bluuebunny/crossref_metadata_2025_split huggingface dataset:
SUN-214 A Novel Glucocorticoid Receptor Antagonist (CORT113176) Reveals Unique Developmental and Tissue-Specific Effects in a Neonatal Rat Model of Human Prematurity
Authors: Welhouse Kyle D , Gehrand Ashley , Phillips Jonathan , Siddiqui Hana , Schulgit Matthew , Raff Hershel 
Published: May 2020

Abstract
Premature birth is a major public health problem worldwide and can lead to transient adrenal insufficiency1,2. The stress of premature birth includes the inability to control blood glucose and maintain normal oxygenation leading to hypoxia3. Corticosteroid administration enhances surfactant production and improves oxygenation in preterm humans. However, corticosteroids can also have negative consequences4,5. We have validated a rat model of separation and hypoxia on post-natal day (PD) 2 that emulates the stress and treatment of hypoxia in the preterm human infant6,7. We hypothesized that the role of endogenous glucocorticoids in our neonatal rat model of preterm birth can be evaluated using the novel selective glucocorticoid receptor (GR) antagonist CORT113176 (Corcept) which is devoid of progesterone receptor effects8. Pups (PD 2, 8, or 15; N=6–8 per treatment/timepoint) were given CORT113176 (60 mg/kg IP) or vehicle, then placed into chambers in room air with mild warming to prevent hypothermia due to maternal separation. 60 min later, one group of pups was euthanized and trunk blood collected (baseline). The remaining pups were exposed to hypoxia (8% O2) or normoxia (time control) for 30 or 60 min at which times trunk blood was collected for the measurement of plasma glucose, insulin, ACTH, and corticosterone. Plasma ACTH, corticosterone, and insulin were measured by immunoassay. Glucose was measured by glucose oxidase method and insulin sensitivity calculated (HOMA-IR). Organs were frozen (brain, pituitary, adrenal glands, kidney, liver, muscle, fat) for future assessment of tissue-specific glucocorticoid-sensitive gene expression. In PD2 rats, basal and hypoxia-stimulated plasma ACTH and corticosterone were lower and basal HOMA-IR greater with CORT113176 pretreatment suggesting (unexpectedly) glucocorticoid agonist activity. In PD8 and PD15 rats, basal and hypoxia-stimulated plasma ACTH and corticosterone were augmented after CORT113176 pretreatment demonstrating classic antagonist activity. However, in PD8 rats, CORT113176 effects were tissue-specific acting as a classic antagonist on the HPA-axis, but as an agonist on whole-body insulin resistance. The differential effects of CORT113176 based on age and target tissue indicate that GR regulation changes in early development in our animal model of human prematurity. These findings may have significant implications in the treatment of hypoxia and transient adrenal insufficiency in the preterm infant1,2 as well as give insight into the nuances of the control of glucocorticoid receptor function.
1Lancet 392:1923–1994, 2018
2Curr Opin Endocrinol Diabetes Obes 17:8–12, 2010
3Compr Ther 13:14–19, 1987
4Int Immunopharmacol 66:242–250, 2019
5J Neuroendocrinol 27:468–480, 2015
6Am J Physiol 300:R708-715, 2011
7Am J Physiol 302:R627-R633, 2012
8Med Chem Lett 25:5720−5725, 2015
MON-716 A Novel Human Heterozygous STAT5B Variant Leads to Impaired Growth and Developmental Defects in Zebrafish Embryos
Authors: Landi Estefania , Karabatas Liliana , Ramirez Laura , Gutierrez Mariana , Scaglia Paula Alejandra , Keselman Ana Claudia , Braslavsky Debora , Sanguineti Nora , Bergada Ignacio , Jasper Hector Guillermo , Domene Horacio M , Plazas Paola , Domene Sabina 
Published: May 2020

Abstract
Signal transducer and activator of transcription 5b (STAT5b) has been identified as a key downstream mediator of GH signaling in somatic growth. Autosomic recessive human mutations in STAT5B lead to severe growth retardation associated to immune dysregulation. On the other hand, some heterozygous STAT5B mutations have been associated to a milder form of the disease. We have identified a heterozygous novel STAT5B mutation by Whole Exome Sequencing (WES) in a 2.2-year-old boy who presented proportionate short stature (height -2.77 SDS) with mild immune dysregulation. He also had normal GH response to provocative tests, low IGF-I levels, and a limited response to IGF generation test. This variant is located within the highly conserved SH2 domain responsible for recognizing and interacting with tyrosine-phosphorylated target peptides. The aim of our study was to evaluate the functional consequences of this novel heterozygous human STAT5B variant (K632N), using the zebrafish as a biosensor system, to determine its pathogenicity. To do this, we performed overexpression experiments microinjecting construct-derived mRNA for the wildtype (WT) and mutant variant into zebrafish embryos at the 1-cell stage and assessed the consequences at 72 hours post fertilization (hpf). The missense variant was introduced into the full length STAT5B cDNA clone (Origene) by site-directed mutagenesis. To generate mRNA, WT and mutant forms of STAT5B cDNAs were linearized by digestion with XhoI, purified and subsequently transcribed with Mmessage Mmachine T7 Transcription Kit. Zebrafish embryos microinjected with 100 and 200 pg of mutant mRNA show a dose dependent significant reduction of body length at 72 hpf compared to those microinjected with the same dose of WT mRNA (p&lt;0.001). Body length reduction with 100 pg of mutant mRNA was 4%, while with 200 pg was 12.7% (p&lt;0.001). In addition, a significant number of embryos injected with mutant mRNA show developmental defects including pericardial edema, bent spine, and cyclopia compared to those injected with WT mRNA (p&lt;0.001). In the case of pericardial edema, the number of affected embryos increased significantly with the mutant mRNA dose (p&lt;0.005). In conclusion, our study was able to evidence the pathogenic nature of the STAT5B K632N variant since it leads to growth and developmental defects in zebrafish embryos. The zebrafish, and its conserved GH-IGF-I axis, constitutes an ideal in vivo model for characterizing the functional effect of genetic variants in ortholog human genes.
SAT-605 Characterization of Dual Projection Patterns of Refeeding-Activated Neurons in the Parasubthalamic Nucleus
Authors: Wittmann Gabor , Cosentino Nicholas , Lechan Ronald M 
Published: May 2020

Abstract
We have observed that following a fast, animals terminate their food intake within 2h after refeeding accompanied by a pattern of neuronal activation as identified by c-fos immunostaining that involves a number of brain regions associated with the regulation of food intake including the nucleus tractus solitarius (NTS), parabrachial nucleus (PBN), central nucleus of the amygdala (CEA), hypothalamic arcuate and paraventricular nuclei, and bed nucleus of the stria terminalis. We also observed striking c-fos activation in the posterior-lateral hypothalamus called the parasubthalamic nucleus or PSTN, raising the possibility that it may also be an important anorectic center in the brain. To establish how the PSTN is integrated into the CNS, we performed dual-label retrograde tract tracing studies to characterize whether refeeding-activated PSTN neurons project to one, or more than one target area in the CNS. Adult, Sprague-Dawley rats received dual stereotaxic injections of Alexa Fluor 488- and Alexa Fluor 555-conjugated cholera toxin β subunit (CTB; 0.1%, 0.5–1 µl volume) into the 1) PBN and NTS, 2) PBN and CEA and 3) NTS and CEA. After 7–12 days, the animals were fasted for 24 h and then given free access to food for 2 h before euthanasia by transcardial perfusion with 4% paraformaldehyde. Brains with successful dual injections were further processed for c-fos immunohistochemistry. The results showed that 26.5±3.8% of PSTN neurons projecting to the PBN also project to the CEA, and 34.6±7.6% of PSTN neurons that project to the CEA also project to the PBN. In addition, 20.2±2.7% of PSTN neurons that project to the PBN also project to the NTS, and 38.1±9.7% of PSTN neurons that project to the NTS also project to the PBN. Furthermore, 35.0±12.5% of PSTN neurons that project to the CEA project to the NTS and 37.1±4.0% of PSTN neurons that project to the NTS project to the CEA. Finally, up to 15% of the neurons with dual projections to the PBN and CEA contained c-fos after refeeding; up to 18% of the neurons with dual projections to the PBN and NTS contained c-fos; and up to 30% of neurons with dual projections to the NTS and CEA contained c-fos. We conclude that a large number of PSTN neurons have more than one projection site within the brain, thus the PSTN appears to have the capability of simultaneously communicating information about appetite to several, major feeding-related sites within the brain, presumably to terminate feeding.
SAT-568 Hypertriglyceridemia-Induced Pancreatitis in a Pregnant Female Treated with Plasmapheresis
Authors: Nath Priti , Shakir Mohammed , Hoang Thanh Duc 
Published: May 2020

Abstract
Hypertriglyceridemia-Induced Pancreatitis in a Pregnant Female Treated with Plasmapheresis
Background: Gestational hypertriglyceridemia can lead to critical and even life-threatening consequences to both mother and fetus. A well-known consequence is hypertriglyceridemia-induced acute pancreatitis. Few case reports described the successful management of triglyceride (TG) induced pancreatitis in pregnant women using plasmapheresis.
Clinical Case:
A 28-year-old primigravida patient, in the 29th week of gestation, was admitted with acute onset of epigastric pain and nausea for 24 hours. Laboratory findings were remarkable for an elevated serum lipase of 505 U/L (ref 23–300) and an abnormal lipid profile. Her total cholesterol was 1651 mg/dl and triglycerides (TG) from an undiluted sample was 1361 mg/dl. When a 1:5 dilution was performed the result was higher at &gt;4000 mg/dl. She was transferred to the ICU for treatment of acute pancreatitis. She has no family history of hypertriglyceridemia. No MRI was obtained. Gemfibrozil, Lovaza™ (omega-3-acid ethyl esters), and an insulin infusion were started but serum TG levels did not improve. On hospital day 2 she developed worsening tachycardia, tachypnea with laboratory findings of metabolic acidosis and hypocalcemia. As there was no reduction in triglyceride levels with medical therapy and her clinical status was deteriorating, the treating multidisciplinary team decided to initiate plasmapheresis. After one session, TG levels decreased from &gt;4000 mg/dl to 1829 mg/dl and continued to decline to 721 mg/dl. Hospital day 6 her TG level rose to 1245 mg/dl prompting a second plasmapheresis. TG levels decreased to 770 mg/dl shortly after but rose the next day to 1365 mg/dl. She underwent a 3rd plasmapheresis after which her TG ranged from 400–700 mg/dl for the remainder of her hospitalization. On the day of discharge, her TG level was 733 mg/dl. She was advised to restrict fat intake and continue both gemfibrozil and Lovaza™ but despite this her TGs again increased to 1693 mg/dl. From that point she started weekly sessions of plasmapheresis for a total of 8 sessions prior to an uneventful vaginal delivery at 36 weeks of gestation. One month later her lipid profile dramatically improved. Total cholesterol was 233 mg/dl and triglycerides were 304 mg/dl while on lipid lowering therapy.
Conclusion: Pancreatitis during pregnancy is associated with a high maternal and fetal death rate. Early treatment is important for the survival of the mother and fetus. Plasmapheresis is an alternative and safe treatment for cases that are not responsive to medical therapy. It can be administered safely to reduce triglyceride levels and diminish the systemic inflammatory response leading to a shortened hospital stay and better outcomes.
SAT-579 Experiences with Hypertriglyceridemic Pancreatitis: A Mini Case Series
Authors: Majety Priyanka , Siegel Richard D 
Published: May 2020

Abstract
Background: Hypertriglyceridemia (HTG) is a well-established cause of acute pancreatitis (AP) in up to 14% of all cases & up to 56% cases during pregnancy. The triad of HTG, Diabetic ketoacidosis (DKA) and AP is rarely seen posing diagnostic challenges. Early recognition of HTG-induced pancreatitis (HTGP) is important to provide appropriate therapy & prevent recurrence. In this case series, we discuss the diagnostic challenges and clinical features of HTGP. Clinical cases: Our first patient was a 65-year-old male with a history of hypertension who presented to the ER with abdominal pain and new-onset pruritic skin rash after a heavy meal. His exam and labs were notable for a diffuse papular rash on his back, triglycerides (TG) of 7073mg/dL (normal: &lt;150mg/dL). The rash improved with the resolution of HTG. Our second patient was a 29-year-old male with a history of alcohol dependence who was found to have AP complicated by ARDS requiring intubation. Further testing revealed that his TG was 12,862mg/dL & his sodium (Na) was 102mEq/L. Although HTG was known to cause pseudohyponatremia, it was a diagnostic challenge to estimate the true Na level. In a third scenario, a 28-year-old female with a history of T2DM on Insulin presented with nausea & abdominal pain. Labs were suggestive of DKA and lipase was normal. CT abdomen showed changes consistent with AP. The TG level that was later added on was elevated to 4413mg/dL. She was treated with insulin that improved her TG level. Discussion: We present three cases of hypertriglyceridemic pancreatitis. While the presentation can be similar to other causes of acute pancreatitis (AP), there are factors in the diagnosis and management of HTGP that are important to understand. Occasionally, physical exam findings can be suggestive of underlying HTG. In the first scenario, our patient presented with eruptive xanthomas - a sudden eruption of crops of papules that can be pruritic. They are highly suggestive of HTG, often associated with serum TG levels &gt; 1500mg/dL. Our second patient presented with pseudohyponatremia. HTG falsely lowers Na level, by affecting the percentage of water in plasma. Identifying this condition is important to prevent possible complications from aggressive treatment. This can be corrected either by using direct ion-specific electrodes or with the formula: Na change = TG * 0.002. DKA is associated with mild-moderate HTG in 30–50% cases. This is due to insulin deficiency causing activation of lipolysis in adipocytes & decreased activity of lipoprotein lipase (LPL). However, severe HTG is a rare complication of DKA, increasing the risk of AP. Diagnosis of AP in DKA poses many challenges: the common presenting complaint of abdominal pain, non-specific hyperlipasemia in DKA. AP with DKA has also been associated with normal lipase levels. A high clinical index of suspicion is required to diagnose HTGP in patients with DKA.
MON-593 Single-Dose Effects of Anti-Obesity Drugs on Human Basal Metabolic Rate
Authors: Israni Nikita Sanjay , Cassimatis Thomas , Fletcher Laura A , Leitner Brooks P , Duckworth Courtney J , Hattenbach Jacob D , Bell Sarah L , McGehee Suzanne , Brychta Robert J , Courville Amber B , Bernstein Shanna B , Muniyappa Ranganath , Reitman Marc L , Cypess Aaron M , Chen Kong Y 
Published: May 2020

Abstract
Design and rationale: Obesity results from energy intake exceeding energy expenditure (EE) over a prolonged period. Many anti-obesity drugs are designed to decrease energy intake. However, their potential impact on EE is not well documented. We designed a placebo-controlled, double-blind, randomized cross-over study to determine the acute effects of several FDA-approved anti-obesity drugs on basal metabolic rate (BMR) under well-controlled conditions.
Protocol and inclusion criteria: This ongoing study is limited to healthy males of all ethnicities aged 18–35 years with a BMI of 18.5 to 25.0 kg/m2. Following an overnight stay in the Metabolic Clinical Research Unit, fasting subjects were measured from 8:00am to 12:00pm in a whole-room indirect calorimeter, which was maintained at a thermoneutral temperature (26.7±0.9°C) to prevent non-shivering thermogenesis. The six treatments include placebo, caffeine as the positive control (300 mg), phentermine (37.5 mg), topiramate (200 mg), Qsymia (phentermine 15 mg / topiramate 92 mg), and naltrexone (100 mg), with a 1-week outpatient washout period after each treatment. Drug-naïve subjects received a single dose of each drug to minimize potential metabolic adaptations that may occur with weight-loss or chronic use. The prespecified primary outcome was a ≥5% increase in BMR vs. placebo for each drug. This difference can be detected for 16 subjects with 0.83 power at α=0.05 allowing for ≤25% dropout. Secondary outcomes include respiratory quotient (RQ), heart rate (HR), mean arterial pressure (MAP), and self-reported hunger.
Preliminary data: To date, 7 subjects were recruited and 6 have completed the study (26.1±4.3 years, BMI 23.1±1.4 kg/m2, body fat percentage 18.4±4.1%). Interim analysis using paired t-tests shows, compared to placebo, caffeine trended towards increasing EE (1.17±0.07 vs. 1.27±0.12 kcal/min; p=0.07) and increased MAP by 5.5±4.2% (88±2 vs. 93±4; p&lt;0.05), but did not change heart rate (59±10 vs. 61±13 bpm). Naltrexone increased EE by 5.9±4.3% (p&lt;0.05). No treatments altered resting RQ compared to placebo (0.83±0.05). Phentermine increased resting HR, both alone (15.7±7.9%, p&lt;0.01) and in Qsymia (9.2±3.6%, p&lt;0.05), compared to placebo. Of the five drug-treatments, only Qsymia reduced self-reported hunger scores compared to placebo.
Summary and future directions: Anti-obesity drugs may increase energy expenditure by upregulating sympathetic nervous system activity. Combined with appetite suppression, the impact on energy balance can lead to weight loss. We aim to complete our study to determine whether these drugs can acutely increase EE with minimal cardiovascular side-effects and compare our findings with long-term interventions.
SUN-561 Genetic Variants Related to Familial Hypercholesterolemia in Clusters from Minas Gerais - a Southeast State of Brazil
Authors: de Paiva Silvino Júnea Paolucci , Jannes Cinthia Elim , Tada Maurício Teruo , Lima Isabella Ramos , Silva Iêda Fátima Oliveira , Gomes Karina Braga , Pereira Alexandre Costa 
Published: May 2020

Abstract
Familial Hypercholesterolemia (FH) is an autosomal dominant genetic disease, characterized by high levels of the cholesterol fraction present in low density lipoprotein (LDLc). FH is associated to early atherosclerotic coronary disease, which can result in acute myocardial infarction and angina pectoris. Clinical diagnosis of FH in adults is based on elevated LDLc levels ≥ 4,9 mmol/L and total cholesterol (TC) ≥ 7,5 mmol/L; in untreated children and adolescents LDLc ≥ 4,0 mmol/L and TC ≥ 6,7 mmol/L, associated or not with physical signs (xanthomas, corneal arch). In Brazil, it is estimated that there are from 402,000 to 607,000 cases of FH. This study aimed to evaluate the genetic variants related to FH in a small region from Minas Gerais, a southeast state in Brazil. Fifteen index cases (IC) were selected in two cities (Bom Despacho and Moema), that comprise 1.416 km2 in that region. Family members (n=69) were also selected, when possible, for genetic analysis, which was carried out by the NGS (Next Generation Sequencing) method, using Illumina® technology. Six different genetic variants were identified: 1) Pathogenic variants in LDLR gene - Asp224Asn in 74 individuals (10 IC); Cys34Arg in 1 individual (1 IC); Asp601His in 2 individuals (1 IC); and Ser854Gly in 2 individuals (1 IC); 2) Variant of uncertain significance (VUS) in APOB gene - Met499Val in 1 individual (1 IC); and 3) VUS in PCSK9 gene - Arg237TRP in 4 individuals (1 IC). All variants were identified in heterozygosis. The data suggest that the high prevalence of FH in that small region in Brazil is related to inbreeding observed in the families investigated. In addition, a founder effect could also contribute to the elevated frequency of LDLR gene variants, mainly Asp224Asn. The data show the importance of molecular investigation on clinical conduct in FH Brazilian patients and their family members.
SUN-508 Dissociation of Clinical Course of Coexisting Autoimmune Hepatitis and Graves Disease
Authors: Patel Aesha , Stanback Camille , Vellanki Priyathama 
Published: May 2020

Abstract
Title: Dissociation of Clinical Course of Coexisting Autoimmune Hepatitis and Graves Disease
Introduction: The association between Graves’ disease and coexisting autoimmune hepatitis is well known. Treatment of autoimmune hepatitis with glucocorticoids can concurrently lower thyroid hormone levels. Additionally, recurrence of hyperthyroidism has been shown to be associated with recurrence of autoimmune hepatitis. We present a case of a patient with autoimmune hepatitis and Graves’ thyrotoxicosis, which initially improved with prednisone therapy, but thyrotoxicosis recurred during the prednisone taper while hepatitis stayed in remission.
Clinical Case: A 47-year old female initially presented with fatigue, nausea, and jaundice. Liver enzymes showed elevated AST (1634 U/L) and ALT (1956 U/L) with total bilirubin 15.1 mg/dL. Liver biopsy was consistent with autoimmune hepatitis. Treatment was initiated with ursodiol 300 mg TID and liver enzymes improved to ALT 579 IU/L and AST 544 IU/L with total bilirubin 1.9 mg/dL. Nine months later, she presented with worsening upper and lower extremity weakness, slurred speech, abdominal pain, and nausea and vomiting. AST and ALT were again elevated to &gt;1,000 U/L. TFTs were checked due to symptoms of palpitations and heat intolerance. TSH was 0.024 uIU/mL with elevated free T4 of 3.74 ng/dL and TSI of 435%. She was treated with prednisone, cholestyramine, and propranolol and discharged with a one-month prednisone taper starting at 60 mg daily. LFTs and TFTs normalized after one month. Cholestyramine was discontinued and prednisone was tapered to 5 mg daily. Seven months later, she had symptoms of palpitations and heat intolerance. TFTs were consistent with hyperthyroidism (TSH 0.049 uIU/mL, free T4 3.96 ng/dL). LFTs remained in normal range. Since thionamides have relative contraindications in patients with liver disease, prednisone was increased from 5 mg to 20 mg daily and cholestyramine was resumed to treat hyperthyroidism. After five months, TSH remained suppressed to 0.019 uIU/mL however free T4 improved to 1.74 ng/dL. The patient was referred for total thyroidectomy.
Conclusion: This case illustrates an example of the rarely reported occurrence of thyrotoxicosis recrudescence despite initial improvement with treatment of underlying autoimmune hepatitis. Recognition of recurrence of hyperthyroidism independent of recurrence of autoimmune hepatitis indicates the need for early definitive therapy for hyperthyroidism.