bluuebunny/crossref_metadata_2025_split huggingface dataset:
MON-389 Fracture Risk Assessment Models for Patients With T2DM
Authors: Banica Andreea Maria , Oprea Luciana Mihaela , Ilie Iuliana , Elian Viviana , Caragheorgheopol Andra , Iordachescu Carmen , Poiana Catalina , Musat Madalina 
Published: May 2020

Abstract
Introduction
Bone mineral density (BMD) measurement, a tool used to diagnose osteoporosis (OP) and to predict fracture risk, has not been found very useful in type 2 diabetic (T2DM) patients. They have a 69% higher fracture risk despite having higher hip and lumbar spine BMD than the non-diabetic population. The aim of this study was to examine the impact of 3 different fracture risk assessment (FRAX) models using surrogate adjustments for T2DM in predicting osteoporotic fracture risk over 10 years.
Material and Methods
Observational retrospective study included 98 patients with OP or osteopenia: 94 women and 4 men admitted in the National Institute of Endocrinology between 2011-2019. 50 % (n= 49) of the patients had T2DM, while the other half were non-diabetic patients. BMI, BMD, lipid profile, serum creatinine, calcium, phosphorus, 25(OH)vitamin D, HbA1c were assessed. BMD was measured on a GE Lunar osteodensitometer. The risk of major osteoporotic fracture in 10 years was assessed with FRAX adjusted for Romania. For diabetic patients, FRAX was adjusted by adding 10 years to patients’ age (model 1), by using rheumatoid polyarthritis as a substitute for T2DM (model 2) or by lowering T score with 0.5 DS (model 3).
Results
Non-diabetic patients had a lower BMI (p=0.001) and a lower BMD (p=0.03) than diabetic patients. A higher BMI correlated with a higher hip BMD (p=0.004).
For diabetic patients, FRAX risk without adjustment was statistically significant lower than FRAX risk calculated with model 1 and 2 (p&lt; 0.001) for both major and hip fracture risk. Unadjusted FRAX risk was lower than the one calculated with model 3 only for hip fracture risk (p&lt;0.001).
Model 1 FRAX adjustment led to a statistically significant risk of both major osteoporotic fracture (p= 0.004) and hip fracture (p=0.04) over 10 years in diabetic patients than non-diabetic patients, though diabetic patients had higher BMD. The same observation was made when FRAX was adjusted by model 2 (p=0.001) or by model 3 (p=0.001).
HbA1c correlated inversely with FRAX adjusted with all three models.
Discussion
FRAX calculator does not include T2DM among secondary causes of OP and this precludes a proper risk assessment independent of BMD. Trabecular bone assessment (TBS) captures a larger portion of the diabetes-associated fracture risk than BMD, however TBS it is not fully independent of the BMD. We examined 3 models of adjusted FRAX in T2DM patients that showed an important increase in fracture risk prediction when adding BMD - independent risk factors into FRAX calculator.
Conclusion
T2DM patients have a greater risk of major osteoporotic fracture in 10 years at the same BMD compared with non-diabetic population. New models of FRAX adjusted for T2DM are needed in assessing the intervention threshold for OP/osteopenia of patients with T2DM.
SAT-009 SSRI Use in the Peripartum Period Regulates Mammary Gland Parathyroid Hormone Related Protein (PTHrP) by a Serotonylation-Dependent Mechanism
Authors: Sheftel Celeste , Sartori Luma C , Hernandez Laura L 
Published: May 2020

Abstract
During lactation, a woman experiences a considerable amount of bone loss and recent studies suggest bone deficits persist years postpartum. Furthermore, selective serotonin uptake inhibitors (SSRIs), which are often prescribed to women experiencing peripartum depression, have been linked to osteopenia. Serotonin signaling can increase parathyroid hormone related protein (PTHrP), a bone remodeling protein which liberates calcium for the milk. Additionally, fluoxetine (a common SSRI) results in increased mammary gland serotonin content and PTHrP, and treatment during the peripartal period reduced maternal bone mineral density. One proposed mechanism of serotonin action is by its covalent addition to proteins by transglutaminase (TG2), termed serotonylation. We therefore investigated whether the combination of fluoxetine and lactation can exacerbate maternal bone loss and the underlying mechanism. We hypothesized that SSRI-induced serotonin signaling in the lactating mammary gland increases PTHrP through a serotonylation-dependent mechanism. Treatment of mouse mammary epithelial cells (HC11) with fluoxetine significantly upregulates PTHrP gene expression and the concentration of its downstream effector, cAMP, over control (P &lt; 0.0004). Furthermore, treatment of the HC11 cells with fluoxetine in addition to a TG2 inhibitor, monodansylcadaverine, restores PTHrP mRNA expression to levels observed in the control. Small g-proteins have emerged as a common target protein for serotonylation. Currently, our data suggest that the g-proteins, RhoA and Rab4, are potential serotonylation targets in the mammary gland. Together these data suggest that the molecular process of serotonyation in HC11 cells links serotonin signaling to increased PTHrP expression. Future work is directed at using the cre-lox system to genetically ablate serotonylation using a WAPCre/TG2Flox transgenic mouse to determine whether decreasing serotonylation in vivo in the mammary gland during lactation improves maternal bone mass.
SUN-552 Follistatin-Like 3 (FSTL3), a Transforming Growth Factor β (TGFβ) Ligand Inhibitor, Regulates Placental Development in Mice
Authors: Huntington Josef , Robertson Rachel , Dhoot Gurtej K , McGonnell Imelda M , Wheeler-Jones Caroline , Mukherjee Abir 
Published: May 2020

Abstract
Follistatin-like 3 (FSTL3), a glycoprotein that inhibits transforming growth factor-β (TGFβ) ligands such as activin, is expressed highly in the placenta and other vascular tissues. In addition, FSTL3 is strongly induced in pre-eclamptic placenta. To test the hypothesis that FSTL3 function is required for capillary bed structure and function we studied the placenta in FSTL3 gene deleted mice (FSTL3 KO). We have previously shown that FSTL3 deletion produces striking defects in the placenta when compared to WT. Placental size increases significantly in comparison to WT, at 16.5 and 18.5 dpc, with concurrent reduction in placental efficiency at 18.5 dpc. Histological analyses reveal structural differences in placental junctional zones in FSTL3 KO placenta compared to WT. Morphometric analyses show that the labyrinth area compared to the placenta area is significantly reduced in FSTL3 KO mice. We also found that activin-responsive FSTL3-synexpression genes are upregulated in FSTL3 KO placenta. Of these, EPHB4 protein is induced in the placenta along with its ligand EphrinB2. Here we show that FSTL3 deletion leads to endothelial cell expansion but reduction in blood vessel density along with increased extracellular matrix deposition. Further investigation of the placental phenotype revealed differential expression patterns of desmin and cytokeratin protein, reduced von Willebrand factor (VWF) and increased CD31 and VEGFR2 labelling within FSTL3 KO mice placental labyrinths. To identify mechanisms that might lead to the altered placental development in FSTL3 KO mice qPCR analyses were performed. Our results identified differences in the expression of crucial transcripts, such as Cdh5, Pgf, Fra1and Cited1, that are associated with the regulation of vascular biology. Additionally, we find increased Histone3 and SMAD2 phosphorylation in FSTL3 KO placenta indicating increased proliferation and activin signalling, respectively. These findings suggest that the balance between cellular proliferation and differentiation might be altered in the absence of FSTL3. Thus, we conclude that FSTL3 function, at least partly through the inhibition of activin action, is necessary for normal placental circulation and development.
MON-033 Androgen Increases the Accumulation of Advanced Glycation End Products in Granulosa Cells by Activating ER Stress in PCOS
Authors: Azhary Jerilee Mariam Khong , Harada Miyuki , Takahashi Nozomi , Hirota Yasushi , Koga Kaori , Osuga Yutaka , Hiraike Osamu , Kunitomi Chisato 
Published: May 2020

Abstract
Polycystic ovarian syndrome (PCOS) is associated with hyperandrogenism. Previously we found that androgen activated endoplasmic reticulum (ER) stress in granulosa cells of antral follicles in PCOS, contributing to ovarian fibrosis (1) and growth arrest of antral follicles (2). In addition, recent studies demonstrated the accumulation of advanced glycation end products (AGEs) in granulosa cells from PCOS patients, which contribute to its pathology. Based on these findings, we hypothesized that androgen upregulates the expression of the receptor for AGEs (RAGE) in granulosa cells of antral follicles by activating ER stress. This in turn, increases the accumulation of AGEs in these cells. In the present study, we found that testosterone induced the expression of RAGE and accumulation of AGE in cultured human granulosa-lutein cells (GLCs). These effects were inhibited with the treatment of tauroursodeoxycholic acid (TUDCA), a clinically available ER stress inhibitor agent. Knockdown of the transcription factor C/EBP homologous protein (CHOP), an unfolded protein response (UPR) factor activated by ER stress, inhibited the testosterone-induced RAGE expression and AGE accumulation. Pretreatment with flutamide, as well as knockdown of androgen receptor decreased the testosterone-induced RAGE expression. Expression of RAGE was increased in GLCs obtained from patients with PCOS. Concomitantly, the expression of RAGE and the accumulation of AGE was increased in granulosa cells of antral follicles from PCOS patients and dehydroepiandrosterone (DHEA)-induced PCOS mice. Administration of the RAGE inhibitor, FPS-ZM1 or TUDCA to PCOS mice, reduced the expression of RAGE and the accumulation of AGE in granulosa cells of antral follicles, accompanied by a reduction of atretic follicles and improvement in the estrous cycle. In summary, our findings indicate that hyperandrogenism in PCOS increases the expression of RAGE and accumulation of AGEs in the ovary by activating ER stress. The potential therapeutic benefit of targeting the AGE-RAGE system, either with a RAGE inhibitor or an ER stress inhibitor agents, may serve as a novel approach for the treatment of PCOS. (1) Takahashi et al. Sci Rep. 2017;7(1):10824. (2) Azhary et al. Endocrinol. 2019;160(1):119–132
MON-464 A Rare Case of Hypocalcemia-Induced Intractable Vomiting Requiring PEG Tube Placement
Authors: Mallari Margaret A , Palmeiro Christopher Robert 
Published: May 2020

Abstract
Introduction: Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia secondary to inadequate PTH secretion. Clinical manifestations are carpopedal spasm, perioral paresthesia, and seizures. Herein, we present a case of hypoparathyroid-induced hypocalcemia requiring PEG tube placement.
Case Presentation: Patient is a 41-year-old female who presents with intractable nausea, continuous vomiting, abdominal pain, and perioral paresthesia for the past 4 days. Patient has a past medical history significant for hypoparathyroidism, severe hypocalcemia, hypomagnesemia, hyperphosphatemia, and iron deficiency anemia. Patient was diagnosed with hypoparathyroidism at the age of 16 when her son was born with congenital abnormalities due to severe maternal hypocalcemia. She has 4 children, 1 son passed away in infancy from severe hypocalcemia. Out of the remaining 3 children, 2 daughters have hypoparathyroidism. Patient has had multiple recurrent admissions for severe hypocalcemia presenting as angina, syncope, and left-sided weakness. Both cardiology work up and neurology workup have been negative. MRI of the brain shows basal ganglia calcifications. Labs are significant for corrected calcium 6.72 mg/dL (n 8 to 10 mg/dL), magnesium 1.4 mg/dL (n 1.7 to 2.2 mg/dL), phosphorus 7.4 mg/dL (n 2.4 to 4.5 mg/dL), Vitamin D 14.9 ng/mL (n 30 to 100 ng/mL), and PTH level 9.8 pg/mL (n 18.5 to 88 pg/mL). Prior ACTH stimulation test was within normal limits excluding adrenal insufficiency. EGD biopsy on prior admission was positive for H. Pylori, however patient left against medical advice and did not receive triple therapy. Patient was admitted for hypocalcemic crisis and placed on a calcium gluconate drip, oral calcium, magnesium, calcitriol, and Vitamin D, in addition to H. pylori triple therapy. During the hospitalization, she was unable to tolerate oral medications for greater than 2 weeks resulting in PEG placement. The patient’s electrolytes were successfully repleted via PEG tube and she was discharged.
Discussion: Spontaneous hypoparathyroidism is a rare metabolic disorder characterized by parathyroid glands that do not produce or secrete enough PTH to maintain normal levels of calcium and phosphorous in the blood. Though GI consequences such as steatorrhea may occur, to our knowledge, this is the first reported case of hypocalcemia-induced intractable vomiting requiring PEG tube. Before PEG placement, the patient had 12 admissions in 1 year. After PEG placement, the number dropped significantly to 4 admissions in 1 year. Due to the unique presentation of hypoparathyroid hypocalcemia, we would like to raise awareness regarding such a presentation which can be challenging for clinicians.
References: Abboud B, Daher R, Boujaoude J. Digestive manifestations of parathyroid disorders. World J Gastroenterol. 2011;17(36):4063-4066. doi:10.3748/wjg.v17.i36.4063.
MON-069 Uncontrolled Central Precocious Puberty Patient Against GnRH Agonist, After Showing Granuloma Formation and Sterile Abscess to Both Leuprorelin Acetate and Triptorelin Actate
Authors: Kim Dae Hyun , Choi Ju-hee 
Published: May 2020

Abstract
For more than 30 years, Gonadotropin-releasing hormone (GnRH) agonist has been the treatment of choice for central precocious puberty (CPP) to expect regression of secondary sexual characteristics, delayed menarche, and maximization of linear growth. There are several kinds of GnRH agonists such as leuprorelin, triptorelin, goserelin and histrelin, etc. In Korea, leuprolide acetate and triptorelin acetate are most common used drugs, and a monthly depot preparation is typically used for suppression of the HPG axis. Local complications related to GnRH agonists, including erythematous macules, granulomas, subcutaneous nodules, and sterile abscesses, occur in 10~15% of patients, and sterile abscesses have been known to occur in less than 2~3% of patients. In present case, we would like to introduce a case of CPP patient who was treated with GnRH agonist, but not suppressed and experienced recurrent vaginal bleeding, after showing granuloma formation and sterile abscess to both leuprorelin acetate and triptoreline actate. A 8.9 year-old girl visited our clinic with breast development and vaginal bleeding. On physical examination, she had enlarged breasts (Tanner stage 4) with pigmentation of the areola. Her height and weight was measured as 144.4cm (98th percentile) and 44.2kg (98th percentile) respectively. Her bone age was advanced as 12~12.6 years of age by TW3 method. Therefore, Leuprolide acetate (Lorelin depot®, Dongkook pharm) 3.75mg was administered to the patient every 4 weeks, and until the 6th injection, she exhibited no other complications. However, after 7th injection, the patient presented with granuloma and subcutaneous nodule at the left injection site and elevated hormone levels. Although that we switched to triptorelin acetate from 8th injection, the patient also showed a sterile abscess at the injection site. We switched from triptorelin acetate to leuprolide acetate again, however, after 2 months of the switch, the patient showed abrupt vaginal bleeding and elevated hormone levels. Therefore, after assumption of unsuppression of HPG axis, leuprolide acetate 3.75mg was administered every 2 weeks for 2 months. However, her vaginal bleeding occurred monthly and hormonal level was still unsuppressed, and also, the granuloma appeared again at the injection site. So, we discussed with her parents about her uncontrolled symptoms, and we discontinued the treatment. There are many theories about the cause of local complications of GnRH agonist, but the mechanism has still not been revealed. Further studies are required to identify the mechanism and the relationship between treatment effect and local complications, which could induce uncontrolled CPP.
SUN-054 Genetic Studies of Height-Associated Protein Expression Levels in Childhood
Authors: Fujimoto Masanobu , Bartell Eric , Khoury Jane C , Khoury Philip R , Vedantam Sailaja , Dauber Andrew Nahum , Hirschhorn Joel N 
Published: May 2020

Abstract
Background: Genome-wide association studies (GWAS) have identified thousands of common genetic variants associated with human height, implicating hundreds of genes and loci. However, the mechanisms by which many of these genetic variants contribute to human adult height are still unknown. Integrating knowledge of the interaction between genetic background and protein levels in childhood can provide insights into the biology of human growth. Objective: To investigate biological associations at height-associated loci in the GH-IGF signaling pathway. Methods: We used data from the Cincinnati Genomic Control Cohort, a community-based cohort comprised of 1,020 children. The study was approved by the institutional review board at Cincinnati Children’s Hospital Medical Center. Protein levels for free and total IGF-I, intact and total IGFBP-3, PAPP-A2, IGF-II, and IGFBP-5 were measured by ELISA in 839 children (ages 3-18 years) and corrected for age- and sex-effects. We associated protein-level phenotypes using plink qassoc and stratified by sex and population, in ~870 European- and African-descent individuals. Meta-analyses were performed using the METAL fixed-effects model. GWAS of anthropometric traits were performed in the UK Biobank of ~400,000 individuals using Bolt-LMM, or curated from publicly available summary statistics. Results: We identified 17 independent genome-wide significant protein-level-associated loci (p&lt;5x10-8). The most robust associations were previously identified expression quantitative trait loci (eQTLs). The IGFBP3 locus was associated with serum total IGFBP3 and IGF-II levels. Despite falling within a height locus, conditional analyses showed that the effect on IGFBP-3 protein levels was independent of the height signal (p=2.8e-31, post conditioning). However, conditional analyses showed that the protein level signal colocalizes with a known GWAS signal for sitting height ratio (SHR). The IGFBP5 locus was associated with IGFBP-5 protein levels and was also independent of height signals identified in the region (p=3.3e-32, post conditioning). Conclusions: We have identified novel pQTLs for IGF2, IGFBP3, and IGFBP5 that act independently from genetic signals in the same regions associated with adult height but may interact with related anthropometric traits including SHR. Additionally, this suggests that SNPs affecting adult height in these loci do not work via increasing serum levels of these proteins but rather through a different and undetermined mechanism.
SAT-101 The Booster Effect of Aromatase Inhibitor to Overcome Waning Effect of Recombinant Human Growth Hormone
Authors: Kim Dae Hyun , Choi Ju-hee 
Published: May 2020

Abstract
Aromatase inhibitor (AI) is a drug that blocks the conversion of androgens to estrogens, originally approved by FDA as a treatment of breast cancer in postmenopausal women. In several studies, it has been proposed that AI appears effective to improve the final adult height especially combined with rhGH therapy, by delaying growth plate closure. Patients treated with rhGH showed highest growth rate during the first year of treatment, with an average increase of 8–10 cm per year (often called “catch-up” growth), however, followed by a progressive decrease in growth rate over the next several years, which is called “waning effect” of rhGH. In this report, we would like to introduce 2 cases of short pubertal boys showing booster effect of AI when co-treated with rhGH, to overcome waning effect of rhGH and improve the final adult height. Case 1. A boy at the age of 8 years and 1 month visited out clinic with short stature. His height was 118cm (4%), weight was 19.2kg (0%). His MPH was calculated as 173cm. Bone age was 6.9 years by the TW3 method. Initial laboratory finding showed no other abnormal findings including normal IGF-1 levels, so we diagnosed the patient as idiopathic short stature (ISS), and started rhGH treatment. During the rhGH treatment of 4 years and 9 months, the patient obtained additional 30.7cm growth to 148.7cm (23%). However, the patient showed decreased growth velocity of 2.2 cm in the last 6 months, which was thought to be “waning effect” of rhGH. The patient and his parents wanted to improve his height using AI, and after taking agreement about the drug, we added AI. During the combined treatment of 1 year and 10 months, his height was improved to 164.9cm (32%) with a gain of 16.2cm, and no adverse reaction was observed. Case 2. A 8 years and 2 months-old boy visited out clinic with short stature. His height was 116.3cm (0%) and weight was 22.6kg (14%). There have been no unusual findings in past history and family history. His MPH was calculated as 165.9cm. Bone age was 8.2 years by the TW3 method. He was also diagnosed as ISS, and started rhGH treatment. During 5 years and 1 month of rhGH treatment, the patient obtained additional 33.3cm growth to 149.6cm (17%). However, the patient showed progressive decreased growth velocity of 3.3 cm in the last 6 months, so we added AI treatment, and after the combined treatment of 1 year and 5 months, his height was 161.6cm (23%). After that, his parents wanted to quit AI, so we maintained only rhGH treatment for 7 months, and his final height was checked as 167cm. In our cases, we suggest that the additional use of AI to patients with progressive decreased growth rate during previous years of GH treatment can improve growth velocity again, and increase the final adult height with successful bone age suppression, which has not been reported before. Therefore, AI could be expected as effective booster drug to overcome waning effect of rhGH.