bluuebunny/crossref_metadata_2025 huggingface dataset:
Unraveling Secretory Mechanisms that Control Pentraxin 3 Secretion in Adipocytes During Inflammation
Authors: Lin Te-Yueh , Chen XiaoLi
Published: May 2021

As a soluble pattern recognition receptor, Pentraxin 3 (PTX3) plays an important role in innate immunity and obesity-associated metabolic inflammation. PTX3 is abundantly expressed and secreted in adipocytes in response to lipopolysaccharide (LPS) stimulation. Appropriate regulation of PTX3 secretion is critical for maintaining inflammatory homeostasis. This study aims to unravel the mechanisms that control PTX3 secretion in adipocytes during LPS-induced inflammation. Upon 6h treatment of LPS, PTX3 expression and secretion were significantly induced in 3T3-L1 and stromal-vascular (SV) differentiated adipocytes, but to a lesser extent in SV cells or 3T3-L1 fibroblasts. However, LPSdoes not significantly stimulate PTX3 expression and secretion in macrophages. Using chemical inhibitors of conventional and unconventional protein secretion, we explored the mechanisms for controlling LPS-stimulated PTX3 secretion. 3T3-L1 adipocytes were treated with LPS for 6h in the presence or absence of various inhibitors blocking protein secretion from the Golgi complex (Monensin and Brefeldin A), mitochondrial oxidation (carbonyl cyanide 3-chlorophenylhydrazone [CCCP]), autophagy-lysosome (chloroquine and 3-methyladenine) and inflammasome (Bay 11–7082 and wedelolactone) activation, or exosome synthesis and trafficking (GW4869, manumycin A, calpeptin, and Y-27632). There were no significant effects of all inhibitors except for Monensin, Brefeldin A, and CCCP on intracellular and secreted levels of PTX3 in adipocytes. We found that Monensin and Brefeldin A significantly blocked LPS-stimulated PTX3 secretion, resulting in cellular PTX3 accumulation in adipocytes. Disrupting mitochondrial membrane potential by CCCP caused the reduction in PTX3 secretion from adipocytes. Additionally, we detected PTX3 in exosomes isolated from LPS-treated adipocytes. Inhibiting exosome synthesis by Manumycin A attenuated LPS-stimulated PTX3 secretion in both adipocyte culture media and isolated exosomes but not in the non-exosomal fraction of media, suggesting the involvement of the exosomal pathway in PTX3 secretion. However, the levels of exosomal PTX3 were significantly lower than that of the non-exosomal PTX3, and only 4.3% of secreted PTX3 was detected in the exosomal fraction of cultural media. Inhibiting the Golgi complex pathway blocked both the exosomal and non-exosomal secretion of PTX3 in adipocytes. After further fractionation of isolated crude exosomes by the iodixanol density gradient centrifugation, we showed that the majority of PTX3 was found in the non-extracellular vesicular (EV) fractions; only a small portion of secreted PTX3 overlapped with the exosomal marker CD63 in the small EV fractions. We conclude that PTX3 is secreted mainly through the conventional protein secretion pathway and minimally through the exosomal or EV pathway in response to LPS stimulation.
Pituitary Lymphoma Presenting as Diabetes Insipidus
Authors: Bashir Bilal , Jacob Deepa Liza , Banerjee Moulinath
Published: May 2021

Introduction: Primary CNS lymphomas are rare accounting for 1-3% of CNS neoplasms. They lack specific clinical or radiological features and are diagnosed histologically. We describe a case of Primary CNS lymphoma involving pituitary gland presenting with confusion and diabetes insipidus. Case: 74-year-old presented with anorexia, weight loss, visual hallucinations and acute confusion. Initial evaluation revealed hypernatremia (148 mmol/L), an old cerebral infarct and new extensive thrombus in aorta and lower limb deep vein thrombosis. During hospital stay, he sustained a fall and a CT head showed a new high attenuation change around the temporal horn and left temporal lobe. MRI head was done to characterize the lesion but because of confusion and irritability, this was inconclusive. Patient continued to have hypernatremia with serum sodium ranging from 148 - 154 mmol/L (135-145 mmol/L) that failed to improve after rehydration. He continued to have negative fluid balance and urine output >2.5 litres a day with dilute urine and urine osmolarity of 134 mosm/L. Due to confusion, we were unable to conduct a water deprivation test. Anterior pituitary profile was consistent with secondary hypothyroidism (TSH was 0.09 (0.02-6.00), Free T4 8.2 (8.0-18.0) and (Free T3 was 2.8 (3.0- 4.8)), and secondary hypogonadism (Testosterone 0.9 nmol/L (6.1-27.1), FSH 1.0 IU/L and LH was <0.2 IU/L). Hypothalamic- adrenal axis was intact as cortisol showed adequate increment after corticotropin stimulation (Cortisol at 0 min 386 nmol/L, 30 minutes 584 nmol/L and 60 minutes 640 nmol/L). Further CT Head with contrast was carried out in view of new findings of hypopituitarism that showed smooth hyperattenuating pituitary gland that was consistent with diabetes insipidus and intense contrast enhancement seen in the periventricular regions and the caudate and dentate nuclei bilaterally. Based on clinical and radiological picture, diagnosis of CNS lymphoma and diabetes insipidus was made and commenced on desmopressin nasal spray. We were unable to perform brain biopsy or quantify the response to desmopressin due to rapid deterioration of patient who died 9 weeks after his initial presentation. An autopsy was carried out and histopathology of pituitary yielded normal anterior pituitary but posterior pituitary was completely infiltrated by Non-Hodgkin’s Lymphoma of Diffuse large B cell type that was also infiltrating parts of the cerebellum, temporal cortex and the basal ganglia hence proving diagnosis of Primary CNS lymphoma. Conclusion: Sudden onset of DI with pathological appearance of posterior pituitary and equivocal/non diagnostic CNS imaging should raise the suspicion of CNS lymphoma. Although diagnosis is histopathological, early detection with high index of suspicion and treatment and lead to better outcomes.
Postpartum Cranial Diabetes Insipidus
Authors: Cairns Ross Andrew , Azharuddin Mohammed K
Published: May 2021

Cranial Diabetes Insipidus is a rare diagnosis and rarer still postpartum. We present the case of 24-year-old woman who developed CDI following pregnancy. The patient had developed persistent polydipsia and polyuria 5 months following her first pregnancy. The pregnancy had been complicated by Gestational Diabetes Mellitus, Obstetric Cholestasis and a Postpartum Haemorrhage which had required a 3 unit transfusion of blood. The patient reported feeling fatigued and lightheaded and stated that she had needed to drink water frequently: around 8 litres throughout the day and 4 litres overnight. She reported that she had been unable to breastfeed but the rest of her systemic enquiry was unremarkable. The patient had attributed her symptoms of lethargy to sleepless nights with her new born baby and the polyuria as a consequence of labour and as such had presented for review at her primary care Physician 18 months following delivery.

Initial investigations revealed a fasting blood glucose of 4.9 mmol/l, an Adj. Calcium of 2.23 mmol/l and a fasting urine osmolality of 85 mmol/kg. A diagnosis of DI was suspected and was confirmed by water deprivation test: the patient had an inappropriately dilute urine osmolality of 111 mmol/kg when compared to the serum osmolality of 301 mOsm/Kg at the start of the test and her urine failed to concentrate as water was withheld. Administration of DDAVP resulted in appropriate concentration of urine and therefore confirmed the diagnosis specifically as Cranial Diabetes Insipidus.

Blood tests revealed normal anterior pituitary function: TSH was 2.78 mU/L, Prolactin was 361 mU/l, LH and FSH were 23.6 U/L and 5.3 U/L, IGF and GH were 197 ug/L and 0.1 ug/l and ACTH was 10 mU/L. Her basal cortisol was 392 nmol/l and was stimulated to 593 nmol/l by SST. MRI Pituitary revealed an unusually flat and broad pituitary gland with a possible tiny lesion in the posterior pituitary suggestive of an adenoma. The patient was established on DDAVP replacement therapy and her quality of life improved: she enjoyed restful sleep and reported less exhaustion. There was no anterior pituitary hormone deficiency 28 months following delivery. DI is a rare diagnosis with an estimated prevalence of 1 in 25000 people. CDI has been commonly reported as being caused by infiltrative or inflammatory pituitary disease, as an iatrogenic sequelae of pituitary surgery or as a result of a congenital defect in the production of vasopressin. We suspect that in this case the patient’s PPH may have resulted in isolated cranial diabetes insipidus though the significance of the MRI scan findings remains unclear. The learning points highlighted by this case are that CDI can occur following pregnancy in an isolated form without anterior pituitary hormone deficiency. We also highlight that patients may misattribute significant symptoms and signs of DI as being a normal part of the postpartum period resulting in a delayed diagnosis.
Rituximab as an Alternative Treatment for Refractory Granulomatous Hypophysitis
Authors: Nokhbehzaeim Mahrokh , Panjirkaran Lloyd , Washington Terri
Published: May 2021

Background: Although glucocorticoids have been adopted as the main stay treatment for granulomatous hypophysitis, refractory cases have been treated by infliximab with success in multiple reported case.[1,2,3] Given the low prevalence, incidence of granulomatous hypophysitis[4] and the advent of biologics, evidence of rituximab’s efficacy are largely based on a handful of case reports[1,2,3] and needs more evidence to label its utility. We describe a case of recurrent primary granulomatous hypophysitis in a 48-year-old female who had significant treatment challenge until there was good response after initiation of rituximab. Clinical Case: Patient was a known case of granulomatous hypophysitis and had undergone total hypophysectomy. Despite this approximately a year after her surgery she had become symptomatic and had MRI changes. She was started on a succession of immunosuppressive agents and high dose steroids to control recurrent symptoms. Due to treatment failure and very high steroid dose, patient was eventually started on Rituximab and patient had significant improvement of her symptoms as well as resolution of the MRI changes. Conclusion: Although there is a lack of prospective, double blind and controlled studies this case study highlights the utility of Rituximab as a potent alternative treatment for refractory given the adverse effect associated with the steroids and other immunosuppressive agents. Reference statement: 1. Schreckinger M, Francis T, Rajah G, Jagannathan J, Guthikonda M, Mittal S. Novel strategy to treat a case of recurrent lymphocytic hypophysitis using rituximab. J Neurosurg. 2012 Jun;116(6):1318-23. doi: 10.3171/2012.2.JNS111456. Epub 2012 Mar 23. PMID: 22443503. 2. Xu C, Ricciuti A, Caturegli P, Keene CD, Kargi AY. Autoimmune lymphocytic hypophysitis in association with autoimmune eye disease and sequential treatment with infliximab and rituximab. Pituitary. 2015 Aug;18(4):441-7. doi: 10.1007/s11102-014-0592-7. PMID: 25224140. 3. Gu WJ, Zhang Q, Zhu J, Li J, Wei SH, Mu YM. Rituximab was used to treat recurrent IgG4-related hypophysitis with ophthalmopathy as the initial presentation: A case report and literature review. Medicine (Baltimore). 2017 Jun;96(24):e6934. doi: 10.1097/MD.0000000000006934. PMID: 28614220; PMCID: PMC5478305. 4. Angelousi A, Alexandraki K, Tsoli M, Kaltsas G, Kassi E. Hypophysitis (Including IgG4 and Immunotherapy). Neuroendocrinology. 2020;110(9-10):822-835. doi: 10.1159/000506903. Epub 2020 Mar 4. PMID: 32126548
Urea Use for SIADH: A Case Report and Review of the Literature
Authors: Flores Monica , Broome David Tyler , Makin Vinni
Published: May 2021

Introduction: Hyponatremia is the most frequent electrolyte abnormality among hospitalized patients associated with increased morbidity and mortality. There is a demanding need for affordable and well-tolerated therapies, and urea is a compelling alternative for the syndrome of inappropriate diuretic hormone (SIADH). Urea increases renal water excretion due to osmotic diuresis and reduce urinary sodium leading to an increase in serum sodium. This case illustrates the effect and safe use of urea in a hospitalized patient with SIADH. Clinical Case: An 80-year-old male with history of recurrent anterior chest wall chondrosarcoma despite 3 chest wall resections presented to the hospital for a 4th anterior chest wall resection with reconstruction. Physical examination was notable for euvolemia with no neurologic deficits. Pre-operative labs were significant for a plasma sodium (PNa) 118 mmol/L, potassium 4 mmol/L, BUN 9 mg/dL, Cr 0.72 mg/dL, TSH 2.9 mIU/L, cortisol 21.3 mcg/dL, serum osmolality 267 mOsm/kg, urine osmolality 423 mOsm/kg, and urine sodium 115 mmol/L. Underlying SIADH was initially treated with water restriction of 800 mL/24 h. Previously, he was given a trial of salt tabs, which he did not tolerate due to nausea and emesis. Due to profound hyponatremia, he was started on 2% hypertonic saline. Once PNa levels reached 130 mmol/L, 2% saline was discontinued. Repeated PNa showed a decrease to 128mmol/L. Tolvaptan was not initiated due to lack of insurance coverage and hepatotoxicity, and demeclocycline was not considered due to his known allergy. He was ultimately started on urea powder at 15 g/day and tittered to 30 g/day. In one week PNa improved to 135 mmol/L and remained stable until discharge. Clinical Lessons: The cornerstone of therapy for SIADH relies on reducing free water intake but this is not always feasible or sufficient. Winzer et al. [1] showed that fluid restriction is effective in only 59% of the patient with SIADH. As a result, pharmacology therapy is often needed. European guidelines, as compared to American guidelines, recommend the use of urea instead of vaptans therapy as second-line treatment. The above is based on different studies [2] that have shown that urea has similar efficacy, is more cost-effective, and safer since it does not cause liver toxicity like vaptans. Given this response, it appears that urea should be considered as a second-line therapy to fluid restriction given its tolerability and cost-effectiveness when compared to its alternatives. References: 1. Winzeler B, Lengsfeld S, Nigro N, Suter-Widmer I, et al. Predictors of nonresponse to fluid restriction in hyponatremia due to the syndrome of inappropriate antidiuresis. J Intern Med 280: 609–617, 20162. Soupart A, Coffernils M, Couturier B, Gankam-Kengne F, et al. Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH. Clin J Am Soc Nephrol 7: 742–747
Body Composition and Nuchal Skinfold Thickness in Pediatric Brain Tumor Patients
Authors: Peng Junxiang , Boekhoff Svenja , Eveslage Maria , Sowithayasakul Panjarat , Bison Brigitte , Muller Hermann Lothar
Published: May 2021

Obesity, cardiovascular disease, and relapse/progression have major impact on prognosis in pediatric brain tumor patients. Cranial MRI is part of routine follow-up. In a cross-sectional study, we analyzed nuchal skinfold thickness (NST) by a standardized method on MRI performed for brain tumor follow-up monitoring as a novel parameter for body composition and cardiovascular disease in 177 brain tumor patients (40 WHO grade 1-2 brain tumors; 31 grade 3-4 brain tumors; 106 craniopharyngioma), and 53 healthy controls. Associations of NST with body mass index (BMI), waist-to-height ratio, caliper-measured skinfold thickness, and blood pressure were analysed in brain tumor patients and healthy controls. Craniopharyngioma patients showed higher BMI, waist-to-height ratio, NST and caliper-measured skinfold thickness when compared with brain tumor patients and healthy controls, whereas these differences were not detectable between brain tumor patients and healthy controls. However, WHO grade 1-2 brain tumor patients were observed with higher BMI, waist circumference and caliper-measured triceps skinfold thickness when compared to WHO grade 3-4 brain tumor patients. NST showed high correlations with BMI, waist-to-height ratio, and caliper-measured skinfold thickness. NST, BMI and waist-to-height ratio had predictive value for cardiovascular disease in terms of increased blood pressure, and in multivariate analysis, only BMI was selected for the final model resulting in an odds ratio of 1.25 (1.14-1.379). In craniopharyngioma patients with hypothalamic involvement/lesion or gross-total resection, rate and degree of obesity were increased. As monitoring of MRI and body composition play an important role in follow-up after brain tumor, we conclude that NST could serve as a novel useful parameter for assessment of body composition and cardiovascular disease risk in brain tumor patients.
Characterizing Immune Checkpoint Inhibitor-Induced Hypophysitis and Obstacles in Diagnosis
Authors: Johnson Jake , Abdallah Dua’A , Kotwal Anupam , Ganti Apar Kishor , Goldner Whitney Sears
Published: May 2021

Background: Immune checkpoint inhibitors (ICI) are used in the treatment of multiple cancers. ICI-induced endocrinopathies are known side effects of many of these agents due to their immunogenic properties. The primary aim of this single institution analysis was to characterize the population who developed hypophysitis and secondary adrenal insufficiency (AI) related to ICI therapy, and identify diagnostic challenges.

Methods: We performed a retrospective cohort study of adult cancer patients who received ICI therapy from 12/1/2012- 12/31/2019. We identified 839 patients who received CTLA-4, PD-1, PDL-1 inhibitors, or a combination during this time. Hypophysitis (H) was defined as low ACTH and low serum cortisol ± other pituitary hormone deficiencies.

Results: Sixteen patients (1.9%; 16/839) developed hypophysitis after a median of 7 months from ICI initiation. The underlying cancers included: uroepithelial (1/48; 2.1 %), neuroendocrine (1/10; 10%), melanoma (9/156; 5.8%), renal cell carcinoma (4/74; 5.4%), and non-small cell lung carcinoma (1/247; 0.4%). Four patients were excluded since they had isolated secondary AI due to exogenous steroids. Two patients with hypophysitis also had exogenous steroid usage. However, these patients had central hypothyroidism + secondary AI so were included. The median age at start of ICI was 61.3 years and 57% were males. Patients who developed hypophysitis were younger compared to the non-hypophysitis (NH) patients (median age: 57 years vs. 65 years; p=0.0113). Time from initiation of ICI to death/last follow-up was longer in the H group (20 months vs. 10.8 months; p=.0013). 87.5% of group H as compared to 47.3% of NH were alive at end of data collection (p=0.0008). In the H cohort, 43.8% (7/16) received combination CTLA-4/PD-1 inhibitors, 43.8% (7/16) PD-1 monotherapy, 6.25% (1/16) CTLA-4 monotherapy, and 6.25% (1/16) PD-L1 monotherapy. Forty-six percent (6/13) of group H had radiographic evidence of hypophysitis on MRI that resolved on follow up imaging. Six patients had concurrent thyroiditis, 2/16 had concurrent type 1 diabetes, 9/16 had central hypothyroidism, 1/16 had secondary hypogonadism, and 2/16 had GH deficiency. In 15/16 patients, secondary AI presented as the first endocrinopathy, while one patient presented with central hypothyroidism.

Conclusions: Development of hypophysitis following ICI therapy was associated with a longer survival. Deficiencies in multiple pituitary hormones occurred in the majority and non-pituitary endocrinopathies occurred in half the cases. High dose steroid usage can also present as secondary AI, making the diagnosis of ICI induced hypophysitis difficult. Further pituitary evaluation must be conducted to differentiate secondary AI due to exogenous steroids from hypophysitis from ICI therapy.
Efficacy, Efficiency and Security of Urea Treatment in the Syndrome of Inappropiate Antidiuretic Hormone Secretion
Authors: Perelló Camacho Eva , Gómez Francisco José Pomares , Penabad Luis López , López Rosa María Mirete , Esteban María Rosa Pinedo , Escribano José Ramón Domínguez
Published: May 2021

Introduction: In the present times, several strategies have been proposed for the treatment of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Urea has demonstrated to be an effective treatment but its use has not been extended. Our work analyzes our experience with urea in the treatment of SIADH. Material and Methods: Observational retrospective analysis of 39 patients with SIADH in which urea has been used in our hospital with pre- and post-analysis of plasmatic sodium concentrations. Results: We included 39 patients with SIADH win a mean age of 76,4 ± 15,8 years. The plasma sodium nadir was 120,0 ± 5,1 mmoL/L and at the initiation of treatment 125,2 ± 4,1 mmoL/L. Total time of treatment was 2,42 ± 3,86 months being the treatment still active in 4 patients. We observed an improvement of sodium in all patients with a mean sodium at the end of treatment of 134.3 + - 5.0 mmol/L being this values statistically significant compared to the initial sodium (p<0.01). As a matter of fact we found significant differences at one week of treatment (p<0.01), keeping sodium stable levels around 135 mmol/L during the treatment period. The treatment was stopped in 3 cases (7.7 %) by the patient, one for mild digestive symptomatology and two for limited palatability. Of them two were treated with tolvaptan and the other did not need any further treatment. There were no adverse events in the rest of the patients. From the economic perspective and considering the duration of treatment, if we compare this to the cost of tolvaptan during the same period and the same number of patients, there was a reduction of cost of 87.9 % in comparison with treatment with tolvaptan. Conclusions: In our experience urea has shown to be a safe and cost effective option in the treatment of hyponatremia caused by SIADH showing improvement in sodium levels from the first week of treatment in all patients. We think it should be considered a valid therapeutic option.
Gonadotropin-Releasing Hormone Agonist Induced Pituitary Apoplexy
Authors: Yu Xiaoling , Guarda Francisco J , Shiraliyeva Naila , Haines Melanie S , Saylor Philip J , Nachtigall Lisa B
Published: May 2021

Background: Gonadotropin-releasing hormone agonists (GnRHa), used in the treatment of prostate cancer (PC) and for reproductive purposes in women, have been implicated as the cause of pituitary apoplexy (PA), a potentially life-threatening condition. The pathophysiology of PA after GnRHa has not been completely elucidated. Proposed mechanisms include a stimulatory effect of GnRHa on pituitary adenoma cell metabolism, causing mismatched blood supply prompting hemorrhage or infarction. Prior documentation of PA associated with GnRHa has been scarce and limited to case reports.

Methods: This is a detailed clinical case series of GnRH-induced PA from a single institution, obtained by a Research Patient Data Repository query. Clinical characteristics of the patients including demographics, detailed history, time interval between GnRHa and PA, physical exam, biochemical data, pituitary imaging and pathology were reviewed. Results: Seven cases were identified between 1990-2020; six men (aged 55 – 83 years) receiving treatment for PC and one woman (aged 22 years) receiving GnRHa for oocyte donation. All patients presented with headache; four within 48 hours of, one >1 month after, and one 5 months after, receiving GnRHa. One patient had insufficient data on time between GnRHa and PA. Most patients (86%) presented with nausea and vomiting. Other symptoms included ophthalmoplegia (43%), visual field defects (17%), and altered consciousness (29%). All patients had sellar masses and/or evidence of hemorrhage on MRI. Five patients underwent pituitary surgery while the others were managed medically. Of those who underwent surgical resection, 80% had positive histopathological staining for gonadotropins. Five patients with reliable hypothalamic-pituitary-adrenal (HPA) axis testing had impairment of this axis after PA; 40% recovered adrenal function. Central hypothyroidism occurred in 60% of whom 66% recovered. Hyponatremia occurred in 43%.

Conclusions: Patients with gonadotrope-secreting adenomas may develop PA in response to GnRHa, more frequently in elderly men who are receiving GnRHa treatment for PC. This may be due to older age and higher prevalence of GnRHa use in this group. However, as demonstrated here and in prior case reports, women are not exonerated from this complication. Headache and adrenal insufficiency are typically present. HPA axis recovers in a subset. While most patients present <48 hours after GnRHa treatment, delayed presentations may occur. Therefore, a history of prior GnRHa exposure should be ascertained in patients presenting with PA. While the incidence of PA after GnRHa is low, this case series and prior case reports suggest that this serious potential complication should be recognized prior to treatment, especially in patients with known pituitary macroadenomas.
Olfactory Performance in Youth With Full and Subthreshold Avoidant/Restrictive Food Intake Disorder
Authors: Stull Madeline Rogers , Harshman Stephanie G , Kuhnle Megan , Wons Olivia , Misra Madhusmita , Eddy Kamryn , Lawson Elizabeth Austen , Thomas Jennifer J
Published: May 2021

Background: Avoidant/restrictive (A/R) food intake disorder (ARFID) is characterized by restrictive eating defined by lack of interest in food, sensory sensitivity, and/or fear of aversive consequences of eating resulting in a failure to meet adequate nutritional and/or energy needs. The complex psychopathology that differentiates ARFID from other eating disorders highlights the need to explore the role of sensory systems in disease etiology. Olfaction has an important role in eating behavior. Specifically, olfactory dysfunction is associated with decreased food intake and appetite. Olfactory performance and associated clinical characteristics have yet to be examined in individuals with ARFID. We hypothesized that higher levels of PYY, which signals satiety, would be associated with poorer olfactory performance; whereas greater food fussiness and A/R eating severity would be associated with stronger olfactory performance. Methods: We evaluated a cross-sectional sample of children and adolescents with full and subthreshold ARFID (n=82, 46.2% female, mean age 15.8±3.8). We measured olfactory performance with the Sniffin’ Sticks test (Burghardt®, Wedel, Germany) which captures odor discrimination, odor identification, and odor threshold. Higher scores on all three indices represent stronger olfactory performance. We also measured fasting serum PYY; severity of A/R eating on the Pica, ARFID and Rumination Disorder Interview (PARDI); and food fussiness as a measure of food-related sensory sensitivity on the Adult Eating Behavior Questionnaire. Statistical analyses included T-test and spearman’s correlations. Results: Greater fasting serum PYY levels were associated with significantly poorer performance on the odor threshold test (r=-0.4, p=0.003). Greater severity of A/R eating (r=-0.3 p=0.008) and food fussiness (r=-0.2, p=0.03) were both associated with significantly poorer performance on the odor discrimination test. Conclusions: As predicted, we found that higher levels of PYY were associated with poorer olfactory performance in youth with full and subthreshold ARFID. However, contrary to hypotheses, we found that greater food fussiness and severity of A/R eating were associated with poorer olfactory performance. Future research should investigate whether high levels of PYY and poor olfactory performance are causes, consequences, or correlates of A/R eating.
Clinical Presentation and Management of Patients With Acromegaly at a University Hospital
Authors: Leao Felipe A , Drummond Juliana B , Bizzi Mariana F , Gainnetti Alexandre , Ribeiro-Oliveira Antonio , Soares Beatriz Santana
Published: May 2021

We conducted a retrospective analysis aiming to evaluate different treatment responses in a cohort of acromegaly patients followed at the Federal University of Minas Gerais Neuroendocrinology Outpatient Clinic who were diagnosed between the years of 1998 and 2020. Results: seventy-two patients with acromegaly were initially identified through chart review. Twelve patients were subsequently excluded from this analysis - nine patients who had been recently diagnosed and were awaiting surgical treatment as well as three patients who had been lost to follow-up. The study sample (n=60) included forty females patients (67%). Mean (range) age at diagnosis was 43.5 years-old (17-76) and mean (range) follow-up time was 107 (1-261) months. At diagnosis, 88.7% of the patients presented with a macroadenoma, and median (range) basal GH and IGF-1 of the studied population were 21.76 (0.89-193) ng/mL and 310 (110-2459) % above the age and sex-adjusted ULN, respectively. Fifty-six (93%) patients underwent transsphenoidal surgery while four patients (6.7%) received primary medical treatment. Amongst patients not cured by surgery (n=42), 37 patients (88%) were sequentially treated with first generation long-acting somatostatin analogues (SSAs) and 3 patients (7%) received cabergoline. Amongst patients sequentially treated with SSAs, 14 (38%) achieved optimal biochemical control, defined as normal age and sex-adjusted IGF-1 levels, under SSAs monotherapy (octreotide LAR maximum dose of 40 mg/28 days or lanreotide autogel maximum dose of 120 mg/28 days) while one out of three patients achieved biochemical control under cabergoline monotherapy (maximum dose of 3 mg/week). All patients who did not achieve biochemical control under SSA or cabergoline monotherapy (n=25) were sequentially treated with SSAs and cabergoline combined therapy and optimal biochemical control was achieved in 13 (52%) of them. Pegvisomant (maximum dose of 30 mg/day) was further added to the therapeutic scheme in seven patients, allowing biochemical control in 4 (57.1%) additional patients. Amongst five patients (8%) patients who were treated with adjuvant radiotherapy, two did not achieved long-term remission, despite combined therapy with SSAs, cabergoline and pegvisomant. Discussion: the high reported prevalence of macroadenomas in our cohort possibly reflects a delay in the diagnosis and may account for the low observed successful surgical rate in comparison to other series, however treatment response rates to SSAs monotherapy as well as combined SSAs and cabergoline therapy here reported are in line with previous reports. Given its low cost and larger availability, cabergolin was amply prescribed as opposed to pegvisomant, which was employed as a third-line treatment showing a disease control rate lower than previously reported in interventional studies but consistent with previous real-world data.
Acute Transcriptional Effects of Dexamethasone on Mouse Adrenal Gland Transcriptome
Authors: Zheng Huifei Sophia , Daniel Jeff , Foradori Chad David , Kemppainen Robert J , Huang Chen-Che Jeff
Published: May 2021

Researchers have long known that dexamethasone causes cellular and functional changes in the adrenal gland. For example, long-term dexamethasone treatment leads to reversible adrenal cortex atrophy. In the adrenal medulla, dexamethasone treatment alters the maturation and function of the neural crest-derived chromaffin cells. Here we aim to study the acute transcriptional effect of dexamethasone on mouse adrenal gland at the transcriptome level. Our data suggested that a one-hour dexamethasone treatment had a cell type-specific effect on the adrenal transcriptome. There were 922 dexamethasone-induced genes and 853 dexamethasone-suppressed genes. GO analysis showed that the upregulated genes were primarily linked to neuronal cell function. Clustered heatmaps further showed that many genes involved in the catecholamine synthesis were upregulated by dexamethasone treatment, whereas most genes involved in the steroidogenesis pathway were downregulated. Interestingly, steroidogenic factor 1 (SF1, encoded by Nr5a1), the critical transcription factor that regulates steroidogenesis, had a >2-fold decrease under the one-hour dexamethasone treatment, suggesting a possible mechanism of the acute suppression of steroidogenic activity. Our findings indicate that the acute effects of dexamethasone stimulate catecholamine synthesis in the medulla, whereas steroidogenesis in the cortex is suppressed by dexamethasone.
Low Risk for All-Cause Mortality Among Patients With Lung Neuroendocrine Tumors Co-Diagnosed With Pituitary Adenoma
Authors: Sinvani Naama Peltz , Percik Ruth , Uri Inbal , Kfir Sapir Kon , Tirosh Amir , Tirosh Amit
Published: May 2021

Context: Lung neoplasm often co-occur with pituitary adenoma (PA). However, whether co-diagnosis of lung neuroendocrine tumors (LNET) and PA constitute unique entity, and the impact of such co-diagnosis on patients outcome is yet to be defined. Objective: To compare the clinical characteristics of patients with LNET to those co-diagnosed with PA. Design: Retrospective, case-control study including patients diagnosed with LNET or PA between 2000 and 2016. Setting: The Surveillance, Epidemiology and End Results database. Patients: 2,947 patients had LNET, including 2,913 with LNET alone (“Sporadic”) and 34 patients with both LNET and PA (“MENx”). Main Outcome Measure(s): All-cause mortality (ACM). Results: PA preceded LNET diagnosis in 85.3% of patients and had higher rates among LNET patients (34/2,947) than with any cancer (p<0.00001) and compared to patients with non-small cell lung cancer (NSCLC) (15/2,378, p=0.047). MENx patients were younger at diagnosis compared with NSCLC patients and PA (p=0.04). Among patients<60 years with LNET, co-diagnosis with PA was associated with lower ACM risk (Log-rank test, p=0.03). Adjusted ACM risk of patients with “MENx” was lower than sporadic LNET (hazard ratio 0.553, 95% confidence interval 0.309-0.99, p=0.046), especially among Caucasians, and a lower overall-mortality risk in patients <60 years with borderline statistical significance (p=0.071). Conclusions: Patients with both LNET and PA constitute a distinct morbidity and mortality profile compared with sporadic LNET possibly suggesting an undefined MEN syndrome. Additional studies to further investigate the natural course and genetic profile of patients with these neoplasms are needed.
Androstenedione Is the Preferred Substrate for Cytochrome P450 11β-hydroxylase Leading to the Production of 11β-Hydroxyandrostenedione in the Adrenal Gland
Authors: Barbier Inge Doney , Gent Rachelle , Du Toit Therina , Swart Amanda C
Published: May 2021

Adrenal cytochrome P450 11β-hydroxylase (CYP11B1) is a mitochondrial enzyme that catalyzes the final step of glucocorticoid synthesis, converting 11-deoxycortisol (S) and deoxycorticosterone (DOC) to cortisol (F) and corticosterone (CORT), respectively. CYP11B1 is predominantly located in the zona fasciculata of the adrenal gland with studies also showing that CYP11B1 catalyzes the conversion of androstenedione (A4) and testosterone (T) to 11β-hydroxyandrostenedione (11OHA4) and 11β-hydroxytestosterone (11OHT), respectively. Adrenal vein sampling in women has shown that 11OHA4 turnover is high, with a marked increase after treatment with ACTH which is known to upregulate CYP11B1 expression. We hypothesized that CYP11B1’s affinity for A4 as a substrate may be favored over glucocorticoids since 11OHA4 is one of the major androgens produced in the adrenalThis study aimed to elucidate the kinetic parameters (Km and Vmax) for A4 and T with respect to CYP11B1. A4 and T (0.2 µM to 5 µM) were assayed in HEK-293 cells transiently transfected with CYP11B1 and the adrenodoxin redox partner. Data was used to generate progress curves and fitted to the Michaelis-Menten equation. A4 had the lowest Km (0.21 μM) with a significantly higher Vmax (315.77 pmol/min/mg protein) in comparison to T, S and DOC. Results suggest that A4 binds more readily to CYP11B1 resulting in the high turnover of substrate. The androgenic activity of CYP11B1 catalyzed steroid products was determined using a luciferase assay conducted in CV1 cells. Both A4 and 11OHA4 showed no androgenic activity, however, the 11βHSD2 product of 11OHA4, 11-ketoandrostenedione (11KA4), elicited a response at 100 nM. 11OHT was an androgen receptor (AR) agonist, however, exhibiting a lower response when compared to T and 11-ketotestosterone over all concentrations tested (1, 10 and 100 nM). As confirmation of CYP11B1 activity in the adrenal, circulatory steroid levels were determined in healthy female subjects (n=88). CORT, F and 11OHA4 were measured at a frequency of 70–100%, compared to 11OHT (40–70%), while 11βHSD2 activity produced 11KA4 (<10%). In conclusion, the catalytic efficiency of CYP11B1 towards A4 is higher compared to T and the classical substrates. The high substrate affinity and turnover provides evidence for 11OHA4 in adrenal vein samples. Concurrently, our analysis suggests that agonism is diminished by the presence of the C11- hydroxyl group, while AR agonistic activity is gained upon its conversion to a keto group. Furthermore, these androgens could perhaps modulate cortisol production in the adrenal due to potential competition between precursor substrates.
Novel Pituitary Organoid Model as Powerful Tool to Unravel Pituitary Stem Cell Biology Across Ages and Disease
Authors: J Vankelecom Hugo E , Laporte Emma , Hermans Florian , Nys Charlotte , Vennekens Annelies
Published: May 2021

The pituitary gland harbors a population of stem cells. However, role and regulation of these cells remain poorly understood. We recently established organoids from mouse pituitary as a novel research tool to explore pituitary stem cell biology (Cox et al., J. Endocrinol. 2019; 240:287-308). In general, organoids represent 3D in vitro cell configurations that develop and self-organize from (single) tissue stem cells under well-defined culture conditions that typically mirror the stem cell niche and/or embryogenic processes. Organoids reliably recapitulate key aspects of the original organ, including of its stem cell compartment. Moreover, organoids are long-term expandable while retaining these properties. We demonstrated that pituitary organoids originate from the resident (SOX2+) stem cells, largely phenocopy these cells and retain the stemness phenotype during expansive culture. Interestingly, the organoids show confident in vivo translatability and, when developed from transgenically damaged gland, recapitulate the activation status of the stem cells as observed in situ following injury. Now, we found that the organoids also mirror the stem cells’ phenotype and biology in physiological conditions in which the stem cell compartment is either activated or compromised. Organoids from the neonatal maturing pituitary reproduce phenotypical and functional aspects of its activated stem cells, whereas organoids from aging gland mimic the declined functional state of the stem cells in old pituitary. Interestingly, this functional decay was found to be reverted during organoid culture, indicating that the old pituitary stem cells retain intrinsic functionality but are in vivo restrained by an obstructive microenvironment, not present in the organoid culture. Indeed, using single-cell transcriptomics and in vivo analysis, we found that the aging pituitary suffers from a prevailing inflammatory state (inflammaging) which appears to raise the threshold for stem cell activation. Interestingly, comparison of young and old pituitary led us to the discovery of pituitary stem cell activators. Finally, we found that activated parameters of organoid formation are also observed when tumorigenesis takes place in the gland, again mimicking the in situ stem cell activation that is occurring in this perturbed, pathological condition. Taken together, we identified, and applied, our new pituitary organoid model as advanced and powerful tool to gain profound insight into pituitary stem cell behavior across life and disease, which is expected to eventually translate into restorative and rejuvenative tactics when pituitary function is compromised by damage or age. In this context, our single-cell transcriptome database has strong potential to unveil appealing targets.
Association Between Dyslipidemia and Helicobacter Pylori Infection
Authors: Hayes Dorado Juan Pablo
Published: May 2021

Introduction: The association between Helicobacter pylori infection and elevated plasma levels of LDL cholesterol and decreased HDL cholesterol has been reported. Objective: To determine the frequency of altered plasma levels of LDL cholesterol, HDL cholesterol and triglycerides in pediatric patients with Helicobacter pylori infection. Materials and Methods: Prospective, observational and analytical study. Pediatric patients with Helicobacter pylori infection, July 2019 - June 2020 period. Exclusion criteria: Obesity, diabetes mellitus, hypothyroidism, hepatopathy, nephropathy, collagen disease, corticotherapy, use of proton pump inhibitors and H2 antihistamines. Antibodies against Helicobacter pylori and plasma levels of total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides were studied. Two groups of patients: Those with Helicobacter pylori infection and the other of uninfected children. Results: Patients attended: 39; studied: 22; excluded: 17. Group of non-infected: 25.Triglyceride levels (mg/dL) were 117 + -21 in patients with Helicobacter pylori and 98 + -19 in those not infected (p = 0.01); HDL cholesterol levels (mg/dL), 39 + -14 in those infected and 47 + -13 in patients without Helicobacter pylori infection (p = 0.03). Conclusions:Patients with Helicobacter pylori infection had a higher frequency of dyslipidemia, compared to the group of uninfected children.
Expression of Vitamin D Receptor Pathway Genes in Subcutaneous Adipose Tissue of Obese Individuals
Authors: Ginnard Olivia Z B , Sisley Stephanie
Published: May 2021

Introduction: Vitamin D deficiency is a substantial comorbidity in 50% of pediatric patients and is linked with poorer health outcomes in children. Vitamin D levels are also shown to be inversely related to BMI. Therefore, there are many more children with low vitamin D levels due to the increasing prevalence of pediatric obesity. Pediatric patients with obesity and vitamin D deficiency also have a uniquely increased risk of metabolic syndrome, as compared to their lean peers. Measured levels of vitamin D correlate with other physiological markers of vitamin D effects in lean individuals but not obese individuals. It is possible that vitamin D levels reflect a storage form of vitamin D rather than a true reflection of vitamin D action in the body in this particular population. The aim of this study was to provide foundational knowledge to understand if expression of vitamin D receptor (VDR)-target genes may be used as a reference standard for vitamin D status in the body. Methods: We performed a secondary analysis of samples obtained from 33 obese adolescents that were consented under a past IRB-approved protocol. They were between the ages of 13 to 18 years that underwent bariatric surgery between 2004 and 2019. Data comprised of age, gender, race/ethnicity, and BMI. Samples collected included blood and subcutaneous adipose tissue. The tissue was analyzed via Real Time-PCR to obtain quantitative levels of VDR-target gene expression, which included PPARg, TLR4, THBD, CYP24A1, and VDR. Gene expression levels were normalized to the average of two housekeeping genes, GAPDH and RPLPO. Blood samples provided vitamin D levels (serum 25(OH)D). Results: VDR-target gene expression was significantly correlated between THBD, VDR, and TLR4 (p <0.05), and PPARg with THBD and TLR4 (p <0.05). There was no correlation observed between CYP24A1 gene expression and the other genes that were evaluated (p >0.05). PPARg, THBD, TLR4, CYP24A1, and VDR gene expression levels did not correlate with circulating serum 25(OH)D levels (p >0.05). Conclusion: These preliminary findings suggest that VDR-target gene expression correlates with each other but not with circulating serum 25(OH)D levels. This discrepancy supports that 25(OH)D levels do not indicate levels of vitamin D action and may not be an appropriate indicator of vitamin D deficiency in the obese population. Also, the observed CYP24A1 gene expression was limited in subcutaneous adipose tissue yet expression was seen in multiple other VDR-target genes. This emphasizes the tissue-specific nature of gene regulation of vitamin D. Further work should investigate VDR-target gene expression levels across multiple tissues of obese individuals to determine if markers of vitamin D action in one tissue are reflective of action across the body. This study may provide the first step in determining a new and more accurate biomarker for vitamin D deficiency and treatment in obesity.
Exploring the Potential Role of DLK1 in Pubertal Initiation
Authors: Jee Youn Hee , Delaney Angela , Jennings Melissa , Yanovski Jack Adam , Baron Jeffrey
Published: May 2021

The mechanisms that orchestrate the initiation of puberty are not well understood. DLK1 encodes a transmembrane protein that interacts with NOTCH1 receptor to negatively regulate NOTCH signaling. Loss-of-function mutations in DLK1 cause central precocious puberty, suggesting that DLK1 normally inhibits the reproductive axis centrally. The soluble form of DLK1, which is generated by proteolytic cleavage of the DLK1 extracellular domain, is measurable in human serum. We hypothesized that serum soluble DLK1 concentrations decline with age and that the decline, either in circulating levels or in tissue expression, contributes to the physiological mechanisms triggering pubertal initiation. Serum DLK1 was measured by immunoassay in 102 healthy subjects (age newborn - 26 yrs, 54 male). DLK1 concentrations did not differ by sex, BMI SDS, height, or status of fasting. DLK1 concentrations declined overall with age (R2=0.04, P<0.001). However, there was not a substantial decline in the peripubertal period (mean± SEM, at Tanner stage 1, 2, 3, 4, 5: 14.8 ± 1.9, 16.4 ± 1.2, 17.0 ± 5, 13.6 ± 3, 9.7 ± 0.9 ng/mL). Serum DLK1, measured in 12 subjects (2 male) with a previous history of idiopathic central precocious puberty, did not differ from healthy controls. We next hypothesized that declining expression of Dlk1 or increasing expression of competing canonical NOTCH ligands in hypothalamus contributes to pubertal onset. The preoptic area (POA) was microdissected from rat brains (age 4 d, 2 w, 6 w, and 8-16 w, n=5 each) and expression was measured by RT-PCR. Dlk1 expression increased with age in both female and male rats (P<0.001). Notch1 expression did not change with age. Expression of two ligands, Jag1 and Dll4, showed a peak at age 6 w, around the time of puberty, but only in males, and none of the other ligands (Jag1, Dll1, and Dll3) showed increasing expression at the age of puberty. In conclusion, we did not find evidence that declining serum soluble DLK1 concentrations in humans, declining DLK1 expression in rat preoptic area, or increasing NOTCH ligand expression in rat preoptic area contribute to pubertal onset.