bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unusual Presentation of Myxedema Coma in Type 1 Diabetes Mellitus With Hyperglycemia and Polysubstance Abuse
Authors: Hamid Yumna , Douedi Steven , Nold Johnathan , Ong Raquel Kristin , Cheng Jennifer , Zin Khin 
Published: May 2021

Abstract
Background: Myxedema coma is a severe manifestation of hypothyroidism that typicallypresents with altered mental status and requires close monitoring in the intensive care unit dueto 30-60% mortality rate. Clinical Case: A 56 year old white male with type 1 diabetes with recurrent DKA, polysubstanceabuse, Bipolar disorder on lithium and post surgical hypothyroidism presented due to change inmental status after being brought in by sister. Patient was found to be lethargic with confusionthat worsened over the last week. The patient was admitted several times in the past monthsecondary to pneumonia, sepsis, and recurrent DKA. On physical examination, he found to have lethargy, macroglossia, hyporeflexia, and periorbitaledema. Patient had acute respiratory failure with metabolic encephalopathy, bradycardia,tachypnea, severe hyperglycemia, hypotension of 77/51, tachypnea of 31 breaths per minuteand hyponatremia. Laboratory findings showed T4 levels 2.87(n=5.28-9.87ug/dL) withundetectable FT4 and elevated TSH (&gt;50, n=0.300-4.500uIU/mL). Electrolyte panel showedhyponatremia (133, n=136-145mmol/L), hyperglycemia up to 532mg/dL and lithium levels werewithin normal limits (n=0.5-1.5 mmol/L). Urine drug screen was positive for cocaine. A CT scanof the head was negative. His myxedema score was diagnostic (&gt;60). The patient wasdiagnosed with myxedema coma and admitted to the ICU. Patient was treated with IV LT4 400mcg, LT3 10mcg and hydrocortisone 100mg and started onIV LT4 100mcg daily, LT3 2.5mcg daily and hydrocortisone 100mg Q8 hours. There was wideglycemic variation from 46-532 mg/dL on POCT. The patient improved clinically, with resolutionof lethargy, confusion, fatigue, improved appetite, and improved lab work of FT3 2.30 (n=2.28-3.96pg/mL), FT4 at 0.76 (n=0.50-1.26ng/dL) and was downgraded from the ICU. On hospitalday four, he was transitioned to oral levothyroxine and discharged home. Conclusion: It is important to diagnose early and promptly manage decompensatedhypothyroidism in the setting of other comorbidities such as hyperglycemia in diabetes andpolysubstance abuse. The cocaine in the system may cause tachypnea and tachycardia. Manyconditions may have altered mental status, but with a history of hypothyroidism, Myxedemacoma should be on the differential due to its high mortality rate.
Atrial Fibrillation Does Not Negatively Impact the Outcomes of Patients Admitted for Hyperthyroidism: Analysis of the National Inpatient Sample
Authors: Akuna Emmanuel , Asemota Iriagbonse , Shaka Hafeez , Edigin Ehizogie , Velazquez Genaro , Nwachukwu Praise , Asotibe Jennifer Chiagoziem 
Published: May 2021

Abstract
Introduction: Hyperthyroidism is a well-known risk factor for the development of atrial fibrillation(AF), but the outcomes hyperthyroidism in patients with atrial fibrillation is unclear. This study aims to compare the outcomes of patients primarily admitted for hyperthyroidism with and without a secondary diagnosis of AF.
Methods: Data were abstracted from the National Inpatient Sample (NIS) 2016 and 2017 Database. NIS is the largest inpatient hospitalization database in the United States. The NIS was searched for hospitalizations with a principal diagnosis of hyperthyroidism with and without AF as secondary diagnosis using ICD-10 codes. Hospitalizations for adult patients (age≥ 18 years) from the above groups were identified. The primary outcome was inpatient mortality. Hospital length of stay (LOS), total hospital charges, cerebrovascular accident and acute respiratory failure were secondary outcomes of interest. Multivariate logistic and linear regression analysis was used accordingly to adjust for confounders.
Results: There were over 71 million discharges included in the combined 2016 and 2017 NIS database. 17,705 hospitalizations were for adult patients who had a principal ICD-10 code for hyperthyroidism. 4,165 (23%) of these hospitalizations had co-existing AF. AF group were older (57 vs 44 years, P &lt; 0.0001) and had less females (65% vs 78%, P &lt; 0.0001). Hospitalizations for Hyperthyroidism with AF had similar inpatient mortality (0.96% vs 0.33%, AOR: 1.7, 95% CI 0.58-5.14, P=0.324) with longer LOS (5.1 vs 3.2 days, P=0.000), increased total hospital charges ($51,904 vs $34,471, P=0.002), increased odds of cerebrovascular accident (0.8% vs 0.1%, AOR: 5.01, 95% CI 1.1-22.2, P&lt;0.034) and increased odds of acute respiratory failure(4.4% vs 1.3%, AOR: 3.01, 95% CI 1.8-5.0, P&lt;0.000) compared to those without AF.
Conclusions: Patients admitted primarily for hyperthyroidism with co-existing AF had similar inpatient mortality but with longer LOS, increased total hospital charges, increased likelihood of having cerebrovascular accident and acute respiratory failure when compared to those without AF.
Chronic Stress During Adolescence Blunts the Exercise-Induced Expression of Thyroid Hormone-Target Genes in Metabolically Active Tissues of Male and Female Rats
Authors: de Oca Marco Antonio Parra-Montes , Garduño-Morales Karen Lissette , Joseph-Bravo Patricia 
Published: May 2021

Abstract
Voluntary exercise activates HPT axis1, that contributes to energy mobilization and energy expenditure. Chronic stress in adulthood inhibits HPT response to voluntary wheel running in a sex dependent manner, inhibiting lipolysis of WAT2. We evaluated the effect of chronic stress during adolescence on HPT axis response to voluntary exercise in adulthood3, with emphasis on metabolic response in skeletal muscle and WAT. Wistar male and female rats (N=36 per sex) were divided in an undisturbed group (Control, C; n=18) and one chronic variable stress during adolescence group (CVS; n=18) (males: PND 30-70; females: PND 30-60). As adults (males: PND 84; females: PND: 74) rats were divided in: 1) exercise group: rats placed individually in a cage with a running wheel per 14 nights, 2) sedentary group with ad libitum feeding, 3) sedentary pair-fed group offered the same amount of food consumed by the exercised group, and kept in individual cages during 14 nights (6 rats/group). WAT weight was determined at sacrifice, hormones quantified by RIA and ELISA, gene expression by RT-PCR. Exercise-induced loss of fat mass was not detected in CVS rats. Exercise decreased corticosterone levels in C males and females of both treatments, supporting sex difference on HPA axis reprogramming by CVS. HPT axis response to voluntary exercise is attenuated by CVS also in a sex dimorphic manner: CVS decreased Trh expression in hypothalamic paraventricular nucleus and no changes in thyroid hormones concentration in males, whereas in females, slightly increased TSH, T4 and T3 levels. Sex also influenced the response of skeletal muscle and WAT to CVS. Dio2 and Pgc1a slightly increased expression in skeletal muscle of males, not of females. Adrb3 expression in WAT increased in females, but not in males; exercise-induced stimulation of Hsl expression was not observed in either sex after CVS. These results suggest that CVS imposed during rat adolescence inhibits the responses to voluntary exercise of HPT axis activity of thyroid hormone-targets in WAT and skeletal muscle in sex dependent manner. These changes could lead to reduced mobilization and the utilization of energy fuels coincident with the fatigue observed after exercise in patients with subclinical or clinical hypothyroidism. (Funded: CONACYT 284883, DGAPA IN213419)1Uribe, Endocrinology 155:2020-2030, 2014.2Parra, Front Endocrinol 10(418):1-13, 2019.3Parra, J Endocr Soc 4(Abstract Supp) Abstract SAT-451, 2020.
iPSC-Derived Human Hepatocytes as a Novel Model to Investigate Thyroid Hormone Action and Signaling
Authors: De Oliveira Lorraine Soares , Lee Nora , Kaserman Joseph , Vella Kristen R , Wilson Andrew , Hollenberg Anthony Neil 
Published: May 2021

Abstract
Thyroid hormone (TH) actions are essential to normal metabolism and neurologic function. Abnormal TH levels can lead to significant morbidity including metabolic abnormalities, cardiac disease, and obesity. TH action is mediated by the thyroid hormone receptor (TR) isoforms and their coregulators. In the disease models of Resistance to Thyroid Hormone (RTH) it is clear that the TR isoforms play tissue-specific roles in humans, however a platform for drug discovery to potentially treat the diseases does not exist. We hypothesize that human hepatocytes (iHeps) derived from induced pluripotent stem cells (iPSCs) will serve as an ideal model to study TH signaling and to delineate mechanisms of TH diseases in humans. To investigate the TH action in humans, we have developed a serum free human iPSC hepatic differentiation protocol that utilizes sequential exposure to growth factors to mimic actual human development. iHeps are robustly responsive to TH with over 1000 regulated genes. Importantly, they allow us to use CRISPR/Cas9 to determine molecular physiology and mechanism of disease. To demonstrate the role of TRs in TH signaling in human liver cells we have focused on TRβ1 the main TR isoform expressed in liver. we knocked out TRβ1 (THRBKO) using guide RNAs (gRNAs) we engineered to specific genomic loci to truncate the expression of this isoform at the DNA binding domain. Also, to define mechanisms of TR action in the context of RTH, we used this same approach to introduce the Δ337T mutation found in human TRβ1 that causes RTH. Both THRBKO and Δ337T lines are karyotypically normal and flow cytometry analysis in both lines demonstrated that these lines differentiated normally into hepatocytes after gene editing with CRISPR/Cas9. Once clones were identified the edited iHeps were treated with PBS (vehicle) or T3 (10nM) for 24 hours. Real-time quantitative PCR (RT qPCR) was done to assess mRNA expression of T3 target genes. RT qPCR analysis confirmed the success of TRβ1 deletion as the response to T3 was lost on both positive and negative THRB targets. In the Δ337T iHeps, the response to TH was diminshed indicating the successful generation of this line. These preliminary results confirm our ability to edit IPSCs and then to differentiate into hepatocytes, allowing us to further study the action of TH and the mutations involved in RTH.
T3 Enters Axon Terminals of Mouse Cortical Neurons, Is Retrogradely Transported to the Cell Nucleus and Activates Gene Expression
Authors: Salas-Lucia Federico , Bocco Barbara M L C , Rada Kristof , Fekete Csaba , Gereben Balazs , Bianco Antonio C 
Published: May 2021

Abstract
Thyroid hormone (TH) is critical for brain development and function. T3 enters neurons through membrane transporters and reaches the cell nucleus where it binds to receptors (TR) to regulate gene transcription. However, neurons also express the type 3 deiodinase (D3), which is located in the cellular and nuclear membranes and inactivates T3. Here, we investigated the fate and biological impact of T3 that enters neurons through axons. Primary cortical neurons were isolated from E16.5 embryos of the TH action indicator (THAI) mice, which were engineered with a TH-responsive transgene where three copies of a T3-responsive element drive a luciferase (Luc) reporter. Neurons were seeded on a microfluidic device consisting of two independent compartments: (i) cellular, where about 70-90,000 cell bodies were located, and (ii) axonal, where a few hundred distal axons were located. Fluidic isolation of the compartments was monitored with Alexa Fluor 594 hydrazide. In the first set of experiments (repeated 3 times), 8-10-day old cultures were incubated for 48h with medium containing 1% charcoal-stripped serum (Tx-medium). Subsequently, 10nM T3 was added to the axonal compartment, and 24h later cell bodies were harvested and Luc mRNA measured by RT-qPCR. There was a 2.4 ± 0.7-fold increase in Luc mRNA levels, but the addition of 2uM Silychristin (MCT8 inhibitor) to the axonal compartment reduced T3 induction of Luc mRNA by 32 ± 4.2%. In the second set of experiments (repeated 3 times), 4.9 ± 2.2pM 125I-T3 (final concentration) was added to the cellular or axonal compartments. Medium was sampled and 125I-T3 and its metabolites were separated/quantified via UPLC linked to a flow scintillation detector. After 72h of adding 125I-T3 to the axonal compartment, about 0.73 % 125I-T3 (0.052 ± 0.025pM) was found in the cellular compartment. In addition, 3,3’-125I-T2 and 125I (0.011 ± 0.003 and 0.052 ± 0.023pM, respectively) were also detected. When 125I-T3 was added to the cellular compartment, about 1.6% 125I-T3 (0.048 ± 0.027pM), no metabolites, was detected in the axonal compartment. Only background radioactivity was detected in the opposing compartment when 125I-T3 was added in the absence of cells. We conclude that T3 can be taken up by neuronal axons, partly via MCT8, and transported retrogradely to the cell nucleus to initiate TH signaling. D3-generated T3 metabolites exit the cell body alongside with small amounts of intact T3. This pathway could explain how D2-generated T3 in tanycytes is taken up by TRH-secreting neurons to mediate negative T3 feedback. Anterograde T3 transport was also detected, the significance of which remains unknown.
Identification of Genes and Pathways Differentially Expressed in Progestin Responsive Endometrial Cancer and Hyperplasia
Authors: Gertz Jay , Rush Craig , Vahrenkamp Jeffery , Szczotka Kathryn , Dodson Mark , Jarboe Elke , Soisson Andrew 
Published: May 2021

Abstract
One of the oldest and most common therapies for endometrial complex atypical hyperplasia (CAH) and low-stage, low-grade endometrioid endometrial carcinoma (EEC) is the use of progestins. Importantly, the use of progestins remains the only fertility-sparing treatment available. Despite frequent initial response to progestins, relapse rates are high (35-50%). Currently, there are no biomarkers available for predicting a woman’s likelihood of successful progestin therapy.
Primary samples (n = 63) were obtained from a total of 31 patients with either CAH or EEC who underwent progestin therapy and were acquired pre- and post-treatment with progestins. Pathological review of the FFPE samples was performed to identify regions of high hyperplastic or neoplastic content for core punches and RNA extraction. RNA-seq was then performed on the FFPE RNA using the TruSeq RNA Exome approach, a method that uses targeted capture to improve sequencing from fragmented samples. Differential expression analysis was performed using two methods: DESeq2 a parametric method and Noiseq a non-parametric method. Both methods were used to obtain an overlapping subset of genes to reduce spurious results due to samples with outlier expression.
Analysis of all samples identified 137 genes significantly associated with outcome. These 137 genes were largely increased in post-treatment samples from progestin responders and were highly enriched for progestogen and estrogen responsive genes, indicating a strong hormonal gene expression response to progestin therapy. Importantly, post-treatment samples from non-responding patients did not show this expression pattern, demonstrating that this set of genes may indicate successful hormone response in post-treatment samples. We also identified a 61 gene signature that remains high in non-responders after treatment compared to responders. Overall, we find that responders show a coordinated change in expression during progestin therapy that is missing from non-responders and this signature could be used in the early evaluation of progestin treatment success.
Focusing solely on pre-treatment samples, we identified more variable expression differences across tumors, suggesting multiple reasons for progestin success/failure. We found that the combined expression of estrogen receptor alpha and progesterone receptor was predictive of progestin therapy success. In addition, non-responding tumors had increased expression of several immune-related genes that we are currently exploring. Overall, these results show that progestin therapy response could be predicted using gene expression signatures and that multiple factors may underlie progestin success/failure.
Recurrent Cushing Syndrome Secondary to Metastatic Adrenocortical Carcinoma in a Patient With Previously Resected Adenoma
Authors: Addasi Noor , Silverman Emily Christine , Ganti Apar , Kotwal Anupam 
Published: May 2021

Abstract
Background: ACTH-independent causes of Cushing Syndrome (CS) have mostly benign etiologies. For the majority of these conditions, surgery is the recommended treatment and is nearly 100% curative. Current guidelines do not specify follow up imaging recommendations in patients with resected adenomas. We present a case of severe CS secondary to an adrenal adenoma that was completely resected, and presented later as a metastatic adrenocortical carcinoma (ACC). Clinical Case: A 34- year-old woman presented with worsening confusion, weight gain and new onset diabetes and hypertension. Her history was significant for a 7 cm left adrenal mass and ACTH- independent CS previously treated with left adrenalectomy 2 years prior to this presentation. She was following with an endocrinologist who weaned her hydrocortisone to 10-5 mg. She completed a successful pregnancy but had worsening depression. Her steroids were stopped on admission and evaluation showed hypokalemia [2.9 mmol/L (n 3.5-5.1)], hypercortisolemia [29.9 mcg/dL (n 6.7-22.6)], and ACTH &lt;12 pg/mL (n&lt;46). This was followed with 1 and 8 mg dexamethasone suppression tests that she failed with cortisol levels of 37.8 and 41.6 mcg/dL respectively, late-night salivary cortisol of 0.974 ug/dL (n &lt;0.181), and extremely elevated 24-hr urinary cortisol of 3,700.2 ug/d (n&lt;45). Of the steroid hormone precursors, 11 deoxycortisol was elevated at 725 ng/dL (n&lt;32) and DHEA-S was 29mcg/dL (n 35-430). A CT scan revealed multiple liver lesions, and no residual nodularity in the left adrenalectomy bed. Liver lesions were PET-avid, and biopsy confirmed metastatic ACC. Due to the extensive hepatic involvement, she was not a candidate for local therapy. She was started on mitotane and metyrapone for CS. She was treated with doxorubicin, cisplatin and etoposide chemotherapy every 4 weeks. Due to insurance issues; metyrapone was replaced by mifepristone. Over 8 weeks, mitotane level became therapeutic at 20 mcg/mL, hepatic masses decreased in size, and she transitioned form CS to adrenal insufficiency (AI) with am cortisol of 3 mcg/dL with accompanying nausea and improved glycemic control without medication. Next generation sequencing studies of the liver biopsy specimen revealed a frameshift loss of function mutation in FH that encodes the protein fumarase (c.912_918del p.F305fs; variant allele fraction - 67.8%). Conclusion: Metastatic ACC presenting with life-threatening CS presents a diagnostic and management challenge. Combination therapy with mitotane and chemotherapy demonstrated benefit in our patient. The transition from severe CS to AI due to mitotane was challenging to monitor biochemically due to mifepristone use. Loss of function FH mutation is associated with cancer progression. Patients with resected large adrenal adenomas require close monitoring to identify malignant behavior.
A Case of Adrenocortical Carcinoma With Severe Hypertension and Hypokalemia
Authors: Yamamoto Naoki , Yamamoto Masaaki , Fukumitsu Hayato , Kanzawa Maki , Fukuoka Hidenori , Ogawa Wataru 
Published: May 2021

Abstract
Case: 70 years old woman was pointed out for hypertension at a medical checkup and visited a primary physician. Severe hypokalemia (2.4 mmol/L) was noted, and abdominal CT scan revealed a right 99 mm diameter adrenal tumor adjacent to a 80 mm diameter liver tumor. She was referred to our hospital for further management. Despite treatment with antihypertensive agents, including ARB, MRB, and CCB, her blood pressure remained around 170/90 mmHg. In the meantime, 120 meq of potassium chloride treatment was needed to keep her serum potassium levels around 3.5 mmol/L. Both her plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were high (6.4 ng/mL/h and 376 pg/mL), indicating renin-dependent hypertension. Since CT angiography revealed the right renal artery compressed downward by the adrenal tumor, renovascular hypertension was suspected. Moreover, both early morning plasma ACTH levels and serum cortisol levels were suppressed (8.5 pmol/L and 5.3 μg/dL), despite elevated urinary free cortisol levels (350 μg/day). Urinary steroid profile analysis detected various elevated precursor steroid metabolites, including deoxycorticosterone (DOC) and corticosterone. DOC levels were 5 folds more than the upper normal limit, suggesting one of the causes of her hypertension with hypokalemia, while elevated corticosterone levels were thought to be contributed to suppressing ACTH. After the right adrenalectomy and hepatic segmentectomy, both of her hypertension and hypokalemia rapidly improved with declining PRA and PAC levels to 0.2 ng/mL/h and &lt; 0.7 pg/mL, respectively. Urinary DOC levels also fell into the normal range. From the pathological findings, she was diagnosed with adrenocortical carcinoma (ACC) infiltrating the liver (pT4N0M0, stage IV). The immunohistochemistry analysis showed disorganized expression of steroidogenic enzymes, including CYP11B1, CYP11B2, and 3β-HSD, supporting a variety production of steroid metabolites from the ACC. Although mitotane was initiated as a adjuvant chemotherapy, multiple metastasis was found at her lung, liver, and vertebrae, 6 months after the operation. Along with that, hypertension and hypokalemia recurred gradually with both of PRA and PAC elevation. However, CT angiography detected no apparent renovascular stenosis. We performed renin immunostaining of ACC specimen revealed partially positive, demonstrating renin production from this ACC. Conclusion: Although juxtaglomerular cell tumor is the most common renin-producing tumor, some cases of renin secreting ACC have been reported as a quite rare case. In the present case, renin secretion from ACC might be contributed to severe hypertension and hypokalemia, and both renal artery stenosis and DOC secretion induced by the ACC are considered to be a major cause.