bluuebunny/crossref_metadata_2025_split huggingface dataset:
RF21 | PSAT77 ROLE OF THE TRANSCRIPTION FACTOR HHEX IN INNER ADRENAL CORTEX HOMEOSTASIS AND RESPONSE TO PROGESTERONE SIGNALING
Authors: Dumontet Typhanie , Basham Kaitlin , Lerario Antonio , Bothou Christina , Brixius Bjoern , Turcu Adina F , Beuschlein Felix , Hammer Gary D 
Published: November 2022

Abstract
Congenital adrenal hyperplasia (CAH) is a set of defects in cortisol synthesis due to mutations in genes encoding steroidogenic enzymes. Consequently, the loss of glucocorticoid-mediated negative feedback on the HPA axis leads to chronically elevated ACTH (Adrenocorticotropin Hormone) secretion. The sustained ACTH elevation, in turn, stimulates proliferation and hypertrophy of the adrenal cortex and leads to overproduction of androgens.
To study the complexity of the ACTH-responsive cell population in the adrenal cortex, we performed single-cell RNA sequencing of the steroidogenic lineage in the adult mouse adrenal. We identified the transcription factor HHEX as a gene with restricted expression in the ACTH-responsive zona fasciculata. Although the role of HHEX in adrenal biology is completely unknown, a meta-analysis identified a germ-line variant of uncertain significance near the gene HHEX associated with increased DHEAS (adrenal-specific androgen) in human serum samples, which led us to hypothesize that HHEX contributes to the unique function of the ACTH-responsive inner cortex.
To investigate the mechanisms by which HHEX controls adrenal differentiation and homeostasis, we generated genetically modified mice harboring a deletion of the Hhex gene in the adrenal cortex. Hhex KO mice exhibited progressive adrenomegaly by 15 weeks of age, accompanied by hypertrophy prominent in the inner cortex and disruption of the endothelial organization. Expression of the transcription factor Nr5a1/Sf-1 and steroidogenic enzymes involved in corticosterone production were significantly upregulated at 6 weeks old, prior to adenomegaly, suggesting a precocious increase in cell production of glucocorticoids. For insights into the signaling pathways controlled by HHEX, we analyzed global transcriptional changes during loss of Hhex and found dramatic downregulation of members of the membranous progesterone receptor family (PAQR). PAQR signaling has been implicated in the downregulation of cAMP, a primary mediator of ACTH signaling, and thereby could, in part, drive the increase in steroidogenesis in Hhex KO mice.
These findings suggest that the inner cortex contains a progesterone-responsive cell population in which HHEX provides additional fine-tuning of ACTH-driven cAMP signaling by progesterone and derivatives. Since we observed an increase in Hhex expression in a mouse model of CAH, experiments are now ongoing to assess the implication of HHEX and autocrine progesterone signaling in contributing to the hypertrophy and steroidogenic phenotype observed in CAH.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:54 p.m. - 12:59 p.m.
RF21 | PSAT90 Lineage Tracing Sonic Hedgehog-Expressing Cells in Adrenal Glands in Post-Weaning Mice
Authors: Laprocina Kari , Zheng Huifei Sophia , Kang Yuan , Huang Chen-Che Jeff 
Published: November 2022

Abstract
The Sonic Hedgehog (Shh) gene expressed in the subcapsular cortical region of the adrenal gland has been found to play a role in adrenal gland development. The Shh(+) cell population at the fetal stages contributes to different cortical layers in the adrenal gland. However, the (1) capability of these cells after weaning and (2) how soon they can renew the adrenal cortex in the postnatal stages is not fully understood. Here, we conducted a lineage tracing experiment to track Shh(+) cells and cells descended from them in post-weaning mice to ultimately better understand the processes of adrenal cortex renewal and remodeling over time in young adult mice.
This experiment used the NuTRAP; Shh-Cre-ERT2 mice as the Shh-reporter mouse model. This tamoxifen-inducible mouse model allows us to specifically target and label Shh-expressing cells and all descendant cells with green fluorescence. Tamoxifen was given at postnatal days (P) 22, P24, and P26 to enable the Cre recombinase activity driven by the Shh promoter. Adrenal glands were then analyzed after two and four months. This lineage tracing experiment found that Shh(+) cells and their descendant cells reached the margin of the Cyp2f2(+) cortical zone in 2 months and the cortical-medullary boundary in 4 months. This finding indicates that the Shh(+) cell population in post-weaning mice can proliferate, differentiate, and eventually renew the entire adrenal cortex over a four-month period of time.
Understanding the adrenal cortex's renewal rate helps us design our follow-up study to test the capability of Shh(+) cells in adult mice at different ages and how their potency changes overtime at the 'omic' level. Because this NuTRAP;Shh-Cre-ERT2 mouse model also allows us to isolate cell-type-specific DNA/RNA, we can further decipher the underlying gene/pathways which control this progenitor cell population of the adrenal gland cortex.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 1:12 p.m. - 1:17 p.m.
RF33 | PSAT92 Glucocorticoid Excess Alters Metabolic Rate in Male and Female C57BL/6J Mice
Authors: Tsintzas Kostas , Heaselgrave Samuel , Heising Silke , Morgan Stuart , Kabli Ali , Doig Craig , Morton Nicholas , Lavery Gareth 
Published: November 2022

Abstract

Introduction
Glucocorticoids are vital for regulating metabolic processes, as well as use in medical treatments. However glucocorticoid excess is known to cause negative metabolic effects including hyperglycaemia, muscle atrophy and fat accumulation, ultimately leading to Cushing's Syndrome. The effect on energy metabolism and metabolic rate remains undefined and merits investigation in both male and female mice.

Methods
24 male and 24 female C57BL/6J mice were randomly assigned to a corticosterone (100mg/L, approximately 300µg/day) or a vehicle control group. Mice were treated ad libitum via drinking water for 3 weeks, whilst being fed a standard chow diet. Mice were placed into a TSE Phenomaster system for the final week of treatment for indirect calorimetry assessment.

Results
Corticosterone treatment resulted in a typical phenotype of glucocorticoid excess, however female mice experienced significantly greater fat accumulation and bodyweight gain compared to males. Females treated with corticosterone exhibited increased energy expenditure (EE, 25±5.9%), oxygen consumption (21.7±10.0%) and carbon dioxide production (36.4±14.3%) during the day compared to controls, but males did not. However, corticosterone did significantly elevate the respiratory exchange ratio (RER) towards 1 in both males (10.7±5.7%) and females (11.8±7.0%) during the day. At night, when mice are naturally more active and EE increases, female corticosterone mice no longer had elevated EE, oxygen consumption and carbon dioxide production compared to controls. However, RER remained elevated in females (7.6%±4.8%) and moderately so in males (3.2±2.6%), staying close to or exceeding 1 in both. Corticosterone treated mice were hyperphagic and polydipsic throughout, eating and drinking significantly more than controls during both night and day, with intake peaking at night. Subsequent metabolomic analysis of tissue samples (skeletal muscle, liver, gonadal fat) revealed significant treatment and sex differences.

Conclusion
and further investigation: These findings provide further insights into the metabolic consequences of glucocorticoid excess in male and female mice. Whilst energy metabolism and metabolic rate are altered in both (especially during the day), the metabolic effects of glucocorticoid excess might be exaggerated in females. Further investigation will determine whether these changes are driven simply by increased animal activity, increased feeding and drinking or another mechanism. Additionally, we will determine whether 11β-HSD1 KO prevents these changes, as it does with other negative metabolic effects associated with glucocorticoid excess.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 1:06 p.m. - 1:11 p.m.
LBODP016 Lithocholic Acid Induced 25-hydroxyvitamin D-1alpha Hydroxylase (cyp27b1) Expression And Activities In Vitro And In Vivo
Authors: Lam Chung Yan , Yu Wenxuan , Kong Tsz Hung , Wong Man-Sau 
Published: November 2022

Abstract
Our previous study reported that oleanolic acid, a natural agonist for bile acid membrane receptor Takeda G protein coupled receptor 5 (TGR5), could exert bone protective effects, increase circulating 1, 25(OH)2D3 level and induce renal CYP27B1 expression and activities. However, it is unclear if bile acids, as the endogenous agonist of bile acid receptors, could regulate CYP27B1 expression and activities in kidney and bone tissues. The present study aimed to characterize the effects of lithocholic acid (LCA), a secondary bile acid, on CYP27B1 expression and activities in vitro using human proximal tubule (HKC-8) and osteosarcoma (MG-63) and in vivo using mature (6-month-old) male C57BL/6 mice. HKC-8 and MG-63 cells were treated with either LCA (10-10 to 10-5 M), PTH (10-7M), or its vehicle for 4 hours. For MG-63 cells, LCA significantly induced CYP27B1 protein expression at 10-10 and 10-9M (P&lt;0. 001) and CYP27B1 mRNA expression at 10-9M (P&lt;0. 001). For HKC-8 cells, LCA significantly induced CYP27B1 protein expression at 10-10 to 10-6M (P&lt;0. 01) and CYP27B1 mRNA expression at 10-10M (P&lt;0. 001). In addition, LCA significantly induced CYP27B1 activity in MG-63 cells (10-10M) (P&lt;0. 05) and in HKC-8 cells (10-6M) (P&lt;0. 01). For the in vivo study, male C57BL/6 mice were fed with 25mg/kg LCA or its vehicle for three consecutive days and sacrificed 5 hours after the last gavage. Serum, kidney, and iliac crests were collected for subsequent analysis. LCA significantly induced circulating 1,25(OH)2D3 levels (P&lt;0. 01) and CYP27B1 protein expression in both kidney and iliac crests in mice (P &lt;0. 05). In addition, the time-dependent change (2, 5, 8 hours) in serum 1,25(OH)2D3 levels were determined upon feeding the male mice with a single dose of 25mg/kg LCA. LCA significantly increased serum 1,25(OH)2D3 levels in male mice at 2 and 5 hours (P &lt;0. 01 and P &lt;0. 05, respectively), and serum 1,25(OH)2D3 levels returned to basal level by 8 hours. LCA significantly increased CYP27B1 protein expression in kidney in mice at 8 hours after treatment (vs. control group, P&lt;0. 05). In summary, our results showed that LCA significantly induced circulating 1,25(OH)2D3 levels, possibly by its actions to induce CYP27B1 expressions and activities in renal and extra-renal (bone) tissues. The study indicated that bile acids and other TGR5 ligands might play an important role in the regulation of vitamin D metabolism.
Presentation: No date and time listed
LBODP017 Unusual Presentation Of Brown Tumors In Tertiary Hyperparathyroidism: A Case-based Review
Authors: ALShehri Sara Mohammed , AlAshgar Lolwah , AlShaygy Ibrahim , AlBoukai Ahmad , Neel Mona Ali Fouda 
Published: November 2022

Abstract
Brown tumor (BT) is a rare non-neoplastic skeletal manifestation of untreated tertiary hyperparathyroidism (THPT) that is associated with renal osteodystrophy in patients with End-Stage Renal Disease (ESRD). Nearly half of patients with ESRD have Osteitis Fibrosa Cystica (OFC) of varying severity, which is the most common form of renal osteodystrophy. BT represents the extreme form of OFC. As a result of frequent monitoring of bone profile and the expansion of pharmacological therapy, the disease is increasingly being diagnosed in its early stages; however, some are still seen at an advanced stage. Depending on the tumor size, the management will range from a conservative approach with supportive parathyroidectomy to a comprehensive surgical removal. Here, we report a rare case of an extensive BT of the pelvis in a patient with ESRD and THPT who was also found to have coincidental papillary thyroid cancer following total thyroidectomy and parathyroidectomy with a postoperative complication of hungry bone syndrome. She then underwent prophylactic intramedullary nail fixation for an impending fracture in the right femur. This case report highlights the importance of considering BT as a differential diagnosis of lytic bone lesions and that measuring serum calcium, phosphorus, and parathyroid hormone as part of the initial evaluation is essential to identify the correct diagnosis. Multidisciplinary team approach with frequent follow-up is crucial to allow early diagnosis and prevent unnecessary surgical interventions.
Presentation: No date and time listed
LBODP021 Multifactorial Hypercalcemia
Authors: Ramachandran Aishwarya , Win Kyaw Zin , Ramachandran Akshaya 
Published: November 2022

Abstract
Hypercalcemia (ca) has been described in many patients (pt) with granulomatous diseases. We present a pt with persistent hyperca from a combination of primary hyperparathyroidism (PHPT) and elevated 1,25 dihydroxyvitamin (OH2) D levels from reactivated tuberculosis (TB). An 82-year-old woman with a past medical history of Waldenström's macroglobulinemia and TB presented to hospital for imbalance and fatigue. Examination was unremarkable. Labs were notable for newly elevated ca of 14.8 mg/dl. After 200 mg of subcutaneous calcitonin on day 1, ca levels transiently improved but worsened by day 3. Calcitonin 200 mg twice daily was given for 2 days. Cinacalcet 60 mg daily was started for persistently elevated ca, which was then increased to twice daily. Two days later, cinacalcet was increased to 90 mg twice daily. Laboratory work-up revealed parathyroid hormone (PTH) to be inappropriately normal (45 pg/ml with concurrent ca levels of 14.8 mg/dl). Serum vitamin D levels were normal. Sestamibi scan showed bilateral PT adenoma for which she underwent parathyroidectomy. Pathology showed PT hyperplasia. Post-surgical PTH levels were down to 15 pg/ml but calcium levels remained elevated at 14 mg/dl, for which pamidronate 30 mg was given. Further work up showed elevated 1,25 OH2 D levels at 278 pg/ml and repeat levels were 261 pg/ml. Dexamethasone 6 mg daily was started while the pt was worked up for etiologies of elevated 1,25 OH2 D levels, with no improvement. PTHrP, SPEP and UPEP with IFE, quantiferon, and thyroid functions tests were normal. Radiology was unremarkable. AntiTB, and antifungal agents were empirically started. The latter was discontinued upon negative cultures.1,25 OH2 D levels improved with antiTB drugs continuation. Dexamethasone was tapered and pt completed antiTB treatment with normalization of ca levels (despite negative TB culture which resulted after the 1,25 OH2 D levels improved). PHPT is the most common cause of hyperca whereas malignancy is the most common cause of non PTH mediated hyperca in hospitalized patients. In our pt, ca remained elevated despite appropriate treatment of PHPT, suggesting other causes for hyperca. Although our pt fit the demographic for neoplasia, elevated 1,25 OH2 D levels indicated non-neoplastic etiology. Improvement in 1,25 OH2 D and ca levels following initiation of antiTB drugs supported mycobacterial infection reactivation as the most likely etiology, especially given pt's history of TB. In pts with granulomatous diseases, activated macrophages convert 25 OH D to 1,25 OH2 D without the usual regulation by PTH, ca and phosphorous that control renal 1-alpha hydroxylase activity. Common etiologies of 1,25 OH2 D include sarcoidosis, mycobacterial infections, and lymphoma. The presence of concurrent PTH and non PTH mediated etiology of hyperca makes this case an interesting one and showcases that multifactorial etiologies of hyperca can coexist.
Presentation: No date and time listed
LBSAT127 An Underrecognized Entity: Hypercalcemia Induced PRES
Authors: Sari Esra , Batch Jennifer Tania , Sultan Senan 
Published: November 2022

Abstract

Introduction
Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological entity that can present with headaches, focal neurological deficits, altered mental status, and seizures. Common etiologies are uncontrolled hypertension, preeclampsia/eclampsia, and chemotherapeutic agents. Hereby, we present a patient with status epilepticus secondary to PRES induced by hypercalcemia due to primary hyperparathyroidism.

Clinical Case
A 59-year-old Caucasian female with history of T2DM, GERD, gout, and bowel resection for an incarcerated abdominal hernia three weeks ago presented to the emergency department due to seizure-like movements. She had no history of seizures. Initial vitals showed HR of 96 bpm, BP of 148/67 mmHg, RR of 20 rpm, Temperature of 97.7F, and a BMI of 31.5 kg/m2. Physical exam revealed the presence of abdominal wound-vac and tonic-clonic movements that failed to improve with lorazepam, midazolam, and levetiracetam; hence she was intubated for airway protection and started on propofol. Lumbar puncture performed in the ED was unremarkable. Laboratory studies were pertinent for acute kidney injury (AKI) with a serum creatinine of 1.78 mg/dL, lactic acid of 6.1 mmol/L, and serum calcium of 14.5 mg/dL (8.7-10.4) with albumin of 4.2 g/dL. AKI and lactic acidosis rapidly improved with IV fluids. CT-head without contrast was negative for any acute pathologies. MRI-brain showed abnormal subcortical FLAIR signals within the bilateral parietal and occipital lobes with corresponding diffusion restriction in bilateral occipital lobes consistent with PRES. Continuous EEG (cEEG) showed ongoing epileptiform activity with an intermittent suppression pattern. Hypercalcemia workup revealed inappropriately normal intact-PTH of 45.9 pg/mL (10. 0-66. 0), PTHrP &lt;2pmol/L, and 25-(OH)-Vitamin-D3 level of 34 ng/mL (30. 0-100. 0). Paraproteinemia work-up was negative. Thyroid ultrasound demonstrated an incidental nodule in the external aspect of the inferior right lobe measuring 6×3×3mm suggestive of parathyroid gland enlargement. Hypercalcemia was successfully treated with aggressive IV fluids and zoledronic acid. Repeat cEEG showed resolution of epileptiform discharges. She was successfully extubated without recurrence of seizures. She was determined to have hypercalcemia induced PRES secondary to primary hyperparathyroidism. Given the significant elevation of calcium and associated neurological symptoms, she met the surgical criteria and was discharged with outpatient parathyroidectomy plan.

Conclusion
PRES secondary to severe hypercalcemia has been described in the literature, albeit rarely. The exact pathophysiology is unclear but thought to be due to vasospasm based on cerebral angiogram studies. Early recognition of hypercalcemia as a culprit for PRES along with prompt treatment is crucial to treat life-threatening complications of PRES.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
LBSAT141 Bone Health In Patients With Adrenal Disorders
Authors: Dogra Prerna , Šambula Lana , Zhang Catherine D , Thangamuthu Karthik , Nathani Rohit , Kastelan Darko , Ambroziak Urszula , Genere Natalia , Delivanis Danae , Bancos Irina 
Published: November 2022

Abstract

Introduction
Limited data suggest low bone density in patients with adrenal adenomas. However, most studies are retrospective, single-center, and none were conducted in the United States. We aimed to determine the impact of cortisol and aldosterone excess on bone density.

Methods
We conducted a preliminary analysis of data from our multicenter, prospective observational study of adult patients with adrenocortical hormone excess and referent subjects without adrenal disorders (January 2019 - March 2022). Patients were diagnosed with non-functioning adenomas (NFA), adenomas with mild autonomous cortisol secretion, MACS (defined as cortisol following an overnight 1-mg dexamethasone suppression test (DST)&gt;1.8 mcg/dL), adrenal or pituitary Cushing syndrome (CS), primary aldosteronism (PA), and concomitant PA-MACS. Referent subjects were patients undergoing cross-sectional imaging for reasons other than adrenal disease. All participants were interviewed about their bone health, and had bone density measurements at the spine, hips, and/or radius. Bone disease was defined as osteopenia (T-score -1.1 to -2.4), or osteoporosis (T-score &lt; -2.5).

Results
A total of 417 participants included 156 referent subjects (88, 56% women, median age 65, range 2-95 years) and 261 patients (190, 73% women, median age 59, range 21-88 years). Patients were diagnosed with NFA (51, 19%), PA (46, 17%), MACS (122, 47%), PA-MACS (12, 5%), and CS (30,12%). When compared to referent subjects, sex- and age-adjusted analysis demonstrated an increased prevalence of bone disease only in patients with CS (OR 4.8, 95%CI 1.7-13), but not in other adrenal disorders. After excluding patients with CS, those with post-DST cortisol &gt;5 mcg/dL demonstrated a higher prevalence of bone disease when compared to patients with post-DST cortisol between 1.8-5 mcg/dL (OR 2.8, 95%CI 1.2-6.5) and those with post-DST cortisol &lt;1.8 mcg/dL (OR 2.7, 95% CI 1.1-6.7). Patients with MACS and post-DST cortisol between 1.8-5 mcg/dL did not demonstrate increased sex and age-adjusted prevalence of bone disease compared to those with post-DST &lt;1.8 mcg/dL or referent subjects. However, using post-DST cortisol as a continuous variable, we found that after adjusting for sex and age, the risk of bone disease in patients increased by 13% (OR 1.13, 95%CI 1.6-1.2) for every 1 mcg/dL increase in post-DST cortisol.

Conclusions
The prevalence of osteopenia and osteoporosis increases proportional to the increase in post-DST cortisol concentrations. Patients with CS, and those with MACS and post-DST cortisol &gt; 5mcg/dL have the highest prevalence of bone disease.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
ODP077 Adipopenia is associated with low bone mass in community-dwelling non-underweight adults, independent of sarcopenia
Authors: Lee Seunghyun , Ko Kyoungmyoung , Shin Sungjae , Park Hye Sun , Hong Namki , Rhee Yumie 
Published: November 2022

Abstract
The interaction between fat, muscle, and bone mass is complex. Although sarcopenia and underweight are well-established risk factors for osteoporosis, the association between low body fat percent (adipopenia) and low bone mass in non-underweight adults remains unclear. In Korean National Health and Nutrition Examination Survey dataset 2008-2011, we analyzed individuals aged 50 or older with body mass index (BMI)≥18.5 kg/m 2 . Appendicular skeletal muscle mass (ASMM) and body fat percent were measured using dual-energy x-ray absorptiometry. Sarcopenia was defined as ASMM/height 2 &lt;7. 0 kg/m 2 and &lt;5.4 kg/m 2 in men and women, respectively. Subjects were grouped into adipopenia (&lt;17% in men and &lt;30% in women; 1 standard deviation below the mean of the study population with round down to integer value), normal, or obesity (&gt;30% in men and &gt;40% in women) according to body fat percent. Osteoporosis was defined as T-score≤ -2.5 at the lumbar spine, femoral neck, or total hip. Among 5830 subjects (women 50.2%, mean age 63.9±8.5 years), 793 subjects had adipopenia (13.6%). The adipopenia group had a higher prevalence of osteoporosis (31%) compared to normal (21%) or obesity groups (27%; p&lt;0. 001). Body fat percent showed a positive association with bone mineral density at all sites after adjustment for age, sex, height, and lean mass. In the multivariable logistic model, the presence of adipopenia was associated with 61% elevated odds of osteoporosis (adjusted odds ratio [aOR] 1.61, p&lt;0. 001), independent of sarcopenia (aOR 1.71, p&lt;0. 001), age, sex, height, and covariates, which remained robust in sensitivity analysis with sex-specific lowest 20% quantile thresholds (roughly &lt;18.4% in men; &lt;31.5% in women). In conclusion, adipopenia was associated with osteoporosis independent of sarcopenia in non-underweight adults, which merits further investigation.
Presentation: No date and time listed