bluuebunny/crossref_metadata_2025_split huggingface dataset:
Postnatal Hypothyroidism Permanently Disrupts Neural Stem Cell Fate in the Murine Subventricular Zone
Authors: Vancamp Pieter , Demeneix Barbara , Remaud Sylvie 
Published: May 2021

Abstract
The subventricular zone (SVZ) of the adult mammalian brain harbors neural stem cells (NSCs) that generate neurons and oligodendrocytes throughout life. Single-cell RNA-Seq analysis on mouse SVZ-NSCs isolated at different developmental stages established they gradually acquire their adult neurogliogenic identity between postnatal day (P) 7 and 20. However, the factors governing this transition remain elusive. As a key factor driving transcriptional responses during brain development, as well as NSC lineage commitment in the adult SVZ, we hypothesized that thyroid hormone (TH) could fulfil this role. TH serum levels rise postnatally and peak around P15. Re-analysis of single-cell data from the P2 and P20 SVZ revealed a dynamically increased expression of the TH transporters Mct8 and Oatp1c1, as well as the TH-(in)activating deiodinases Dio2 and Dio3 in NSCs, signs that local TH action is promoted. Immunostainings showed a concomitant burst in SVZ-neurogenesis between P4 and P21. Then, to study what occurs if TH synthesis is blocked, we fed dams a 0.15% propylthiouracil-enriched diet from embryonic day 15 to P21. Postnatal hypothyroidism decreased PH3-positive mitotic cell numbers at P4 and P21, whereas increased Sox2 expression coincided with a larger proportion SOX2-positive SVZ-NSCs and progenitors. In the dorsal SVZ, the main site of neurogliogenesis, less neuroblasts were detected at P21, while numbers of OLIG2-positive oligodendroglia precursors did not change significantly. Next, we prepared in vitro neurospheres from dissected SVZs of control and PTU-treated mice, and allowed them differentiate with or without exogenous T3. The neuro/glia balance in neurosphere cultures prepared from P4 animals of either condition did not change when T3 was added, suggesting perinatal NSCs are irresponsive to TH. The balance did change in T3-treated neurospheres prepared from control P21 animals, however, not in those from P21 PTU-exposed mice, suggesting hypothyroid NSCs are irresponsive to T3. Lastly, we examined 3-month-old mice that regained a normal diet following developmental PTU exposure. Fewer oligodendroglia precursors in the SVZ resulted in a lasting altered neuro/glia output. A reduced ability to remember earlier-presented odors indicates impaired olfaction, a behavior strongly depending on SVZ-neurogenesis. Taken together the data indicate that developmental hypothyroidism affects postnatal SVZ organization and permanently alters NSC lineage commitment. Our study allows to determine relevant new read-outs to identify adverse outcome events on brain development and will permit comparison with events following exposure to endocrine disruptors.
Reverse T3 Level and T3 to Reverse T3 Ratio in Dried Blood Spot Samples at Birth May Facilitate Early Diagnosis of MCT8 Deficiency
Authors: Iwayama Hideyuki , Kakita Hiroki , Iwasa Masumi , Adachi Shinsuke , Takano Kyoko , Kikuchi Masahiro , Fujisawa Yasuko , Osaka Hitoshi , Yamada Yasumasa , Okumura Akihisa , Refetoff Samuel 
Published: May 2021

Abstract
Background: Monocarboxylate transporter 8 (MCT8) deficiency is an X- chromosome-linked neurodevelopmental disorder resulting from impaired thyroid hormone transporter across cell membrane. The diagnosis of MCT8 deficiency is typically delayed owing to the late appearance of signs and symptoms as well as inability of standard biomarkers of neonatal screening to make an early diagnosis. Here, we report for the first time the ability to identify MCT8 deficiency at birth using dried blood spot (DBS) samples.
Methods: We measured T3, T4, and reverse T3 (rT3) levels in DBS samples obtained at birth in healthy neonates (n = 42) and neonates with genetically confirmed diagnosis of MCT8 deficiency (n = 6). T3, rT3 and T4 levels were measured in 8 mm diameter DBS samples using liquid chromatography-tandem mass spectrometry.
Results: Mean ± SD level of T3 tended to be higher in the MCT8 group than that in healthy neonates (0.941 ± 0.183 ng/mL vs. 0.742 ± 0.195 ng/mL, p = 0.0525). More importantly rT3 level in the MCT8 group was significantly lower than that in healthy neonates (0.317 ± 0.065 ng/mL vs. 0.768 ± 0.196 ng/mL, p &lt; 0.0001) and the T3/rT3 ratio in the MCT8 group was significantly higher (3.04 ± 0.67 vs. 1.01 ± 0.34, p &lt; 0.0001) with no overlap of values. T4 was lower in the MCT8 group than in healthy babies (93.4 ± 22.4 ng/mL vs. 156.7 ± 35.9 ng/mL, p &lt; 0.0005) and the T3/T4 ratio of the MCT8 deficient group was higher (0.0105 ± 0.0029 vs. 0.0051 ± 0.0010, p&lt; 0.0001).
Conclusion: rT3 and T3/rT3 ratio measured in the DBS obtained from neonates can serve as biomarkers for diagnosis of MCT8 deficiency at birth.
Thyroid Function in 3000 Cases of Patients With Atrial Fibrillation Treated With Catheter Ablation
Authors: Yamada Sayaka , Nakajima Yasuyo , Nishikido Ayaka , Akuzawa Masako , Sakamaki Koji , Toki Akiko , Ishida Emi , Shimomura Yonosuke , Kobayashi Isao , Ando Yoshitaka , Maruhashi Michiyo , Naito Shigeto , Yamada Masanobu 
Published: May 2021

Abstract
Objective: Thyroid hormones have various effects on cardiac and circulatory systems, leading to arrhythmias and heart failure. In Europe and the United States, it has been reported that elevated thyroid hormones within the normal range have been reported to be associated with a risk of atrial fibrillation, however, there was no report on Japanese cases, a country that differs in iodine intake and ethnicity from the West. Therefore, we evaluated the abnormality of thyroid function in a large number of cases of atrial fibrillation (AF) who received catheter ablation (RFCA) in Japan. Methods: We evaluated 2,937 cases of atrial fibrillation (2,084 males, mean age 64.1±10.7 years and 853 females, 69.0±8.5 years) who underwent RFCA at the Gunma Prefectural Cardiovascular Center between 2012 and 2018. As a control we used a total of 15,660 participants for health check-up (9,176 males, mean age 49.7±9.8 years and 6,484 females, 48.9±10.3 years) from 2006 to 2013, and we evaluated thyroid function after adjusting for gender-specific age. Results: The prevalence of overt hyperthyroidism was significantly higher in the RFCA-treated male group (0.43%) than in the control group (0.07%), even after adjusting for age (p&lt;0.01). Similarly, the prevalence of subclinical hyperthyroidism was also significantly higher in the RFCA-treated male group (3.12%) than in the control group (0.94%) after adjusting for age (p&lt;0.01). On the other hand, subclinical hypothyroidism was significantly lower in the RFCA-treated group after adjusting for age (2.97% in the RFCA-treated group and 3.93% in the control group, p&lt;0.01). Females showed the same results as males. Conclusions: In an iodine rich country Japan, not only overt hyperthyroidism but also subclinical hyperthyroidism is an obvious risk factor for severe atrial fibrillation in Japan. Intriguingly, subclinical hypothyroidism might contribute to the prevention of atrial fibrillation, suggesting that slightly higher serum TSH levels might be better for elderlies.
Urinary Steroid Metabolome Signature is Associated With Cognitive Function in Older Adults
Authors: Singh Sumitabh , Ebbehoj Andreas , Stricker Nikki , Mielke Michelle , Bostwick J Michael , Rivard Ann L , Singh Ravinder J , Grebe Stefan Karl Gunther , Thomas Melinda , Khosla Sundeep , Rocca Walter A , Bancos Irina 
Published: May 2021

Abstract
Background: Elevated urine cortisol (&lt;1% of urinary steroid metabolome) was reported to predict future development of dementia. Our objective was to determine the association of urine steroid metabolome and its diurnal variation with cognitive function in men and women. Methods: Cross-sectional study of community-dwelling adults ≥ 50 years. Participants with adrenal disorders, end-stage renal or liver disease, on exogenous steroids or drugs affecting steroid metabolism were excluded. All participants completed day and night separate urine collection. A series of seven IPad-based tests using the National Institute of Health Toolbox Cognition Battery were administered to evaluate five key domains; performance was reported using fully corrected T-scores for age, sex, education, and race with a national normative mean of 50. T-scores were generated for the two summary measures: 1) fluid cognition (includes executive function, episodic memory, working memory, and processing speed), and 2) total composite (composite of fluid and language score). Urine samples were analyzed with the liquid-chromatography, high-resolution, accurate-mass mass spectrometry for 25 urine steroid metabolites. Results: Of 109 participants, 56 (51%) were women, and age and educational status were similar in men and women. On cognitive assessment, men and women had similar median composite cognition (T-score of 53 vs 54, p=0.74) and fluid cognition (T-score of 53 vs 51, p-value 0.96). Urine steroid metabolome analysis demonstrated 21/25 steroids were higher in men vs women. In both women and men, the ratio of total cortisol metabolites/total androgen metabolites (TCM/TAM) was associated with lower fluid cognition (women: ρ= -0.34, p=0.01, men: ρ= -0.43, p=0.001) and composite cognition (women: ρ= -0.27, p=0.04, men: ρ= -0.39, p=0.004). Higher ratio of day to night TCM were associated with a better fluid cognition in men (ρ= 0.35, p=0.01), but not in women (ρ= -0.11, p=0.41). Steroid ratios suggesting a relative enzymatic deficiency of 5α-Reductase type 2 was associated with lower fluid cognition in women (ρ= -0.29, p=0.03). In men, the fluid composite score was associated with a relative deficiency in 21-Hydroxylase (ρ= 0.42, p=0.002), 3β-Hydroxysteroid dehydrogenase (ρ= 0.43, p=0.001), and P450oxidoreductase (ρ= -0.35, p=0.01). Conclusion: We showed that a higher glucocorticoid to androgen ratio and a flattened circadian steroid variation were associated with lower global and fluid cognition score. Steroid ratios reflecting steroidogenesis enzymatic activity demonstrated sex differences in relation to cognition. Additional studies should examine whether the steroid fingerprint associated with lower cognition is predictive of a future dementia onset.
“The Way to a Man’s Heart” - Adrenocortical Carcinoma With Vascular Invasion Into the Right Atrium and Ventricle
Authors: Aftab Hassaan B , Newton Kaye-Anne L , Kantorovich Vitaly 
Published: May 2021

Abstract
Background: Adrenocortical carcinoma (ACC) is a rare aggressive malignant neoplasm which may present with intravascular extension into the inferior vena cava (IVC) and rarely into the right atrium (RA). Clinical Case: 62-year-old male with no prior known significant medical history presented to ED with 2-day history of mild hematuria with 3-week history of headache. Vital signs were normal other than blood pressure of 198/88 while physical exam was unremarkable. Headache subsided and blood pressure improved to 130/60 range after IV labetalol administration. CT abdomen and pelvis with contrast revealed a large right suprarenal mass extending into the right hepatic vein, IVC, and RA. The right adrenal gland was not visualized while the left adrenal gland and bilateral kidneys were normal. MRI chest, heart and abdomen with contrast showed heterogeneously enhancing lobulated right adrenal mass measuring 11.4 x 11 x 14 cm (AP, transverse, CC, respectively) with extensive tumor thrombus invading the right hepatic vein, IVC, RA and notably protruding into the right ventricle (RV) through the tricuspid valve during diastole. Technitium-99m MDP whole body scan did not show any uptake suspicious for metastases. Pre-op lab assessment showed mildly abnormal 1 mg dexamethasone suppression test but no evidence of ACTH suppression, elevated catecholamines or excess adrenal steroidogenesis. He underwent combined cardiothoracic and abdominal surgery on cardiopulmonary bypass with resection of adrenal mass, removal of thrombus from IVC, RA, RV and patch angioplasty of IVC with bovine pericardium. Pathology report was consistent with ACC (AJCC stage III). On 1 month postoperative follow-up, patient is clinically doing well with plans to start mitotane with addition of etoposide/doxorubicin/cisplatin (EDP) chemotherapy. Conclusion: ACC is a rare, highly aggressive malignancy which may produce extensive intravascular invasion. It may rarely extend to the RA and even rarer into the RV; with 42 and 1 reported cases, respectively. No study has conclusively found that vascular extension of ACC is a poor prognostic factor, hence surgical management is the primary strategy including cases with RA/RV involvement. There is lack of data and consensus regarding adjuvant or palliative medical therapy. However, in phase II trials combination of EDP chemotherapy and mitotane have shown response rates ranging from 11% to 54%. Reference: Alghulayqah, Abdulaziz, et al. “Long-term recurrence-free survival of adrenocortical cancer extending into the inferior vena cava and right atrium: Case report and literature review.” Medicine 96.18 (2017).
A Case of Improvement of Insulinoma Symptoms in Pregnancy
Authors: Syed Shumail , George Andrea 
Published: May 2021

Abstract
Background: Insulinomas are rare tumors with an incidence of approximately 4 cases per million person per year. Only 39 cases of pancreatic neuroendocrine tumors have been reported in pregnancy. We report a case of pregnancy protecting the mother from manifesting the symptoms of insulinoma. Clinical Case: This case describes a 25-year old female who initially noticed symptoms of generalized weakness and oral tingling sensation in Fall 2018. She became pregnant in March 2019. She noticed an immediate reduction of the intensity of her symptoms during pregnancy. Her pregnancy was uneventful, and she delivered a healthy newborn in November 2019. Two months postpartum, she had worsening symptoms including syncopal episodes, confusion, difficulty ambulating and visual changes that improved with PO intake specifically carbohydrate intake. She was evaluated in March 2020 and labs showed the following: venous glucose 32 mg/dL, C-peptide 1.7 nmol/L, BOHB 0.4 mmol/L, Insulin 6.1 microU/ml, Proinsulin 25.8 pmol/L, IGF-2 354 ng/mL, negative insulin antibodies and negative oral hypoglycemic agent screen. TSH was unremarkable and AM cortisol was 16.1 mcg/dL. She was started on diazoxide twice a day. She underwent MRI of abdomen, which was negative followed by an EUS which was also negative. She had run out of her diazoxide and became severely symptomatic resulting in an ER visit where she was found to be hypoglycemic. Further evaluation was done with a Triple Phase spiral CT which showed a 1 cm arterial enhancing focal lesion within the pancreatic neck compatible with insulinoma. This was further evaluated with EUS FNA which confirmed the diagnosis of insulinoma on pathology. Her chromogranin A was 46.5 ng/mL. She is scheduled for surgical removal of the lesion. Conclusion: Pregnancy leads to an increased insulin resistance through hormonal changes with increased expression of placental growth hormone, human placental lactogen and the placental variant of corticotrophin-releasing hormone (via ACTH and cortisol production), TNF-alpha and leptin. These changes that increase the insulin resistance act as a protective mechanism against the detrimental effects of an insulinoma. Pregnancy most likely also delayed the diagnosis of the insulinoma in this patient. Further research is warranted to evaluate the effects of an insulinoma on the mother and fetus. References: 1) Lowy AJ, Chisholm DJ. Insulinoma masked by pregnancy. Intern Med J. 2001 Mar;31(2):128-9. doi: 10.1046/j.1445-5994.2001.00017.x. PMID: 11480477.
A Mass in Disguise: A Rare Case of High-Attenuation Adrenal Myelolipoma
Authors: Kim Yoon Kook , Malek Rana 
Published: May 2021

Abstract
Background: Adrenal incidentalomas are common, and imaging studies play a large role in reaching the diagnosis in many cases. Adrenal myelolipomas are classically diagnosed by CT as a hypodense well circumscribed heterogenous mass with low attenuation. Clinical Case: A 51-year-old man with history of resistant hypertension presented with neck pain after a motor vehicle crash. After a cervical X-ray revealed an odontoid fracture, a whole body CT was obtained. The CT incidentally identified a massive heterogeneous left adrenal mass measuring 22.3 × 15.5 × 20.6 cm, with multiple attenuation measurements ranging from 20 to 53 Hounsfield units (HU). The patient’s physical examination and hormonal assessment were both unrevealing, with normal catecholamine, androgen, and an unremarkable renin aldosterone ratio. Inpatient urinary cortisol levels were elevated, however a repeat urinary cortisol as an outpatient weeks after repair of the odontoid fracture showed normal levels, suggesting physiologic stress response. Positron emission tomography showed a metabolically inactive adrenal mass without metastatic diseases. The patient eventually underwent a left adrenalectomy, and pathology revealed a myelolipoma measuring 24.2 × 20.5 × 8.3 cm. Imaging characteristics for adrenal incidentalomas are considered useful diagnostic information according to most clinical guidelines. Lesions with high HU are typically pheochromocytomas, adrenocortical carcinoma, metastatic disease, or lipid poor adenomas. Myelolipomas are identified on CT by their characteristically low HU (often -30). In this case of a massive myelolipoma with high HU, the unique imaging characteristics posed a diagnostic challenge. The patient’s history of resistant hypertension combined with the high HU led to the patient undergoing extensive testing for a functional mass or cancer. Conclusion: This is a rare case of a massive myelolipoma with low attenuation. The role of imaging studies in the diagnosis of adrenal incidentalomas is not definitive, and detailed exam along with hormonal assessment may be warranted in atypical cases. Providers should consider myelolipoma in the differential diagnosis of a large adrenal mass with a negative hormonal evaluation even in the setting of high HU.
A Rare Case of Chronic Diarrhea in a Pediatric Patient
Authors: Srivastava Priya S , Yen Kevin , Lindquist Robert , Rangaswami Arun , Ozgediz Doruk , Nakakura Erik , Lodish Maya Beth 
Published: May 2021

Abstract
Background: VIPoma, also known as Watery Diarrhea-Hypokalemia- achlorhydria (WDHA) Syndrome is a rare manifestation of multiple endocrine neoplasia syndrome type 1 (MEN1). Vasoactive intestinal peptide, part of the secretin-glucagon family, may be overexcreted in tumors associated with MEN1 and results in diarrhea that persists while fasting, resulting in massive secretion of water and electrolytes. First-line treatment is surgical resection.
Clinical Case: We present a 13-year-old male with a past medical history of chronic diarrhea for four years who was transferred from an outside hospital for severe diarrhea and associated electrolyte derangements, including hypokalemia of &lt;1.0 mmol/L (3.5-5.0 mmol/L), sodium of 120 (135-145 mmol/L), and chloride of 84 mmol/L (101-110 mmol/L). Family history was significant for pancreatic, breast, thyroid, stomach, parathyroid, and uterine cancer, as well as hyperparathyroidism and nephrolithiasis. The patient had been admitted to the hospital before for a similar episode of acute on chronic diarrhea but was treated for infectious diarrhea during that admission. CT enterography was obtained during this hospitalization and it revealed multiple solid and heterogeneous appearing pancreatic masses in the head and tail of the pancreas. Work-up was significant for pancreatic polypeptide of 1,523 pg/mL (92-752 pg/mL) and vasoactive intestinal peptide of 1,105 pg/mL (&lt;75 pg/mL). Pancreatic biopsy revealed a grade 2 pancreatic neuroendocrine tumor. Genetic testing revealed a known pathogenic mutation in the menin gene p.R526 (c. 1579&gt;T, pArg527). A pylorus-preserving total pancreatectomy, duodenectomy, cholecystectomy, and splenectomy was performed and surgical pathology revealed a well-differentiated grade 1 neuroendocrine tumor in the head of the pancreas and a well-differentiated grade 2 neuroendocrine tumor in the tail of the pancreas. Since the surgery, the patient currently has no signs of other neuroendocrine tumors associated with MEN1 but continues to follow-up for regular screening for other tumors associated with MEN1.
Clinical Lessons: 1. VIPoma, also known as Watery Diarrhea- Hypokalemia- Achlorhydria Syndrome, is characterized by secretory diarrhea that persists while fasting. 2. VIPoma should be considered in patients with a history of chronic diarrhea and a significant family history of neuroendocrine tumors.
A Rare Presentation of Multiple Endocrine Neoplasia Type 1
Authors: Pradeep Pallavi , Eisenberg Yuval 
Published: May 2021

Abstract
Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare, autosomal dominant inherited syndrome caused by mutations in the MEN1 tumor suppressor gene with a reported incidence of 2 in 100,000.
Clinical Case: A 26-year-old Caucasian female was seen for surveillance screening given positive familial mutation in the MEN1 gene. She had a significant family history of pathogenic MEN1 in her son, brother, father and paternal aunt. On presentation, she denied any history of headache, nipple discharge, kidney stones, fractures, heart burn, abdominal pain, diarrhea, hypoglycemia, flushing, lightheadedness. She was on hormonal IUD for contraception and had not had menstrual cycles for the last 6 months. Vital signs and physical examination were unremarkable. Her initial evaluation included a normal calcium of 9.8mg/dL (RR:8.6-10.6mg/dL), PTH of 70pg/ml (RR:12-88pg/ml), 25OH-vitamin-D of 11ng/ml (RR:20-80ng/ml). She had normal gastrin, chromogranin A, glucagon, and vasoactive intestinal peptide levels. Prolactin was 17.6ng/ml (RR:3.3-26.7 ng/ml). MRI pituitary showed a 6mm lesion representing a Rathke’s cleft cyst, not compressing surrounding structures.
Two months following the initial encounter, she presented with abdominal pain, nausea, vomiting. She was found to have an obstructing renal stone requiring stent placement. Calcium was 10.1mg/dl. She was also noted to have an incidental pancreatic tail mass of 4.2cm on CT abdomen. She underwent laparoscopic robotic distal spleno-pancreatectomy. Surgical pathology showed a well differentiated 3.5cm neuroendocrine tumor with negative margins, which stained positively for insulin. She had not reported symptoms of weight gain or any episodes suspicious for sympathoadrenal activation or neuroglycopenia, and was again confirmed after surgery.
Patient was re-admitted to the hospital for right-sided flank pain and was found to have a new 6mm obstructing calculus with moderate hydronephrosis of the right kidney. Corrected calcium level was found to be mildly elevated at 11.1mg/dL. Repeat PTH was stable at 81pg/ml, and urinary calcium was elevated at 447.3mg/24h (RR:50-250mg/24h). Subsequently, she underwent 3.5 gland parathyroidectomy and thymectomy. On POD20, PTH was 29pg/ml and calcium was 8.6mg/dl.
Conclusion: This case highlights a rare presentation of MEN1 with an asymptomatic insulinoma and nephrolithiasis, despite having normal calcium and PTH levels initially. Primary hyperparathyroidism is the most common presentation of MEN1, seen in up to 90% of patients. The second most common finding in MEN1 patients, reported in 70% of the cases, are entero-pancreatic tumors, the most common being gastrinoma. Insulinoma, which is less common and is seen in only 10-30% patients, needs documentation of Whipple’s triad. Interestingly, our patient never had any history of hypoglycemia.