsson, Jan
    Uppsala University, Uppsala, Sweden.
    Gebre-Medhin, Gennet
    Uppsala University, Uppsala, Sweden.
    Björnsdottir, Sigridur
    Karolinska In Karolinska University Hospital, Stockholm, Sweden.
    Janson, Annika
    Karolinska Institutet, Stockholm, Sweden.
    Åkerman, Anna-Karin
    Örebro University, Örebro, Sweden.
    Åman, Jan
    Örebro University, Örebro, Sweden.
    Duchen, Karel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Bergthorsdottir, Ragnhildur
    Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Johannsson, Gudmundur
    Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Lindskog, Emma
    The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Landin-Olsson, Mona
    Skåne University Hospital, Malmö, Sweden..
    Elfving, Maria
    Lund University, Lund, Sweden..
    Waldenström, Erik
    Skåne University Hospital, Malmö, Sweden.
    Hulting, Anna-Lena
    Karolinska Institutet, Stockholm, Sweden.
    Kämpe, Olle
    Karolinska University Hospital, Stockholm, Karolinska Institutet, Stockholm, Sweden.
    Bensing, Sophie
    Karolinska University Hospital, Stockholm, Karolinska Institutet, Stockholm, Sweden.
    Clinical and immunological characteristics of Autoimmune Addison's disease: a nationwide Swedish multicenter study.2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 2, 379-389 p.Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.

    OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.

    DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.

    MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.

    RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p<0.0001). AAD patients had lower BMI (p<0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).

    CONCLUSIONS: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.

  • 9.
    Ekstrom, Klas
    et al.
    Karolinska Hospital and Institute, Sweden.
    Pulkkinen, Mari-Anne
    Karolinska Hospital and Institute, Sweden; University of Helsinki, Finland.
    Carlsson-Skwirut, Christine
    Karolinska Hospital and Institute, Sweden.
    Brorsson, Anna-Lena
    Karolinska Hospital and Institute, Sweden.
    Ma, Zhulin
    Aarhus University, Denmark.
    Frystyk, Jan
    Aarhus University, Denmark.
    Bang, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Tissue IGF-I Measured by Microdialysis Reflects Body Glucose Utilization After rhIGF-I Injection in Type 1 Diabetes2015In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 11, 4299-4306 p.Article in journal (Refereed)
    Abstract [en]

    Context: Type 1 diabetes is associated with portal insulin deficiency and disturbances in the GH-IGF axis including low circulating IGF-I and GH hypersecretion. Whether peripheral hyperinsulinemia and GH hypersecretion, which are relevant to the development of vascular complications, result in elevated tissue IGF-I remains unknown. Objective: The purpose of this study was to determine the relationship between whole-body glucose uptake and tissue IGF-I measured by microdialysis. Design: This was a single-blind placebo-controlled crossover study. Setting: The setting was a tertiary pediatric endocrine referral center. Participants: The participants were seven young male adults with type 1 diabetes. Intervention: After an overnight fast, a 6-h lasting euglycemic clamp was performed (constant insulin infusion at 0.5mU/kg x minute and variable glucose infusion rate [GIR]) and a subcutaneous injection of recombinant human (rh) IGF-I (120 mu g/kg) or saline was given after 2 hours. In parallel, tissue IGF-I levels were determined by microdialysis (md-IGF-I). Main Outcome Measures: md-IGF-I levels in muscle and subcutaneous fat, and GIR were determined. Results: md-IGF-I levels were detectable but unchanged after saline. After rhIGF-I, muscle and subcutaneous fat md-IGF-I increased during the second and third hour and then reached a plateau up to 10-fold higher than baseline (P less than .001). GIR was unchanged after saline, whereas it increased 2.5-fold concomitantly with the increase in md-IGF-I (P less than .0001). In contrast, serum IGF-I was increased already at 30 minutes after rhIGF-I and reached a plateau 2-fold above baseline (P less than .0001). Conclusion: We demonstrate that md-IGF-I measurements are valid and physiologically relevant by reflecting rhIGF-I-induced glucose uptake. Future studies should be conducted to elucidate the role of local tissue IGF-I in diabetic vascular complications.

  • 10.
    Fjalldal, Sigridur
    et al.
    Skåne University Hospital, Sweden .
    Holmer, Helene
    Central Hospital Kristianstad, Sweden .
    Rylander, Lars
    Lund University, Sweden .
    Elfving, Maria
    Skåne University Hospital, Sweden .
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Osterberg, Kai
    Lund University, Sweden .
    Erfurth, Eva Marie
    Skåne University Hospital, Sweden .
    Hypothalamic Involvement Predicts Cognitive Performance and Psychosocial Health in Long-term Survivors of Childhood Craniopharyngioma2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 8, 3253-3262 p.Article in journal (Refereed)
    Abstract [en]

    Context: Hypothalamic damage caused by craniopharyngioma (CP) is associated with poor functional outcome. less thanbrgreater than less thanbrgreater thanObjective: To assess cognitive function and quality of life in childhood-onset CP on hormonal replacement, including GH treatment. less thanbrgreater than less thanbrgreater thanDesign: A cross-sectional study with a median follow-up time of 20 years (1-40). less thanbrgreater than less thanbrgreater thanSetting: Patients were recruited from the South Medical Region of Sweden. less thanbrgreater than less thanbrgreater thanParticipants: The study included 42 patients (20 women) surgically treated for a childhood-onset CP between 1958 and 2000. Patients were aged andgt;= 17 years. Equally many controls, matched for age, sex, residence, and smoking habits, were included. Tumor growth into the third ventricle was found in 25 patients. less thanbrgreater than less thanbrgreater thanMain Outcome Measures: All subjects were examined with a battery of cognitive tests and the following questionnaires: Symptom Checklist-90, the Interview Schedule for Social Interaction, and the Social Network concept. less thanbrgreater than less thanbrgreater thanResults: The CP patients had lower cognitive performance, reaching statistical significance in 12 of 20 test variables, including executive function and memory. Comparison of patients with tumor growth into the third ventricle to controls revealed a significant lower mean total score (P = .006). A significant negative correlation was recorded between mean z-score of cognitive performance and years since operation (r = -0.407; P = .014). No statistically significant group differences were observed across any of the 9 Symptom Checklist-90 subscales. less thanbrgreater than less thanbrgreater thanConclusions: Adults with childhood-onset CP, on hormone replacement, including GH treatment, have memory defects, disturbed attention, and impaired processing speed. Patients with hypothalamic involvement are more affected. Patients rated their quality of life as good as their matched controls.

  • 11.
    Franck, Niclas
    et al.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Gummesson, Anders
    Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Jernås, Margareta
    Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Guillot, Gilles
    Department of Mathematical Statistics, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden; Applied Mathematics and Computer Sciences Department,National Research Institute for Agronomy, Paris, France; Centre for Ecology and Evolutionary Synthesis, Department of Biology, University of Oslo, Oslo, Norway.
    Glad, Camilla
    Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Svensson, Per-Arne
    Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden;.
    Rudemo, Mats
    Department of Mathematical Statistics, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden.
    Nyström, Fredrik H.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Carlsson, Lena M. S.
    Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Olsson, Bob
    Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Identification of adipocyte genes regulated by caloric intake2011In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 96, no 2, E413-E418 p.Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Changes in energy intake have marked and rapid effects on metabolic functions and some of the effects may be due to changes in adipose tissue gene expression that precede alterations in body weight.

    OBJECTIVE: To identify genes in adipose tissue regulated by changes in caloric intake independent of changes in body weight.

    RESEARCH DESIGN AND METHODS: Obese subjects were given a very-low calorie diet (VLCD; 450 kcal/day) for 16 weeks. After the diet, ordinary food was gradually reintroduced during 2 weeks while there were minimal changes in body weight. Adipose tissue gene expression was measured by microarray analysis. First, genes regulated during caloric restriction and in the opposite direction during the weight stable re-feeding phase were identified. To verify opposite regulation to that observed during caloric restriction, identified genes were further analyzed using adipocyte expression profiles from healthy subjects before and after overfeeding. Results were confirmed using real time PCR or immunoassay.

    RESULTS: Using a significance level of p<0.05 for all comparisons, 52 genes were downregulated and 50 were up-regulated by caloric restriction and regulated in the opposite direction by re-feeding and overfeeding. Among these were genes that affect lipogenesis (ACLY, ACACA, FASN, SCD), protein synthesis (4EBP1, 4EBP2), beta-oxidation (CPT1B), liberation of fatty acids (CIDEA) and glyceroneogenesis (PCK2). Interestingly, several of these are under control of the master regulator mTOR.

    CONCLUSIONS: The observed transcriptional changes indicate that mTOR plays a central role in the control of diet-regulated adipocyte genes involved in lipogenesis and protein synthesis.

  • 12.
    Georgitsi, Marianthi
    et al.
    Department of Medical Genetics, 00014 University of Helsinki, Finland.
    Raitila, Anniina
    Department of Medical Genetics, 00014 University of Helsinki, Finland.
    Karhu, Auli
    Department of Medical Genetics, 00014 University of Helsinki, Finland.
    van der Luijt, Rob B
    Department of Medical Genetics, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands.
    Aalfs, Cora M
    Department of Clinical Genetics, Academic Medical Centre, 1105 AZ Amsterdam, The Netherlands.
    Sane, Timo
    Department of Endocrinology, Helsinki University Central Hospital, 00029 Helsinki, Finland.
    Vierimaa, Outi
    Department of Clinical Genetics, Oulu University Hospital, 90029 Oulu, Finland.
    Mäkinen, Markus J
    Department of Pathology, University of Oulu, 90014 Oulu, Finland.
    Tuppurainen, Karoliina
    Department of Pathology, University of Oulu, 90014 Oulu, Finland.
    Paschke, Ralph
    Medical Department III, Leipzig University, 04103 Leipzig, Germany.
    Gimm, Oliver
    Department of Surgery, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany.
    Koch, Christian A
    Division of Endocrinology, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
    Gündogdu, Sadi
    Division of Endocrinology-Metabolism and Diabetes, Cerrahpaşa Medical Faculty, University of Istanbul, 34303 Istanbul, Turkey.
    Lucassen, Anneke
    Wessex Clinical Genetics Service, Princess Anne Hospital, SO16 5YA Southampton, United Kingdom.
    Tischkowitz, Marc
    Departments of Human Genetics, Oncology, and Medicine, McGill University, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2.
    Izatt, Louise
    Department of Clinical Genetics, New Guy’s House, Guy’s Hospital, London SE1 9RT, United Kingdom.
    Aylwin, Simon
    Department of Medicine, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.
    Bano, Gul
    Department of Endocrinology and Diabetes, Thomas Addison Unit, London SW17 0QT, United Kingdom.
    Hodgson, Shirley
    Department of Clinical Genetics, St. Georges, University of London, London SW17 ORE, United Kingdom.
    De Menis, Ernesto
    Department of Internal Medicine, General Hospital, 31100 Treviso, Italy.
    Launonen, Virpi
    Department of Medical Genetics, 00014 University of Helsinki, Finland.
    Vahteristo, Pia
    Department of Medical Genetics, 00014 University of Helsinki, Finland.
    Aaltonen, Lauri A
    Department of Medical Genetics, 00014 University of Helsinki, Finland.
    Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia.2007In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, no 8, 3321-5 p.Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20-25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27(Kip1), was reported in one suspected MEN1 family with two acromegalic patients.

    OBJECTIVE: Our objective was to evaluate the role of CDKN1B/p27(Kip1) in human tumor predisposition in patients clinically suspected of MEN1 but testing negative for MEN1 germline mutation as well as in familial and sporadic acromegaly/pituitary adenoma patients.

    DESIGN: Genomic DNA was analyzed for germline mutations in the CDKN1B/p27(Kip1) gene by PCR amplification and direct sequencing.

    SETTING: The study was conducted at nonprofit academic research and medical centers.

    PATIENTS: Thirty-six Dutch and one German suspected MEN1 patient, who previously tested negative for germline MEN1 gene mutations, were analyzed. In addition, 19 familial and 50 sporadic acromegaly/pituitary adenoma patients from Europe and the United States were included in the study.

    MAIN OUTCOME MEASURES: We analyzed germline CDKN1B/p27(Kip1) mutations in individuals with pituitary adenoma and MEN1-like features.

    RESULTS: A heterozygous 19-bp duplication (c.59_77dup19) leading to a truncated protein product was identified in one Dutch patient with suspected MEN1 phenotype, pituitary adenoma, carcinoid tumor, and hyperparathyroidism (one of 36, 2.8%). No mutations were detected in either familial or sporadic acromegaly/pituitary adenoma patients.

    CONCLUSIONS: Our results support the previous finding that germline CDKN1B/p27(Kip1) mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or nonexistent in familial or sporadic acromegaly/pituitary adenoma patients.

  • 13.
    Gertow, K.
    et al.
    Department of Medicine, Atherosclerosis Research Unit, King Gustaf V Research Institute, S-171 76 Stockholm, Sweden.
    Bellanda, M.
    Department of Organic Chemistry, University of Padova, 35131 Padova, Italy.
    Eriksson, P.
    Department of Medicine, Atherosclerosis Research Unit, King Gustaf V Research Institute, S-171 76 Stockholm, Sweden.
    Boquist, S.
    Department of Medicine, Atherosclerosis Research Unit, King Gustaf V Research Institute, S-171 76 Stockholm, Sweden.
    Hamsten, A.
    Department of Medicine, Atherosclerosis Research Unit, King Gustaf V Research Institute, S-171 76 Stockholm, Sweden.
    Sunnerhagen, Maria
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology .
    Fisher, R.M.
    Department of Medicine, Atherosclerosis Research Unit, King Gustaf V Research Institute, S-171 76 Stockholm, Sweden, King Gustaf V Research Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden.
    Genetic and Structural Evaluation of Fatty Acid Transport Protein-4 in Relation to Markers of the Insulin Resistance Syndrome2004In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, Vol. 89, no 1, 392-399 p.Article in journal (Refereed)
    Abstract [en]

    Disturbances in fatty acid metabolism are involved in the etiology of insulin resistance and the related dyslipidemia, hypertension, and procoagulant state. The fatty acid transport proteins (FATPs) are implicated in facilitated cellular uptake of nonesterified fatty acids (NEFAs), thus potentially regulating NEFA concentrations and metabolism. The aim of this study was to investigate polymorphic loci in the FATP4 gene with respect to associations with fasting and postprandial lipid and lipoprotein variables and markers of insulin resistance in 608 healthy, middle-aged Swedish men and to evaluate possible mechanisms behind any associations observed. Heterozygotes for a Gly209Ser polymorphism (Ser allele frequency 0.05) had significantly lower body mass index and, correcting for body mass index, significantly lower triglyceride concentrations, systolic blood pressure, insulin concentrations, and homeostasis model assessment index compared with common homozygotes. A three-dimensional model of the FATP4 protein based on structural and functional similarity with adenylate-forming enzymes revealed that the variable residue 209 is exposed in a region potentially involved in protein-protein interactions. Furthermore, the model indicated functional regions with respect to NEFA transport and acyl-coenzyme A synthase activity and membrane association. These findings propose FATP4 as a candidate gene for the insulin resistance syndrome and provide a structural basis for understanding FATP function in NEFA transport and metabolism.

  • 14.
    Hedman, Christina
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Frystyk, Jan
    Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark.
    Lindström, Torbjörn
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Chen, Jian-Wen
    Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark.
    Flyvbjerg, Allan
    Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark.
    Ørskov, Hans
    Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark.
    Arnqvist, Hans
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Residual β-cell function more than glycemic control determines abnormalities of the insulin-like growth factor system in type 1 diabetes2004In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 89, no 12, 6305-6309 p.Article in journal (Refereed)
    Abstract [en]

    The GH-IGF-I axis is disturbed in patients with type 1 diabetes. Our aim was to investigate whether abnormalities are found in patients in very good glycemic control and, if so, to estimate the role of residual β-cell function. Patients with hemoglobin A 1c (HbA 1c) less than 6% (reference range, 3.6-5.4%) were selected for the study. Twenty-two men and 24 women, aged 41.3 ± 13.8 yr (mean ± SD), with a diabetes duration of 17.8 ± 14.6 yr participated. Healthy controls (15 women and nine men), aged 41.3 ± 13.0 yr, were also studied. Overnight fasting serum samples were analyzed for HbA 1c, C peptide, free and total IGFs, IGF-binding proteins (IGFBPs), GH-binding protein, and IGFBP-3 proteolysis. HbA 1c was 5.6 ± 0.5% in patients and 4.4 ± 0.3% in controls. Total IGF-I was 148 ± 7 μg/liter in patients and 178 ± 9 μg/liter in controls (P < 0.001). Free IGF-I, total IGF-II, IGFBP-3, and GH-binding protein were lower, whereas IGFBP-1, IGFBP-1-bound IGF-I, and IGFBP-2 were elevated compared with control values. Patients with detectable C peptide (≥100 pmol/liter) had higher levels of total IGF-I, free IGF-I, and total IGF-II and lower levels of IGFBP-1 and IGFBP-2 than those with an undetectable C peptide level despite having identical average HbA 1c. IGFBP-3 proteolysis did not differ between patients and controls. Despite very good glycemic control, patients with type 1 diabetes and no endogenous insulin production have low free and total IGF-I. Residual β-cell function, therefore, seems more important for the disturbances in the IGF system than good metabolic control per se, suggesting that portal insulin delivery is needed to normalize the IGF system.

  • 15.
    Holmer, Helene
    et al.
    Central Hospital, Kristianstad, Sweden.
    Pozarek, Gabriella
    Lund-Malmö University Hospital, Lund, Sweden.
    Wirfält, Elisabet
    Lund University, Sweden.
    Popovic, Vera
    University Clinical Center, Belgrade, Serbia.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Björk, Jonas
    Lund University Hospital, Sweden.
    Erfurth, Eva-Marie
    Lund-Malmö University Hospital, Lund, Sweden.
    Reduced Energy Expenditure and Impaired Feeding-Related Signals But Not High Energy Intake Reinforces Hypothalamic Obesity in Adults with Childhood Onset Craniopharyngioma2010In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, no 12, 5395-5402 p.Article in journal (Refereed)
    Abstract [en]

    Context: Obesity is a frequent manifestation of hypothalamic damage from a craniopharyngioma (CP). It is not yet clarified whether the obesity is due to alterations in energy expenditure, i.e. basal metabolic rate (BMR) and physical activity, or to increased energy intake (EI). Objective: The aim was to investigate whether energy expenditure and EI differed between childhood onset CP patients and matched population controls and whether these measures were related to hypothalamic damage, as tumor growth into the third ventricle (TGTV). Design and Methods: Forty-two CP patients (20 women) aged 28 yr (range, 17-57 yr) operated between 1958 and 2000 in the South Medical Region of Sweden (population, 2.5 million) were studied. Body composition, satiety hormones, BMR (indirect calorimetry), physical activity, EI, and attitudes toward eating were assessed. Comparisons were made with matched controls and between patients with (n = 25) and without (n = 17) TGTV. Results: After adjustment, patients had lower BMR compared to controls (-90 kcal/24 h; P = 0.02) and also had lower EI (1778 vs. 2094 kcal/24h; P = 0.008), and the EI/BMR ratio was significantly lower in TGTV patients. Similar dietary macronutrient composition was found, and only significantly higher scales in restricting food intake were recorded in patients. Ghrelin levels were significantly lower in patients, whereas serum insulin and leptin levels were higher (P less than 0.001), and both ghrelin and insulin correlated significantly to tumor growth. Lower levels of physical activity (P less than 0.01) were recorded in patients. Conclusions: The major mechanisms that reinforced obesity were hypothalamic damage causing disrupted or impaired sensitivity to feeding-related signals for leptin, insulin, and ghrelin, and reductions in both BMR and physical activity.

  • 16.
    Holmer, Helene
    et al.
    Centralsjukhuset, Kristianstad, Sweden.
    Svensson, Johan
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Rylander, Lars
    Lund University, Sweden.
    Johansson, Gudmundur
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Rosén, Thord
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Bengtsson, Bengt Åke
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Thorén, Marja
    Karolinska University Hospital Solna, Stockholm, Sweden .
    Höybye, Charlotte
    Karolinska University Hospital Solna, Stockholm, Sweden.
    Degerblad, Marie
    Karolinska University Hospital Solna, Stockholm, Sweden.
    Bramnert, Margareta
    University Hospital, Malmö, Sweden.
    Hägg, Erik
    University Hospital, Umeå, Sweden.
    Edén Engström, Britt
    Uppsala University Hospital, Sweden.
    Ekman, Bertil
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Norrving, Bo
    Lund University Hospital, Sweden.
    Hagmar, Lars
    Lund University, Sweden.
    Erfurth, Eva-Marie
    Lund University Hospital, Sweden.
    Nonfatal stroke, cardiac disease, and diabetes mellitus in hypopituitary patients on hormone replacement including growth hormone2007In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, no 9, 3560-3567 p.Article in journal (Refereed)
    Abstract [en]

    Context: The impact of long-term GH replacement on cerebrovascular and cardiovascular diseases and diabetes mellitus in hypopituitary patients is unknown. Objective: The incidence of nonfatal stroke and cardiac events, and prevalence of type 2 diabetes mellitus (T2D) and cardioprotective medication were compared between cohorts of GH-deficient (GHD) patients and population controls. Design and Participants: The incidence of nonfatal stroke and cardiac events was estimated retrospectively from questionnaires in 750 GHD patients and 2314 matched population controls. A prevalence of T2D and cardioprotective medication was recorded at the distribution of questionnaires. Time since first pituitary deficiency to start of GH therapy was 4 and 2 yr, and time on GH therapy was 6 yr for GHD women and men, respectively. Results: Lifelong incidence of nonfatal stroke was tripled in GHD women and doubled in GHD men, but a decline was seen in both genders during periods after first pituitary hormone deficiency and GHD, during which most patients had GH therapy. The lifelong incidence of nonfatal cardiac events declined in GHD men during first pituitary hormone deficiency and GHD periods. GHD women had a higher prevalence of T2D and lipid-lowering medication, whereas GHD men had a higher prevalence of antihypertensive medication. Conclusions: The declined risks of nonfatal stroke in both genders and of nonfatal cardiac events in GHD men during periods on GH replacement may be caused by prescription of cardioprotective drugs and 6-yr GH replacement. GHD women had an increased prevalence of T2D, partly attributed to higher body mass index and lower physical activity. Copyright © 2007 by The Endocrine Society.

  • 17. Hull, Rebecca L
    et al.
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Westermark, Per
    Kahn, Steven E
    Islet amyloid: A critical entity in the pathogenesis of type 2 diabetes2004In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, Vol. 89, no 8, 3629-3643 p.Article in journal (Refereed)
    Abstract [en]

    Islet amyloid deposition is a pathogenic feature of type 2 diabetes, and these deposits contain the unique amyloidogenic peptide islet amyloid polypeptide. Autopsy studies in humans have demonstrated that islet amyloid is associated with loss of β-cell mass, but a direct role for amyloid in the pathogenesis of type 2 diabetes cannot be inferred from such studies. Animal studies in both spontaneous and transgenic models of islet amyloid formation have shown that amyloid forms in islets before fasting hyperglycemia and therefore does not arise merely as a result of the diabetic state. Furthermore, the extent of amyloid deposition is associated with both loss of β-cell mass and impairment in insulin secretion and glucose metabolism, suggesting a causative role for islet amyloid in the islet lesion of type 2 diabetes. These animal studies have also shown that β-cell dysfunction seems to be an important prerequisite for islet amyloid formation, with increased secretory demand from obesity and/or insulin resistance acting to further increase islet amyloid deposition. Recent in vitro studies suggest that the cytotoxic species responsible for islet amyloid-induced β-cell death are formed during the very early stages of islet amyloid formation, when islet amyloid polypeptide aggregation commences. Interventions to prevent islet amyloid formation are emerging, with peptide and small molecule inhibitors being developed. These agents could thus lead to a preservation of β-cell mass and amelioration of the islet lesion in type 2 diabetes.

  • 18.
    Johansson, G.
    et al.
    Sahlgrenska Academy, University of Gothenburg.
    Nilsson, A. G.
    Sahlgrenska Academy, University of Gothenburg.
    Bergthorsdottir, R.
    Sahlgrenska Academy, University of Gothenburg.
    Burman, P.
    Skånes University Hospital, Malmö.
    Dahlqvist, P.
    Umeå University.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Engström, B. E
    Uppsala University.
    Olsson, T.
    Umeå University.
    Ragnarsson, O.
    Sahlgrenska Academy, University of Gothenburg.
    Ryberg, M.
    Umeå University.
    Wahlberg, Jeanette
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Biller, B. M. K.
    Massachusetts General Hospital, Harvard Medical School, Boston.
    Monson, J. P.
    St. Bartholomew's Hospital, Queen Mary University of London.
    Stewart, P. M.
    University of Birmingham.
    Lennernäs, H.
    Uppsala University.
    Skrtic, S.
    Sahlgrenska Academy, University of Gothenburg.
    Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomised trial of a novel hydrocortisone dual-release formulation2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 2, 473-481 p.Article in journal (Refereed)
    Abstract [en]

    Context: Patients with treated adrenal insufficiency (AI) have increased morbidity and mortality rate. Our goal was to improve outcome by developing a once-daily (OD) oral hydrocortisone dual-release tablet with a more physiological exposure-time cortisol profile.

    Objective: The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily (TID) dose of conventional hydrocortisone tablets.

    Design and Setting: We conducted an open, randomized, two-period, 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers.

    Patients: The trial enrolled 64 adults with primary AI; 11 had concomitant diabetes mellitus (DM).

    Intervention: The same daily dose of hydrocortisone was administered as OD dual-release or TID.

    Main Outcome Measure: We evaluated cortisol pharmacokinetics.

    Results: Compared with conventional TID, OD provided a sustained serum cortisol profile 0-4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure. The mean weight (difference = -0.7 kg, P = 0.005), systolic blood pressure (difference = -5.5 mm Hg, P = 0.0001) and diastolic blood pressure (difference: -2.3 mm Hg; P = 0.03), and glycated hemoglobin (absolute difference = -0.1%, P = 0.0006) were all reduced after OD compared with TID at 12 wk. Compared with TID, a reduction in glycated hemoglobin by 0.6% was observed in patients with concomitant DM during OD (P = 0.004).

    Conclusion: The OD dual-release tablet provided a more circadian-based serum cortisol profile. Reduced body weight, reduced blood pressure, and improved glucose metabolism were observed during OD treatment. In particular, glucose metabolism improved in patients with concomitant DM.

  • 19.
    Jonsdottir, Berglind
    et al.
    Department of Clinical Sciences, Lund University, Skåne University Hospital Malmö, Sweden.
    Larsson, Christer
    Department of Laboratory Medicine, Lund University, Lund. Sweden.
    Carlsson, Annelie
    Department of Pediatrics, Lund University, Skåne University Hospital, Lund, Sweden.
    Forsander, Gun
    Department of Pediatrics, The Queen Silvia Children´s Hospital, Gothenburg, Sweden.
    Ivarsson, Sten Anders
    Department of Clinical Sciences, Lund University, Skåne University Hospital Malmö, Sweden.
    Lernmark, Åke
    Department of Clinical Sciences, Lund University, Skåne University Hospital Malmö, Sweden.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Marcus, Claude
    Division of Pediatrics, Department of Clinical Science, Intervention and Technology Karolinska Institute, Stockholm, Sweden.
    Samuelsson, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Örtqvist, Eva
    Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institute, Stockholm, Sweden.
    Elding Larsson, Helena
    Department of Clinical Sciences, Lund University, Skåne University Hospital Malmö, Sweden.
    Thyroid and islet autoantibodies predict autoimmune thyroid disease already at Type 1 diabetes diagnosis.2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 4, 1277-1285 p.Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Screening of autoimmune thyroid disease in children and young adults with Type 1 diabetes is important but vary greatly between clinics.

    OBJECTIVE: The aim was to determine the predictive value of thyroid autoantibodies, thyroid function, islet autoantibodies, and HLA- DQ at diagnosis of Type 1 diabetes for autoimmune thyroid disease during subsequent follow-up.

    SETTING: 43 Paediatric Endocrinology units Sweden. Design, patients and main outcome measures: At diagnosis of Type 1 diabetes, samples from 2433 children were analysed for autoantibodies against thyroid peroxidase (TPOAb), thyroglobulin (TGAb), glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated protein-2 (IA-2A), and the three variants of the zinc transporter 8 (ZnT8W/R/QA) as well as HLA-DQA1-B1 genotypes and thyroid function. After 5.1-9.5 years disease duration, children treated with thyroxine were identified in the Swedish National Board of Health and Welfare Prescribed Drug Register.

    RESULTS: Thyroxine had been prescribed to 6% (147/2433; 66% girls). In patients below 5 years, female gender (HR=4.60, p=0.008) and GADA (HR=5.80, p=0.02) were significant predictors. In patients 5-10 years, TPOAb (HR=20.56, p<0.0001), TGAb (HR=3.40, p=0.006) and TSH outside the reference limit (HR=3.64, p<0.001) were predictors while in the 10-15 year olds, TPOAb (HR=17.00, p<0.001) and TSH outside the reference limit (HR=4.11, p<0.001) predicted future thyroxine prescription.

    CONCLUSION: In addition to TPOAb and TSH, positive GADA tested at the diagnosis of type 1 diabetes is important for the prediction of autoimmune thyroid disease in children below 5 years of age.

  • 20.
    Krause, Kerstin
    et al.
    Department of Internal Medicine, University of Leipzig, 04103 Leipzig, Germany.
    Eszlinger, Markus
    Department of Internal Medicine, University of Leipzig, 04103 Leipzig, Germany.
    Gimm, Oliver
    Department of Surgery, University of Halle, 06120 Halle, Germany .
    Karger, Stefan
    Department of Internal Medicine, University of Leipzig, 04103 Leipzig, Germany.
    Engelhardt, Cornelia
    Department of Internal Medicine, University of Leipzig, 04103 Leipzig, Germany.
    Dralle, Henning
    Department of Surgery, University of Halle, 06120 Halle, Germany .
    Fuhrer, Dagmar
    Department of Internal Medicine, University of Leipzig, 04103 Leipzig, Germany.
    TFF3-based candidate gene discrimination of benign and malignant thyroid tumors in a region with borderline iodine deficiency.2008In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, no 4, 1390-3 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: With the advent of microarray technology, increasing numbers of marker genes are proposed to distinguish benign and malignant thyroid lesions. However, most markers await confirmation through independent studies. In this paper, we re-evaluate the diagnostic potential of 10 proposed candidate genes in benign and malignant thyroid pathologies in a region with borderline iodine deficiency.

    METHODS: Quantitative real-time PCR was performed for CCND2, PLAB, PCSK2, HGD1, TFF3, B4GALT, LGALS3, ETS1, ADM3, and TG in 150 thyroid specimens, including 52 benign thyroid nodules (28 follicular adenoma and 24 adenomatous nodules), 52 corresponding normal thyroid tissues, 20 follicular carcinomas, 20 papillary carcinomas, and six undifferentiated carcinomas.

    RESULTS: On a single-gene basis, significant differences in mRNA expression were found for TFF3, PLAB, and ADM3 in benign thyroid nodules and thyroid malignancy. Using two-marker gene sets, we identified 11 combinations, which allowed both a distinction of benign and malignant thyroid nodules and a discrimination of follicular adenoma and carcinoma. However, for cancer prediction, analysis of a minimum of six genes per sample was necessary and allowed correct prediction of a benign thyroid lesion and thyroid cancer with 94% accuracy in the most discriminative set (TFF3/PLAB/TG/ADM3/HGD1/LGALS3).

    CONCLUSION: We confirm the applicability of a number of recently proposed marker genes for the distinction of benign and malignant thyroid tumor and suggest that their diagnostic usefulness is independent of the iodide supply. We propose that the most discriminative marker set identified in our validation study together with marker combinations proposed by other investigators should now be evaluated in multicenter trials.

  • 21.
    Morad, Vivian
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Abrahamsson, Annelie
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Estradiol Affects Extracellular Leptin: Adiponectin Ratio in Human Breast Tissue in Vivo2014In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 9, 3460-3467 p.Article in journal (Refereed)
    Abstract [en]

    Context: Exposure to sex steroids is associated with increased breast cancer risk, and adipokines, leptin and adiponectin have been implicated in cancer progression. However, it is not known whether sex steroids affect adipokine secretion in breast tissue. Objective: To elucidate the role of estrogen and tamoxifen on adipokine release in normal human breast tissue and breast cancer. Setting and Design: Microdialysis sampling was used to collect extracellular in vivo leptin and adiponectin from normal human breast tissue in premenopausal healthy volunteers during the menstrual cycle and in postmenopausal women before tamoxifen treatment and after 6 weeks of treatment. In women with breast cancer, microdialysis was performed intratumorally before surgery. In addition, whole normal breast tissue biopsies were cultured ex vivo, and murine breast cancer models were evaluated. Results: In normal breast tissue, plasma estradiol negatively correlated with local extracellular adiponectin levels (r = -0.34; P less than .05) and positively correlated with leptin (r = 0.37; P less than .05) and leptin: adiponectin ratio (r = 0.38; P less than .05). In postmenopausal women, tamoxifen treatment increased adiponectin (P less than 0.05) and decreased leptin (P less than .01) and the leptin: adiponectin ratio (P less than .01). These in vivo results were confirmed in breast tissue biopsies cultured ex vivo. In patients with breast cancer, extracellular leptin was higher (P less than .01) and adiponectin lower (P less than .05) in tumors than in normal adjacent breast tissue. In a murine model of breast cancer, estrogen exposure increased leptin secretion (P less than .05). Conclusions: Estrogen exposure may have a critical role in the regulation of adipokines in human breast tissue and may serve as therapeutic targets for treatment and prevention.

  • 22.
    Norjavaara, Ensio
    et al.
    AstraZeneca, Sweden .
    Ericsson, Hans
    AstraZeneca, Sweden .
    Sjöberg, Folke
    Linköping University, Department of Clinical and Experimental Medicine, Burn Center. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Plastic Surgery, Hand surgery UHL. Östergötlands Läns Landsting, Sinnescentrum, Department of Anaesthesiology and Surgery UHL.
    Leonsson-Zachrisson, Maria
    AstraZeneca, Sweden .
    Sjostrand, Mikaela
    AstraZeneca, Sweden .
    A Morrow, Linda
    Profil Institute Clin Research, USA .
    Hompesch, Marcus
    Profil Institute Clin Research, USA .
    Glucokinase Activators AZD6370 and AZD1656 Do Not Affect the Central Counterregulatory Response to Hypoglycemia in Healthy Males2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 9, 3319-3325 p.Article in journal (Refereed)
    Abstract [en]

    Context: Glucokinase is expressed in the hypothalamus, but effects of glucokinase activators (GKAs) on counterregulatory responses to hypoglycemia are unknown. less thanbrgreater than less thanbrgreater thanObjective: Two separate studies assessed the counterregulatory hormone responses to hypoglycemia induced by the GKAs, AZD6370 and AZD1656, compared with insulin infusion. less thanbrgreater than less thanbrgreater thanDesign and Setting: Both studies were randomized, open, two-way crossover studies, conducted in separate clinical research centers. less thanbrgreater than less thanbrgreater thanParticipants: Both studies involved 12 healthy adult male volunteers. less thanbrgreater than less thanbrgreater thanInterventions: Each subject received two treatments in randomized order, separated by a washout. In the AZD6370 study, overnight-fasted subjects received either a single oral AZD6370 dose (300 mg) or insulin infusion (0.8 mU/kg . min). In the AZD1656 study, overnight-fasted subjects received either a single oral dose of AZD1656 (80 mg) plus supporting insulin (1 mU/kg . min) or insulin alone (1 mU/kg . min). Insulin was added to support AZD1656 because AZD1656 alone did not produce the desired hypoglycemia. Plasma glucose was lowered during a stepwise hypoglycemic clamp with a glycemic nadir of 2.7 mmol/liter for 30 min. less thanbrgreater than less thanbrgreater thanMain Outcome Measures: Epinephrine, norepinephrine, GH, cortisol, and glucagon plasma levels were assessed. Results: No safety issues were raised. AZD6370 and AZD1656 had no effect on counterregulatory responses for norepinephrine, GH, or cortisol, but epinephrine increased slightly with AZD1656. Glucagon responses were reduced by approximately 30% with both GKAs vs. insulin. less thanbrgreater than less thanbrgreater thanConclusions: These data suggest the central nervous system-mediated counterregulatory response during GKA-induced hypoglycemia was preserved, whereas the glucagon response was attenuated; the latter was possibly mediated by a local pancreatic effect (intraislet hyperinsulinemia) rather than by impairment of the central nervous system-mediated response.

  • 23.
    Onnestam, Lisa
    et al.
    University of Gothenburg, Sweden .
    Berinder, Katarina
    Karolinska University Hospital Solna, Sweden .
    Burman, Pia
    Skåne University Hospital, Sweden .
    Dahlqvist, Per
    Umeå University, Sweden .
    Eden Engstrom, Britt
    University of Uppsala Hospital, Sweden .
    Wahlberg Topp, Jeanette
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Filipsson Nystrom, Helena
    University of Gothenburg, Sweden .
    National Incidence and Prevalence of TSH-Secreting Pituitary Adenomas in Sweden2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 2, 626-635 p.Article in journal (Refereed)
    Abstract [en]

    Context: TSH-secreting pituitary adenomas (TSHomas) are rare. Epidemiological data are scant and there are no reports on national incidence. less thanbrgreater than less thanbrgreater thanObjective: The objective of the study was to estimate the national Swedish incidence and prevalence of TSHomas. less thanbrgreater than less thanbrgreater thanDesign: This was an observational study. less thanbrgreater than less thanbrgreater thanSetting: The study was conducted at tertiary referral centers. less thanbrgreater than less thanbrgreater thanPatients: The Swedish Pituitary Registry and World Health Organization International Statistical Classification of Diseases and Related Health Problems coding at all university hospitals were used to identify patients diagnosed with TSHomas 1990-2010. The identified patients medical records were studied until the latest follow-up [median 5.0 years (range andlt; 1-20 years)]. less thanbrgreater than less thanbrgreater thanMain Outcome Measurements: Incidence, prevalence, demographics, tumor characteristics, treatment outcome, and thyroid hormone level at diagnosis were measured. less thanbrgreater than less thanbrgreater thanResults: The age-standardized national incidence of 28 TSHoma patients was 0.15 per 1 million inhabitants per year, with an increasing incidence over time (0.05 per 1 million per year in 1990-1994 to 0.26 per 1 million per year in 2005-2009). The national prevalence in 2010 was 2.8 per 1 million inhabitants, in which 0.85 per 1 million had active disease. Most patients (n = 22) underwent pituitary surgery, 5 had radiotherapy, and 6 had somatostatin analogues. Eighteen patients were considered cured at the latest follow-up; 25% remained uncontrolled. Subjects treated for putative primary hyperthyroidism prior to diagnosis had TSH levels more than double those with intact thyroid at diagnosis (P = .013). The median time to diagnosis was longer for women than men (4 vs andlt; 1 year, P = .026). More women than men were treated surgically (94.1% vs 54.5%, P = .022). less thanbrgreater than less thanbrgreater thanConclusion: This is the first estimate of a national incidence of TSHoma. Additional epidemiological studies are needed to compare these results with other geographical areas. This study suggests an increased incidence of TSHomas, in agreement with reports on other pituitary adenomas. (J Clin Endocrinol Metab 98: 626-635, 2013)

  • 24.
    Orlefors, H
    et al.
    Uppsala University.
    Sundin, A
    Uppsala University.
    Garske, U
    Uppsala University.
    Juhlin, Claes
    Uppsala University.
    Oberg, K
    Uppsala University.
    Skogseid, B
    Uppsala University.
    Langström, B
    Uppsala University.
    Bergström, M
    Uppsala University.
    Eriksson, B
    Uppsala University.
    Whole-body 11C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: Comparison with somatostatin receptor scintigraphy and computed tomography2005In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 90, no 6, 3392-3400 p.Article in journal (Refereed)
    Abstract [en]

    Neuroendocrine tumors (NETs) can be small and situated almost anywhere throughout the body. Our objective was to investigate whether whole-body (WB) positron emission tomography (PET) with 11C-5-hydroxytryptophan (5-HTP) can be used as a universal imaging technique for NETs and to compare this technique with established imaging methods. Forty-two consecutive patients with evidence of NET and a detected lesion on any conventional imaging (six bronchial, two foregut, 16 midgut, and two thymic carcinoids; one ectopic Cushing’s syndrome; four gastrinomas; one insulinoma; six nonfunctioning endocrine pancreatic tumors; one gastric carcinoid, one paraganglioma; and two endocrine-differentiated pancreatic carcinomas) were studied. The WB-11C-5-HTP-PET examinations were compared with WB-computed tomography (CT) and somatostatin receptor scintigraphy (SRS). Tumor lesions were imaged with PET in 95% of the patients. In 58% of the patients, PET could detect more lesions than SRS and CT and equal numbers in 34%, whereas in three cases, SRS or CT showed more lesions. In 84% (16 of 19 patients), PET could visualize the primary tumor compared with 47 and 42% for SRS and CT, respectively. The surgically removed PET-positive primary tumor sizes were 6–30 mm. To conclude, this study indicates that WB-11C-5-HTP-PET can be used as a universal imaging method for detection of NETs. This study also shows that WB-11C-HTP-PET is sensitive in imaging small NET lesions, such as primary tumors, and can in a majority of cases image significantly more tumor lesions than SRS and CT.

  • 25.
    Perren, Aurel
    et al.
    Department of Pathology, Institute of Surgical Pathology, University Hospital, CH-8091 Zürich, Switzerland / Institute of Pathology, Technische Universitaet Muenchen, D-81675 Munich, Germany.
    Anlauf, Martin
    Department of Pathology, University of Kiel, D-24105 Kiel, Germany.
    Henopp, Tobias
    Department of Pathology, University of Kiel, D-24105 Kiel, Germany.
    Rudolph, Thomas
    Department of Pathology, Institute of Surgical Pathology, University Hospital, CH-8091 Zürich, Switzerland.
    Schmitt, Anja
    Department of Pathology, Institute of Surgical Pathology, University Hospital, CH-8091 Zürich, Switzerland.
    Raffel, Andreas
    Department of General, Visceral, and Pediatric Surgery, University of Düsseldorf, D-40225 Düsseldorf, Germany.
    Gimm, Oliver
    Department of General, Visceral, and Vascular Surgery, University of Halle, D-06120 Halle, Germany.
    Weihe, Eberhard
    Departments of Molecular Neuroscience and Anatomy and Cell Biology, University of Marburg, D-35037 Marburg, Germany.
    Knoefel, Wolfram T
    Department of General, Visceral, and Pediatric Surgery, University of Düsseldorf, D-40225 Düsseldorf, Germany.
    Dralle, Henning
    Department of General, Visceral, and Vascular Surger, University of Halle, D-06120 Halle, Germany.
    Heitz, Philipp U
    Department of Pathology, Institute of Surgical Pathology, University Hospital, CH-8091 Zürich, Switzerland.
    Komminoth, Paul
    Institute of Pathology, Stadtspital Triemli, CH-8063 Zurich, Switzerland .
    Klöppel, Günter
    Department of Pathology, University of Kiel, D-24105 Kiel, Germany.
    Multiple endocrine neoplasia type 1 (MEN1): loss of one MEN1 allele in tumors and monohormonal endocrine cell clusters but not in islet hyperplasia of the pancreas.2007In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, no 3, 1118-28 p.Article in journal (Refereed)
    Abstract [en]

    CONTEXT: The occurrence of multiple small pancreatic endocrine tumors in patients suffering from multiple endocrine neoplasia type 1 (MEN1) represents a unique possibility to study early neoplasms and their potential precursor lesions. To date, it is unknown whether small islet-like endocrine cell clusters found in MEN1 patients are neoplastic or rather hyperplastic. It is also unclear whether microadenomas develop from islets.

    DESIGN: We hypothesized that monohormonal endocrine cell clusters observed in MEN1 patients are small neoplasms with loss of heterozygosity of the MEN1 locus. Using a technique combining fluorescence in situ hybridization of the MEN1 locus and the centromeric region of chromosome 11q with hormone immunostaining, we examined resection specimens from four MEN1 patients. We focused our investigations on the following: 1) typical microadenomas; 2) monohormonal endocrine cell clusters; 3) endocrine and exocrine structures entrapped in microadenomas; and 4) morphologically normal islets.

    RESULTS: Loss of one MEN1 allele was found in all 27 microadenomas and 19 of 20 (95%) monohormonal endocrine cell clusters. By contrast, it was absent in islets and ductal or acinar structures. Our results indicate that monohormonal endocrine cell clusters represent a minute form of microadenomas.

    CONCLUSION: The frequent presence of single nonneoplastic insulin cells in microadenomas and the occurrence of microadenomas in islets suggest an islet origin of microadenomas. Islet hyperplasia does not seem to be an obligatory stage in pancreatic MEN1-associated tumor development.

  • 26.
    Tham, E.
    et al.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden, Department of Molecular Medicine and Surgery, Center of Molecular Medicine L8:02, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden.
    Grandell, U.
    Department of Clinical Genetics, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden.
    Lindgren, E.
    Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
    Toss, Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Skogseid, B.
    Department of Medical Sciences, Uppsala University, Uppsala University Hospital, 75185 Uppsala, Sweden.
    Nordenskjold, M.
    Nordenskjöld, M., Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.
    Clinical testing for mutations in the MEN1 gene in Sweden: A report on 200 unrelated cases2007In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, Vol. 92, no 9, 3389-3395 p.Article in journal (Refereed)
    Abstract [en]

    Context: Multiple endocrine neoplasia type 1 (MEN1) is a tumor syndrome of the parathyroid, endocrine pancreas, and anterior pituitary caused by mutations in the MEN1 gene on 11q13. Objective: The goal of this study was to determine the MEN1 mutation spectrum and detection rate among Swedish patients and identify which patient categories should be tested for MEN1 mutations. Design/Setting/Patients: DNA sequences and referral forms from patients referred to the Department of Clinical Genetics at Karolinska University Hospital, Sweden, for clinical MEN1 mutation screening were analyzed. The mutation status of 371 patients (including 200 probands) was ascertained, and the multiplex ligation-dependent probe amplification (MLPA) assay was evaluated for the detection of large deletions. Main Outcome Measure: The main outcome measure was MEN1 genotypes. Results: Forty-eight of 200 index cases (24%) shared 40 different mutations (18 novel). A total of 69% of all mutations resulted in a truncated protein. Two large deletions were detected by MLPA. A total of 94% of all MEN1 families had a mutation in the coding region of the MEN1 gene. A total of 6% of sporadic cases had MEN1 mutations. There was no correlation between severe disease and mutation type or location. Conclusions: A total of 4% of all mutations were large deletions, and MLPA is now included in our standard MEN1 mutation screening. Individuals with at least one typical endocrine tumour and at least one of the following: 1) a first-degree relative with a major endocrine tumor, 2) an age of onset less than 30 yr, and/or 3) multiple pancreatic tumors/parathyroid hyperplasia were most likely to harbor a mutation, thus these patients should be screened for MEN1 mutations. Copyright © 2007 by The Endocrine Society.

  • 27. Törn, C
    et al.
    Landin-Olsson, M
    Lernmark, Å
    Palmer, JP
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    Blohmé, G
    Lithner, F
    Littorin, B
    Nyström, L
    Scherstén, B
    Sundkvist, G
    Wibell, L
    Östman, J
    Prognostic factors for the course of beta cell function in autoimmune diabetes2000In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, Vol. 85, no 12, 4619-4623 p.Article in journal (Refereed)
    Abstract [en]

    This study presents a 2-yr follow-up of 281 patients, aged 15-34 yr, diagnosed with diabetes between 1992 and 1993. At diagnosis, 224 (80%) patients were positive for at least one of the following autoantibodies: islet cell antibodies (ICAs), glutamic acid decarboxylase antibodies (GADAs), or tyrosine phosphatase antibodies (IA-2As), the remaining 57 (20%) patients were negative for all three autoantibodies. At diagnosis, C-peptide levels were lower (0.27, 0.16-0.40 nmol/L) in autoantibody-positive patients compared with autoantibody-negative patients (0.51, 0.28-0.78 nmol/L, P < 0.001). After 2 yr, C-peptide levels had decreased significantly in patients with autoimmune diabetes (0.20, 0.10-0.37 nmol/L, P = 0.0018), but not in autoantibody-negative patients. In patients with autoimmune diabetes, a low initial level of C-peptide (odds ratio, 2.6, 95% confidence interval, 1.7-4.0) and a high level of GADAs (odds ratio, 2.5, 95% confidence interval, 1.1-5.7) were risk factors for a C-peptide level below the reference level of 0.25 nmol/L 2 yr after diagnosis. Body mass index had a significant effect in the multivariate analysis only when initial C-peptide was not considered. Factors such as age, gender, levels of ICA or IA-2A or insulin autoantibodies (analyzed in a subset of 180 patients) had no effect on the decrease in ▀-cell function. It is concluded that the absence of pancreatic islet autoantibodies at diagnosis were highly predictive for a maintained ▀-cell function during the 2 yr after diagnosis, whereas high levels of GADA indicated a course of decreased ▀-cell function with low levels of C-peptide. In autoimmune diabetes, an initial low level of C-peptide was a strong risk factor for a decrease in ▀-cell function and conversely high C-peptide levels were protective. Other factors such as age, gender, body mass index, levels of ICA, IA-2A or IAA had no prognostic importance.

  • 28.
    van Dijk, Peter R.
    et al.
    Isala, Netherlands.
    Logtenberg, Susan J. J.
    Isala, Netherlands; Diakonessen Hospital, Netherlands.
    Chisalita, Ioana Simona
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hedman, Christina
    Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Groenier, Klaas H.
    Isala, Netherlands; University of Groningen, Netherlands.
    Gans, Reinold O. B.
    University of Groningen, Netherlands.
    Kleefstra, Nanne
    Isala, Netherlands; University of Groningen, Netherlands; Langerhans Medical Research Grp, Netherlands.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Bilo, Henk J. G.
    Isala, Netherlands; Isala, Netherlands; University of Groningen, Netherlands.
    Different Effects of Intraperitoneal and Subcutaneous Insulin Administration on the GH-IGF-1 Axis in Type 1 Diabetes2016In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, no 6, 2493-2501 p.Article in journal (Refereed)
    Abstract [en]

    Context: In type 1 diabetes mellitus, low levels of insulin-like growth factor -1 (IGF-1) and IGF binding protein-3 (IGFBP-3) and high levels of GH and IGFBP-1 are present, probably due to portal vein insulinopenia. Objective: To test the hypothesis that continuous ip insulin infusion (CIPII) has a more pronounced effect than sc insulin therapy on regulation of the GH-IGF-1 axis. Design: This was a prospective, observational case-control study. Measurements were performed twice at a 26-week interval. Setting: Two secondary care hospitals in the Netherlands participated in the study. Patients: There were a total of 184 patients, age-and gender-matched, of which 39 used CIPII and 145 sc insulin therapy for the past 4 years. Outcomes: Primary endpoint included differences in IGF-1. Secondary outcomes were differences in GH, IGFBP-1, and IGFBP-3. Results: IGF-1 was higher with CIPII as compared to SC insulin therapy: 124 mu g/liter (95% confidence interval [CI], 111-138) vs 108 mu g/liter (95% CI 102-115) (P = .035). Additionally, IGFBP-3 concentrations were higher and IGFBP-1 and GH concentrations were lower with CIPII as compared to SC insulin therapy: 3.78 mg/liter (95% CI, 3.49 - 4.10) vs 3.31 mg/liter (95% CI, 3.173.47) for IGFBP-3, 50.9 mu g/liter (95% CI, 37.9 - 68.2) vs 102.6 mu g/liter (95% CI, 87.8 - 119.8) for IGFBP-1 and 0.68 mu g/liter (95% CI, 0.44 - 1.06) vs 1.21 mu g/liter (95% CI, 0.95-1.54) for GH, respectively. In multivariate analysis, IGF-1 had no significant association with HbA1c. Conclusions: The GH-IGF-1 axis may be affected by the route of insulin administration with CIPII counteracting dysregulation of the GH-IGF1 axis present during sc insulin therapy.

  • 29.
    Welander, Jenny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Andreasson, Adam
    Karolinska Institute, Sweden; Karolinska University Hospital Solna, Sweden; Karolinska University Hospital, Sweden.
    Juhlin, C. Christofer
    Karolinska Institute, Sweden; Karolinska University Hospital Solna, Sweden; Karolinska University Hospital, Sweden.
    Wiseman, Roger W.
    University of Wisconsin, WI 53715 USA.
    Backdahl, Martin
    Karolinska University Hospital, Sweden.
    Hoog, Anders
    Karolinska Institute, Sweden; Karolinska University Hospital Solna, Sweden.
    Larsson, Catharina
    Karolinska Institute, Sweden; Karolinska University Hospital Solna, Sweden; Karolinska University Hospital, Sweden.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Rare Germline Mutations Identified by Targeted Next-Generation Sequencing of Susceptibility Genes in Pheochromocytoma and Paraganglioma2014In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 7, E1352-E1360 p.Article in journal (Refereed)
    Abstract [en]

    Context: Pheochromocytomas and paragangliomas have a highly diverse genetic background, with a third of the cases carrying a germline mutation in 1 of 14 identified genes. Objective: This study aimed to evaluate next-generation sequencing for more efficient genetic testing of pheochromocytoma and paraganglioma and to establish germline and somatic mutation frequencies for all known susceptibility genes. Design: A targeted next-generation sequencing approach on an Illumina MiSeq instrument was used for a mutation analysis in 86 unselected pheochromocytoma and paraganglioma tumor samples. The study included the genes EGLN1, EPAS1, KIF1B beta, MAX, MEN1, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL. Results were verified in tumor and constitutional DNA with Sanger sequencing. Results: In all cases with clinical syndromes or known germline mutations, a mutation was detected in the expected gene. Among 68 nonfamilial tumors, 32 mutations were identified in 28 of the samples (41%), including germline mutations in EGLN1, KIF1B beta, SDHA, SDHB, and TMEM127 and somatic mutations in EPAS1, KIF1B beta, MAX, NF1, RET, and VHL, including one double monoallelic EPAS1 mutation. Conclusions: Targeted next-generation sequencing proved to be fast and cost effective for the genetic analysis of pheochromocytoma and paraganglioma. More than half of the tumors harbored mutations in the investigated genes. Notably, 7% of the apparently sporadic cases carried germline mutations, highlighting the importance of comprehensive genetic testing. KIF1B beta, which previously has not been investigated in a large cohort, appears to be an equally important tumor suppressor as MAX and TMEM127 and could be considered for genetic testing of these patients.

  • 30.
    Welander, Jenny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Garvin, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Bohnmark, Rickard
    Cty Council Ostergotland, Dept Radiol, SE-58185 Linkoping, Sweden .
    Isaksson, Lars
    Cty Council Ostergotland, Dept Vasc Surg, SE-58185 Linkoping, Sweden .
    Wiseman, Roger W.
    University of Wisconsin, WI USA .
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Editorial Material: Germline SDHA Mutation Detected by Next-Generation Sequencing in a Young Index Patient With Large Paraganglioma2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 8, E1379-E1380 p.Article in journal (Other academic)
    Abstract [en]

    n/a

1 - 30 of 30
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