bluuebunny/crossref_metadata_2025_split huggingface dataset:
SAT-482 Simultaneous Hashimoto/Graves Disease or Prolonged Hashitoxicosis? A Diagnostic Challenge with Therapeutic Implications
Authors: Penaherrera Carlos A , Rodriguez Valentina 
Published: May 2020

Abstract
Background: Some individuals with Hashimoto’s thyroiditis (HT), characterized by anti-TPO antibodies (Abs), can also have positive TSI Abs in up to 20% of cases, without necessarily having Graves disease (GD). Patients with signs of both hyper-and-hypothyroidism with positivity to these two Abs can pose a diagnostic and therapeutic dilemma, as their course is often unpredictable. Clinical Case: A 49-year-old woman was diagnosed with hypothyroidism and took levothyroxine (LT4) for about 1 year, after which she developed symptoms of hyperthyroidism and was switched to methimazole (MMI), which she only took for 1 year. At her initial visit at our clinic she had been off of MMI for 12 months and she was biochemically hyperthyroid (TSH of 0.01 mcIU/ml, f-T4 of 2.26 ng/dl). TSI Abs were positive at 461, but she also tested positive for anti-TPO at 673. Thyroid receptor Abs (TRAb) were also elevated at 54.8. Her vital signs were stable, but she had marked proptosis and complained of eye dryness, so MMI was restarted. A RAIU scan could not be obtained, but a thyroid US showed a heterogeneous and hypervascular gland. On MMI, her thyroid function tests normalized, and her eye disease vastly improved over 2 years. Her MMI dose was progressively decreased until it was stopped completely. On re-evaluation a few months later, she had newly elevated TSH of 8.7 mcIU/ml and low f-T4 of 0.87 ng/dl, with no symptoms of hypothyroidism, so we opted for management with active surveillance instead of starting her on LT4. Her TSI level improved to 240, but remains elevated. Discussion: It is unclear if our patient has a mixed condition with features of both GD and HT, or if she has HT with a very prolonged hyperthyroid phase (hashitoxicosis). Extended periods of hashitoxicosis have been described, the longest reported lasted for 2 years[1]. Simultaneous presentation of GD and HT is very rare, with only a few cases described in the literature. RAIU scan is often diagnostic, showing increased uptake as seen in GD, but patchy areas of decreased uptake can also be seen. In our case it is likely that HT and GD were coexisting, with GD masking the hypothyroidism, until the former remitted with MMI, and her HT took over. Though no RAIU scan was available, the TSI positivity, clinical response of her hyperthyroidism to MMI and the presence of orbitopathy rule in favor of co-existing GD. Decision to treat with LT4 should be weighed against the risk of causing recurrence of hyperthyroidism. Special considerations should be taken in women of childbearing age due to the difficult management that overlapping hyper/hypothyroidism would entail during pregnancy. References: 1. Shahbaz, A et al. Prolonged Duration of Hashitoxicosis in a Patient with Hashimoto’s Thyroiditis: A Case Report and Review of Literature. Cureus. 2018; 10(6):e2804
SUN-635 Profiling of Activation Patterns of Placental mTOR in Pregnancies Complicated by Gestational Diabetes Mellitus
Authors: Papadopoulou Anna , Thymara Irene , Valsamakis Georgios , Laryngaki Anastasia , Theodorou Spyridoula , Papaevangelou Vasiliki , Grammatopoulos Dimitris , Mastorakos Georgios 
Published: May 2020

Abstract
The mammalian target of rapamycin (mTOR) couples’ energy and nutrient abundance to cell growth and is critically involved in the onset and progression of diabetes, cancer and ageing. Placental mTOR is involved in nutrient sensing and transfer to the fetus; animal models suggest that placental mTOR is upregulated in pregnancies complicated by hyperglycaemia (1). In this study we investigated expression patterns and activation of placental mTOR and possible effects of gestational diabetes (GDM). Our study consisted of GDM-mothers (n=28) and their offspring and ii) mothers (n=33) with normal pregnancies (non-GDM) and their infants. Total and phospho-mTOR (Ser2448) expression were determined in placental biopsies using either immunoblotting and immunohistochemistry (IHC) analysis. Newborn anthropometric parameters were also determined at delivery. GDM pregnant women presented with higher fasting glucose levels than non-GDM (98.12±22.82mg/dL; 73.61±9.89mg/dL; p&lt;0.001). No significant difference was found in birth weight or baby length between GDM and non-GDM infants. IHC analysis showed that both total and activated mTOR were predominantly expressed in trophoblasts and to a lesser extend in syncytiotrophoblasts, in both GDM and non-GDM placentas. GDM placentas exhibited a higher mTOR H-score (2) compared to non-GDM (p&lt;0.012), and WB analysis showed a higher phosphor-mTOR signal intensity (p=0.047) in the same group, most likely due to increased total mTOR expression. mTOR expression was also increased in both GDM syncytiotrophoblasts and endothelial cells compared to non-GDM (p&lt;0.001) whereas a reduced signal was detected in stromal phospho-mTOR (p=0.004). No difference was found in trophoblasts or endothelial cells between the 2 study groups suggesting that activation of this kinase is tightly regulated and is relatively independent of changes in total kinase levels. Interestingly bivariate correlation analysis identified an extensive network of significant associations in the expression levels of total, phosphor-mTOR and P/T mTOR between trophoblasts, stroma, endothelial and syncytiotrophoblastsin control placental biopsies; this network was significantly disrupted in GDM placentas, identifying a disheveled regulation of placental mTOR activity. In conclusion, placental mTOR/PmTOR expression is differentially regulated across different placental cell types and is sensitive to hyperglycaemia associated with gestational diabetes mellitus.(1)M. Castillo-Castrejon and TL. Powell. Front Endocrinol (Lausanne). 2017; 8: 306. (2) E. Lakiotaki, et al., Scientific Reports 2016; 6, 21252.
OR19-05 Steroid:Corticosteroid-Binding Globulin Interactions; Effects of Neutrophil Elastase Cleavage, Pyrexia and Acidosis
Authors: Meyer Emily Jane , Torpy David J , Chernykh Anastasia , Thaysen-Anderson Morten , Nenke Marni Anne , Lewis John , Rankin Wayne , Polyak Steven 
Published: May 2020

Abstract
Context Corticosteroid-binding globulin (CBG) transports cortisol and other steroid hormones1,2. High-affinity CBG (haCBG) undergoes proteolysis of the reactive centre loop (RCL) by neutrophil elastase (NE) at inflammatory sites, liberating immunomodulatory cortisol and altering conformation to low-affinity CBG (laCBG). Pyrexia reduces CBG:cortisol binding affinity, an interaction at the RCL is speculated3. Objective To measure the equilibrium binding constants of a panel of steroids to glycosylated haCBG and laCBG over temperature and pH ranges mimicking the pathophysiological conditions of septic shock. Design Surface plasmon resonance was used to determine the binding profiles of 19 steroid ligands to haCBG and laCBG at temperatures 25°C, 37°C and 39°C and pH 7.4 and 7.0. The RCL-recognizing 9G12 antibody was used to assess cleavage and epitope availability of the RCL across conditions. Results A 4–8 fold reduction in affinity for cortisol, cortisone, corticosterone, 11-deoxycortisol, progesterone, 17-hydroxyprogesterone and prednisolone occurred with NE-mediated haCBG-to-laCBG conversion, cortisol expectedly displayed the highest binding affinity. Binding affinity consistently decreased at higher temperatures and at acidic pH for both haCBG and laCBG. 9G12 antibody RCL binding was preserved for haCBG across temperatures. Conclusions These studies reveal that steroid binding to CBG is selective and in all cases reduced upon NE-mediated haCBG-to-laCBG transition. Moreover, reduced CBG:cortisol binding affinity at elevated temperature occurs with an intact and accessible RCL epitope, suggesting a non-RCL mechanism for the delivery of anti-inflammatory cortisol in pyrexia. Synergy of NE cleavage and pyrexia/acidosis may serve for local inflammatory site cortisol delivery and increase free cortisol. These findings demonstrate the modifiable hormone binding characteristics of CBG in (patho-)physiological conditions, supporting its significance in cortisol delivery in obviating systemic inflammation and multiorgan-organ failure in patients with septic shock and its association with mortality4.
1. Pemberton PA, Stein PE, Pepys MB, et al. Hormone binding globulins undergo serpin conformational change in inflammation. Nature. 1988;336(6196):257–258.
2. Pugeat MM, Dunn JF, Nisula BC. Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab. 1981;53(1):69–75.
3. Cameron A, Henley D, Carrell R, et al. Temperature-responsive release of cortisol from its binding globulin: a protein thermocouple. J Clin Endocrinol Metab. 2010;95(10):4689–4695.
4. Meyer EJ, Nenke MA, Rankin W, et al. Total and high-affinity corticosteroid-binding globulin depletion in septic shock is associated with mortality. Clin Endocrinol (Oxf). 2019;90(1):232–240.
SAT-290 Food Restriction Effects on the Hypothalamus-Pituitary-Gonadal Axis
Authors: Mansano Naira Silva , Bohlen Tabata Mariz , Frazao Renata 
Published: May 2020

Abstract
It is well known that nutritional status affects the reproduction, since an adequate amount of energy is necessary for puberty onset and fertility. However, the neural mechanisms by which energy homeostasis affects reproduction is not completely elucidated. To determine if acute or chronic food restriction (FR) are able to modulate the estrous cycle, adult female mice were used in the experiments. The estrous cycle was evaluated by daily observation of vaginal smear. To determine the effects of an acute FR protocol on estrous cycle, females were individualized and kept on ad libitum diet (control, n=17) or fasted for 24 hours (n= 21). A subgroup of animals was euthanized shortly after the 24-hours test to collect hypothalamus and determinate Kiss1 mRNA levels, while another group of mice were regrouped and fed ad libitum. To determine the effects of a chronic FR protocol on estrous cycle, control mice were individualized and maintained with 100% of daily food content (average of 5 g per day, n = 6), or submitted to 60% of FR (n= 12). Animals were fed ad libitum after test. As expected, mice fasted for 24-hours exhibited a significant weight loss (control: 21.7 g ± 0.5 vs 21.6 ± 0.5 g; fasted: 22.7g ± 0.5 vs 18.7g ± 0.4, P=0.0001). This effect was followed by a significant reduction of hypothalamic Kiss1 mRNA expression (control: 1.0 ± 0.2; fasted: 0.3 ± 0.05, P=0.04, n=4/4 per group). Surprisingly, even under lower Kiss1 mRNA levels, 24-hours fasting induced no changes on estrous cycle. On the other hand, chronic FR induced a gradual weight loss (body weight at the 5th day of FR, control: 21.5g ± 0.2; FR: 17.3g ± 0.7, P=0.0002). The chronic FR was follow by the disruption of estrous cyclicity. While control mice exhibited a regular pattern of cyclicity during the period of evaluation, only leukocytes were identified in the vaginal smear of mice submitted to 60% of FR, even though they had a normal cycling pattern before the test. Therefore, by comparing 30 days of estrous cycle evaluation, including the period before chronic FR, while control mice exhibited cornified cells in the vaginal smear 58.5 ± 4.9% of days, female mice submitted to FR exhibited cornified cells in 38.3 ± 3.8% of days (P= 0.0068). Approximately 3-4 days after the end of the chronic FR females returned to exhibit estrous cyclicity, however the length of the estrous cycle was prolonged compared to control group. Our data suggest that chronic nutritional status variations are required to disrupt the hypothalamus-pituitary-gonadal axis and therefore the estrous cyclicity.
SAT-655 Bile Acid Sequestration Synergistically Accelerates Glucagon Receptor-Stimulated Body Weight Loss in Diet-Induced Obese Mice
Authors: Kim Teayoun , Nason Shelly R , Antipenko Jessica , Presedo Natalie , Finan Brian , DiMarchi Richard D , Habegger Kirk M 
Published: May 2020

Abstract
Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss in obese mice. We have shown that hepatic Farnesoid X Receptor (FXR, a bile acid receptor) and bile acids (BA) play an important role in the anti-obesity effect of glucagon in mice. Specifically, glucagon-receptor (GCGR) agonism is a potent regulator of BA metabolism, increasing total plasma BA levels and preferentially raising cholic and chenodeoxycholic acid levels. These findings led us to hypothesize that BA, signaling via hepatic FXR, contributes to GCGR-stimulated weight loss. Furthermore, we reasoned that BA sequestration may impair GCGR-mediated weight loss by reducing the availability of BA to stimulate FXR-action. Thus, to elucidate the role of BA in GCGR-mediated weight loss, we utilized anion-exchange BA-binding resins (BARS; Cholestyramine and Colesevelam) to prevent intestinal (ileal) re-uptake and reduce plasma total cholesterol, LDL, and BAs via fecal excretion. Diet-induced obese (DIO) C57Bl/6J mice were randomized to groups matched for body-weight and administered daily GCGR agonism (IUB288, 10 nmol/kg, s.c.) or vehicle, in the presence or absence of BARS. Consistent with our prior findings, IUB288-treatment reduced body weight in DIO mice. Counter to our original hypothesis, IUB288+Cholestyramine (3% in high fat diet, HFD [58% kcal%]) enhanced IUB288-stimulated weight loss. Similar body-weight loss effects following combined IUB288 and BARS treatment were replicated both at a lower dose of Cholestyramine (1.5% in HFD), as well as in combination with both low- (2% in HFD) and high- (4% in HFD) dose Colesevelam. IUB288-stimulated weight loss is accompanied by suppression of food intake (FI), while Colesevelam alone did not significantly lower FI at either dose (2 or 4% in HFD). However, 4% Colesevelam with IUB288 completely suppressed FI, while 2% Colesevelam stimulated a reduced, though not complete suppression. GCGR agonism is a potent stimulus of weight loss; however, its impairment of glucose tolerance reduces its value as a monotherapy. Excitingly, Cholestyramine (3% in HFD) rescued IUB288-induced glucose intolerance, restoring glucose excursion to levels observed in control (vehicle-treated) mice. Together these studies suggest BARS may enhance the anti-obesity effect of GCGR agonism, beneficially regulate feeding behaviors, and prevent GCGR-stimulated glucose dysregulation in DIO mice. Furthermore, these studies argue that GCGR agonsim combined with BARS treatment may represent a novel therapeutic approach for obesity and obesity-associated glucose intolerance.
MON-358 Hypercalcemia During Teriparatide Therapy
Authors: Milosavljevic Jovan , Thomas Asha Mary 
Published: May 2020

Abstract
Background : Teriparatide (TPTD) is a recombinant PTH analog used as an anabolic agent in the treatment of osteoporosis that stimulates bone formation and activates bone remodeling. The most common side effects are nausea, vomiting, hypertension and dizziness. Transient hypercalcemia is a known adverse effect which is usually seen a few hours after administration and resolves within 16 hours. However, marked late hypercalcemia is a rare event and may be of concern in clinical practice.
Clinical Cases : Case 1 is a 54-year-old man with a history of osteoporosis (lumbar spine T-score of -2.8), previously treated with bisphosphonates and who had been on a course of TPTD for about 6 months in but had not been consistent in taking the medication. Prior to subsequently restarting TPTD, his initial labs were notable for a normal Ca 9.3 mg/dl (8.5 - 10.1 mg/dl), vitamin D 25 OH 49 ng/ml (30.0 - 100.0 ng/ml) and PTH 41.3 pg/ml (8.7 - 77.1 pg/ml). Six months into the treatment, he was noted to have asymptomatic hypercalcemia of 11.2 mg/dl approximately 24 hrs after the last TPTD injection. A repeat calcium of 10.7 mg/dl was obtained while still on therapy with TPTD with normal levels of vitamin D 25 OH of 45 ng/ml.
Case 2 is a 75-year-old woman with a history of osteopenia and severe scoliosis, who had been on a course of raloxifene and then preventive doses of alendronate previously. Prior to starting TPTD, her Ca levels were normal at 9.3 mg/dl, PTH was 24 pg/ml and vitamin D 25 OH was 33 ng/ml. However, six months into the treatment she was noted to have elevated Ca of 12.5 mg/dl (24 hrs after the last TPTD dose), with low levels of vitamin D 25 OH of 24.2 ng/ml. Ca levels returned to the baseline of 9.3 mg/dl when TPTD was held.
Conclusion : Teriparatide has a long track record of safety and does have the rare side effect of hypercalcemia. 1-3% of patients may have mild hypercalcemia after administration. Intake of calcium and vitamin D should be monitored at the start of therapy given these concerns. Although almost never a cause of discontinuation of treatment in clinical practice, it is important to be aware of this side effect in patients who may be at risk of complications of hypercalcemia.
OR12-04 Regulatory Sharing between Estrogen Receptor Alpha Bound Enhancers
Authors: Gertz Jay , Carleton Julia , Ginley-Hidinger Matthew 
Published: May 2020

Abstract
Mammalian genomes encode an order of magnitude more gene expression enhancers than promoters, suggesting that most genes are regulated by combinations of enhancers. We previously found that neighboring estrogen-responsive enhancers exhibit cooperative/synergistic contributions to an estrogenic transcriptional response1. However, when the same combinations of enhancers are targeted with synthetic activators in the absence of estrogens, then the regulatory regions exhibit independent effects on gene expression2. Taken together, these findings indicate that estrogen receptor alpha (ER) bound enhancers cooperate with each other in cis but influence target gene promoters independently. To determine the molecular underpinnings of enhancer cooperativity, we generated genetic deletions of individual ER bound enhancers. We discovered “regulatory sharing” between enhancers in which loci containing full estrogen response elements (EREs) contribute ER binding to neighboring sites, while enhancers with pre-existing histone acetylation/accessibility contribute this permissible chromatin environment to the neighboring enhancers upon estrogen induction. Genome engineering revealed that a cluster of two half ERE enhancers could not compensate for a full ERE site loss within the cluster. However, two full ERE enhancers produced a transcriptional response greater than the wild-type locus, suggesting that combinations of enhancers are not necessarily configured for a maximal response. By swapping genomic sequences, we found that the genomic location in which a full ERE resides strongly influences enhancer activity. Our results lead to a model in which a full ERE is critical for ER recruitment, but the presence of pre-existing histone acetylation and accessibility within an enhancer cluster is also needed in order for estrogen-induced gene regulation to occur.
References 1. Carleton JB, Berrett KC, Gertz J (2017). Multiplex Enhancer Interference Reveals Collaborative Control of Gene Regulation by Estrogen Receptor α-Bound Enhancers. Cell Syst, 5(4), 333-344.e5.2. 2. Ginley-Hidinger M, Carleton JB, Rodriguez AC, Berrett KC, Gertz J. Sufficiency analysis of estrogen responsive enhancers using synthetic activators. Life Sci Alliance, 2(5).
SUN-517 Methimazole-Induced Neutropenia in Premature Twins with Graves’ Disease
Authors: Ballestas Estefania Rodriguez , Ejaz Sehar 
Published: May 2020

Abstract
Introduction: Neonatal Graves’ disease (NGD) occurs in approximately 1-5% of infants born to women with Graves’ disease. It is caused by trans-placental crossing of thyroid stimulating immunoglobulin (TSI) antibodies during third trimester. Hyperthyroidism during pregnancy can lead to craniosynostosis, goiter, premature bone maturation, developmental delay or even heart failure in the neonate. Neonatal Hyperthyroidism is usually transient and resolves in few weeks. Treatment consists of beta blockers and Methimazole. Studies in adults recommend discontinuing of Methimazole if patients develop neutropenia. However due to lack of alternatives, we present a case of continued use of Methimazole with neutropenia in newborn twins.
Case Report:
33 weeks gestational age mono-chorionic/di-amniotic twins born to a 34-year-old woman with poorly controlled hyperthyroidism. Mother diagnosed with Graves’ disease during 2nd trimester with poor control throughout pregnancy. At the time of delivery, maternal TSH was &lt;0.005uIU/mL(0.358-3.74uIU/mL) and FT4 2.18ng/dL(0.76-1.46ng/dL). Antenatal ultrasound at 32 weeks showed homogeneous enlargement of fetal thyroid glands with increased vascularity in both twins. Babies found to have diffuse goiter and exophthalmos at birth. Thyroid tests remained normal for first 3 days of life. By day 3, babies labs showed TSH &lt;0.005uIU/mL, FT4 -8 ug/dL and TSI &gt;700%. Baseline CBC showed ANC of 4.95K/mm3. Babies were started on Methimazole 0.5mg/kg/day and Propranolol 2mg/kg/day. TFTs fluctuated throughout their stay in NICU and they developed neutropenia with ANC 1.23K/mm3 on day 20 of life. Methimazole was initially discontinued then restarted at 0.25 mg/kg/day 3 days later. There is no recommended protocol for restarting Methimazole. Further follow up showed persistent neutropenia despite multiple dose adjustments in Methimazole, including dosing every other day. ANC was maintained around 800-1100K/mm3. At age 2 months, Methimazole was discontinued completely after TSI antibodies decreased to 400%. ANC remained low until 6 months of life, even after discontinuing Methimazole. Both babies ultimately developed central hypothyroidism and were started on l-thyroxine.
Discussion:
NGD can range anywhere from transient hyperthyroidism to persistent central hypothyroidism. Early diagnosis and treatment is crucial to prevent significant morbidity and mortality. Methimazole is the only approved treatment at this age, and management of Methimazole-induced neutropenia has not been established. Adult studies recommend discontinuing Methimazole in context of neutropenia; we took an approach of decreasing dose gradually. Further studies are needed to establish step-wise approach in managing Methimazole-induced neutropenia.