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Stefan Pilz Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

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Armin Zittermann Clinic for Thoracic and Cardiovascular Surgery, Herz- und Diabeteszentrum NRW, Ruhr University Bochum, Bad Oeynhausen, Germany

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Christian Trummer Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

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Verena Theiler-Schwetz Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

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Elisabeth Lerchbaum Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

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Martin H Keppel University Institute for Medical and Chemical Laboratory Diagnostics, Paracelsus Medical University, Salzburg, Austria

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Martin R Grübler Department of Cardiology, Swiss Cardiovascular Center Bern, Bern University Hospital, University of Bern, Bern, Switzerland

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Winfried März Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, Ruperto-Carola University of Heidelberg, Heidelberg, Germany
Synlab Medical Center of Human Genetics Mannheim, Mannheim, Germany

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Marlene Pandis Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

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Vitamin D testing and treatment is a subject of controversial scientific discussions, and it is challenging to navigate through the expanding vitamin D literature with heterogeneous and partially opposed opinions and recommendations. In this narrative review, we aim to provide an update on vitamin D guidelines and the current evidence on the role of vitamin D for human health with its subsequent implications for patient care and public health issues. Vitamin D is critical for bone and mineral metabolism, and it is established that vitamin D deficiency can cause rickets and osteomalacia. While many guidelines recommend target serum 25-hydroxyvitamin D (25[OH]D) concentrations of ≥50 nmol/L (20 ng/mL), the minimum consensus in the scientific community is that serum 25(OH)D concentrations below 25–30 nmol/L (10–12 ng/mL) must be prevented and treated. Using this latter threshold of serum 25(OH)D concentrations, it has been documented that there is a high worldwide prevalence of vitamin D deficiency that may require public health actions such as vitamin D food fortification. On the other hand, there is also reason for concern that an exploding rate of vitamin D testing and supplementation increases costs and might potentially be harmful. In the scientific debate on vitamin D, we should consider that nutrient trials differ from drug trials and that apart from the opposed positions regarding indications for vitamin D treatment we still have to better characterize the precise role of vitamin D for human health.

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Barbara J Boucher Blizard Institute, Barts & The London school of Medicine & Dentistry, Queen Mary University of London, London, UK

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Our knowledge of vitamin D has come a long way since the 100 years it took for doctors to accept, between 1860 and 1890, that both sunlight and cod liver oil (a well-known folk remedy) cured and prevented rickets. Vitamins D2/D3 were discovered exactly a hundred years ago, and over the last 50 years vitamin D has been found to have many effects on virtually all human tissues and not just on bone health, while mechanisms affecting the actions of vitamin D at the cellular level are increasingly understood, but deficiency persists globally. Observational studies in humans have shown that better provision of vitamin D is strongly associated, dose-wise, with reductions in current and future health risks in line with the known actions of vitamin D. Randomised controlled trials, commonly accepted as providing a ‘gold standard’ for assessing the efficacy of new forms of treatment, have frequently failed to provide supportive evidence for the expected health benefits of supplementation. Such RCTs, however, have used designs evolved for testing drugs while vitamin D is a nutrient; the appreciation of this difference is critical to identifying health benefits from existing RCT data and for improving future RCT design. This report aims, therefore, to provide a brief overview of the evidence for a range of non-bony health benefits of vitamin D repletion; to discuss specific aspects of vitamin D biology that can confound RCT design and how to allow for them.

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Eric Seidel Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Nephrology and Medical Intensive Care, BCRT – Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
Berlin Institute of Health (BIH), Berlin, Germany
Department of Nephrology, School of Medicine, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany

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Gudrun Walenda Department of Nephrology, School of Medicine, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany

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Clemens Messerschmidt Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
Core Unit Bioinformatics, Berlin Institute of Health, Berlin, Germany

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Benedikt Obermayer Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
Core Unit Bioinformatics, Berlin Institute of Health, Berlin, Germany

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Mirko Peitzsch Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

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Paal Wallace Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

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Rohini Bahethi Department of Nephrology, School of Medicine, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany

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Taekyeong Yoo Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea

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Murim Choi Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea

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Petra Schrade Charité – Universitaetsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Vegetative Anatomie, Berlin, Germany

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Sebastian Bachmann Charité – Universitaetsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Vegetative Anatomie, Berlin, Germany

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Gerhard Liebisch Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany

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Graeme Eisenhofer Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

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Dieter Beule Core Unit Bioinformatics, Berlin Institute of Health, Berlin, Germany
Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

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Ute I Scholl Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Nephrology and Medical Intensive Care, BCRT – Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
Berlin Institute of Health (BIH), Berlin, Germany
Department of Nephrology, School of Medicine, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany

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Mitotane is the only drug approved for the therapy of adrenocortical carcinoma (ACC). Its clinical use is limited by the occurrence of relapse during therapy. To investigate the underlying mechanisms in vitro, we here generated mitotane-resistant cell lines. After long-term pulsed treatment of HAC-15 human adrenocortical carcinoma cells with 70 µM mitotane, we isolated monoclonal cell populations of treated cells and controls and assessed their respective mitotane sensitivities by MTT assay. We performed exome sequencing and electron microscopy, conducted gene expression microarray analysis and determined intracellular lipid concentrations in the presence and absence of mitotane. Clonal cell lines established after pulsed treatment were resistant to mitotane (IC50 of 102.2 ± 7.3 µM (n = 12) vs 39.4 ± 6.2 µM (n = 6) in controls (biological replicates, mean ± s.d., P = 0.0001)). Unlike nonresistant clones, resistant clones maintained normal mitochondrial and nucleolar morphology during mitotane treatment. Resistant clones largely shared structural and single nucleotide variants, suggesting a common cell of origin. Resistance depended, in part, on extracellular lipoproteins and was associated with alterations in intracellular lipid homeostasis, including levels of free cholesterol, as well as decreased steroid production. By gene expression analysis, resistant cells showed profound alterations in pathways including steroid metabolism and transport, apoptosis, cell growth and Wnt signaling. These studies establish an in vitro model of mitotane resistance in ACC and point to underlying molecular mechanisms. They may enable future studies to overcome resistance in vitro and improve ACC treatment in vivo.

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Kennett Sprogøe Ascendis Pharma A/S, Hellerup, Denmark

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Eva Mortensen Ascendis Pharma, Inc., Palo Alto, California, USA

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David B Karpf Ascendis Pharma, Inc., Palo Alto, California, USA

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Jonathan A Leff Ascendis Pharma, Inc., Palo Alto, California, USA

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The fundamental challenge of developing a long-acting growth hormone (LAGH) is to create a more convenient growth hormone (GH) dosing profile while retaining the excellent safety, efficacy and tolerability of daily GH. With GH receptors on virtually all cells, replacement therapy should achieve the same tissue distribution and effects of daily (and endogenous) GH while maintaining levels of GH and resulting IGF-1 within the physiologic range. To date, only two LAGHs have gained the approval of either the Food and Drug Administration (FDA) or the European Medicines Agency (EMA); both released unmodified GH, thus presumably replicating distribution and pharmacological actions of daily GH. Other technologies have been applied to create LAGHs, including modifying GH (for example, protein enlargement or albumin binding) such that the resulting analogues possess a longer half-life. Based on these approaches, nearly 20 LAGHs have reached various stages of clinical development. Although most have failed, lessons learned have guided the development of a novel LAGH. TransCon GH is a LAGH prodrug in which GH is transiently bound to an inert methoxy polyethylene glycol (mPEG) carrier. It was designed to achieve the same safety, efficacy and tolerability as daily GH but with more convenient weekly dosing. In phase 2 trials of children and adults with growth hormone deficiency (GHD), similar safety, efficacy and tolerability to daily GH was shown as well as GH and IGF-1 levels within the physiologic range. These promising results support further development of TransCon GH.

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Stine Linding Andersen Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

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Stig Andersen Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Department of Geriatrics, Aalborg University Hospital, Aalborg, Denmark

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The management of hyperthyroidism in pregnant patients has been a topic of raised clinical awareness for decades. It is a strong recommendation that overt hyperthyroidism of Graves’ disease in pregnant women should be treated to prevent complications. The consequences of hyperthyroidism in pregnancy are less studied than hypothyroidism, and a literature review illustrates that the main burden of evidence to support current clinical guidance emerges from early observations of severe complications in Graves’ disease patients suffering from untreated hyperthyroidism in the pregnancy. On the other hand, the more long-term consequences in children born to mothers with hyperthyroidism are less clear. A hypothesis of fetal programming by maternal hyperthyroidism implies that excessive levels of maternal thyroid hormones impair fetal growth and development. Evidence from experimental studies provides clues on such mechanisms and report adverse developmental abnormalities in the fetal brain and other organs. Only few human studies addressed developmental outcomes in children born to mothers with hyperthyroidism and did not consistently support an association. In contrast, large observational human studies performed within the last decade substantiate a risk of teratogenic side effects to the use of antithyroid drugs in early pregnancy. Thus, scientific and clinical practice are challenged by the distinct role of the various exposures associated with Graves’ disease including the hyperthyroidism per se, the treatment, and thyroid autoimmunity. More basic and clinical studies are needed to extend knowledge on the effects of each exposure, on the potential interaction between exposures and with other determinants, and on the underlying mechanisms.

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Aldo Bonaventura Department of Internal Medicine, Division of Cardiology, Division of Laboratory Medicine, First Clinic of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

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Fabrizio Montecucco Department of Internal Medicine, Division of Cardiology, Division of Laboratory Medicine, First Clinic of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
Department of Internal Medicine, Division of Cardiology, Division of Laboratory Medicine, First Clinic of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
Department of Internal Medicine, Division of Cardiology, Division of Laboratory Medicine, First Clinic of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

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Franco Dallegri Department of Internal Medicine, Division of Cardiology, Division of Laboratory Medicine, First Clinic of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

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The prevalence of type 2 diabetes mellitus (T2DM) is increasing all over the world. Targeting good glycemic control is fundamental to avoid the complications of diabetes linked to hyperglycemia. This narrative review is based on material searched for and obtained via PubMed up to April 2015. The search terms we used were: ‘hypoglycemia, diabetes, complications’ in combination with ‘iatrogenic, treatment, symptoms.’ Serious complications might occur from an inappropriate treatment of hyperglycemia. The most frequent complication is iatrogenic hypoglycemia that is often associated with autonomic and neuroglycopenic symptoms. Furthermore, hypoglycemia causes acute cardiovascular effects, which may explain some of the typical symptoms: ischemia, QT prolongation, and arrhythmia. With regards to the latter, the night represents a dangerous period because of the major increase in arrhythmias and the prolonged period of hypoglycemia; indeed, sleep has been shown to blunt the sympatho-adrenal response to hypoglycemia. Two main strategies have been implemented to reduce these effects: monitoring blood glucose values and individualized HbA1c goals. Several drugs for the treatment of T2DM are currently available and different combinations have been recommended to achieve individualized glycemic targets, considering age, comorbidities, disease duration, and life expectancy. In conclusion, according to international guidelines, hypoglycemia-avoiding therapy must reach an individualized glycemic goal, which is the lowest HbA1c not causing severe hypoglycemia and preserving awareness of hypoglycemia.

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Adriano N Cury Pediatric Endocrinology Unit, Endocrinology and Metabolism, Nuclear Medicine Laboratory, Pediatrics Department, Irmandade da Santa Casa de Misericórdia de São Paulo, 01221-020 São Paulo, Brazil

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Verônica T Meira Pediatric Endocrinology Unit, Endocrinology and Metabolism, Nuclear Medicine Laboratory, Pediatrics Department, Irmandade da Santa Casa de Misericórdia de São Paulo, 01221-020 São Paulo, Brazil

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Osmar Monte Pediatric Endocrinology Unit, Endocrinology and Metabolism, Nuclear Medicine Laboratory, Pediatrics Department, Irmandade da Santa Casa de Misericórdia de São Paulo, 01221-020 São Paulo, Brazil
Pediatric Endocrinology Unit, Endocrinology and Metabolism, Nuclear Medicine Laboratory, Pediatrics Department, Irmandade da Santa Casa de Misericórdia de São Paulo, 01221-020 São Paulo, Brazil

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Marília Marone Pediatric Endocrinology Unit, Endocrinology and Metabolism, Nuclear Medicine Laboratory, Pediatrics Department, Irmandade da Santa Casa de Misericórdia de São Paulo, 01221-020 São Paulo, Brazil

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Nilza M Scalissi Pediatric Endocrinology Unit, Endocrinology and Metabolism, Nuclear Medicine Laboratory, Pediatrics Department, Irmandade da Santa Casa de Misericórdia de São Paulo, 01221-020 São Paulo, Brazil

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Cristiane Kochi Pediatric Endocrinology Unit, Endocrinology and Metabolism, Nuclear Medicine Laboratory, Pediatrics Department, Irmandade da Santa Casa de Misericórdia de São Paulo, 01221-020 São Paulo, Brazil

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Luís E P Calliari Pediatric Endocrinology Unit, Endocrinology and Metabolism, Nuclear Medicine Laboratory, Pediatrics Department, Irmandade da Santa Casa de Misericórdia de São Paulo, 01221-020 São Paulo, Brazil

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Carlos A Longui Pediatric Endocrinology Unit, Endocrinology and Metabolism, Nuclear Medicine Laboratory, Pediatrics Department, Irmandade da Santa Casa de Misericórdia de São Paulo, 01221-020 São Paulo, Brazil

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Background/aims

Treatments for Graves' disease (GD) in children and adolescents include oral antithyroid drugs (ATDs), near total thyroidectomy, and radioactive iodine (RAI). ATDs remain the preferred choice in this age group, but because persistent remission occurs in 30% of cases, RAI is becoming a common option for definitive therapy.

Methods

We performed a review of 65 medical records of GD patients under age 19 years who were followed between 1985 and 2005.

Results

The prevalence of GD was higher in females (3:1) and during puberty (for both genders). If no remission was detected during ATD treatment, RAI was indicated when the following criteria were present: non-compliance, relapse, or side effects that were related to ATDs, large goiter, and long-term use of ATDs. The majority of patients developed hypothyroidism within 6 months after RAI. A progressive higher dose regimen was implemented in the last 10 years of the study period. A second RAI dose was necessary in eight cases. During the follow-up period, three pregnancies occurred. One patient with a thyroid nodule and benign cytology was detected.

Conclusions

RAI therapy is effective and safe in the treatment of GD in children and adolescents.

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Lu Liu
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Chunyan Li
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Peng Yang
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Jian Zhu Department of Endocrinology, Department of Internal Medicine, Department of Paediatrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Middle Road, Shanghai 200072, China

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Dongmei Gan Department of Endocrinology, Department of Internal Medicine, Department of Paediatrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Middle Road, Shanghai 200072, China

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Le Bu
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Manna Zhang
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Chunjun Sheng
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Hong Li
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Shen Qu
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Alendronate (ALN) is a commonly used drug for the treatment of osteoporosis. Atypical femur fractures (AFFs) have been associated with long-term use of ALN and have recently become the subject of considerable attention as ALN use increases. This meta-analysis aimed to determine the relationship between ALN and AFF. The Embase, PubMed, and Cochrane library databases were searched for relevant studies published before November 6, 2014. Studies clearly reporting the relationship between ALN and AFF were selected for our analysis. From these results, the relationship between ALN and AFF was analyzed. Weighted mean differences were calculated using a random-effects model. Five studies were included in this meta-analysis. The results revealed that the use of ALN will not increase the risk of AFF in short term (P>0.05), but there will be a risk of AFF (P<0.05) with long-term (>5 years) use of ALN. These findings indicate that long-term use of ALN is a risk factor for AFF and that more attention should be paid to the clinical applications of ALN.

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Anastasia K Armeni Division of Reproductive Endocrinology, Department of Obstetrics and Gynaecology, University of Patras Medical School, Patras, Greece

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Konstantinos Assimakopoulos Department of Psychiatry, University of Patras Medical School, Patras, Greece

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Dimitra Marioli Division of Reproductive Endocrinology, Department of Obstetrics and Gynaecology, University of Patras Medical School, Patras, Greece

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Vassiliki Koika Division of Reproductive Endocrinology, Department of Obstetrics and Gynaecology, University of Patras Medical School, Patras, Greece

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Euthychia Michaelidou Department of Biology, University of Patras, Patras, Greece

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Niki Mourtzi Department of Biology, University of Patras, Patras, Greece

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Gregoris Iconomou Department of Psychiatry, University of Patras Medical School, Patras, Greece

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Neoklis A Georgopoulos Division of Reproductive Endocrinology, Department of Obstetrics and Gynaecology, University of Patras Medical School, Patras, Greece

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Over the past decades, research attention has increasingly been paid to the neurobiological component of sexual behavior. The aim of the present study was to investigate the correlation of estrogen receptor α (ERA) gene polymorphism (rs2234693-PvuII) (T→C substitution) and oxytocin receptor gene polymorphism (rs53576) (G→A substitution) with sexuality parameters of young, healthy women. One hundred thirty-three Greek heterosexual women, students in higher education institutions, 20–25 years of age, sexually active, with normal menstrual cycles (28–35 days), were recruited in the study. Exclusion criteria were chronic and/or major psychiatric diseases, use of oral contraceptive pills (OCs), polycystic ovary syndrome (PCOS), thyroid diseases as well as drugs that are implicated in hypothalamus–pituitary–gonadal axis. T allele (wildtype) of rs2234693 (PvuII) polymorphism of ERA gene was correlated with increased levels of arousal and lubrication, whereas A allele (polymorphic) of rs53576 (OXTR) polymorphism was correlated with increased arousal levels. The simultaneous presence of both T allele of rs2234693 (PvuII) and A allele of rs53576 (OXTR) polymorphisms (T + A group) was correlated with increased arousal, orgasm levels as well as female sexual function index full score. To our knowledge, this is the first study to investigate the interaction between ERA and OXTR with regard to sexual function in women. Female sexuality is a complex behavioral trait that encompasses both biological and psychological components. It seems that variability in female sexual response stems from genetic variability that characterizes endocrine, neurotransmitter and central nervous system influences.

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Ashley N Reeb Department of Otolaryngology, Head and Neck Surgery, Saint Louis University School of Medicine, Saint Louis, Missouri, USA

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Andrea Ziegler Department of Otolaryngology, Head and Neck Surgery, Saint Louis University School of Medicine, Saint Louis, Missouri, USA

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Reigh-Yi Lin Department of Otolaryngology, Head and Neck Surgery, Saint Louis University School of Medicine, Saint Louis, Missouri, USA

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Follicular thyroid cancer (FTC) is the second most common type of thyroid cancers. In order to develop more effective personalized therapies, it is necessary to thoroughly evaluate patient-derived cell lines in in vivo preclinical models before using them to test new, targeted therapies. This study evaluates the tumorigenic and metastatic potential of a panel of three human FTC cell lines (WRO, FTC-238, and TT1609-CO2) with defined genetic mutations in two in vivo murine models: an orthotopic thyroid cancer model to study tumor progression and a tail vein injection model to study metastasis. All cell lines developed tumors in the orthotopic model, with take rates of 100%. Notably, WRO-derived tumors grew two to four times faster than tumors arising from the FTC-238 and TT2609-CO2 cell lines. These results mirrored those of a tail vein injection model for lung metastasis: one hundred percent of mice injected with WRO cells in the tail vein exhibited aggressive growth of bilateral lung metastases within 35 days. In contrast, tail vein injection of FTC-238 or TT2609-CO2 cells did not result in lung metastasis. Together, our work demonstrates that these human FTC cell lines display highly varied tumorigenic and metastatic potential in vivo with WRO being the most aggressive cell line in both orthotopic and lung metastasis models. This information will be valuable when selecting cell lines for preclinical drug testing.

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