bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physical and Sociodemographic Features Associated With Quality of Life in Transgender Individuals Using Gender-Affirming Hormone Therapy
Authors: Da Silva Eliane Dias , Fighera Tayane Muniz , Allgayer Roberta Martins Costa Moreira , Lobato Maria Inês Rodrigues , Spritzer Poli Mara 
Published: May 2021

Abstract
Background: Gender dysphoria is defined as a feeling of distress resulting from the incongruence between the gender assigned at birth and the identity gender and lasting longer than 6 months. In individuals with gender dysphoria, gender-affirming hormone therapy(GAHT) may improve quality of life (QoL). Objectives: Here, we aimed to assess perceived QoL and possible contributing factors in a sample of transgender women and transgender men using GAHT. Methods: In this cross-sectional study, transgender women and men were recruited by availability sampling from a national transgender health service. Individuals over 18 years old with a confirmed diagnosis of gender dysphoria receiving medically prescribed GAHT for at least 6 months were consecutively included. Also included were trans men who had undergone mastectomy and trans women who had received breast augmentation surgery. Individuals who had undergone gender affirmation surgery (specifically genital surgery) or with uncontrolled clinical/psychiatric conditions at the time of the initial assessment were excluded. Sociodemographic, physical, and hormone data were collected from all participants. The WHOQOL-BREF questionnaire was used to evaluate QoL. A total of 135 transgender individuals were invited. Seventeen individuals with previous genital surgery (12.6%) and five who refused to participate (3.7%) were excluded. Therefore, 113 patients were enrolled in the study (60 trans women and 53 trans men). Results: There was no significant difference in QoLbetween the groups. In trans women, greater breast development and stable relationships, and higher body mass index were associated with higher QoLdomain scores. In trans men, higher domain scores were found in individuals with a stable relationship, increased body hair, physical activity practice, and being employed. Conclusion: Data from this study suggest that GAHT-related physical characteristics are associated with higher QoLscores, and that sociodemographic parameters may impact these associations. Healthcare providers might consider these factors when planning interventions to improve QoLin transgender individuals.
Copy Number Variations Are More Frequent on Chromosome 14 as Compared to X Chromosome in Suspected Turner Syndrome Girls - A Chromosomal Microarray Analysis
Authors: Purwar Naincy , Tiwari Pradeep , Saxena Aditya , Mathur Nitish , Sharma Himanshu , Sharma Balram , Mathur Sandeep Kumar 
Published: May 2021

Abstract
Introduction: Turner syndrome(TS) is defined by complete/partial monosomy of X chromosome in association with classic clinical manifestations. Conventional karyotyping is the gold standard test for diagnosis of TS. However it is labour intensive and inaccurate for detecting mosaicism, marker chromosomes and sub-microscopic deletions/duplications. TS is characterized by heterogeneous phenotypes despite identical karyotypes and precise genotype-phenotype correlations have not yet been deciphered. Presence of TS specific features in absence of X chromosome abnormality, evokes the hypothesis of possible autosomal involvement. Here, we report detailed Chromosomal microarray (CMA) analysis of 47 girls with clinically suspected TS, using Affymetrix CytoScan 750K array. Materials and Methods: The clinical diagnosis of TS was based on recommendations by clinical practice guidelines from 2016 Cincinnati International TS meeting. Peripheral venous sample was collected in EDTA tubes and DNA was extracted using Qiagen-DNAeasy Blood and Tissue kit (Cat No. 69504). DNA samples were then hybridized to the Affymetrix CytoScan 750K array as per manufacturer’s instructions. The data obtained was analysed using Chromosomal Analysis suite software and public genomic databases- ISCA, OMIM, DGV, DECIPHER. For bioinformatic analysis, all the genes (172) implicated in TS were retrieved from DisGeNET database. A TS-interactome of 4033 genes was then constructed from these genes and their first-degree neighbours from complete human interactome. Thereafter compilation was done based on CMA results and a protein-protein interaction network of 316 nodes was constructed. Results: Mean age of study cohort was 15.8 ± 3.64 years with short stature being the most common presenting phenotype (91.4%). CMA analysis detected copy number variations (CNVs) on chromosome 14 in 42 (89.3%) of 47 cases while X chromosome CNVs were present in only 28 (59.5%) cases, with all patients clinically qualifying as TS. Total 445 CNVs were discovered on X chromosome and 64 CNVs were found on Chromosome 14 exhibiting either CNV gain at 14q32.33 or CNV loss at 14q11.2 or both. The 30 cell karyotype was available for 27 patients and was found to be false negative in 7 (14.8%) patients. Also, 6 out of 47 cases had Y chromosome translocation detected on CMA that failed detection by karyotype. On enrichment analysis, thirty KEGG pathways were found to be enriched by the overlapping genes between TS-interactome and the interactome constructed by genes located within 14q11.2, and 14q32.33 67% of genes (212) in this network overlap with TS-interactome.
Conclusions: CMA is a superior diagnostic modality for TS than karyotyping. Functional interactomes between Chromosome X and Chromosome 14 on enrichment analysis reveal novel pathways underlying phenotypic manifestations.
Evaluation of Turner Syndrome International Consensus Guideline Compliance in Multiple Subspecialty Clinics Verses a Coordinated Multidisciplinary Clinic Format
Authors: Hoag Benjamin Donald , Tsai Sarah J L , Cernich Joseph Theodore , Williams David 
Published: May 2021

Abstract
Turner syndrome’s (TS) lifelong association with multi-organ system comorbidities necessitates the effective implementation of, and adherence to, screening guidelines. Our team evaluated the effectiveness in implementing the 2016 Cincinnati International Turner Syndrome consensus guidelines [1] in a single, coordinated, multidisciplinary clinic (MDC) day format compared to multiple separate subspecialty clinic visits. A retrospective analysis of patients with TS followed at our pediatric tertiary referral center between December 2016 and April 2020 was conducted. Exclusion criteria included patients that were not seen in our pediatric endocrine clinic for over 24 months, age over 22 years, and those without confirmed genetic diagnosis of TS. The population was separated into two groups; girls who attended at least 1 MDC day each year and girls who had at least 1 endocrinology clinic visit in the last 14 months, but who were not part of the MDC (non-MDC). Age appropriate screenings included TSH, hepatic function test, Vitamin D level, blood glucose and/or HgA1C, celiac screening panel, hearing/auditory screening, eye examination, electrocardiogram, and echocardiogram. A total of 112 girls met study criteria. Sixty-eight were managed in the MDC and 44 managed in non-MDC. Only 36.6% of all the girls met all the above age-appropriate screening recommendations, 75.6% of which were managed in MDC (p-value 0.014). MDC girls had higher screening compliance rates vs non-MDC girls for TSH (95% vs 76%, p-value 0.017), auditory evaluation (85% vs 50%, p-value &lt;0.001), HgA1c and/or serum blood glucose levels (97% vs 76%, p-value 0.017), and tissue transglutaminase levels (95% vs 83%, p-value 0.048). No statistically significant difference was found with overall screening guideline compliance and insurance status, race/ethnicity, or age at time of the patients last recorded clinic visit. In conclusion, the MDC day format showed superior screening guideline compliance, both overall and to multiple specific screening tests, compared to those seen in multiple uncoordinated, single-disciplinary individual provider clinics. Overall guideline adherence remained low (36.6%), highlighting the need for continued optimization and improvement in guideline compliance. Reference: [1] Gravholt, C.H., et al., Eur J Endocrinol, 2017. 177(3): p. G1-G70.
The Population Prevalence, Thyroid Cancer and Mortality Risk for Turner Syndrome in South Korea Based on National Health Insurance Service (NHIS) Data
Authors: Kim Sungeun , Park Sang Hyun , Han Kyungdo , Cho Won Kyoung , Suh Byung-Kyu , Park Yong-Gyu 
Published: May 2021

Abstract
Background: In the present study, we estimated the population prevalence, cancer and mortality risk for Turner syndrome (TS) using data from National Health Insurance Service (NHIS) and Rare Diseases Registry (RDR). Methods: We collected data on subjects with TS who were registered in the RDR between 2012 and 2017. To estimate cancer and mortality risk of TS, the data of TS subjects were compared with and 1:5 age and sex matched controls. Results: In 2017, 2054 individuals with TS were identified out of the total population of 26,249,201 South Korean females and the prevalence was 7.83 per 100,000 persons. In 2017, the distributions of TS prevalence across 10 year old age groups showed 11.44 per 100,000 persons in the group under the age of 10 years, 22.43 per 100,000 persons in teenagers, 18.40 per 100,000 persons in twentieth, 10.24 per 100,000 persons in thirtieth, 4.05 per 100,000 persons in fortieth and 0.39 per 100,000 persons after fiftieth. During 5.3 years, the cancer risk in patients with TS was higher than that of age matched controls [hazard ratio (HR) = 1.813, 95% CI 1.009-3.257]. When cancer is categorized by each organs, thyroid cancer risk in patients with TS was significantly higher than that of age matched controls [hazard ratio (HR) =2.697, 95% CI 1.025-7.097]. The all cause of mortality risk of TS was higher than that of age matched controls [hazard ratio (HR) =3.421, 95% CI 1.623-7.212]. Conclusions: In South Korea, the TS population prevalence was 7.83 per 100,000 persons in 2017. The subjects with TS have higher thyroid cancer and mortality risk than healthy controls. Key words: Prevalence, Turner syndrome, thyroid cancer risk, mortality risk.
Calcineurin-NFATc4 Pathway Is Activated Upon K+-stimulation of Adrenal Aldosterone Production
Authors: Berber Mesut , Leng Sining , Beuschlein Felix , Breault David T , Loffing Johannes , Ribas David Penton 
Published: May 2021

Abstract
The mineralocorticoid aldosterone secreted by the adrenal zona glomerulosa (ZG) cells promote renal K+ secretion and Na+ reabsorption; thereby it is critical for the control of ion homeostasis and blood pressure. While the Ca2+/calmodulin-dependent protein kinase (CAMK) pathway regulating K+ stimulated aldosterone production is well studied, little is known about the potentially involved phosphatases. Interestingly, immunosuppression therapy of transplanted patients with protein phosphatase 3 (calcineurin) inhibitors often results in rather low plasma aldosterone levels despite a concomitant hyperkalemia and hyperreninemia. Calcineurin (Cn) is a calcium and calmodulin-dependent protein phosphatase expressed in the adrenal cortex. We tested the hypothesis that Cn participates in the signal transduction pathway mediating the K+-dependent stimulation of aldosterone production. To address this question, we used the adrenocortical cell model NCI-H295R, mouse and human ex vivo adrenal preparations and a ZG-specific and inducible Cn knockout mouse model (ZG-CnB1-KO). Inhibition of Cn with tacrolimus abolished the K+-stimulated expression of CYP11B2 in NCI-H295R cell line as well as mouse and human adrenal pieces, ex vivo. Using a phosphoproteomics analysis, we identified nuclear factor of activated T-cells, cytoplasmic 4 (NFATc4) as a critical downstream factor mediating Cn function. In support of this result, genetic deletion of NFATc4 reduced the basal expression of CYP11B2 and impaired the K+-stimulated expression of this gene. Conversely, the expression of a constitutively active form of NFATc4 drastically increased the expression of CYP11B2 in NCI-H295R cells which remained unaltered upon treatment with K+ or tacrolimus. Finally, preliminary experiments using ZG-CnB1-KO mice suggest that Cn deletion in the ZG blunts the increase in aldosterone excretion triggered by high K+ diet. Altogether, our data indicate that Cn function is indispensable for the physiological regulation of aldosterone production. Moreover, Cn may represent a novel molecular target for the pharmacological treatment of primary aldosteronism.
Deliberate Compensated Vasoplegia - a Novel Pharmacological Regimen for Controlling Arterial Blood Pressure During Surgery for Pheochromocytoma
Authors: Mazeh Haggi , Weiss Daniel J , Peter Michael , Grozinsky-Glasberg Simona , Oleinikov Kira , Szalat Auryan , Ronen Ariel , Koganov Evgeny 
Published: May 2021

Abstract
Background: Intraoperative hemodynamic fluctuations are the most dreaded phenomenon associated with the treatment of pheochromocytoma. Preoperative alpha-adrenergic blockade protocols aimed at abating these fluctuations have achieved controversial results. No study to date has evaluated the use of intraoperative treatment protocols during surgery for pheochromocytoma. Deliberate compensated vasoplegia (DCV) is a novel pharmacological regimen developed at our institution intended to decrease severe hypertensive events. The aim of this study is to compare outcomes of pheochromocytoma resection with and without the DCV protocol. Methods: A retrospective analysis of all pheochromocytoma resections between the years 2012 and 2020 was performed. Resections performed with and without the DCV protocol were compared. The primary outcome measured was the incidence of severe intraoperative hypertension (mean arterial pressure ≥ 150 mmHg). Secondary outcomes included other abnormal blood pressure measurements as well as perioperative data and complications. Results: A total of 41 pheochromocytoma resections were included: 21 performed using standard practice and 20 with the DCV protocol. Analysis demonstrated no significant difference in preoperative parameters including tumor size, catecholamine levels, or alpha-blockade protocol. The use of the DCV protocol resulted in a significant decrease in the incidence of severe hypertensive episodes from 1.95±3.6 to 0.03±0.13 events/hour (p=0.008). The DCV protocol was not associated with any adverse events. Conclusions: This study demonstrates that DCV anesthesia protocol significantly decreases the incidence of severe hypertensive episodes during pheochromocytoma resection. This is the first study describing a highly effective protocol for controlling intraoperative hypertension and hemodynamic instability in pheochromocytoma patients.
Deletion of Nuclear Receptor Constitutive Androstane Receptor CAR Increases Anxiety and Lowers Androgen Levels
Authors: Hernandez Juan P , Asokakumar Anjana , Xiao Rui , Moore David D , Anakk Sayeepriyadarshini 
Published: May 2021

Abstract
The orphan nuclear receptor, Constitutive Androstane Receptor (CAR, NR1I3) is primarily known to regulate the transcriptional networks involved in detoxification. We have identified a novel extra-hepatic role of CAR in regulating androgen levels and modulating testis function. Previous data has revealed that CAR activation by estradiol and inactivation by androstanol suggests an intricate link between sex hormones and CAR. We investigated control wild type and CARKO mice and found that the serum testosterone and androstenedione levels were lower in the absence of CAR. As expected, we did not find any induction of the genes in the detoxification machinery including, Cyp3a, Cyp2b, Cyp2c family, Sult2a1 and Mrp. The decrease in the androgen levels in the CARKO mice is consistent with decrease in the anogenital distance, increased anxiety as measured by marble burying and elevated plus maze but no change in testis weight. H&E staining of CARKO mice shows accumulation of fat in the Leydig cells and lower numbers of Leydig cells which are in accordance with the loss of androgen levels. In addition, we will examine the consequence of reduced androgen and the hypothalamus-pituitary-gonadal axis in the CARKO mice.
Melanocortin 2 Receptor Antagonists in Canine Cushing’s Disease: In Vitro Studies
Authors: Sanders Karin , Slob Adri , Betz Steven F , Kooistra Hans S , Galac Sara 
Published: May 2021

Abstract
Melanocortin 2 receptor antagonists in canine Cushing’s disease: in vitro studies
Cushing’s disease (CD), caused by an ACTH-secreting pituitary adenoma, is one of the most common endocrinopathies in dogs. The current medical treatment options involve adrenocortical steroid synthesis inhibitors, but a selective targeted approach to block ACTH receptor at its receptor would be much more attractive. The objective of this study was to preclinically investigate the effect of MC2R antagonists on adrenocortical hormone production, cell viability, and mRNA expression of steroidogenic enzymes in canine primary adrenocortical cell cultures from adrenal glands of healthy dogs. Three different MC2R antagonists were used: CRN.1, CRN.2, and CRN.4. Canine primary adrenocortical cell cultures (n = 8) were incubated with 50 nM ACTH for 24h, to mimic CD. Thereafter, 10 nM (IC50) and 2 μM (maximal concentration) of CRN.1, CRN.2, and CRN.4 were added. The two concentrations were established based on preliminary studies. After 24 hours of incubation, adrenocortical hormone concentrations were measured in the culture medium using liquid chromatography-mass spectrometry. RNA was isolated from the cells using the RNeasy Microkit (Qiagen) for subsequent real-time quantitative PCR analysis. Cell viability was assessed after 24 hours of incubation using alamarBlue™ Cell Viability Reagent. All CRN compounds effectively inhibited cortisol concentrations, while leaving aldosterone concentrations unaffected. In incubations with a maximal concentration of the three compounds, cortisol concentration decreased to undetectable levels. The mRNA expression levels of steroidogenic enzymes StAR, CYP11A1, CYP17A1, HSD3B2, CYP21, and CYP11B were significantly inhibited in most conditions when compared to the ACTH-stimulated control. The mRNA expression of melanocortin 2 receptor accessory protein (MRAP) was suppressed as well. Cell viability was not affected by CNR.1 or CNR.4, but was slightly inhibited by CRN.2. In summary, canine adrenocortical cell culture is a useful model system for drug testing. Incubation with MC2R antagonists demonstrated the potential of CNR.1 and CNR.4 as new treatment options for CD. Future in vivo studies in dogs with spontaneous CD are indicated.
The Effect of a Novel Glucocorticoid Receptor Antagonist (CORT113176) on Glucocorticoid and Insulin Receptor Sensitive Hepatic Gene (mRNA) Expression in a Neonatal Rat Model of Human Prematurity
Authors: Gehrand Ashley , Phillips Jonathan , Welhouse Kyle D , Schulgit Matthew , Siddiqui Hana , Raff Hershel 
Published: May 2021

Abstract
Preterm birth is a global health problem the sequelae of which are not well understood. Hypoxia, a common stressor with prematurity, can affect blood glucose via stress-induced increases in glucocorticoids (GC). GCs are also administered to preterm infants to improve oxygenation; however, this is controversial. CORT113176 (Corcept Therapeutics) is a novel, selective glucocorticoid receptor (GR) antagonist that does not bind to the progesterone receptor. We have demonstrated that CORT113176 (in our rat model of preterm birth) increases baseline corticosterone (due to loss of GC negative feedback) and attenuates hypoxia-induced increases in insulin resistance implicating endogenous corticosterone in post-natal metabolic adaptations to stress. We now propose that CORT113176 is useful to evaluate the hepatic effects of endogenous GCs in our rat model of preterm birth by measuring critical GC and insulin receptor sensitive gene mRNAs. Postnatal day (PD) 2 rat pups of both sexes (N=5 per treatment/sex) were pretreated with CORT113176 (600 mg/kg IP) or vehicle. After 60 minutes, a group of pups were euthanized with livers collected and preserved in RNAlater (baseline). The remaining pups were separated from their dams, exposed to normoxia (control) or hypoxia (8% O2) for 60 minutes, and livers obtained. Total hepatic RNA was extracted, and mRNA expression was analyzed (RT-qPCR) for GC and insulin receptor sensitive genes: GC: Fkbp5, Gilz, Nr3c1 (Gr), Nr3c2 (Mr), Per1, Ttpa. INSULIN: Akt2, G6Pase, Igf1r, Insr, Irs1, Irs2, Pik3cb, Pik3r1, Srebp1c. CORT113176 decreased the expression of all baseline hepatic insulin receptor mRNAs in both sexes, except for G6Pase. Pik3r1 mRNA expression significantly decreased with 60 minutes of normoxic separation (fasting) in males and females compared to baseline and hypoxic separation; this was blocked by CORT113176. In the GC receptor sensitive panel, CORT113176 decreased basal Nr3c1 (Gr) mRNA. Normoxic and hypoxic separation increased Per1 and Gilz mRNA expression; this effect was blocked by CORT113176. Interestingly, Fkbp5 expression, a proposed clinical marker for GR antagonism, was not altered by CORT113176. The hepatic GC and insulin receptor sensitive gene mRNA panels we developed are sensitive to GR antagonism suggesting they may be a useful addition to Fkbp5. The increase in endogenous corticosterone, acting via GR, is critical in the hepatic response to stress in our neonatal rat model of hypoxia and prematurity.
Gene Expression to Guide Glucocorticoid Replacement in Autoimmune Addison’s Disease
Authors: Sævik Åse Bjorvatn , Wolff Anette , Björnsdottir Sigridur , Simunkova Katerina , Hynne Martha S , Dolan David , Bratland Eirik , Knappskog Per , Methlie Paal , Carlsen Siri , Isaksson Magnus , Bensing Sophie , Kämpe Olle , Husebye Eystein Sverre , Løvås Kristian , Øksnes Marianne 
Published: May 2021

Abstract
Objective: Deciding the optimal doses of glucocorticoid (GC) replacement treatment in autoimmune Addison’s disease (AAD) is impeded by the lack of reliable biomarkers. This frequently results in over-treatment, with alarming and persistent side-effects, or under-replacement, which could be fatal. There is a need to think new in the quest for robust biomarkers to optimize GC replacement in AAD at an individual level.
Aim: We aimed to identify genes that are consistently up- or down-regulated in patients with AAD in response to different GC replacement doses. This information can be used to establish novel biomarkers to guide GC treatment in AAD.
Methods: Step 1: Global microarray expression analysis on RNA from whole blood before and after intravenous infusion of 100 mg hydrocortisone (HC) in 10 patients with AAD. To verify the results, we performed real-time PCR to compare gene expression levels of three of the highly differentially expressed genes (FKBP5, MMP9, and DSIPI) to compare gene expression levels before and two, four, and six hours after the HC infusion. Step 2: Rt-PCR to compare expression levels of 93 GC-regulated genes in normal versus very low morning cortisol levels in 27 patients with AAD.
Results: Step 1: Two hours after infusion of 100 mg HC, there was a marked increase in FKBP5, MMP9, and DSIPI expression levels. MMP9 and DSIPI expression levels correlated with serum cortisol. Step 2: Expression levels of CEBPB, DDIT4, FKBP5, DSIPI, and VDR were increased and ADARB1, ARIDB5, and POU2F1 decreased in normal versus very low morning cortisol. Normal serum cortisol levels positively correlated with DSIPI, DDIT4, and FKBP5 expression.
Conclusions: We introduce gene expression as a novel approach to guide GC replacement in AAD. We suggest that gene expression of DSIPI, DDIT4, and FKBP5 are particularly promising candidate biomarkers of GC replacement, followed by MMP9, CEBPB, VDR, ADARB1, ARID5B, and POU2F1.