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Sample records for human h295r adrenocortical

  1. H295R Human Adrenocortical Carcinoma Cells as a Screening Platform for Steroidogenesis (NC SOT)

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    Proper biosynthesis and metabolism of steroid hormones is essential for development and reproduction. Disruption of steroidogenesis by environmental toxicants results in altered hormone levels causing adverse reproductive and developmental effects. H295R human adrenocortical carc...

  2. Effects of ToxCast Phase I Chemicals on Steroidogenesis in H295R Human Adrenocortical Carcinoma cells (SOT)

    Science.gov (United States)

    Steroid hormones are essential for proper development and reproduction. Disruption of steroidogenesis by environmental toxicants results in altered hormone levels causing adverse reproductive and developmental effects. H295R human adrenocortical carcinoma cells were used to evalu...

  3. High-throughput screening of chemical effects on steroidogenesis using H295R human adrenocortical carcinoma cells

    Science.gov (United States)

    Disruption of steroidogenesis by environmental chemicals can result in altered hormone levels causing adverse reproductive and developmental effects. A high-throughput assay using H295R human adrenocortical carcinoma cells was used to evaluate the effect of 2,060 chemical samples...

  4. Antiandrogenic mechanisms of pesticides in human LNCaP prostate and H295R adrenocortical carcinoma cells.

    Science.gov (United States)

    Robitaille, Christina N; Rivest, Patricia; Sanderson, J Thomas

    2015-01-01

    Several pesticides suspected or known to have endocrine disrupting effects were screened for pro- or antiandrogenic properties by determining their effects on proliferation, prostatic-specific antigen (PSA) secretion and androgen receptor (AR) expression, and AR phosphorylation in androgen-dependent LNCaP human prostate cancer cells, as well as on the expression and catalytic activity of the enzyme CYP17 in H295R human adrenocortical carcinoma cells, an in vitro model of steroidogenesis. Effects on SRD5A gene expression were determined in both cell lines. Benomyl, vinclozolin, and prochloraz, but not atrazine, concentration dependently (1-30 μM) decreased dihydrotestosterone (DHT)-stimulated proliferation of LNCaP cells. All pesticides except atrazine decreased DHT-stimulated PSA secretion, AR nuclear accumulation, and AR phosphorylation on serines 81 and 213 in LNCaP cells. Benomyl and prochloraz, but not vinclozolin or atrazine, decreased levels of CYP17 gene and protein expression, as well as catalytic activity in H295R cells. In the case of prochloraz, some of these effects corresponded with cytotoxicity. H295R cells expressed AR protein and SRD5A1, but not SRD5A2 transcripts. SRD5A1 gene expression in H295R cells was increased by 10 nM DHT, whereas in LNCaP cells significant induction was observed by 0.1 nM DHT. AR protein expression in H295R cells was not increased by DHT. Vinclozolin decreased DHT-induced SRD5A1 gene expression in LNCaP, but not H295R cells, indicating a functional difference of AR between the cell lines. In conclusion, pesticides may exert antiandrogenic effects through several mechanisms that are cell type-specific, including AR antagonism and down-regulation or catalytic inhibition of androgen biosynthetic enzymes, such as CYP17 and SRD5A1. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  5. High-Throughput Screening of Chemical Effects on Steroidogenesis Using H295R Human Adrenocortical Carcinoma Cells.

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    Karmaus, Agnes L; Toole, Colleen M; Filer, Dayne L; Lewis, Kenneth C; Martin, Matthew T

    2016-04-01

    Disruption of steroidogenesis by environmental chemicals can result in altered hormone levels causing adverse reproductive and developmental effects. A high-throughput assay using H295R human adrenocortical carcinoma cells was used to evaluate the effect of 2060 chemical samples on steroidogenesis via high-performance liquid chromatography followed by tandem mass spectrometry quantification of 10 steroid hormones, including progestagens, glucocorticoids, androgens, and estrogens. The study employed a 3 stage screening strategy. The first stage established the maximum tolerated concentration (MTC; ≥ 70% viability) per sample. The second stage quantified changes in hormone levels at the MTC whereas the third stage performed concentration-response (CR) on a subset of samples. At all stages, cells were prestimulated with 10 µM forskolin for 48 h to induce steroidogenesis followed by chemical treatment for 48 h. Of the 2060 chemical samples evaluated, 524 samples were selected for 6-point CR screening, based in part on significantly altering at least 4 hormones at the MTC. CR screening identified 232 chemical samples with concentration-dependent effects on 17β-estradiol and/or testosterone, with 411 chemical samples showing an effect on at least one hormone across the steroidogenesis pathway. Clustering of the concentration-dependent chemical-mediated steroid hormone effects grouped chemical samples into 5 distinct profiles generally representing putative mechanisms of action, including CYP17A1 and HSD3B inhibition. A distinct pattern was observed between imidazole and triazole fungicides suggesting potentially distinct mechanisms of action. From a chemical testing and prioritization perspective, this assay platform provides a robust model for high-throughput screening of chemicals for effects on steroidogenesis.

  6. Orexin-A regulates cell apoptosis in human H295R adrenocortical cells via orexin receptor type 1 through the AKT signaling pathway.

    Science.gov (United States)

    Chang, Xiaocen; Zhao, Yuyan; Ju, Shujing; Guo, Lei

    2015-11-01

    Numerous studies have demonstrated the ability of orexin-A to regulate adrenocortical cells through the mitogen-activated protein kinase signaling pathway. In the present study, human H295R adrenocortical cells were exposed to orexin‑A (10‑10-10‑6 M), with orexin receptor type 1 (OX1 receptor) antagonist SB334867 or AKT antagonist PF‑04691502. It was found that orexin‑A stimulated H295R cell proliferation, reduced the pro‑apoptotic activity of caspase‑3 to protect against apoptotic cell death and increased cortisol secretion. Furthermore, phospho‑AKT protein was increased by orexin‑A. SB334867 (10‑6 M) and PF‑04691502 (10‑6 M) abolished the effects of orexin‑A (10‑6 M). These results suggested that the orexin‑A/OX1 receptor axis has a significant pro-survival function in adrenal cells, which is mediated by AKT activation. Further studies investigating the effects of orexin-A-upregulation may further elucidate the diverse biological effects of orexin-A in adrenal cells.

  7. Effects of Neonicotinoids on Promoter-Specific Expression and Activity of Aromatase (CYP19) in Human Adrenocortical Carcinoma (H295R) and Primary Umbilical Vein Endothelial (HUVEC) Cells.

    Science.gov (United States)

    Caron-Beaudoin, Élyse; Denison, Michael S; Sanderson, J Thomas

    2016-01-01

    The enzyme aromatase (CYP19; cytochrome P450 19) in humans undergoes highly tissue- and promoter-specific regulation. In hormone-dependent breast cancer, aromatase is over-expressed via several normally inactive promoters (PII, I.3, I.7). Aromatase biosynthesizes estrogens, which stimulate breast cancer cell proliferation. The placenta produces estrogens required for healthy pregnancy and the major placental CYP19 promoter is I.1. Exposure to certain pesticides, such as atrazine, is associated with increased CYP19 expression, but little is known about the effects of neonicotinoid insecticides on CYP19. We developed sensitive and robust RT-qPCR methods to detect the promoter-specific expression of CYP19 in human adrenocortical carcinoma (H295R) and primary umbilical vein endothelial (HUVEC) cells, and determined the potential promoter-specific disruption of CYP19 expression by atrazine and the commonly used neonicotinoids imidacloprid, thiacloprid, and thiamethoxam. In H295R cells, atrazine concentration-dependently increased PII- and I.3-mediated CYP19 expression and aromatase catalytic activity. Thiacloprid and thiamethoxam induced PII- and I.3-mediated CYP19 expression and aromatase activity at relatively low concentrations (0.1-1.0 µM), exhibiting non-monotonic concentration-response curves with a decline in gene induction and catalytic activity at higher concentrations. In HUVEC cells, atrazine slightly induced overall (promoter-indistinct) CYP19 expression (30 µM) and aromatase activity (≥ 3 µM), without increasing I.1 promoter activity. None of the neonicotinoids increased CYP19 expression or aromatase activity in HUVEC cells. Considering the importance of promoter-specific (over)expression of CYP19 in disease (breast cancer) or during sensitive developmental periods (pregnancy), our newly developed RT-qPCR methods will be helpful tools in assessing the risk that neonicotinoids and other chemicals may pose to exposed women.

  8. Endocrine disruptive effects of cadmium on steroidogenesis: human adrenocortical carcinoma cell line NCI-H295R as a cellular model for reproductive toxicity testing.

    Science.gov (United States)

    Knazicka, Zuzana; Forgacs, Zsolt; Lukacova, Jana; Roychoudhury, Shubhadeep; Massanyi, Peter; Lukac, Norbert

    2015-01-01

    Cadmium (Cd) is a known endocrine disruptor with the ability to affect the production of hormones involved in the regulation of reproductive processes. In this study human adrenocortical carcinoma cell line NCI-H295R was used as an in vitro biological model to study the effect of cadmium (CdCl2) on steroidogenesis. The cell cultures were exposed to different concentrations of CdCl2 (1.90, 3.90, 7.80, 15.60, 31.20 and 62.50 μM) and compared to control (medium without CdCl2). Cell viability was measured by the metabolic activity (MTT) assay for estimation of mitochondria structural integrity. Quantification of sexual steroid production directly from aliquots of the medium was performed by enzyme linked immunosorbent assay (ELISA). Following 48 h culture of the cells in the presence of CdCl2 a concentration-dependent depletion in progesterone production was observed at the lower concentrations of CdCl2. The lowest amount of progesterone was significantly detected in groups with the higher doses (≥ 31.20 μM) of CdCl2, which elicited significant (P 75%) up to 7.80 μM of CdCl2 and significantly (P disruptive effects on sexual steroid synthesis even at very low concentrations.

  9. Resveratrol inhibits androgen production of human adrenocortical H295R cells by lowering CYP17 and CYP21 expression and activities

    Science.gov (United States)

    Marti, Nesa; Bouchoucha, Nadia; Sauter, Kay-Sara

    2017-01-01

    Resveratrol, a natural compound found in grapes, became very popular for its suggested protective effects against aging. It was reported to have similar positive effects on the human metabolism as caloric restriction. Recently, positive effects of resveratrol on steroid biosynthesis in cell systems and in humans suffering from polycystic ovary syndrome have also been reported, but the exact mechanism of this action remains unknown. Sirtuins seem targeted by resveratrol to mediate its action on energy homeostasis. In this study, we investigated the mechanisms of action of resveratrol on steroidogenesis in human adrenal H295R cells. Resveratrol was found to inhibit protein expression and enzyme activities of CYP17 and CYP21. It did not alter CYP17 and CYP21 mRNA expression, nor protein degradation. Only SIRT3 mRNA expression was found to be altered by resveratrol, but SIRT1, 3 and 5 overexpression did not result in a change in the steroid profile of H295R cells, indicating that resveratrol may not engage sirtuins to modulate steroid production. Previous studies showed that starvation leads to a hyperandrogenic steroid profile in H295R cells through inhibition of PKB/Akt signaling, and that resveratrol inhibits steroidogenesis of rat ovarian theca cells via the PKB/Akt pathway. Therefore, the effect of resveratrol on PKB/Akt signaling was tested in H295R cells and was found to be decreased under starvation growth conditions, but not under normal growth conditions. Overall, these properties of action together with recent clinical findings make resveratrol a candidate for the treatment of hyperandrogenic disorders such as PCOS. PMID:28323907

  10. Mitotane effects in a H295R xenograft model of adjuvant treatment of adrenocortical cancer.

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    Lindhe, O; Skogseid, B

    2010-09-01

    Adrenocortical cancer is one of the most aggressive endocrine malignancies. Growth through the capsule or accidental release of cancer cells during surgery frequently results in metastatic disease. We investigated the antitumoral effect of 2 adrenocorticolytic compounds, O, P'-DDD and MeSO2-DDE, in the adrenocortical cell line H295R both in vitro and as a xenograft model in vivo. H295R cells were injected s. c. in nude mice. O, P'-DDD, MeSO2-DDE, or oil (control) was administered i. p., either simultaneously with cell injection at day 0 (mimicking adjuvant treatment), or at day 48 (established tumors). Accumulation of PET tracers [ (11)C]methionine (MET), [ (11)C] metomidate (MTO), 2-deoxy-2-[ (18)F]fluoro-d-glucose (FDG), and [ (18)F]-l-tyrosine (FLT) in the aggregates were assessed +/- drug treatment in vitro. Tumor growth was significantly inhibited when O, P'-DDD was given at the same time as injection of tumor cells. No significant growth inhibition was observed after treatment with O, P'-DDD at day 48. A significant reduction in FLT uptake and an increased FDG uptake, compared to control, were observed following treatment with 15 microM O, P'-DDD (p<0.01) in vitro. MeSO2-DDE (15 microM) treatment gave rise to a reduced MET and an increased FLT uptake (p<0.01). Both compounds reduced the uptake of MTO compared to control (p<0.01). Treatment with O, P'-DDD simultaneously to inoculation of H295R cells in mice, imitating release of cells during surgery, gave a markedly better effect than treatment of established H295R tumors. We suggest that FLT may be a potential PET biomarker when assessing adrenocortical cancer treatment with O,P'-DDD. Further studies in humans are needed to investigate this.

  11. Exposure to the three structurally different PCB congeners (PCB 118, 153, and 126) results in decreased protein expression and altered steroidogenesis in the human adrenocortical carcinoma cell line H295R.

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    Tremoen, Nina Hårdnes; Fowler, Paul A; Ropstad, Erik; Verhaegen, Steven; Krogenæs, Anette

    2014-01-01

    Polychlorinated biphenyls (PCB), synthetic, persistent organic pollutants (POP), are detected ubiquitously, in water, soil, air, and sediments, as well as in animals and humans. PCB are associated with range of adverse health effects, such as interference with the immune system and nervous system, reproductive abnormalities, fetotoxicity, carcinogenicity, and endocrine disruption. Our objective was to determine the effects of three structurally different PCB congeners, PCB118, PCB 126, and PCB 153, each at two concentrations, on the steroidogenic capacity and proteome of human adrenocortical carcinoma cell line cultures (H295R) . After 48 h of exposure, cell viability was monitored and estradiol, testosterone, cortisol and progesterone secretion measured to quantify steroidogenic capacity of the cells. Two-dimensional (2D) gel-based proteomics was used to screen for proteome alterations in H295R cells in response to the PCB. Exposure to PCB 118 increased estradiol and cortisol secretion, while exposure to PCB 153 elevated estradiol secretion. PCB 126 was the most potent congener, increasing estradiol, cortisol, and progesterone secretion in exposed H295R cells. Seventy-three of the 711 spots analyzed showed a significant difference in normalized spot volumes between controls (vehicle only) and at least one exposure group. Fourteen of these protein spots were identified by liquid chromatography with mass spectroscopy (LC-MS/MS). Exposure to three PCB congeners with different chemical structure perturbed steroidogenesis and protein expression in the H295R in vitro model. This study represents an initial analysis of the effects on proteins and hormones in the H295R cell model, and additional studies are required in order to obtain a more complete understanding of the pathways disturbed by PCB congeners in H295R cells. Overall, alterations in protein regulation and steroid hormone synthesis suggest that exposure to PCB disturbs several cellular processes, including

  12. Effects of bisphenol A-related diphenylalkanes on vitellogenin production in male carp (Cyprinus carpio) hepatocytes and aromatase (CYP19) activity in human H295R adrenocortical carcinoma cells.

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    Letcher, Robert J; Sanderson, J Thomas; Bokkers, Abraham; Giesy, John P; van den Berg, Martin

    2005-12-01

    The present study investigated the effects of the known xenoestrogen bisphenol A (BPA) relative to eight BPA-related diphenylalkanes on estrogen receptor (ER)-mediated vitellogenin (vtg) production in hepatocytes from male carp (Cyprinus carpio), and on aromatase (CYP19) activity in the human adrenocortical H295R carcinoma cell line. Of the eight diphenylalkanes, only 4,4'-(hexafluoropropylidene)diphenol (BHF) and 2,2'-bis(4-hydroxy-3-methylphenyl)propane (BPRO) induced vtg, i.e., to a maximum of 3% to 4% (at 100 microM) compared with 8% for BPA relative to the maximum induction by 17beta-estradiol (E2, 1 microM). Bisphenol A diglycidyl ether (BADGE) was a potent antagonist of vtg production with an IC50 of 5.5 microM, virtually 100% inhibition of vtg at 20 microM, and an inhibitive (IC50) potency about one-tenth that of the known ER antagonist tamoxifen (IC50, 0.6 microM). 2,2'-Diallyl bisphenol A, 4,4'-(1,4-phenylene-diisopropylidene)bisphenol, BPRO, and BHF were much less inhibitory with IC50 concentrations of 20-70 microM, and relative potencies of 0.03 and 0.009 with tamoxifen. Bisphenol ethoxylate showed no anti-estrogenicity (up to 100 microM), and 4,4'-isopropylidene-diphenol diacetate was only antagonistic at 100 microM. When comparing the (anti)estrogenic potencies of these bisphenol A analogues/diphenylalkanes, anti-estrogenicity occurred at lower concentrations than estrogenicity. 4,4'-Isopropylidenebis(2,6-dimethylphenol) (IC50, 2.0 microM) reduced E2-induced (EC50, 100 nM) vtg production due to concentration-dependent cytotoxicity as indicated by a parallel decrease in MTT activity and vtg, whereas the remaining diphenylalkanes did not cause any cytotoxicity relative to controls. None of the diphenylalkanes (up to 100 microM) induced EROD activity indicating that concentration-dependent, CYP1A enzyme-mediated metabolism of E2, or any Ah-receptor-mediated interaction with the ER, was not a likely explanation for the observed anti-estrogenic effects. At

  13. Rosiglitazone induces autophagy in H295R and cell cycle deregulation in SW13 adrenocortical cancer cells

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    Cerquetti, Lidia; Sampaoli, Camilla [Endocrinology, Department of Clinical and Molecular Medicine, Sant' Andrea Hospital, Faculty of Medicine and Psychology ' Sapienza' University of Rome, Via di Grottarossa, 1035-00189 Rome (Italy); Research Center S. Pietro Hospital, Via Cassia, 600-00189 Rome (Italy); Amendola, Donatella; Bucci, Barbara [Research Center S. Pietro Hospital, Via Cassia, 600-00189 Rome (Italy); Masuelli, Laura [Department of Experimental Medicine, ' Sapienza' University of Rome, Rome (Italy); Marchese, Rodolfo [Research Center S. Pietro Hospital, Via Cassia, 600-00189 Rome (Italy); Misiti, Silvia [Endocrinology, Department of Clinical and Molecular Medicine, Sant' Andrea Hospital, Faculty of Medicine and Psychology ' Sapienza' University of Rome, Via di Grottarossa, 1035-00189 Rome (Italy); Research Center S. Pietro Hospital, Via Cassia, 600-00189 Rome (Italy); De Venanzi, Agostino; Poggi, Maurizio; Toscano, Vincenzo [Endocrinology, Department of Clinical and Molecular Medicine, Sant' Andrea Hospital, Faculty of Medicine and Psychology ' Sapienza' University of Rome, Via di Grottarossa, 1035-00189 Rome (Italy); Stigliano, Antonio, E-mail: antonio.stigliano@uniroma1.it [Endocrinology, Department of Clinical and Molecular Medicine, Sant' Andrea Hospital, Faculty of Medicine and Psychology ' Sapienza' University of Rome, Via di Grottarossa, 1035-00189 Rome (Italy); Research Center S. Pietro Hospital, Via Cassia, 600-00189 Rome (Italy)

    2011-06-10

    Thiazolidinediones, specific peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) ligands, used in type-2 diabetes therapy, show favourable effects in several cancer cells. In this study we demonstrate that the growth of H295R and SW13 adrenocortical cancer cells is inhibited by rosiglitazone, a thiazolidinediones member, even though the mechanisms underlying this effect appeared to be cell-specific. Treatment with GW9662, a selective PPAR-{gamma}-inhibitor, showed that rosiglitazone acts through both PPAR-{gamma}-dependent and -independent mechanisms in H295R, while in SW13 cells the effect seems to be independent of PPAR-{gamma}. H295R cells treated with rosiglitazone undergo an autophagic process, leading to morphological changes detectable by electron microscopy and an increased expression of specific proteins such as AMPK{alpha} and beclin-1. The autophagy seems to be independent of PPAR-{gamma} activation and could be related to an increase in oxidative stress mediated by reactive oxygen species production with the disruption of the mitochondrial membrane potential, triggered by rosiglitazone. In SW13 cells, flow cytometry analysis showed an arrest in the G0/G1 phase of the cell cycle with a decrease of cyclin E and cdk2 activity, following the administration of rosiglitazone. Our data show the potential role of rosiglitazone in the therapeutic approach to adrenocortical carcinoma and indicate the molecular mechanisms at the base of its antiproliferative effects, which appear to be manifold and cell-specific in adrenocortical cancer lines.

  14. Orexin-stimulated MAP kinase cascades are activated through multiple G-protein signalling pathways in human H295R adrenocortical cells: diverse roles for orexins A and B.

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    Ramanjaneya, Manjunath; Conner, Alex C; Chen, Jing; Kumar, Prashanth; Brown, James E P; Jöhren, Olaf; Lehnert, Hendrik; Stanfield, Peter R; Randeva, Harpal S

    2009-08-01

    Orexins A and B (ORA and ORB) are neuropeptide hormones found throughout the central nervous system and periphery. They are required for a host of physiological processes including mitogen-activated protein kinase (MAPK) regulation, steroidogenesis, appetite control and energy regulation. While some signalling mechanisms have been proposed for individual recombinant orexin receptors in generic mammalian cell types, it is clear that the peripheral effects of orexin are spatially and temporally complex. This study dissects the different G-protein signalling and MAPK pathways activated in a pluripotent human adrenal H295R cell line capable of all the physiological steps involved in steroidogenesis. Both extracellular receptor kinase 1/2 (ERK1/2) and p38 were phosphorylated rapidly with a subsequent decline, in a time- and dose-dependent manner, in response to both ORA and ORB. Conversely, there was little or no direct activation of the ERK5 or JNK pathway. Analysis using signalling and MAPK inhibitors as well as receptor-specific antagonists determined the precise mediators of the orexin response in these cells. Both ERK1/2 and p38 activation were predominantly G(q)- and to a lesser extent G(s)-mediated; p38 activation even had a small G(i)-component. Effects were broadly comparable for both orexin sub-types ORA and ORB and although most of the effects were transmitted through the orexin receptor-1 subtype, we did observe a role for orexin receptor-2-mediated activation of both ERK1/2 and p38. Cortisol secretion also differed in response to ORA and ORB. These data suggest multiple roles for orexin-mediated MAPK activation in an adrenal cell-line, this complexity may help to explain the diverse biological actions of orexins with wide-ranging consequences for our understanding of the mechanisms initiated by these steroidogenic molecules.

  15. NCI-H295R, a human adrenal cortex-derived cell line, expresses purinergic receptors linked to Ca²⁺-mobilization/influx and cortisol secretion.

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    Haruhisa Nishi

    Full Text Available Purinergic receptor expression and involvement in steroidogenesis were examined in NCI-H295R (H295R, a human adrenal cortex cell line which expresses all the key enzymes necessary for steroidogenesis. mRNA/protein for multiple P1 (A(2A and A(2B, P2X (P2X₅ and P2X₇, and P2Y (P2Y₁, P2Y₂, P2Y₆, P2Y₁₂, P2Y₁₃, and P2Y₁₄ purinergic receptors were detected in H295R. 2MeS-ATP (10-1000 µM, a P2Y₁ agonist, induced glucocorticoid (GC secretion in a dose-dependent manner, while other extracellular purine/pyrimidine agonists (1-1000 µM had no distinct effect on GC secretion. Extracellular purines, even non-steroidogenic ones, induced Ca²⁺-mobilization in the cells, independently of the extracellular Ca²⁺ concentration. Increases in intracellular Ca²⁺ concentration induced by extracellular purine agonists were transient, except when induced by ATP or 2MeS-ATP. Angiotensin II (AngII: 100 nM and dibutyryl-cyclic AMP (db-cAMP: 500 µM induced both GC secretion and Ca²⁺-mobilization in the presence of extracellular Ca²⁺ (1.2 mM. GC secretion by AngII was reduced by nifedipine (10-100 µM; whereas the Ca²⁺ channel blocker did not inhibit GC secretion by 2MeS-ATP. Thapsigargin followed by extracellular Ca²⁺ exposure induced Ca²⁺-influx in H295R, and the cells expressed mRNA/protein of the component molecules for store-operated calcium entry (SOCE: transient receptor C (TRPC channels, calcium release-activated calcium channel protein 1 (Orai-1, and the stromal interaction molecule 1 (STIM1. In P2Y₁-knockdown, 2MeS-ATP-induced GC secretion was significantly inhibited. These results suggest that H295R expresses a functional P2Y₁ purinergic receptor for intracellular Ca²⁺-mobilization, and that P2Y₁ is linked to SOCE-activation, leading to Ca²⁺-influx which might be necessary for glucocorticoid secretion.

  16. Screening Chemical Effects on Steroidogenesis in H295R Human Adrenocortical Carcinoma Cells (SOT)

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    Proper endocrine function requires steroid hormone biosynthesis and metabolism (steroidogenesis). Disruption of steroidogenesis by environmental chemicals can result in altered hormone levels causing adverse reproductive and developmental effects. This study is the first to estab...

  17. Effects of bisphenol analogues on steroidogenic gene expression and hormone synthesis in H295R cells.

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    Feng, Yixing; Jiao, Zhihao; Shi, Jiachen; Li, Ming; Guo, Qiaozhen; Shao, Bing

    2016-03-01

    The use of Bisphenol A (BPA) has been regulated in many countries because of its potential adverse effects on human health. As a result of the restriction, structural anologues such as bisphenol S (BPS) and bisphenol F (BPF) have already been used for industrial applications as alternatives to BPA. Bisphenol AF (BPAF) is mainly used as a crosslinker in the synthesis of specialty fluoroelastomers. These compounds have been detected in various environmental matrices and human samples. Previous studies have shown that these compounds have potential endocrine disrupting effects on wildlife and mammals in general. However, the effects on adrenocortical function and the underlying mechanisms are not fully understood. In the present study, the H295R cell line was used as a model to compare the cell toxicity and to investigate the potential endocrine disrupting action of four BPs (including BPA, BPS, BPF, and BPAF). The half lethal concentration (LC50) values at 72 h exposure indicated that the rank order of toxicities of the chemicals was BPAF > BPA > BPS > BPF. The hormone results demonstrated that BPA analogues, such as BPF, BPS and BPAF were capable of altering steroidogenesis in H295R cells. BPA and BPS exhibited inhibition of hormone production, BPF predominantly led to increased progesterone and 17β-estradiol levels and BPAF showed induction of progesterone and reduction of testosterone. Inhibition effects of BPA and BPAF on hormone production were probably mediated by down-regulation of steroidogenic genes in H295R cells. However, the mechanisms of the endocrine interrupting action of BPF and BPS are still unclear, which may have additional mechanisms that have not been detected with BPA.

  18. Perfluorooctyl Iodide Stimulates Steroidogenesis in H295R Cells via a Cyclic Adenosine Monophosphate Signaling Pathway.

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    Wang, Chang; Ruan, Ting; Liu, Jiyan; He, Bin; Zhou, Qunfang; Jiang, Guibin

    2015-05-18

    Perfluorinated iodine alkanes (PFIs) are used widely in the organic fluorine industry. Increased production of PFIs has caused environmental health concerns. To evaluate the potential endocrine-disrupting effect of PFIs, we investigated the effects of perfluorooctyl iodide (PFOI) on steroidogenesis in human adrenocortical carcinoma cells (H295R). Levels of aldosterone, cortisol, 17β-estradiol, and testosterone were measured in H295R culture medium upon treatment with perfluorooctanoic acid (PFOA) and PFIs. Expression of 10 steroidogenic genes (StAR, HMGR, CYP11A1, 3βHSD2, 17βHSD, CYP17, CYP21, CYP11B1, CYP11B2, and CYP19) was measured by real-time polymerase chain reaction. Levels of cyclic adenosine monophosphate (cAMP) and adenylate cyclase (AC) activity were measured to understand the underlying mechanism of steroidogenic perturbations. Levels of production of aldosterone, cortisol, and 17β-estradiol were elevated significantly, and the level of testosterone generation decreased upon treatment with 100 μM PFOI. Similar to the effect induced by forskolin (AC activator), expression of all 10 genes involved in the synthesis of steroid hormones was upregulated significantly upon exposure to 100 μM PFOI. PFOA had no effect on steroid hormone production or steroidogenic gene expression even though it is highly structurally similar with PFOI. Therefore, the terminal -CF2I group in PFOI could be a critical factor for mediation of steroidogenesis. PFOI increased AC activity and cAMP levels in H295R cells, which implied an underlying mechanism for the disturbance of steroidogenesis. These data suggest that PFOI may act as an AC activator, thereby stimulating steroidogenesis by activating a cAMP signaling pathway.

  19. Steroid hormone related effects of marine persistent organic pollutants in human H295R adrenocortical carcinoma cells

    NARCIS (Netherlands)

    Dungen, van den M.W.; Rijk, J.C.W.; Kampman, E.; Steegenga, W.T.; Murk, A.J.

    2015-01-01

    Persistent organic pollutants (POPs) such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorobiphenyl (PCB) 126 and 153, perfluorooctanesulfonic acid (PFOS), hexabromocyclododecane (HBCD), 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), tributyltin (TBT), and methylmercury (MeHg) can be accumulat

  20. Corticosteroid production in H295R cells during exposure to 3 endocrine disrupters analyzed with LC-MS/MS

    DEFF Research Database (Denmark)

    Winther, Christina S; Nielsen, Frederik K; Hansen, Martin

    2013-01-01

    The adrenocortical human cell line H295R is a valuable tool for screening endocrine disrupting compounds. In general, previous research focus has been on the production of the 2 sex steroids, 17β-estradiol and testosterone, and less attention has been paid to other important steroid end points......295R cell line. The method was applied by studying the effects of 2 model endocrine disrupters, ketoconazole and prochloraz, the pharmaceutical budesonide, and the inducer forskolin on the steroid production in this cell line. Dose-response curves were obtained for the correlation between hormone...... concentrations and the concentration of the individual disruptors. Exposing cells to ketoconazole resulted in a decrease in cortisol and corticosterone concentrations in a dose-dependent manner with EC₅₀ values of 0.24 and 0.40 μmol/L, respectively. The same applied for cells exposed to prochloraz with EC₅₀...

  1. Mixture Effects of 3 Mechanistically Different Steroidogenic Disruptors (Prochloraz, Genistein, and Ketoconazole) in the H295R Cell Assay

    DEFF Research Database (Denmark)

    Nielsen, Frederik Knud; Hansen, Cecilie Hurup; Fey, Jennifer Anna

    2015-01-01

    Mixture effects of 3 model endocrine disruptors, prochloraz, ketoconazole, and genistein, on steroidogenesis were tested in the adrenocortical H295R cell line. Seven key steroid hormones (pregnenolone, progesterone, dehydroepiandrosterone, androstenedione, testosterone, estrone, and 17β...... the H295R cell line was suitable for evaluating mixture toxicity of endocrine disruptors with different modes of action. The compounds were chosen because they interfere with steroidogenesis in different ways. They all individually decrease the concentrations of the main sex steroids downstream...... with the H295R cell assay is a useful tool also for studying how mixtures of endocrine disruptors with differing modes of action interfere with the steroidogenic pathway and that existing models like concentration addition are insufficient in such cases. Furthermore, for end points where compounds exert...

  2. Estimation of the Mechanism of Adrenal Action of Endocrine-Disrupting Compounds Using a Computational Model of Adrenal Steroidogenesis in NCI-H295R Cells

    Directory of Open Access Journals (Sweden)

    Ryuta Saito

    2016-01-01

    Full Text Available Adrenal toxicity is one of the major concerns in drug development. To quantitatively understand the effect of endocrine-active compounds on adrenal steroidogenesis and to assess the human adrenal toxicity of novel pharmaceutical drugs, we developed a mathematical model of steroidogenesis in human adrenocortical carcinoma NCI-H295R cells. The model includes cellular proliferation, intracellular cholesterol translocation, diffusional transport of steroids, and metabolic pathways of adrenal steroidogenesis, which serially involve steroidogenic proteins and enzymes such as StAR, CYP11A1, CYP17A1, HSD3B2, CYP21A2, CYP11B1, CYP11B2, HSD17B3, and CYP19A1. It was reconstructed in an experimental dynamics of cholesterol and 14 steroids from an in vitro steroidogenesis assay using NCI-H295R cells. Results of dynamic sensitivity analysis suggested that HSD3B2 plays the most important role in the metabolic balance of adrenal steroidogenesis. Based on differential metabolic profiling of 12 steroid hormones and 11 adrenal toxic compounds, we could estimate which steroidogenic enzymes were affected in this mathematical model. In terms of adrenal steroidogenic inhibitors, the predicted action sites were approximately matched to reported target enzymes. Thus, our computer-aided system based on systems biological approach may be useful to understand the mechanism of action of endocrine-active compounds and to assess the human adrenal toxicity of novel pharmaceutical drugs.

  3. Estimation of the Mechanism of Adrenal Action of Endocrine-Disrupting Compounds Using a Computational Model of Adrenal Steroidogenesis in NCI-H295R Cells.

    Science.gov (United States)

    Saito, Ryuta; Terasaki, Natsuko; Yamazaki, Makoto; Masutomi, Naoya; Tsutsui, Naohisa; Okamoto, Masahiro

    2016-01-01

    Adrenal toxicity is one of the major concerns in drug development. To quantitatively understand the effect of endocrine-active compounds on adrenal steroidogenesis and to assess the human adrenal toxicity of novel pharmaceutical drugs, we developed a mathematical model of steroidogenesis in human adrenocortical carcinoma NCI-H295R cells. The model includes cellular proliferation, intracellular cholesterol translocation, diffusional transport of steroids, and metabolic pathways of adrenal steroidogenesis, which serially involve steroidogenic proteins and enzymes such as StAR, CYP11A1, CYP17A1, HSD3B2, CYP21A2, CYP11B1, CYP11B2, HSD17B3, and CYP19A1. It was reconstructed in an experimental dynamics of cholesterol and 14 steroids from an in vitro steroidogenesis assay using NCI-H295R cells. Results of dynamic sensitivity analysis suggested that HSD3B2 plays the most important role in the metabolic balance of adrenal steroidogenesis. Based on differential metabolic profiling of 12 steroid hormones and 11 adrenal toxic compounds, we could estimate which steroidogenic enzymes were affected in this mathematical model. In terms of adrenal steroidogenic inhibitors, the predicted action sites were approximately matched to reported target enzymes. Thus, our computer-aided system based on systems biological approach may be useful to understand the mechanism of action of endocrine-active compounds and to assess the human adrenal toxicity of novel pharmaceutical drugs.

  4. Steroid profiling in H295R cells to identify chemicals potentially disrupting the production of adrenal steroids.

    Science.gov (United States)

    Strajhar, Petra; Tonoli, David; Jeanneret, Fabienne; Imhof, Raphaella M; Malagnino, Vanessa; Patt, Melanie; Kratschmar, Denise V; Boccard, Julien; Rudaz, Serge; Odermatt, Alex

    2017-02-21

    The validated OECD test guideline 456 based on human adrenal H295R cells promotes measurement of testosterone and estradiol production as read-out to identify potential endocrine disrupting chemicals. This study aimed to establish optimal conditions for using H295R cells to detect chemicals interfering with the production of key adrenal steroids. H295R cells' supernatants were characterized by liquid chromatography-mass spectrometry (LC-MS)-based steroid profiling, and the influence of experimental conditions including time and serum content was assessed. Steroid profiles were determined before and after incubation with reference compounds and chemicals to be tested for potential disruption of adrenal steroidogenesis. The H295R cells cultivated according to the OECD test guideline produced progestins, glucocorticoids, mineralocorticoids and adrenal androgens but only very low amounts of testosterone. However, testosterone contained in Nu-serum was metabolized during the 48h incubation. Thus, inclusion of positive and negative controls and a steroid profile of the complete medium prior to the experiment (t=0h) was necessary to characterize H295R cells' steroid production and indicate alterations caused by exposure to chemicals. Among the tested chemicals, octyl methoxycinnamate and acetyl tributylcitrate resembled the corticosteroid induction pattern of the positive control torcetrapib. Gene expression analysis revealed that octyl methoxycinnamate and acetyl tributylcitrate enhanced CYP11B2 expression, although less pronounced than torcetrapib. Further experiments need to assess the toxicological relevance of octyl methoxycinnamate- and acetyl tributylcitrate-induced corticosteroid production. In conclusion, the extended profiling and appropriate controls allow detecting chemicals that act on steroidogenesis and provide initial mechanistic evidence for prioritizing chemicals for further investigations.

  5. Aldosterone breakthrough caused by chronic blockage of angiotensin II type 1 receptors in human adrenocortical cells: Possible involvement of bone morphogenetic protein-6 actions

    OpenAIRE

    Otani, Hiroyuki; Otsuka, Fumio; Inagaki, Kenichi; Suzuki, Jiro; Miyoshi, Tomoko; KANO, YOSHIHIRO; GOTO, Junko; Ogura, Toshio; Makino, Hirofumi

    2008-01-01

    Circulating aldosterone concentrations occasionally increase after initial suppression with angiotensin II (Ang II) converting enzyme inhibitors or Ang II type 1 receptor blockers (ARBs), a phenomenon referred to as aldosterone breakthrough. However, the underlying mechanism causing the aldosterone breakthrough remains unknown. Here we investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6...

  6. Role of AMP-activated protein kinase on steroid hormone biosynthesis in adrenal NCI-H295R cells.

    Directory of Open Access Journals (Sweden)

    Andrea Hirsch

    Full Text Available Regulation of human androgen biosynthesis is poorly understood. However, detailed knowledge is needed to eventually solve disorders with androgen dysbalance. We showed that starvation growth conditions shift steroidogenesis of human adrenal NCI-H295R cells towards androgen production attributable to decreased HSD3B2 expression and activity and increased CYP17A1 phosphorylation and 17,20-lyase activity. Generally, starvation induces stress and energy deprivation that need to be counteracted to maintain proper cell functions. AMP-activated protein kinase (AMPK is a master energy sensor that regulates cellular energy balance. AMPK regulates steroidogenesis in the gonad. Therefore, we investigated whether AMPK is also a regulator of adrenal steroidogenesis. We hypothesized that starvation uses AMPK signaling to enhance androgen production in NCI-H295R cells. We found that AMPK subunits are expressed in NCI-H295 cells, normal adrenal tissue and human as well as pig ovary cells. Starvation growth conditions decreased phosphorylation, but not activity of AMPK in NCI-H295 cells. In contrast, the AMPK activator 5-aminoimidazole-4-carboxamide (AICAR increased AMPKα phosphorylation and increased CYP17A1-17,20 lyase activity. Compound C (an AMPK inhibitor, directly inhibited CYP17A1 activities and can therefore not be used for AMPK signaling studies in steroidogenesis. HSD3B2 activity was neither altered by AICAR nor compound C. Starvation did not affect mitochondrial respiratory chain function in NCI-H295R cells suggesting that there is no indirect energy effect on AMPK through this avenue. In summary, starvation-mediated increase of androgen production in NCI-H295 cells does not seem to be mediated by AMPK signaling. But AMPK activation can enhance androgen production through a specific increase in CYP17A1-17,20 lyase activity.

  7. Enantioselective endocrine disrupting effects of omeprazole studied in the H295R cell assay and by molecular modeling

    DEFF Research Database (Denmark)

    Sørensen, Amalie Møller; Hansen, Cecilie Hurup; Bonomo, Silvia

    2016-01-01

    ) and its two enantiomers on the human steroidogenesis using the H295R cell line. Differences in production of 16 steroid hormones were analyzed using LC-MS/MS. Additionally, to evaluate the differences in binding modes of these enantiomers, docking and molecular dynamics (MD) simulations of S-omeprazole (S......-OME) and R-omeprazole (R-OME) in CYP17A1, CYP19A1 and CYP21A2 were carried out. Exposing H295R cells to OME and its enantiomers resulted in an increase of progesterone (PRO) and 17α-hydroxy-progesterone (OH-PRO) levels. At the same time, a decrease in the corticosteroid and androgen synthesis was observed...... of the heme for S-OME in CYP17A1 and S- and R-OME in CYP21A2. However, density functional theory calculations suggest that the direct N-Fe interaction is weak. The study demonstrates enantioselective differences in the endocrine disrupting potential of chiral drugs such as omeprazole. These findings may have...

  8. Enantioselective endocrine disrupting effects of omeprazole studied in the H295R cell assay and by molecular modeling.

    Science.gov (United States)

    Sørensen, Amalie Møller; Hansen, Cecilie Hurup; Bonomo, Silvia; Olsen, Lars; Jørgensen, Flemming Steen; Weisser, Johan Juhl; Kretschmann, Andreas Christopher; Styrishave, Bjarne

    2016-08-01

    Enantiomers possess different pharmacokinetic and pharmacodynamic properties and this may not only influence the therapeutic effect of a drug but also its toxicological effects. In the present work we investigated the potential enantioselective endocrine disrupting effects of omeprazole (OME) and its two enantiomers on the human steroidogenesis using the H295R cell line. Differences in production of 16 steroid hormones were analyzed using LC-MS/MS. Additionally, to evaluate the differences in binding modes of these enantiomers, docking and molecular dynamics (MD) simulations of S-omeprazole (S-OME) and R-omeprazole (R-OME) in CYP17A1, CYP19A1 and CYP21A2 were carried out. Exposing H295R cells to OME and its enantiomers resulted in an increase of progesterone (PRO) and 17α-hydroxy-progesterone (OH-PRO) levels. At the same time, a decrease in the corticosteroid and androgen synthesis was observed, indicating inhibition of CYP21A2 and CYP17A1. In both cases, the effect of R-OME was smaller compared to that of the S-OME and a certain degree of enantioselectivity of CYP17A1 and CYP21A2 was suggested. Docking indicated that the N-containing rings of OME possibly could interact with the iron atom of the heme for S-OME in CYP17A1 and S- and R-OME in CYP21A2. However, density functional theory calculations suggest that the direct N-Fe interaction is weak. The study demonstrates enantioselective differences in the endocrine disrupting potential of chiral drugs such as omeprazole. These findings may have potential implications for drug safety and drug design.

  9. Simvastatin decreases steroid production in the H295R cell line and decreases steroids and FSH in female rats

    DEFF Research Database (Denmark)

    Jensen, Anna Guldvang; Hansen, Cecilie Hurup; Weisser, Johan J;

    2015-01-01

    .3 (L), 5.0 (M), and 20.0 (H)mg SV/kg bw/day for 14 days. 10 Steroids were investigated in H295R growth media, and in tissues and plasma from rats using GC-MS/MS. Plasma LH and FSH were quantified by ELISA. In the H295R assay, SV and SVA particularly decreased progestagens with IC50-values from 0...

  10. THE MERCURY AS ENDOCRINE DISRUPTOR ON THE ADRENOCARCINOMA CELL LINE H295R

    Directory of Open Access Journals (Sweden)

    Mária Rácz

    2012-02-01

    Full Text Available Mercury (Hg is one of the oldest heavy metals, which has various effects on the endocrine system. Target of this in vitro study was to determine the effects of mercuric chloride (HgCl2 on the steroidogenesis in adrenocarcinoma cells isolated from the cell line H295R. We examined the dose-dependent changes of HgCl2 on the production of testosterone (T. Release of steroid hormone by adrenocarcinoma cells was determined after 48 h HgCl2 exposure (1.0; 5.0; 25; 50; 100 µmol.dm-3 using an ELISA assay. Decreased hormone production was detected in all experimental groups with the addition of HgCl2. In regards to the release of T, significant differences (P<0.01 between the control group and all experimental groups was recorded. The lowest amount of T was found after administration at doses >50 μmol.dm-3 of HgCl2. Obtained data indicate, that Hg has toxic effect on the testosterone production and its toxicity can reflect also in the others pathways of the cells.

  11. Role of ALADIN in human adrenocortical cells for oxidative stress response and steroidogenesis.

    Directory of Open Access Journals (Sweden)

    Ramona Jühlen

    Full Text Available Triple A syndrome is caused by mutations in AAAS encoding the protein ALADIN. We investigated the role of ALADIN in the human adrenocortical cell line NCI-H295R1 by either over-expression or down-regulation of ALADIN. Our findings indicate that AAAS knock-down induces a down-regulation of genes coding for type II microsomal cytochrome P450 hydroxylases CYP17A1 and CYP21A2 and their electron donor enzyme cytochrome P450 oxidoreductase, thereby decreasing biosynthesis of precursor metabolites required for glucocorticoid and androgen production. Furthermore we demonstrate that ALADIN deficiency leads to increased susceptibility to oxidative stress and alteration in redox homeostasis after paraquat treatment. Finally, we show significantly impaired nuclear import of DNA ligase 1, aprataxin and ferritin heavy chain 1 in ALADIN knock-down cells. We conclude that down-regulating ALADIN results in decreased oxidative stress response leading to alteration in steroidogenesis, highlighting our knock-down cell model as an important in-vitro tool for studying the adrenal phenotype in triple A syndrome.

  12. Histamine inhibits adrenocortical cell proliferation but does not affect steroidogenesis.

    Science.gov (United States)

    Pagotto, Romina Maria; Pereyra, Elba Nora; Monzón, Casandra; Mondillo, Carolina; Pignataro, Omar Pedro

    2014-04-01

    Histamine (HA) is a neurotransmitter synthesized in most mammalian tissues exclusively by histidine decarboxylase enzyme. Among the plethora of actions mediated by HA, the modulatory effects on steroidogenesis and proliferation in Leydig cells (LCs) have been described recently. To determine whether the effects on LCs reported could be extrapolated to all steroidogenic systems, in this study, we assessed the effect of this amine on adrenal proliferation and steroidogenesis, using two adrenocortical cell lines as experimental models, murine Y1 cells and human NCI-H295R cells. Even when steroidogenesis was not modified by HA in adrenocortical cells, the biogenic amine inhibited the proliferation of H295R cells. This action was mediated by the activation of HRH1 subtype and an increase in the production of inositol phosphates as second messengers, causing cell-cycle arrest in the G2/M phase. These results indicate a new role for HA in the proliferation of human adrenocortical cells that could contribute to a better understanding of tumor pathology as well as to the development of new therapeutic agents.

  13. The OECD validation program of the H295R steroidogenesis assay: Phase 3. Final inter-laboratory validation study

    DEFF Research Database (Denmark)

    Hecker, Markus; Hollert, Henner; Cooper, Ralph

    2011-01-01

    for Economic Cooperation and Development (OECD) test guideline.A previously optimized and pre-validated protocol was used to assess the potential of 28 chemicals of diverse structures and properties to validate the H295R steroidogenesis assay. These chemicals are comprised of known endocrine-active chemicals...... on hormone production, confounding factors, such as cell viability and possible direct interference of test substances with antibody-based hormone detection assays, were assessed. Prior to and during the conduct of exposure experiments, each laboratory had to demonstrate that they were able to conduct...... associated with only one laboratory after a personnel change occurred. Significant interference of test chemicals with some of the antibody-based hormone detection systems occurred for four chemicals. Only one of these chemicals, however, significantly affected the ability of the detection system...

  14. Effects of selective serotonin reuptake inhibitors on three sex steroids in two versions of the aromatase enzyme inhibition assay and in the H295R cell assay

    DEFF Research Database (Denmark)

    Jacobsen, Naja Wessel; Hansen, Cecilie Hurup; Nellemann, Christine

    2015-01-01

    Selective serotonin reuptake inhibitors are known to have a range of disorders that are often linked to the endocrine system e.g. hormonal imbalances, breast enlargement, sexual dysfunction, and menstrual cycle disorders. The mechanisms behind most of these disorders are not known in details....... In this study we investigated whether the endocrine effect due to SSRI exposure could be detected in well adopted in vitro steroidogenesis assays, two versions of the aromatase enzyme inhibition assay and the H295R cell assay. The five drugs citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, were......M for sertraline and fluvoxamine, respectively. In general the H295R cell assay was more sensitive to SSRI exposure than the two aromatase assays, up to 20 times more sensitive. This indicates that the H295R cell line is a better tool for screening endocrine disrupting effects. Our findings show that the endocrine...

  15. Development of a solid phase extraction method for the simultaneous determination of steroid hormones in H295R cell line using liquid chromatography-tandem mass spectrometry

    DEFF Research Database (Denmark)

    Abdel-Khalik, Jonas; Björklund, Erland; Hansen, Martin

    2013-01-01

    The H295R in vitro cell line produces the majority of the steroidogenesis, for which reason it is commonly used as a screening tool for endocrine disrupting chemicals. Simultaneous determination of the precursor cholesterol and key steroid hormones could give a broad insight into the mechanistic...... disruption of the steroidogenesis. Steroid hormones have primarily been extracted from H295R incubation medium by means of liquid-liquid extraction (LLE) and the obtained recoveries and matrix effects have typically not been stated or assessed. In the present study a solid-phase extraction (SPE) method...... was developed and validated for the simultaneous extraction of cholesterol and five key steroid hormones pregnenolone, 17-hydroxyprogesterone, testosterone, cortisol and aldosterone from H295R incubation medium, and finally detected by LC-MS/MS. Cholesterol was recovered at a level of 55.7%, while steroid...

  16. Effects of mixtures of persistent organic pollutants (POPs) derived from cod liver oil on H295R steroidogenesis.

    Science.gov (United States)

    Montaño, M; Zimmer, K E; Dahl, E; Berg, V; Olsaker, I; Skaare, J U; Murk, A J; Ropstad, E; Verhaegen, S

    2011-09-01

    Crude cod liver oil and liver oil supplements are consumed as a source of vitamin A, D and polyunsaturated fatty acids; during winter and early pregnancy. Crude cod liver oil however constitutes a considerable source of persistent organic pollutants (POPs). This paper aimed at characterizing and quantifying the influence of POP mixtures extracted from three different steps in the cod liver oil industrial process on hormone production and the expression of steroidogenesis-related genes in H295R cells. Exposure to extracts from crude cod liver oil and from its industrial waste increased progesterone (P4), cortisol (Cort), testosterone (T) and estradiol (E2) production; and among others, the expression of MC2R, CYP11B1 and HSD3B2 genes. Observed effects after exposure to pharmaceutical cod liver oil extract were considerably lower. The type of effects on gene expression and hormone production were similar to those induced by forskolin and PCBs, the latter being the major contaminants within the extracts. Additional research is required to further unveil the mechanisms behind the observed steroidogenic effects and to assess whether the potential risk might outweigh the potential benefits of crude and processed cod liver oil consumption. Copyright © 2011 Elsevier Ltd. All rights reserved.

  17. Development of a solid phase extraction method for the simultaneous determination of steroid hormones in H295R cell line using liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Abdel-Khalik, Jonas; Björklund, Erland; Hansen, Martin

    2013-09-15

    The H295R in vitro cell line produces the majority of the steroidogenesis, for which reason it is commonly used as a screening tool for endocrine disrupting chemicals. Simultaneous determination of the precursor cholesterol and key steroid hormones could give a broad insight into the mechanistic disruption of the steroidogenesis. Steroid hormones have primarily been extracted from H295R incubation medium by means of liquid-liquid extraction (LLE) and the obtained recoveries and matrix effects have typically not been stated or assessed. In the present study a solid-phase extraction (SPE) method was developed and validated for the simultaneous extraction of cholesterol and five key steroid hormones pregnenolone, 17-hydroxyprogesterone, testosterone, cortisol and aldosterone from H295R incubation medium, and finally detected by LC-MS/MS. Cholesterol was recovered at a level of 55.7%, while steroid hormone recoveries ranged from 98.2 to 109.4%. Matrix effects varied between -0.6% and 62.8%. Intra-day precision was deemed acceptable, but the inter-day precision for pregnenolone and aldosterone exceeded the precision limit of 15% RSD. Although LLE has been the most frequently used extraction method in H295R studies, however, our investigation has shown that SPE may relatively easily extract and recover steroid hormones, potentially replacing LLE.

  18. Aldosterone breakthrough caused by chronic blockage of angiotensin II type 1 receptors in human adrenocortical cells: possible involvement of bone morphogenetic protein-6 actions.

    Science.gov (United States)

    Otani, Hiroyuki; Otsuka, Fumio; Inagaki, Kenichi; Suzuki, Jiro; Miyoshi, Tomoko; Kano, Yoshihiro; Goto, Junko; Ogura, Toshio; Makino, Hirofumi

    2008-06-01

    Circulating aldosterone concentrations occasionally increase after initial suppression with angiotensin II (Ang II) converting enzyme inhibitors or Ang II type 1 receptor blockers (ARBs), a phenomenon referred to as aldosterone breakthrough. However, the underlying mechanism causing the aldosterone breakthrough remains unknown. Here we investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6, which is expressed in adrenocortical cells, enhances Ang II- but not potassium-induced aldosterone production in human adrenocortical cells. Accordingly, we examined the roles of BMP-6 in aldosterone breakthrough induced by long-term treatment with ARB. Ang II stimulated aldosterone production by adrenocortical cells. This Ang II stimulation was blocked by an ARB, candesartan. Interestingly, the candesartan effects on Ang II-induced aldosterone synthesis and CYP11B2 expression were attenuated in a course of candesartan treatment for 15 d. The impairment of candesartan effects on Ang II-induced aldosterone production was also observed in Ang II- or candesartan-pretreated cells. Levels of Ang II type 1 receptor mRNA were not changed by chronic candesartan treatment. However, BMP-6 enhancement of Ang II-induced ERK1/2 signaling was resistant to candesartan. The BMP-6-induced Smad1, -5, and -8 phosphorylation, and BRE-Luc activity was augmented in the presence of Ang II and candesartan in the chronic phase. Chronic Ang II exposure decreased cellular expression levels of BMP-6 and its receptors activin receptor-like kinase-2 and activin type II receptor mRNAs. Cotreatment with candesartan reversed the inhibitory effects of Ang II on the expression levels of these mRNAs. The breakthrough phenomenon was attenuated by neutralization of endogenous BMP-6 and activin receptor-like kinase-2. Collectively, these data suggest that changes in BMP-6 availability and response may be involved

  19. Rooibos Flavonoids Inhibit the Activity of Key Adrenal Steroidogenic Enzymes, Modulating Steroid Hormone Levels in H295R Cells

    Directory of Open Access Journals (Sweden)

    Lindie Schloms

    2014-03-01

    Full Text Available Major rooibos flavonoids—dihydrochalcones, aspalathin and nothofagin, flavones—orientin and vitexin, and a flavonol, rutin, were investigated to determine their influence on the activity of adrenal steroidogenic enzymes, 3β-hydroxysteroid dehydrogenase (3βHSD2 and cytochrome P450 (P450 enzymes, P450 17α-hydroxylase/17,20-lyase (CYP17A1, P450 21-hydroxylase (CYP21A2 and P450 11β-hydroxylase (CYP11B1. All the flavonoids inhibited 3βHSD2 and CYP17A1 significantly, while the inhibition of downstream enzymes, CYP21A2 and CYP11B1, was both substrate and flavonoid specific. The dihydrochalcones inhibited the activity of CYP21A2, but not that of CYP11B1. Although rutin, orientin and vitexin inhibited deoxycortisol conversion by CYP11B1 significantly, inhibition of deoxycorticosterone was <20%. These three flavonoids were unable to inhibit CYP21A2, with negligible inhibition of deoxycortisol biosynthesis only. Rooibos inhibited substrate conversion by CYP17A1 and CYP21A2, while the inhibition of other enzyme activities was <20%. In H295R cells, rutin had the greatest inhibitory effect on steroid production upon forskolin stimulation, reducing total steroid output 2.3-fold, while no effect was detected under basal conditions. Nothofagin and vitexin had a greater inhibitory effect on overall steroid production compared to aspalathin and orientin, respectively. The latter compounds contain two hydroxyl groups on the B ring, while nothofagin and vitexin contain a single hydroxyl group. In addition, all of the flavonoids are glycosylated, albeit at different positions—dihydrochalcones at C3' and flavones at C8 on ring A, while rutin, a larger molecule, has a rutinosyl moiety at C3 on ring C. Structural differences regarding the number and position of hydroxyl and glucose moieties as well as structural flexibility could indicate different mechanisms by which these flavonoids influence the activity of adrenal steroidogenic enzymes.

  20. A sensitive and selective LC-MS/MS analysis coupled with an online sample enrichment technique for H295R steroidogenesis assay and its application in the investigation of the effect of sildenafil on steroidogenesis.

    Science.gov (United States)

    Kang, Soyoung; Park, Sol; Kim, Mi Jie; Oh, Seung Min; Chung, Kyu Hyuck; Lee, Sooyeun

    2013-11-01

    An in vitro steroidogenesis assay using H295R human adenocarcinoma cells is a useful tool for the fast identification of compounds that affect the production of testosterone and 17β-estradiol. Selective and sensitive hormone measurement by liquid chromatography-tandem mass spectrometry (LC-MS/MS) can make this assay more reliable. Therefore, in the present study, a sensitive and selective method for the quantification of testosterone and 17β-estradiol in the H295R steroidogenesis assay was developed and fully validated using LC-MS/MS coupled with an online sample enrichment technique. To prove its usefulness, the method developed was applied to investigate the effect of sildenafil on steroidogenesis. Cell medium samples were diluted and prepared using solid-phase extraction. The samples were prepared on ice and were not kept for more than 30 min to prevent degradation of hormones. The extracts were dried, reconstituted, filtered, and analyzed by LC-MS/MS with polarity switching electrospray ionization. The validation results for selectivity, matrix effect, recovery, linearity, precision, and accuracy were satisfactory. The limits of detection for testosterone and 17β-estradiol were 5 and 10 pg/mL, respectively, and the limit of quantification for both testosterone and 17β-estradiol was 10 pg/mL, which was in accordance with the OECD guideline. No degradation was observed under the storage conditions for 7 and 14 days at -80 °C as well as after three freeze-thaw cycles, whereas 17β-estradiol was degraded after 1 h on ice during sample processing. The method developed was successfully used for the investigation of the effect of sildenafil on steroidogenesis. This method can be very useful for the initial selection of drugs with androgenic and/or estrogenic effects for specific purposes, e.g., in the selection of drugs that are used to reverse the effects of chemical castration.

  1. Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer

    Science.gov (United States)

    Grolmusz, Vince Kornél; Karászi, Katalin; Micsik, Tamás; Tóth, Eszter Angéla; Mészáros, Katalin; Karvaly, Gellért; Barna, Gábor; Szabó, Péter Márton; Baghy, Kornélia; Matkó, János; Kovalszky, Ilona; Tóth, Miklós; Rácz, Károly; Igaz, Péter; Patócs, Attila

    2016-01-01

    Adrenocortical cancer (ACC) is a rare, but agressive malignancy with poor prognosis. Histopathological diagnosis is challenging and pharmacological options for treatment are limited. By the comparative reanalysis of the transcriptional malignancy signature with the cell cycle dependent transcriptional program of ACC, we aimed to identify novel biomarkers which may be used in the histopathological diagnosis and for the prediction of therapeutical response of ACC. Comparative reanalysis of publicly available microarray datasets included three earlier studies comparing transcriptional differences between ACC and benign adrenocortical adenoma (ACA) and one study presenting the cell cycle dependent gene expressional program of human ACC cell line NCI-H295R. Immunohistochemical analysis was performed on ACC samples. In vitro effects of antineoplastic drugs including gemcitabine, mitotane and 9-cis-retinoic acid alone and in combination were tested in the NCI-H295R adrenocortical cell line. Upon the comparative reanalysis, ribonucleotide reductase subunit 2 (RRM2), responsible for the ribonucleotide dezoxyribonucleotide conversion during the S phase of the cell cycle has been validated as cell cycle dependently expressed. Moreover, its expression was associated with the malignancy signature, as well. Immunohistochemical analysis of RRM2 revealed a strong correlation with Ki67 index in ACC. Among the antiproliferative effects of the investigated compounds, gemcitabine showed a strong inhibition of proliferation and an increase of apoptotic events. Additionally, RRM2 has been upregulated upon gemcitabine treatment. Upon our results, RRM2 might be used as a proliferation marker in ACC. RRM2 upregulation upon gemcitabine treatment might contribute to an emerging chemoresistance against gemcitabine, which is in line with its limited therapeutical efficacy in ACC, and which should be overcome for successful clinical applications.

  2. Lipoprotein-Free Mitotane Exerts High Cytotoxic Activity in Adrenocortical Carcinoma.

    Science.gov (United States)

    Hescot, Ségolène; Seck, Atmane; Guerin, Maryse; Cockenpot, Florence; Huby, Thierry; Broutin, Sophie; Young, Jacques; Paci, Angelo; Baudin, Eric; Lombès, Marc

    2015-08-01

    Mitotane (o,p'-DDD), the only approved drug for advanced adrenocortical carcinoma (ACC), is a lipophilic agent that accumulates into circulating lipoprotein fractions and high-lipid-containing tissues. The aim of our study was to evaluate the in vivo and in vitro biological implication of serum lipoproteins on pharmacological action of mitotane. Distribution and concentration of mitotane were studied in plasma and adrenal tissue samples from mitotane-treated patients. The effect of lipoprotein-bound or lipoprotein-free (LP-F) mitotane was analyzed on proliferation and apoptosis of human adrenocortical H295R cells. A retrospective study of patients with ACC treated or not with statins was also performed. o,p'-DDD distribution among very low-density lipoprotein, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and LP-F fractions obtained after plasma ultracentrifugation of 23 of mitotane-treated patients was widely distributed in each subfraction. A positive correlation was observed between mitotane levels in plasma and in LDL, HDL, but also LP-F compartment. Intratumor o,p'-DDD concentrations in five ACC samples of mitotane-treated patients were found to be independent of cholesterol transporter expression, scavenger receptors, and LDL receptors. In vitro studies showed significant higher antiproliferative and proapoptotic effects and higher cell and mitochondrial uptake of mitotane when H295R cells were grown in LP-F medium. Finally, retrospective study of an ACC cohort of 26 mitotane-treated patients revealed that statin therapy was significantly associated with a higher rate of tumor control. Altogether, our in vitro and in vivo studies provided compelling evidence for a greater efficacy of LP-F mitotane. Patients with ACC may thus benefit from therapeutic strategies that aim to increase LP-F mitotane fraction.

  3. The OECD validation program of the H295R steroidogenesis assay for the identification of in vitro inhibitors and inducers of testosterone and estradiol production. Phase 2: Inter-laboratory pre-validation studies

    DEFF Research Database (Denmark)

    Hecker, Markus; Hollert, Henner; Cooper, Ralph

    2007-01-01

    related to one laboratory there were unexplained minor uncertainties related to the inter-laboratory hormone production variation. Based on the findings from this Phase 2 prevalidation study, the H295R Steroidogenesis Assay protocol is currently being refined. The next phase of the OECD validation program...... their potential to interact with the endocrine system of vertebrates. Study Design. Six laboratories from five countries participated in the pre-validation studies. Each laboratory tested the effects of three model chemicals on the production of testosterone (T) and estradiol (E2) using the H295R Steroidogenesis...... Assay. Chemicals tested were well described inducers or inhibitors of steroidogenic pathways (forskolin, prochloraz and fadrozole). All experiments were conducted in 24 well plates following standard protocols. Six different doses per compound were analyzed in triplicate per plate. A quality control (QQ...

  4. Fluconazole inhibits human adrenocortical steroidogenesis in vitro

    NARCIS (Netherlands)

    R. van der Pas (Rob); L.J. Hofland (Leo); J. Hofland (Johannes); A.E. Taylor (A.); W. Arlt (Wiebke); J. Steenbergen (Jacobie); P.M. van Koetsveld (Peter); W.W. de Herder (Wouter); F.H. de Jong (Frank); R.A. Feelders (Richard)

    2012-01-01

    textabstractThe antifungal agent ketoconazole is often used to suppress cortisol production in patients with Cushing's syndrome (CS). However, ketoconazole has serious side effects and is hepatotoxic. Here, the in vitro effects of ketoconazole and fluconazole, which might be less toxic, on human adr

  5. No evidence for oncogenic mutations in the adrenocorticotropin receptor gene in human adrenocortical neoplasms

    Energy Technology Data Exchange (ETDEWEB)

    Latronico, A.C.; Reincke, M.; Mendonca, B.B. [National Inst. of Child Health and Human Development, Bethesda, MD (United States)] [and others

    1995-03-01

    The mechanism(s) of tumorigenesis for the majority of adrenocortical neoplasms remain unknown. G-Protein-coupled receptors were recently proposed as candidate protooncogenes. That activating mutations of this class of receptors might be important for tumor induction or progression of endocrine neoplasms was strengthened by the recent identification of such mutations in hyperfunctioning thyroid adenomas. To examine whether the ACTH receptor (ACTH-R) gene could be an oncogene in human adrenocortical tumors, we amplified by the polymerase chain reaction and directly sequenced the entire exon of the ACTH-R gene in 25 adrenocortical tumors (17 adenomas and 8 carcinomas) and 2 adrenocortical cancer cell lines. We found no missense point mutations or even silent polymorphisms in any of the tumors and cell lines studied. We conclude that activating mutations of the ACTH-R gene do not represent a frequent mechanism of human adrenocortical tumorigenesis. 15 refs., 2 tabs.

  6. Incorporation of (14)C-cholesterol in human adrenal corticocarcinoma H295R cell line and online-radiodetection of produced (14)C-steroid hormone metabolites

    DEFF Research Database (Denmark)

    Abdel-Khalik, Jonas; Björklund, Erland; Nielsen, Frederik Knud

    2017-01-01

    of steroid hormones was estimated. Multiple radiolabeled steroid hormones were identified by means of analytical standards and UV (ultraviolet) co-chromatography, though the elucidation of multiple metabolites remains unresolved. Although online radiodetection proved to suffer from suboptimal sensitivity...

  7. The effect of types I and III interferons on adrenocortical cells and its possible implications for autoimmune Addison's disease.

    Science.gov (United States)

    Hellesen, A; Edvardsen, K; Breivik, L; Husebye, E S; Bratland, E

    2014-06-01

    Autoimmune Addison's disease (AAD) is caused by selective destruction of the hormone-producing cells of the adrenal cortex. As yet, little is known about the potential role played by environmental factors in this process. Type I and/or type III interferons (IFNs) are signature responses to virus infections, and have also been implicated in the pathogenesis of autoimmune endocrine disorders such as type 1 diabetes and autoimmune thyroiditis. Transient development of AAD and exacerbation of established or subclinical disease, as well as the induction of autoantibodies associated with AAD, have been reported following therapeutic administration of type I IFNs. We therefore hypothesize that exposure to such IFNs could render the adrenal cortex susceptible to autoimmune attack in genetically predisposed individuals. In this study, we investigated possible immunopathological effects of type I and type III IFNs on adrenocortical cells in relation to AAD. Both types I and III IFNs exerted significant cytotoxicity on NCI-H295R adrenocortical carcinoma cells and potentiated IFN-γ- and polyinosine-polycytidylic acid [poly (I : C)]-induced chemokine secretion. Furthermore, we observed increased expression of human leucocyte antigen (HLA) class I molecules and up-regulation of 21-hydroxylase, the primary antigenic target in AAD. We propose that these combined effects could serve to initiate or aggravate an ongoing autoimmune response against the adrenal cortex in AAD. © 2014 British Society for Immunology.

  8. Transcriptional changes in steroidogenesis by perfluoroalkyl acids (PFOA and PFOS) regulate the synthesis of sex hormones in H295R cells.

    Science.gov (United States)

    Kang, Jae Soon; Choi, Jin-Soo; Park, June-Woo

    2016-07-01

    Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are two of the most widely used perfluoroalkyl acids (PFAAs). Because of their strong persistence, they have become widely distributed throughout the environment and human bodies. PFOA and PFOS are suspected to disrupt the endocrine system based upon many in vivo studies, but the underlying mechanisms are currently unclear. In this study, we investigated the endocrine-related effects of PFOA and PFOS using in vitro estrogen receptor (ER) and androgen receptor (AR) transactivation assays and steroidogenesis assay. The results showed that PFOA and PFOS exhibited weak antagonistic ER transactivation but did not exhibit agonistic ER or AR transactivation. In the steroidogenesis assay, PFOA and PFOS induced 17β-estradiol (E2) level and reduced testosterone level, which would be caused by the induction of aromatase activity. The qPCR analysis of genes involved in steroidogenesis indicates that PFOA and PFOS associate with sex hormone synthesis by the transcriptional induction of two genes, cyp19 and 3β-hsd2. Moreover, the transcriptional induction of cyp11b2 by PFOS suggests that this chemical may underlie the disruption of several physiological functions related to aldosterone. The results of the current study suggest that PFOA and PFOS are potential endocrine disrupting chemicals (EDCs) and provide information for further studies on the molecular events that initiate the adverse endocrine effects.

  9. Resveratrol inhibits steroidogenesis in human fetal adrenocortical cells at the end of first trimester

    DEFF Research Database (Denmark)

    Savchuk, Iuliia; Morvan, Marie-Line; Søeborg, Tue

    2017-01-01

    steroidogenesis at gestational weeks (GW) 9-12. METHODS AND RESULTS: Adrenals from aborted fetuses (GW10-12) were used to prepare primary cultures of human fetal adrenocortical cells (HFAC). HFAC were treated in the presence or absence of ACTH (10 ng/ml) with or without resveratrol (10 μM) for 24 hours...

  10. Endocrine activity of persistent organic pollutants accumulated in human silicone implants--Dosing in vitro assays by partitioning from silicone.

    Science.gov (United States)

    Gilbert, Dorothea; Mayer, Philipp; Pedersen, Mikael; Vinggaard, Anne Marie

    2015-11-01

    Persistent organic pollutants (POPs) accumulated in human tissues may pose a risk for human health by interfering with the endocrine system. This study establishes a new link between actual human internal POP levels and the endocrine active dose in vitro, applying partitioning-controlled dosing from silicone to the H295R steroidogenesis assay: (1) Measured concentrations of POPs in silicone breast implants were taken from a recent study and silicone disks were loaded according to these measurements. (2) Silicone disks were transferred into H295R cell culture plates in order to control exposure of the adrenal cells by equilibrium partitioning. (3) Hormone production of the adrenal cells was measured as toxicity endpoint. 4-Nonylphenol was used for method development, and the new dosing method was compared to conventional solvent-dosing. The two dosing modes yielded similar dose-dependent hormonal responses of H295R cells. However, with the partitioning-controlled freely dissolved concentrations (Cfree) as dose metrics, dose-response curves were left-shifted by two orders of magnitude relative to spiked concentrations. Partitioning-controlled dosing of POPs resulted in up to 2-fold increases in progestagen and corticosteroid levels at Cfree of individual POPs in or below the femtomolar range. Silicone acted not only as source of the POPs but also as a sorption sink for lipophilic hormones, stimulating the cellular hormone production. Methodologically, the study showed that silicone can be used as reference partitioning phase to transfer in vivo exposure in humans (silicone implants) to in vitro assays (partition-controlled dosing). The main finding was that POPs at the levels at which they are found in humans can interfere with steroidogenesis in a human adrenocortical cell line. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. High risk of adrenal toxicity of N1-desoxy quinoxaline 1,4-dioxide derivatives and the protection of oligomeric proanthocyanidins (OPC) in the inhibition of the expression of aldosterone synthetase in H295R cells.

    Science.gov (United States)

    Wang, Xu; Yang, Chunhui; Ihsan, Awais; Luo, Xun; Guo, Pu; Cheng, Guyue; Dai, Menghong; Chen, Dongmei; Liu, Zhenli; Yuan, Zonghui

    2016-02-01

    Quinoxaline 1,4-dioxide derivatives (QdNOs) with a wide range of biological activities are used in animal husbandry worldwide. It was found that QdNOs significantly inhibited the gene expression of CYP11B1 and CYP11B2, the key aldosterone synthases, and thus reduced aldosterone levels. However, whether the metabolites of QdNOs have potential adrenal toxicity and the role of oxidative stress in the adrenal toxicity of QdNOs remains unclear. The relatively new QdNOs, cyadox (CYA), mequindox (MEQ), quinocetone (QCT) and their metabolites, were selected for elucidation of their toxic mechanisms in H295R cells. Interestingly, the results showed that the main toxic metabolites of QCT, MEQ, and CYA were their N1-desoxy metabolites, which were more harmful than other metabolites and evoked dose and time-dependent cell damage on adrenal cells and inhibited aldosterone production. Gene and protein expression of CYP11B1 and CYP11B2 and mRNA expression of transcription factors, such as NURR1, NGFIB, CREB, SF-1, and ATF-1, were down regulated by N1-desoxy QdNOs. The natural inhibitors of oxidant stress, oligomeric proanthocyanidins (OPC), could upregulate the expression of diverse transcription factors, including CYP11B1 and CYP11B2, and elevated aldosterone levels to reduce adrenal toxicity. This study demonstrated for the first time that N1-desoxy QdNOs have the potential to be the major toxic metabolites in adrenal toxicity, which may shed new light on the adrenal toxicity of these fascinating compounds and help to provide a basic foundation for the formulation of safety controls for animal products and the design of new QdNOs with less harmful effects.

  12. The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells.

    Science.gov (United States)

    Pan, Zhi-qiang; Xie, Ding; Choudhary, Vivek; Seremwe, Mutsa; Tsai, Ying-Ying; Olala, Lawrence; Chen, Xunsheng; Bollag, Wendy B

    2014-08-25

    Pioglitazone belongs to the class of drugs called thiazolidinediones (TZDs), which are widely used as insulin sensitizers in the treatment of diabetes. A major side effect of TZDs is fluid retention. The steroid hormone aldosterone also promotes sodium and fluid retention; however, the effect of pioglitazone on aldosterone production is controversial. We analyzed the effect of pioglitazone alone and in combination with angiotensin II (AngII) on the late rate-limiting step of adrenocortical steroidogenesis in human adrenocortical carcinoma HAC15 cells. Treatment with pioglitazone for 24 h significantly increased the expression of CYP11B2 and enhanced AngII-induced CYP11B2 expression. Despite the observed changes in mRNA levels, pioglitazone significantly inhibited AngII-induced aldosterone production and CYP11B2 protein levels. On the other hand, pioglitazone stimulated the expression of the unfolded protein response (UPR) marker DDIT3, with this effect occurring at early times and inhibitable by the PPARγ antagonist GW9962. The levels of DDIT3 (CHOP) and phospho-eIF2α (Ser51), a UPR-induced event that inhibits protein translation, were also increased. Thus, pioglitazone promotes CYP11B2 expression but nevertheless inhibits aldosterone production in AngII-treated HAC15 cells, likely by blocking global protein translation initiation through DDIT3 and phospho-eIF2α. In contrast, pioglitazone promoted AngII-induced CYP11B1 expression and cortisol production. Since cortisol enhances lipolysis, this result suggests the possibility that PPARs, activated by products of fatty acid oxidation, stimulate cortisol secretion to promote utilization of fatty acids during fasting. In turn, the ability of pioglitazone to stimulate cortisol production could potentially underlie the effects of this drug on fluid retention.

  13. Adrenocortical cancer

    DEFF Research Database (Denmark)

    Payabyab, Eden C.; Balasubramaniam, Sanjeeve; Edgerly, Maureen

    2016-01-01

    The development of new therapies has lagged behind for rare cancers without defined therapeutic targets. Adrenocortical cancer is no exception. Mitotane, an older agent considered "adrenolytic," is used both to control symptoms in advanced disease and as adjuvant therapy after surgical resection....... Molecular characterization of adrenocortical cancer has deepened our understanding of this genetically complex disease while identifying subgroups whose importance remains to be determined. Unfortunately, such studies have yet to demonstrate a therapeutic target for drug development, and to date......, no targeted therapy has achieved meaningful outcomes. Consequently, first-line therapy for metastatic disease remains a combination regimen of etoposide, doxorubicin, and cisplatinum established in a randomized clinical trial. In addition to evaluating recent studies in adrenocortical cancer, we raise one...

  14. Molecular pathways of human adrenocortical carcinoma - translating cell signalling knowledge into diagnostic and treatment options.

    Science.gov (United States)

    Szyszka, Paulina; Grossman, Ashley B; Diaz-Cano, Salvador; Sworczak, Krzysztof; Dworakowska, Dorota

    2016-01-01

    Adrenocortical carcinoma is associated with a low cure rate and a high recurrence rate. The prognosis is poor, and at diagnosis 30-40% of cases are already metastatic. The current therapeutic options (surgical resection, followed by adjuvant mitotane treatment +/- chemotherapy) are limited, and the results remain unsatisfactory. Key molecular events that contribute to formation of adrenocortical cancer are IGF2 overexpression, TP53-inactivating mutations, and constitutive activation of the Wnt/b-catenin signalling pathway via activating mutations of the b-catenin gene. The underlying genetic causes of inherited tumour syndromes have provided insights into molecular pathogenesis. The increased occurrence of adrenocortical tumours in Li-Fraumeni and Beckwith-Wiedemann syndromes, and Carney complex, has highlighted the roles of specific susceptibility genes: TP53, IGF2, and PRKAR1A, respectively. Further studies have confirmed that these genes are also involved in sporadic tumour cases. Crucially, transcriptome-wide studies have determined the differences between malignant and benign adrenocortical tumours, providing potential diagnostic tools. In conclusion, enhancing our understanding of the molecular events of adrenocortical tumourigenesis, especially with regard to the signalling pathways that may be disrupted, will greatly contribute to improving a range of available diagnostic, prognostic, and treatment approaches. (Endokrynol Pol 2016; 67 (4): 427-440).

  15. IGF2 promotes growth of adrenocortical carcinoma cells, but its overexpression does not modify phenotypic and molecular features of adrenocortical carcinoma.

    Directory of Open Access Journals (Sweden)

    Marine Guillaud-Bataille

    Full Text Available Insulin-like growth factor 2 (IGF2 overexpression is an important molecular marker of adrenocortical carcinoma (ACC, which is a rare but devastating endocrine cancer. It is not clear whether IGF2 overexpression modifies the biology and growth of this cancer, thus more studies are required before IGF2 can be considered as a major therapeutic target. We compared the phenotypical, clinical, biological, and molecular characteristics of ACC with or without the overexpression of IGF2, to address these issues. We also carried out a similar analysis in an ACC cell line (H295R in which IGF2 expression was knocked down with si- or shRNA. We found no significant differences in the clinical, biological and molecular (transcriptomic traits between IGF2-high and IGF2-low ACC. The absence of IGF2 overexpression had little influence on the activation of tyrosine kinase pathways both in tumors and in H295 cells that express low levels of IGF2. In IGF2-low tumors, other growth factors (FGF9, PDGFA are more expressed than in IGF2-high tumors, suggesting that they play a compensatory role in tumor progression. In addition, IGF2 knock-down in H295R cells substantially impaired growth (>50% inhibition, blocked cells in G1 phase, and promoted apoptosis (>2-fold. Finally, analysis of the 11p15 locus showed a paternal uniparental disomy in both IGF2-high and IGF2-low tumors, but low IGF2 expression could be explained in most IGF2-low ACC by an additional epigenetic modification at the 11p15 locus. Altogether, these observations confirm the active role of IGF2 in adrenocortical tumor growth, but also suggest that other growth promoting pathways may be involved in a subset of ACC with low IGF2 expression, which creates opportunities for the use of other targeted therapies.

  16. Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells.

    Science.gov (United States)

    Asp, V; Cantillana, T; Bergman, A; Brandt, I

    2010-03-01

    Adrenocortical carcinoma (ACC) is a rare malignant disease with poor prognosis. The main pharmacological choice, o,p'-DDD (mitotane), produces severe adverse effects. Since o,p'-DDD is a chiral molecule and stereoisomers frequently possess different pharmacokinetic and/or pharmacodynamic properties, we isolated the two o,p'-DDD enantiomers, (R)-(+)-o,p'-DDD and (S)-(-)-o,p'-DDD, and determined their absolute structures. The effects of each enantiomer on cell viability and on cortisol and dehydroepiandrosterone (DHEA) secretion in the human adrenocortical cell line H295R were assessed. We also assayed the o,p'-DDD racemate and the m,p'- and p,p'-isomers. The results show small but statistically significant differences in activity of the o,p'-DDD enantiomers for all parameters tested. The three DDD isomers were equally potent in decreasing cell viability, but p,p'-DDD affected hormone secretion slightly less than the o,p'- and m,p'-isomers. The small chiral differences in direct effects on target cells alone do not warrant single enantiomer administration, but might reach importance in conjunction with possible stereochemical effects on pharmacokinetic processes in vivo.

  17. Knockdown of SF-1 and RNF31 affects components of steroidogenesis, TGFβ, and Wnt/β-catenin signaling in adrenocortical carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Anna Ehrlund

    Full Text Available The orphan nuclear receptor Steroidogenic Factor-1 (SF-1, NR5A1 is a critical regulator of development and homeostasis of the adrenal cortex and gonads. We recently showed that a complex containing E3 ubiquitin ligase RNF31 and the known SF-1 corepressor DAX-1 (NR0B1 interacts with SF-1 on target promoters and represses transcription of steroidogenic acute regulatory protein (StAR and aromatase (CYP19 genes. To further evaluate the role of SF-1 in the adrenal cortex and the involvement of RNF31 in SF-1-dependent pathways, we performed genome-wide gene-expression analysis of adrenocortical NCI-H295R cells where SF-1 or RNF31 had been knocked down using RNA interference. We find RNF31 to be deeply connected to cholesterol metabolism and steroid hormone synthesis, strengthening its role as an SF-1 coregulator. We also find intriguing evidence of negative crosstalk between SF-1 and both transforming growth factor (TGF β and Wnt/β-catenin signaling. This crosstalk could be of importance for adrenogonadal development, maintenance of adrenocortical progenitor cells and the development of adrenocortical carcinoma. Finally, the SF-1 gene profile can be used to distinguish malignant from benign adrenocortical tumors, a finding that implicates SF-1 in the development of malignant adrenocortical carcinoma.

  18. Stages of Adrenocortical Carcinoma

    Science.gov (United States)

    ... Symptoms of adrenocortical carcinoma include pain in the abdomen. These and other signs and symptoms may be caused by adrenocortical carcinoma: A lump in the abdomen . Pain the abdomen or back. A feeling of ...

  19. ChIP-on-chip analysis reveals angiopoietin 2 (Ang2, ANGPT2) as a novel target of steroidogenic factor-1 (SF-1, NR5A1) in the human adrenal gland.

    Science.gov (United States)

    Ferraz-de-Souza, Bruno; Lin, Lin; Shah, Sonia; Jina, Nipurna; Hubank, Mike; Dattani, Mehul T; Achermann, John C

    2011-04-01

    The nuclear receptor steroidogenic factor-1 (SF-1, NR5A1) is a key regulator of adrenal and gonadal biology. Disruption of SF-1 can lead to disorders of adrenal development, while increased SF-1 dosage has been associated with adrenocortical tumorigenesis. We aimed to identify a novel subset of SF-1 target genes in the adrenal by using chromatin immunoprecipitation (ChIP) microarrays (ChIP-on-chip) combined with systems analysis. SF-1 ChIP-on-chip was performed in NCI-H295R human adrenocortical cells using promoter tiling arrays, leading to the identification of 445 gene loci where SF-1-binding regions were located from 10 kb upstream to 3 kb downstream of a transcriptional start. Network analysis of genes identified as putative SF-1 targets revealed enrichment for angiogenic process networks. A 1.1-kb SF-1-binding region was identified in the angiopoietin 2 (Ang2, ANGPT2) promoter in a highly repetitive region, and SF-1-dependent activation was confirmed in luciferase assays. Angiogenesis is paramount in adrenal development and tumorigenesis, but until now a direct link between SF-1 and vascular remodeling has not been established. We have identified Ang2 as a potentially important novel target of SF-1 in the adrenal gland, indicating that regulation of angiogenesis might be an important additional mechanism by which SF-1 exerts its actions in the adrenal gland.

  20. Animal models of adrenocortical tumorigenesis

    NARCIS (Netherlands)

    Beuschlein, F.; Galac, S.; Wilson, D.B.

    2012-01-01

    Over the past decade, research on human adrenocortical neoplasia has been dominated by gene expression profiling of tumor specimens and by analysis of genetic disorders associated with a predisposition to these tumors. Although these studies have identified key genes and associated signaling pathway

  1. Origin and Molecular Pathology of Adrenocortical Neoplasms

    Science.gov (United States)

    Bielinska, M.; Parviainen, H.; Kiiveri, S.; Heikinheimo, M.; Wilson, D.B.

    2008-01-01

    Neoplastic adrenocortical lesions are common in humans and several species of domestic animals. Although there are unanswered questions about the origin and evolution of adrenocortical neoplasms, analysis of human tumor specimens and animal models indicates that adrenocortical tumorigenesis involves both genetic and epigenetic alterations. Chromosomal changes accumulate during tumor progression, and aberrant telomere function is one of the key mechanisms underlying chromosome instability during this process. Epigenetic changes serve to expand the size of the uncommitted adrenal progenitor population, modulate their phenotypic plasticity (i.e., responsiveness to extracellular signals), and increase the likelihood of subsequent genetic alterations. Analyses of heritable and spontaneous types of human adrenocortical tumors have documented alterations in either cell surface receptors or their downstream effectors that impact neoplastic transformation. Many of the mutations associated with benign human adrenocortical tumors result in dysregulated cyclic AMP signaling, whereas key factors/signaling pathways associated with adrenocortical carcinomas include dysregulated expression of the IGF2 gene cluster, activation of the Wnt/β-catenin pathway, and inactivation of the p53 tumor suppressor. A better understanding of the factors and signaling pathways involved in adrenal tumorigenesis is necessary to develop targeted pharmacologic and genetic therapies. PMID:19261630

  2. Endocrine activity of persistent organic pollutants accumulated in human silicone implants — Dosing in vitro assays by partitioning from silicone

    DEFF Research Database (Denmark)

    Gilbert, Dorothea; Mayer, Philipp; Pedersen, Mikael;

    2015-01-01

    Persistent organic pollutants (POPs) accumulated in human tissues may pose a risk for human health by interfering with the endocrine system. This study establishes a new link between actual human internal POP levels and the endocrine active dose in vitro, applying partitioning-controlled dosing...... from silicone to the H295R steroidogenesis assay: (1) Measured concentrations of POPs in silicone breast implants were taken from a recent study and silicone disks were loaded according to these measurements. (2) Silicone disks were transferred into H295R cell culture plates in order to control...

  3. Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro.

    Science.gov (United States)

    Albert, O; Desdoits-Lethimonier, C; Lesné, L; Legrand, A; Guillé, F; Bensalah, K; Dejucq-Rainsford, N; Jégou, B

    2013-07-01

    Do mild analgesics affect the endocrine system of the human adult testis? Mild analgesics induce multiple endocrine disturbances in the human adult testis in vitro. Mild analgesics have recently been incriminated as potential endocrine disruptors. Studies of the effects of these widely used molecules on the androgenic status of men are limited and somewhat contradictory. This prompted us to investigate whether these compounds could alter the adult human testicular function. We therefore assessed in parallel the effects of paracetamol, aspirin and indomethacin on organo-cultured adult human testis and on the NCI-H295R steroid-producing human cell line. Adult human testis explants or NCI-H295R adrenocortical human cells were cultured with 10(-4) or 10(-5) M paracetamol, aspirin or indomethacin for 24-48 h. The effect of 10(-5) M ketoconazole, used as an anti-androgenic reference molecule, was also assessed. Testes were obtained from prostate cancer patients, who had not received any hormone therapy. The protocol was approved by the local ethics committee of Rennes, France and informed consent was given by the donors. Only testes displaying spermatogenesis, as assessed by transillumination, were used in this study. Hormone levels in the culture media were determined by radioimmunoassay (testosterone, insulin-like factor 3), Enzyme-Linked Immunosorbent Assay (inhibin B) or Enzyme Immunosorbent Assay [prostaglandin (PG) D2, and PGE2]. Tissues were observed and cells counted using classical immunohistochemical methods. The three mild analgesics caused multiple endocrine disturbances in the adult human testis. This was particularly apparent in the interstitial compartment. Effective doses were in the same range as those measured in blood plasma following standard analgesic treatment. The production of testosterone and insulin-like factor 3 by Leydig cells was altered by exposure to all these drugs. Inhibin B production by Sertoli cells was marginally affected by aspirin

  4. Autoimmune polyglandular syndrome type 2 manifested as Hashimoto's thyroiditis and adrenocortical insufficiency, in Turner syndrome woman, with onset following introduction of treatment with recombinant human growth hormone.

    Science.gov (United States)

    Cyniak-Magierska, Anna; Lasoń, Agnieszka; Smyczyńska, Joanna; Lewiński, Andrzej

    2015-01-01

    Autoimmune polyglandular syndrome is a constellation of signs and symptoms of simultaneous insufficiencies of several endocrine glands. Autoimmune polyglandular syndrome type 2 (APS 2) may be diagnosed when the adrenocortical insufficiency is associated with an autoimmune thyroid disease (Hashimoto's thyroiditis or Graves' disease), and/or insulin-dependent diabetes mellitus. Turner syndrome is the most common chromosomal disorder in females, caused by complete or partial X chromosome monosomy. We present the case of a 20-year-old woman with Turner syndrome, in whom APS 2 (Hashimoto's thyroiditis and adrenocortical insufficiency) has been diagnosed after introduction of recombinant human growth hormone (rhGH) therapy. In Turner syndrome, examination of the patient must regularly be conducted in order to diagnose a possible onset of autoimmune diseases; respective treatment must be applied as soon as the diagnosis is established. In particular, therapy of rhGH, used for short stature treatment, may be a trigger factor of adrenal insufficiency. The cortisol level in blood should be assessed before rhGH administration and carefully monitored during the therapy, especially in case of autoimmune thyroid disease coexistence.

  5. Metformin and Melatonin in Adrenocortical Carcinoma: Morphoproteomics and Biomedical Analytics Provide Proof of Concept in a Case Study.

    Science.gov (United States)

    Brown, Robert E; Buryanek, Jamie; McGuire, Mary F

    2017-08-01

    Metformin has been proposed as a novel anti-cancer drug for adrenocortical carcinoma (ACC) based upon Poli's recent preclinical studies that 1. "in vitro" metformin modulates the ACC cell model H295R and 2. "in vivo" metformin inhibits tumor growth in a xenograft model as confirmed by a significant reduction of Ki67 [1]. Here we report on our prior clinical case study that provides proof of concept for Poli's studies. We were requested to perform morphoproteomic analysis to further define the biology of, and raise targeted therapeutic options, for a case of post-treatment and chemoresistant ACC metastatic to the liver and the lung. Profiling the patient's ACC from the liver resulted in the recommendation of metformin as a maintenance therapy, which was supported by biomedical data analysis. The patient remains on maintenance therapy with metformin and melatonin and is free of disease some 7 years post diagnosis, thus underscoring the recommendation for clinical trials employing these therapeutic agents. © 2017 by the Association of Clinical Scientists, Inc.

  6. Psychobiological mechanisms underlying the social buffering of the hypothalamic-pituitary-adrenocortical axis: a review of animal models and human studies across development.

    Science.gov (United States)

    Hostinar, Camelia E; Sullivan, Regina M; Gunnar, Megan R

    2014-01-01

    Discovering the stress-buffering effects of social relationships has been one of the major findings in psychobiology in the last century. However, an understanding of the underlying neurobiological and psychological mechanisms of this buffering is only beginning to emerge. An important avenue of this research concerns the neurocircuitry that can regulate the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis. The present review is a translational effort aimed at integrating animal models and human studies of the social regulation of the HPA axis from infancy to adulthood, specifically focusing on the process that has been named social buffering. This process has been noted across species and consists of a dampened HPA axis stress response to threat or challenge that occurs with the presence or assistance of a conspecific. We describe aspects of the relevant underlying neurobiology when enough information exists and expose major gaps in our understanding across all domains of the literatures we aimed to integrate. We provide a working conceptual model focused on the role of oxytocinergic systems and prefrontal neural networks as 2 of the putative biological mediators of this process, and propose that the role of early experiences is critical in shaping later social buffering effects. This synthesis points to both general future directions and specific experiments that need to be conducted to build a more comprehensive model of the HPA social buffering effect across the life span that incorporates multiple levels of analysis: neuroendocrine, behavioral, and social.

  7. General Information about Adrenocortical Carcinoma

    Science.gov (United States)

    ... that forms in the adrenal medulla is called pheochromocytoma and is not discussed in this summary. See the PDQ summary on Pheochromocytoma and Paraganglioma for more information. Adrenocortical carcinoma and ...

  8. Treatment Option Overview (Adrenocortical Carcinoma)

    Science.gov (United States)

    ... that forms in the adrenal medulla is called pheochromocytoma and is not discussed in this summary. See the PDQ summary on Pheochromocytoma and Paraganglioma for more information. Adrenocortical carcinoma and ...

  9. Interferon-β is a potent inhibitor of cell growth and cortisol production in vitro and sensitizes human adrenocortical carcinoma cells to mitotane

    NARCIS (Netherlands)

    P.M. van Koetsveld (Peter); G. Vitale (Giovanni); R.A. Feelders (Richard); M. Waaijers (Marlijn); D. Sprij-Mooij (Diana); R.R. de Krijger (Ronald); E.J. Speel (Ernst-Jan); J. Hofland (Johannes); S.W.J. Lamberts (Steven); W.W. de Herder (Wouter); L.J. Hofland (Leo)

    2013-01-01

    textabstractAdrenocortical carcinoma (ACC) is an aggressive tumor with very poor prognosis. Novel medical treatment opportunities are required. We investigated the effects of interferon-β (IFN-β), alone or in combination with mitotane, on cell growth and cortisol secretion in primary cultures of 13

  10. Adrenocortical reserves in hyperthyroidism.

    Science.gov (United States)

    Agbaht, Kemal; Gullu, Sevim

    2014-02-01

    Explicit data regarding the changes in adrenocortical reserves during hyperthyroidism do not exist. We aimed to document the capability (response) of adrenal gland to secrete cortisol and DHEA-S during hyperthyroidism compared to euthyroidism, and to describe factors associated with these responses. A standard-dose (0.25 mg/i.v.) ACTH stimulation test was performed to the same patients before hyperthyroidism treatment, and after attainment of euthyroidism. Baseline cortisol (Cor(0)), DHEA-S (DHEA-S(0)), cortisol binding globulin (CBG), ACTH, calculated free cortisol (by Coolen's equation = CFC), free cortisol index (FCI), 60-min cortisol (Cor(60)), and DHEA-S (DHEA-S(60)), delta cortisol (ΔCor), delta DHEA-S (ΔDHEA-S) responses were evaluated. Forty-one patients [22 females, 49.5 ± 15.2 years old, 32 Graves disease, nine toxic nodular goiter] had similar Cor(0), DHEA-S(0), CFC, FCI, and DHEA-S(60) in hyperthyroid and euthyroid states. Cor(60), ΔCor, and ΔDHEA-S were lower in hyperthyroidism. In four (10 %) patients the peak ACTH-stimulated cortisol values were lower than 18 μg/dL. When the test repeated after attainment of euthyroidism, all of the patients had normal cortisol response. Regression analysis demonstrated an independent association of Cor(60) with free T3 in hyperthyroidism. However, the predictors of CFC, FCI, and DHEA-S levels were serum creatinine levels in hyperthyroidism, and both creatinine and transaminase levels in euthyroidism. ACTH-stimulated peak cortisol, delta cortisol, and delta DHEA-S levels are decreased during hyperthyroidism, probably due to increased turnover. Since about 10 % of the subjects with hyperthyroidism are at risk for adrenal insufficiency, clinicians dealing with Graves' disease should be alert to the possibility of adrenal insufficiency during hyperthyroid stage.

  11. Adrenocortical tumors in children

    Directory of Open Access Journals (Sweden)

    R.C. Ribeiro

    2000-10-01

    Full Text Available Childhood adrenocortical tumors (ACT are rare. In the USA, only about 25 new cases occur each year. In Southern Brazil, however, approximately 10 times that many cases are diagnosed each year. Most cases occur in the contiguous states of São Paulo and Paraná. The cause of this higher rate has not been identified. Familial genetic predisposition to cancer (p53 mutations and selected genetic syndromes (Beckwith-Wiedemann syndrome have been associated with childhood ACT in general but not with the Brazilian counterpart. Most of the affected children are young girls with classic endocrine syndromes (virilizing and/or Cushing. Levels of urinary 17-ketosteroids and plasma dehydroepiandrosterone sulfate (DHEA-S, which are abnormal in approximately 90% of the cases, provide the pivotal clue to a diagnosis of ACT. Typical imaging findings of pediatric ACT consist of a large, well-defined suprarenal tumor containing calcifications with a thin capsule and central necrosis or hemorrhage. The pathologic classification of pediatric ACT is troublesome. Even an experienced pathologist can find it difficult to differentiate carcinoma from adenoma. Surgery is the single most important procedure in the successful treatment of ACT. The role of chemotherapy in the management of childhood ACT has not been established although occasional tumors are responsive to mitotane or cisplatin-containing regimens. Because of the heterogeneity and rarity of the disease, prognostic factors have been difficult to establish in pediatric ACT. Patients with incomplete tumor resection or with metastatic disease at diagnosis have a dismal prognosis. In patients with localized and completely resected tumors, the size of the tumor has predictive value. Patients with large tumors have a much higher relapse rate than those with small tumors.

  12. Primary pigmented nodular adrenocortical disease

    Directory of Open Access Journals (Sweden)

    Marie T Manipadam

    2011-01-01

    Full Text Available Primary pigmented nodular adrenocortical disease (PPNAD is a rare cause of ACTH-independent Cushing′s syndrome and has characteristic gross and microscopic pathologic findings. We report a case of PPNAD in a 15-year-old boy, which was not associated with Carney′s complex. Bilateral adrenalectomy is the treatment of choice.

  13. Isolation of rat adrenocortical mitochondria

    Energy Technology Data Exchange (ETDEWEB)

    Solinas, Paola [Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106 (United States); Department of Medicine, Center for Mitochondrial Disease, School of Medicine, Case Western Reserve University, Cleveland, OH 44106 (United States); Fujioka, Hisashi [Electron Microscopy Facility, Department of Pharmacology, Center for Mitochondrial Disease, School of Medicine, Case Western Reserve University, Cleveland, OH 44106 (United States); Tandler, Bernard [Department of Biological Sciences, School of Dental Medicine, Center for Mitochondrial Disease, School of Medicine, Case Western Reserve University, Cleveland, OH 44106 (United States); Hoppel, Charles L., E-mail: charles.hoppel@case.edu [Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106 (United States); Department of Medicine, Center for Mitochondrial Disease, School of Medicine, Case Western Reserve University, Cleveland, OH 44106 (United States)

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer A method for isolation of adrenocortical mitochondria from the adrenal gland of rats is described. Black-Right-Pointing-Pointer The purified isolated mitochondria show excellent morphological integrity. Black-Right-Pointing-Pointer The properties of oxidative phosphorylation are excellent. Black-Right-Pointing-Pointer The method increases the opportunity of direct analysis of adrenal mitochondria from small animals. -- Abstract: This report describes a relatively simple and reliable method for isolating adrenocortical mitochondria from rats in good, reasonably pure yield. These organelles, which heretofore have been unobtainable in isolated form from small laboratory animals, are now readily accessible. A high degree of mitochondrial purity is shown by the electron micrographs, as well as the structural integrity of each mitochondrion. That these organelles have retained their functional integrity is shown by their high respiratory control ratios. In general, the biochemical performance of these adrenal cortical mitochondria closely mirrors that of typical hepatic or cardiac mitochondria.

  14. Feminizing Adrenocortical Carcinoma Without Gynecomastia

    Directory of Open Access Journals (Sweden)

    Farida Chentli1*,

    2017-07-01

    Full Text Available Malignant feminizing adrenocortical tumors are exceedingly rare. Their main presentation is gynecomastia. In these estrogen secreting tumors (with or without other adrenocortical hormones lack of gynecomastia is exceptional as in our case. A 44-year-old man presented with abdominal pain. Radiological assessment revealed a tumor measuring 120 × 95 mm in the retroperitoneal area with numerous metastases. Pathological examination pleaded for an adrenal origin with a Weiss’s score of 5. Six months later, the tumor relapsed, and he had a second surgery and was sent for hormone assessment. Clinical examination showed a skinny man with severe fatigue. He had no Cushingoid features. Gynecomastia and galactorrhea were absent. Penile length, testicular volume, and body hair growth were normal. Several cutaneous nodules were present. Biological assessment showed high morning plasma cortisol, which failed to be suppressed by treatment with 2 mg dexamethasone. Plasma estradiol and 17OH progesterone levels were high, but his testosterone levels were low. Radiological exploration showed numerous metastases: pleural, pulmonary, retroperitoneal, and abdominal. He was treated with classical chemotherapy, but he died four months after diagnosis.

  15. Treatment Options by Stage (Adrenocortical Carcinoma)

    Science.gov (United States)

    ... that forms in the adrenal medulla is called pheochromocytoma and is not discussed in this summary. See the PDQ summary on Pheochromocytoma and Paraganglioma for more information. Adrenocortical carcinoma and ...

  16. Adrenocortical carcinoma in pregnancy: A diagnostic dilemma.

    Science.gov (United States)

    Jairath, Ankush; Aulakh, Baldev S

    2014-07-01

    Adrenocortical carcinoma is a rare disease. Additionally, in the case of coexisting pregnancy, there are diagnostic difficulties due to associated physiological hormonal changes as well as imaging limitations. Cushing's syndrome and virilization during pregnancy is a rare entity with few cases reported in the literature. Misdiagnosis is common as the syndrome may be easily confused with preeclampsia or gestational diabetes. We present the case of a 31-year-old pregnant woman with rapidly developing symptoms related to hormonally active adrenocortical cancer.

  17. Effects of mixtures of persistent organic pollutants (POPs) derived from cod liver oil on H295R steroidogenesis

    NARCIS (Netherlands)

    Montano, M.; Zimmer, K.E.; Dahl, E.; Berge, V.; Olsaker, I.; Skaare, J.U.; Murk, A.J.; Ropstad, E.; Verhaegen, S.

    2011-01-01

    Crude cod liver oil and liver oil supplements are consumed as a source of vitamin A, D and polyunsaturated fatty acids; during winter and early pregnancy. Crude cod liver oil however constitutes a considerable source of persistent organic pollutants (POPs). This paper aimed at characterizing and qua

  18. Understanding the Effects of Atrazine on Steroidogenesis in rat granulosa and H295R adrenal cortical carcinoma cells

    Science.gov (United States)

    Atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine) was introduced in the 1950s as a broad spectrum herbicide, and remains one of the most widely used herbicides in the United States. Several studies have suggested that atrazine modifies steroidogenesis and may disrupt r...

  19. Effects of mixtures of persistent organic pollutants (POPs) derived from cod liver oil on H295R steroidogenesis

    NARCIS (Netherlands)

    Montano, M.; Zimmer, K.E.; Dahl, E.; Berge, V.; Olsaker, I.; Skaare, J.U.; Murk, A.J.; Ropstad, E.; Verhaegen, S.

    2011-01-01

    Crude cod liver oil and liver oil supplements are consumed as a source of vitamin A, D and polyunsaturated fatty acids; during winter and early pregnancy. Crude cod liver oil however constitutes a considerable source of persistent organic pollutants (POPs). This paper aimed at characterizing and qua

  20. Understanding the Effects of Atrazine on Steroidogenesis in rat granulosa and H295R adrenal cortical carcinoma cells

    Science.gov (United States)

    Atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine) was introduced in the 1950s as a broad spectrum herbicide, and remains one of the most widely used herbicides in the United States. Several studies have suggested that atrazine modifies steroidogenesis and may disrupt r...

  1. Expression of receptors for luteinizing hormone, gastric-inhibitory polypeptide, and vasopressin in normal adrenal glands and cortisol-secreting adrenocortical tumors in dogs

    NARCIS (Netherlands)

    Galac, S.; Kars, V.J.; Klarenbeek, S.; Teerds, K.J.; Mol, J.A.; Kooistra, H.S.

    2010-01-01

    Hypercortisolism caused by an adrenocortical tumor (AT) results from adrenocorticotropic hormone (ACTH)-independent hypersecretion of glucocorticoids. Studies in humans demonstrate that steroidogenesis in ATs may be stimulated by ectopic or overexpressed eutopic G protein-coupled receptors. We repor

  2. Experiment list: SRX233549 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Tissue Diagnosis=Carcinoma 22458543,85.7,7.4,1284 GSM1080951: input DNA (reps 1-2); Homo sapiens; ChIP-Seq s...ource_name=H295R/TR SF-1 cells || cell line=H295R adrenocortical tumor cell line || chip antibody=None (input

  3. Adrenocortical carcinoma in pregnancy: A diagnostic dilemma

    OpenAIRE

    2014-01-01

    Adrenocortical carcinoma is a rare disease. Additionally, in the case of coexisting pregnancy, there are diagnostic difficulties due to associated physiological hormonal changes as well as imaging limitations. Cushing's syndrome and virilization during pregnancy is a rare entity with few cases reported in the literature. Misdiagnosis is common as the syndrome may be easily confused with preeclampsia or gestational diabetes. We present the case of a 31-year-old pregnant woman with rapidly deve...

  4. Alterations of Phosphodiesterases in Adrenocortical Tumors

    Directory of Open Access Journals (Sweden)

    Fady Hannah-Shmouni

    2016-08-01

    Full Text Available Alterations in the cyclic (c AMP-dependent signaling pathway have been implicated in the majority of benign adrenocortical tumors (ACTs causing Cushing syndrome (CS. Phosphodiesterases (PDEs are enzymes that regulate cyclic nucleotide levels, including cAMP. Inactivating mutations and other functional variants in PDE11A and PDE8B, two cAMP-binding PDEs, predispose to ACTs. The involvement of these two genes in ACTs was initially revealed by a genome-wide association study in patients with micronodular bilateral adrenocortical hyperplasia. Thereafter, PDE11A or PDE8B genetic variants have been found in other ACTs, including macronodular adrenocortical hyperplasias and cortisol-producing adenomas. In addition, down-regulation of PDE11A expression and inactivating variants of the gene have been found in hereditary and sporadic testicular germ cell tumors, as well as in prostatic cancer. PDEs confer an increased risk of ACT formation probably through, primarily, their action on cAMP levels, but other actions might be possible. In this report, we review what is known to date about PDE11A and PDE8B and their involvement in the predisposition to ACTs.

  5. Pathway Implications of Aberrant Global Methylation in Adrenocortical Cancer.

    Directory of Open Access Journals (Sweden)

    Christophe R Legendre

    Full Text Available Adrenocortical carcinomas (ACC are a rare tumor type with a poor five-year survival rate and limited treatment options.Understanding of the molecular pathogenesis of this disease has been aided by genomic analyses highlighting alterations in TP53, WNT, and IGF signaling pathways. Further elucidation is needed to reveal therapeutically actionable targets in ACC.In this study, global DNA methylation levels were assessed by the Infinium HumanMethylation450 BeadChip Array on 18 ACC tumors and 6 normal adrenal tissues. A new, non-linear correlation approach, the discretization method, assessed the relationship between DNA methylation/gene expression across ACC tumors.This correlation analysis revealed epigenetic regulation of genes known to modulate TP53, WNT, and IGF signaling, as well as silencing of the tumor suppressor MARCKS, previously unreported in ACC.DNA methylation may regulate genes known to play a role in ACC pathogenesis as well as known tumor suppressors.

  6. Adrenocortical carcinoma: Report of two cases

    Directory of Open Access Journals (Sweden)

    C Aparna

    2011-01-01

    Full Text Available Adrenocortical carcinoma (ACC is a rare neoplasm with a slight predilection for female patients. We report two cases of ACC. The first case was of a 7-year-old girl who presented with clitoromegaly. The second case was of a 22-Year-old female who presented with a lump in the abdomen and features of Cushing′s syndrome with virilization.The clinical, biochemical, histological features along with differential diagnosis are discussed. These cases are presented because of their rarity, and also to highlight the importance of differentiating ACC from an adenoma particularly in pediatric patients.

  7. Myxoid Adrenocortical Adenoma: Magnetic resonance imaging and pathology correlation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Tae Un [Dept. of Radiology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Kim, Suk; Lee, Jun Woo; Lee, Nam Kyung; Ha, Hong Koo; Park, Won Young [Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan (Korea, Republic of)

    2014-04-15

    We report a case of a 74-year-old female with myxoid adrenocortical adenoma which showed different magnetic resonance imaging findings compared to those of a typical adrenocortical adenoma. The myxoid change in the adrenocortical adenoma is a rare form of degeneration. It presents a considerable diagnostic challenge to both radiologists and clinicians because it can mimic other adrenal tumor types on imaging. The MRI findings of the presented case included a high signal intensity on T2-weighted images similar to that of fluid and delayed progressive enhancement.

  8. Primary pigmented nodular adrenocortical disease presenting with a unilateral adrenocortical nodule treated with bilateral laparoscopic adrenalectomy: a case report

    Directory of Open Access Journals (Sweden)

    Kaltsas Gregory

    2010-07-01

    Full Text Available Abstract Introduction Primary pigmented nodular adrenocortical disease is a rare cause of adrenocorticotropic hormone-independent Cushing's syndrome. We report an uncommon primary pigmented nodular adrenocortical disease case presenting with a unilateral adrenocortical nodule and provide a brief overview of the existing literature. Case presentation A 27-year-old Caucasian woman was admitted to our Department with adrenocorticotropic hormone-independent Cushing's syndrome. Its cause was initially considered a left adrenocortical adenoma based on computer tomography imaging. The patient underwent left laparoscopic adrenalectomy and histological examination revealed pigmented micronodular adrenal hyperplasia. Evaluation for the presence of Carney complex was negative. Six months later recurrence of hypercortisolism was documented and a right laparoscopic adrenalectomy was performed further establishing the diagnosis of primary pigmented nodular adrenocortical disease. After a nine-year follow-up there is no evidence of residual disease. Conclusions Even though primary pigmented nodular adrenocortical disease is a rare cause of Cushing's syndrome, it should be included in the differential diagnosis of adrenocorticotropic hormone-independent Cushing's syndrome, especially because adrenal imaging can be misleading mimicking other adrenocortical diseases. Bilateral laparoscopic adrenalectomy is the preferred treatment in these subjects.

  9. Effects of multiwalled carbon nanotubes and triclocarban on several eukaryotic cell lines: elucidating cytotoxicity, endocrine disruption, and reactive oxygen species generation

    OpenAIRE

    Simon,Anne; Maletz, Sibylle X; Hollert, Henner; Schäffer, Andreas; Maes, Hanna M

    2014-01-01

    To date, only a few reports about studies on toxic effects of carbon nanotubes (CNT) are available, and their results are often controversial. Three different cell lines (rainbow trout liver cells (RTL-W1), human adrenocortical carcinoma cells (T47Dluc), and human adrenocarcinoma cells (H295R)) were exposed to multiwalled carbon nanotubes, the antimicrobial agent triclocarban (TCC) as well as the mixture of both substances in a concentration range of 3.13 to 50 mg CNT/L, 31.25 to 500 μg TCC/L...

  10. Comparison of adrenocortical responses to acute stress in lowland and highland Eurasian tree sparrows (Passer montanus): similar patterns during the breeding, but different during the prebasic molt.

    Science.gov (United States)

    Li, Dongming; Wu, Junzhe; Zhang, Xiaorui; Ma, Xiaofei; Wingfield, John C; Lei, Fumin; Wang, Gang; Wu, Yuefeng

    2011-11-01

    Previous studies indicate most free-living avian species in both extreme and temperate environments seasonally modulate the adrenocortical responses to acute stress, and those breeding in harsh environments always express reduced adrenocortical responses, which may allow them to obtain maximal reproductive success. However, recent investigations showing a human commensal species, house sparrows (Passer domesticus), expressed similar corticosterone (CORT) responses in both benign and harsh environments. In this study, focusing on another human commensal species, Eurasian tree sparrows (P. montanus), we examined the adrenocortical response to acute stress in lowland populations, among the early and late breeding, the prebasic molt, and the wintering stages, and compared them with previously published data from populations on the Tibetan Plateau. Our results show: (1) similar to highland Eurasian tree sparrows, lowland populations show no differences in baseline CORT levels among life history stages, and the stress-induced CORT (maximal CORT, total and corrected integrated CORT) levels are lower during the early breeding and the prebasic molt stages than those in the late breeding and the wintering stages; (2) highland Eurasian tree sparrows show stronger adrenocortical responses during the prebasic molt stage than lowland populations, whereas there are no differences between the early and the breeding stages (except for maximal CORT). Our results suggest that Eurasian tree sparrows from both harsh and benign environments have similar patterns of adrenocortical responses in the breeding stage, whereas they are different in the prebasic molt stage. In highland birds, the increased maximal CORT levels during the late breeding and the small increases in adrenocortical responses during the prebasic molt are interesting but remain unexplained.

  11. Imaging findings in pediatric adrenocortical carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro, J. [International Outreach Program, St. Jude Children' s Research Hospital, Memphis, TN (United States); Department of Radiology, Instituto Materno Infantil de Pernambuco, Recife (Brazil); Ribeiro, R.C. [International Outreach Program, St. Jude Children' s Research Hospital, Memphis, TN (United States); Department of Hematology-Oncology, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Department of Pediatrics, University of Tennessee-Memphis, Tennessee (United States); Fletcher, B.D. [International Outreach Program, St. Jude Children' s Research Hospital, Memphis, TN (United States); Department of Pediatrics, University of Tennessee-Memphis, Tennessee (United States); Department of Diagnostic Imaging, St. Jude Children' s Research Hospital, 332 N. Lauderdale St., Memphis, TN 38105 (United States); Department of Radiology, University of Tennessee-Memphis, TN (United States)

    2000-01-01

    Background. Adrenocortical carcinoma (ACC), a tumor that is rare among children, causes clinically evident hormonal disturbances. Imaging methods are used to stage disease and to plan surgical resection. Objective. To describe the findings of the various imaging methods used to evaluate ACC. Materials and methods. We reviewed the records of ten consecutive patients (mean age, 8.1 years) who presented from 1987 to 1998 with ACC. All patients underwent computed tomography (CT) scanning; five underwent magnetic resonance (MR) imaging; four underwent ultrasonography (US); and eight underwent radionuclide bone scans. Results. Seven patients presented with signs of hormonally functional tumors. Typical imaging findings consisted of a large, well-defined suprarenal tumor, containing calcifications (seven patients) with a thin capsule and central necrosis or hemorrhage (six patients). The inferior vena cava (IVC) was compressed by tumor in three patients, and ultrasonography demonstrated invasion of the IVC wall in one of these. Three patients' bone scans showed that the primary tumor took up radioactive tracer. Spread to lungs or liver or both was demonstrated in six patients. Conclusions. CT, US and MR imaging are effective methods of imaging the primary tumor. Chest CT and bone scintigraphy should be performed to detect metastases. The presence of a thin tumor capsule, a stellate central zone of necrosis, and evidence of hormonal function help distinguish ACC from neuroblastoma. (orig.)

  12. Estrogen receptor expression in adrenocortical carcinoma

    Institute of Scientific and Technical Information of China (English)

    Xiao-cao SHEN; Cai-xiao GU; Yi-qing QIU; Chuan-jun DU; Yan-biao FU; Jian-jun WU

    2009-01-01

    Objective: Adrenocortical carcinoma (ACC) is a rare but highly malignant tumor, and its diagnosis is mostly delayed and prognosis is poor. We report estrogen receptor (ER) expression in this tumor and our clinical experiences with 17 ACC cases. Methods: The data of the 17 patients (9 females and 8 males, age range from 16 to 69 years, mean age of 42.6 years) with ACC were reviewed, and symptoms, diagnostic procedures, treatment, and results of follow-up were evaluated. Immunohistochemistry was used to detect ER expression in tumor samples from the 17 patients. Results: At the time of diagnosis, 4 tumors were classified as Stage Ⅰ, 4 as Stage Ⅱ, 3 as Stage Ⅲ, and 6 as Stage Ⅳ. Eight patients demonstrated positive nuclear immunostaining of ER. The prognosis of patients with ER positive was significantly better (P<0.05) than that of patients with ER negative, with 1- and 5-year survival rates at 86% and 60% for ER-positive patients, and 38% and 0% for ER-negative patients, respectively. Conclusion: ER-positivity may be one of the factors associated with a worse prognosis of ACC.

  13. The endocrine disruption properties of an adipose contaminant mixture extracted from East Greenland polar bears studied in the H295R cell line

    DEFF Research Database (Denmark)

    Hjorth, R.; Letcher, R. J.; Blair, D.

    been well described and especially the polar bear (Ursus maritimus) is recognized as being one of the most contaminated species in the Arctic. The present study investigated the in vitro endocrine disruptive effects of the POP mixture found in adipose tissue from 10 East Greenland polar bears collected...... (dehydroepiandrosterone and androstenedione). These results demonstrated comprehensive in vitro effects of POPs extracted from polar bear adipose tissue on key elements in the steroidogenesis, and identifies disruption of CYP17 activity as a mode of action. A POP-induced interference with CYP17 can potentially explain...... previously observed hormone levels in polar bears and could pose a risk to their reproductive health....

  14. Evaluation of Endocrine Disrupting Effects of Nitrate after In Utero Exposure in Rats and of Nitrate and Nitrite in the H295R and T-Screen Assay

    DEFF Research Database (Denmark)

    Hansen, Pernille Reimer; Taxvig, Camilla; Christiansen, Sofie;

    2009-01-01

    Animal studies have shown that nitrate acts as an endocrine disrupter affecting the androgen production in adult males. This raises a concern for more severe endocrine disrupting effects after exposure during the sensitive period of prenatal male sexual development. As there are no existing studi...

  15. Adrenocortical scintigraphy with {sup 131}I-6-beta-iodomethyl-norcholesterol (NP 59) in bilateral adrenocortical carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Ruiz Hernandez, G.; Pallares, F.J.C.; Avila y Avalos, C.R. de [Hospital Clinic Universitari de Valencia (Spain). Servei de Medicina Nuclear; Bartual, A.R.; Rodrigo, S.T.; Ampudia-Blasco, F.J. [Hospital Clinic Universitari de Valencia (Spain). Servei d`Endocrinologia

    1998-06-01

    A case of a 49-year-old man suffering from bilateral adrenocortical carcinoma with local and secondary rapid progression is reported. The results of adrenocortical scintigraphy (NP 59) and histological findings allowed the diagnosis. This case report and a literature review showed the importance of using adrenocortical scintigraphy as a complementary imaging procedure of CT or MR images. (orig.) [Deutsch] Es wird ueber einen 49jaehrigen Mann berichtet, der an einem beidseitigen Nebennierenrinden-Karzinom mit schneller lokaler und sekundaerer Progression leidet. Die Ergebnisse der Nebennierenrinden-Szintigraphie (NP 59) und Histologie ermoeglichten die Diagnose: Dieser Fallbericht und ein Literaturueberblick zeigen die Bedeutung der Nebennierenrinden-Szintigraphie als ein zusaetzliches bildgebendes Verfahren neben CT und NMR. (orig.)

  16. Expression of Wnt and TGF-β pathway components and key adrenal transcription factors in adrenocortical tumors – association to carcinoma aggressiveness

    Science.gov (United States)

    Parviainen, Helka; Schrade, Anja; Kiiveri, Sanne; Prunskaite-Hyyryläinen, Renata; Haglund, Caj; Vainio, Seppo; Wilson, David B.; Arola, Johanna; Heikinheimo, Markku

    2013-01-01

    Factors controlling benign and malignant adrenocortical tumorigenesis are largely unknown, but several mouse models suggest an important role for inhibin-alpha (INHA). To show that findings in the mouse are relevant to human tumors and clinical outcome, we investigated the expression of signaling proteins and transcription factors involved in the regulation of INHA in human tumor samples. Thirty-one adrenocortical tumor samples, including 13 adrenocortical carcinomas (ACCs), were categorized according to Weiss score, hormonal profile, and patient survival data and analyzed using immunohistochemistry and RT-PCR. Expression of the TGF-β signaling mediator SMAD3 varied inversely with Weiss score, so that SMAD3 expression was lowest in the most malignant tumors. By contrast, SMAD2 expression was upregulated in most malignant tumors. Wnt pathway co-receptors LRP5 and LRP6 were predominantly expressed in benign adrenocortical tumors. In ACCs, expression of transcription factors GATA-6 and SF-1 correlated with that of their target gene INHA. Moreover, the diminished expression of GATA-6 and SF-1 in ACCs correlated with poor outcome. We conclude that the factors driving INHA expression are reduced in ACCs with poor outcome, implicating a role for INHAas a tumor suppressor in humans. PMID:23866946

  17. Expression of Wnt and TGF-β pathway components and key adrenal transcription factors in adrenocortical tumors: association to carcinoma aggressiveness.

    Science.gov (United States)

    Parviainen, Helka; Schrade, Anja; Kiiveri, Sanne; Prunskaite-Hyyryläinen, Renata; Haglund, Caj; Vainio, Seppo; Wilson, David B; Arola, Johanna; Heikinheimo, Markku

    2013-08-01

    Factors controlling benign and malignant adrenocortical tumorigenesis are largely unknown, but several mouse models suggest an important role for inhibin-alpha (INHA). To show that findings in the mouse are relevant to human tumors and clinical outcome, we investigated the expression of signaling proteins and transcription factors involved in the regulation of INHA in human tumor samples⋅ Thirty-one adrenocortical tumor samples, including 13 adrenocortical carcinomas (ACCs), were categorized according to Weiss score, hormonal profile, and patient survival data and analyzed using immunohistochemistry and RT-PCR. Expression of the TGF-β signaling mediator SMAD3 varied inversely with Weiss score, so that SMAD3 expression was lowest in the most malignant tumors. By contrast, SMAD2 expression was upregulated in most malignant tumors. Wnt pathway co-receptors LRP5 and LRP6 were predominantly expressed in benign adrenocortical tumors. In ACCs, expression of transcription factors GATA-6 and SF-1 correlated with that of their target gene INHA. Moreover, the diminished expression of GATA-6 and SF-1 in ACCs correlated with poor outcome. We conclude that the factors driving INHA expression are reduced in ACCs with poor outcome, implicating a role for INHA as a tumor suppressor in humans.

  18. Adrenocortical carcinoma (ACC: diagnosis, prognosis and treatment.

    Directory of Open Access Journals (Sweden)

    Rossella eLibé

    2015-07-01

    Full Text Available Adrenocortical carticnoma (ACC is a rare malignancy with an incidence of 0.7–2.0 cases/million habitants/year. The diagnosis of malignancy relies on careful investigations of clinical, biological and imaging features before surgery and pathological examination after tumor removal. Most patients present with steroid hormone excess or abdominal mass effects, but 15% of patients with ACC is initially diagnosed incidentally. After the diagnosis, in order to assess the ACC prognosis and establish an adequate basis for treatment decisions different tools are proposed. The stage classification pro¬posed by the European Network for the Study of Adrenal Tumors (ENSAT is recommended. Pathology reports define the Weiss score, the resection status and the proliferative index, including the mitotic count and the Ki67 index. As far as the treatment is concerned, in case of tumor limited to the adrenal gland, the complete resection of the tumor is the first option. Most patients benefit from adjuvant mitotane treatment. In metastatic disease, mitotane is the cornerstone of initial treatment, and cytotoxic drugs should be added in case of progression. Recently, the First International Randomised (FIRM-ACT Trial in metastatic ACC reported the association between mitotane and etoposide/ doxorubicin/cisplatin (EDP as the new standard in first line treatment of ACC. In last years, new targeted therapies, including the IGF 1 receptor inhibitors, have been investigated, but their efficacy remains limited. Thus, new treatment concepts are urgently needed. The ongoing omic approaches and next-generation sequencing will improve our understanding of the pathogenesis and hopefully will lead to better therapies.

  19. Pathogenesis of canine cortisol-secreting adrenocortical tumors

    NARCIS (Netherlands)

    Kool, Miriam

    2015-01-01

    In dogs, hypercortisolism is one of the most frequently observed endocrine disorders, with an estimated incidence of about 1-2 cases per 1000 dogs per year. Approximately 15% of these cases is due to a cortisol-secreting adrenocortical tumor (AT). Cortisol-secreting ATs are characterized by uncontro

  20. Metabolic reprogramming: a new relevant pathway in adult adrenocortical tumors

    Science.gov (United States)

    Longatto-Filho, Adhemar; Faria, André M.; Fragoso, Maria C. B. V.; Lovisolo, Silvana M.; Lerário, Antonio M.; Almeida, Madson Q.

    2015-01-01

    Adrenocortical carcinomas (ACCs) are complex neoplasias that may present unexpected clinical behavior, being imperative to identify new biological markers that can predict patient prognosis and provide new therapeutic options. The main aim of the present study was to evaluate the prognostic value of metabolism-related key proteins in adrenocortical carcinoma. The immunohistochemical expression of MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX was evaluated in a series of 154 adult patients with adrenocortical neoplasia and associated with patients' clinicopathological parameters. A significant increase in was found for membranous expression of MCT4, GLUT1 and CAIX in carcinomas, when compared to adenomas. Importantly MCT1, GLUT1 and CAIX expressions were significantly associated with poor prognostic variables, including high nuclear grade, high mitotic index, advanced tumor staging, presence of metastasis, as well as shorter overall and disease free survival. In opposition, MCT2 membranous expression was associated with favorable prognostic parameters. Importantly, cytoplasmic expression of CD147 was identified as an independent predictor of longer overall survival and cytoplasmic expression of CAIX as an independent predictor of longer disease-free survival. We provide evidence for a metabolic reprogramming in adrenocortical malignant tumors towards the hyperglycolytic and acid-resistant phenotype, which was associated with poor prognosis. PMID:26587828

  1. Acute self-suppression of corticosteroidogenesis in isolated adrenocortical cells.

    Science.gov (United States)

    Carsia, R V; Malamed, S

    1979-10-01

    The relation between steroidogenesis induced by ACTH and that induced by exogenous concentrations of glucocorticoids was studied in isolated adrenocortical cells. Exogenous corticosterone and cortisol, in concentrations within the production capacity of the adrenal gland, suppressed steroidogenesis induced by ACTH in rat and beef cells, respectively. The precursors pregnenolone and progesterone enhanced steroidogenesis in both rat and beef cells. Aldosterone in rat cells and 17 beta-estradiol in rat and beef cells had little if any effect on steroidogenesis. Either suppression or stimulation by exogenous steroids was acute, that is, after 2-h incubation for rat cells and 1-h incubation for beef cells. A direct suppressive action of end product glucocorticoids is indicated. This observed self-suppression of adrenocortical cells suggests the existence of a mechanism for the find adjustment of steroidogenesis that operates in addition to the classical control exerted by the anterior pituitary.

  2. Adrenocortical oncocytic neoplasm presenting with Cushing's syndrome: a case report

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    Kabayegit Ozlem

    2008-07-01

    Full Text Available Abstract Introduction Oncocytic neoplasms occur in several organs and are most commonly found in the thyroid, kidneys and salivary glands. Oncocytic neoplasms of the adrenal cortex are extremely rare and are usually non-functioning. Case presentation We report the case of an adrenocortical oncocytic neoplasm with uncertain malignant potential in a 31-year-old man with Cushing's syndrome. The patient had been operated on following diagnosis of a 7 cm adrenal mass. Following surgery, the Cushing's syndrome resolved. The patient is still alive with no metastases one year after the surgery. Conclusion Adrenocortical oncocytic neoplasms must be considered in the differential diagnosis of both functioning and non-functioning adrenal masses.

  3. [Irreversible coma following hypoglycemia in Sheehan syndrome with adrenocortical insufficiency].

    Science.gov (United States)

    Sas, A M; Meynaar, I A; Laven, J S; Bakker, S L; Feelders, R A

    2003-08-23

    A 24-year-old woman of Somali origin delivered at term after an uncomplicated pregnancy. Post-partum haemorrhage resulted in hypovolaemic shock which was treated by hysterectomy. Five days later she became comatose due to unrecognised hypoglycaemia which caused severe irreversible brain damage and status epilepticus. Treatment in the intensive care unit with artificial respiration, prednisolone, desmopressin, inotropic support, barbiturates and an anaesthetic under EEG guidance was unsuccessful. The patient died 28 days post-partum. The hypoglycaemia was due to a combination of (a) inadequate glucose intake and (b) lack of counter-regulatory mechanisms due to a deficiency of steroids and growth hormone as a result of loss of pituitary function (Sheehan syndrome) together with adrenocortical insufficiency. The combination of Sheehan syndrome and primary adrenocortical insufficiency has not been described previously in the literature.

  4. Adrenocortical tumors and insulin resistance: What is the first step?

    Science.gov (United States)

    Altieri, Barbara; Tirabassi, Giacomo; Della Casa, Silvia; Ronchi, Cristina L; Balercia, Giancarlo; Orio, Francesco; Pontecorvi, Alfredo; Colao, Annamaria; Muscogiuri, Giovanna

    2016-06-15

    The pathogenetic mechanisms underlying the onset of adrenocortical tumors (ACTs) are still largely unknown. Recently, more attention has been paid to the role of insulin and insulin-like growth factor (IGF) system on general tumor development and progression. Increased levels of insulin, IGF-1 and IGF-2 are associated with tumor cell growth and increased risk of cancer promotion and progression in patients with type 2 diabetes. Insulin resistance and compensatory hyperinsulinemia may play a role in adrenal tumor growth through the activation of insulin and IGF-1 receptors. Interestingly, apparently non-functioning ACTs are often associated with a high prevalence of insulin resistance and metabolic syndrome. However, it is unclear if ACT develops from a primary insulin resistance and compensatory hyperinsulinemia or if insulin resistance is only secondary to the slight cortisol hypersecretion by ACT. The aim of this review is to summarize the current evidence regarding the relationship between hyperinsulinemia and adrenocortical tumors.

  5. Pubertal outcome in a female with virilizing adrenocortical carcinoma

    Science.gov (United States)

    Breidbart, Emily; Cameo, Tamara; Garvin, James H.; Hibshoosh, Hanina

    2016-01-01

    Adrenocortical tumors are neoplasms that rarely occur in pediatric patients. Adrenocortical carcinoma (ACC) is even more uncommon, and is an aggressive malignancy with 5-year survival of 55% in a registry series. There is a lack of information on long-term endocrine outcome in survivors. We describe a 10-year follow-up in a patient who presented at 3 years 5 months with a 1-year history of axillary odor and 6 months’ history of pubic hair development with an increased clitoral size. Androgen levels were increased and a pelvic sonogram revealed a suprarenal mass of the left kidney. The tumor was successfully removed. At 6 years 11 months, androgen levels increased again. Workup for tumor recurrence was negative and the findings likely represented early adrenarche. The patient had menarche at an appropriate time and attained a height appropriate for her family. PMID:26812773

  6. Plurihormonal Cosecretion by a Case of Adrenocortical Oncocytic Neoplasm

    Directory of Open Access Journals (Sweden)

    J. J. Corrales

    2016-01-01

    Full Text Available Adrenocortical oncocytic neoplasms (oncocytomas are extremely rare; only approximately 159 cases have been described so far. The majority are nonfunctional and benign. We describe an unusual case of a functional oncocytoma secreting an excess of glucocorticoids (cortisol and androgens (androstenedione and DHEAS, a pattern of plurihormonal cosecretion previously not reported in men, presenting with endocrine manifestations of Cushing’s syndrome. The neoplasm was considered to be of uncertain malignant potential (borderline according to the Lin-Weiss-Bisceglia criteria.

  7. Virilizing Adrenocortical Carcinoma Advancing to Central Precocious Puberty after Surgery

    OpenAIRE

    Kim, Min Sun; Yang, Eu Jeen; Cho, Dong Hyu; Hwang, Pyung Han; Lee, Dae-Yeol

    2015-01-01

    Adrenocortical carcinoma (ACC) in pediatric and adolescent patients is rare, and it is associated with various clinical symptoms. We introduce the case of an 8-year-old boy with ACC who presented with peripheral precocious puberty at his first visit. He displayed penis enlargement with pubic hair and facial acne. His serum adrenal androgen levels were elevated, and abdominal computed tomography revealed a right suprarenal mass. After complete surgical resection, the histological diagnosis was...

  8. Conventional and novel strategies in the treatment of adrenocortical cancer

    Directory of Open Access Journals (Sweden)

    D.E. Schteingart

    2000-10-01

    Full Text Available Adrenocortical carcinoma is a highly malignant neoplasm with an incidence of two per million people per year. Several treatment strategies have resulted in temporary or partial tumor regression but very few cases have attained long survival. Surgical resection of the primary tumor and metastases is most effective. Several chemotherapeutic protocols have been employed with variable success. Mitotane (o,p'-DDD is an adrenalytic drug effective in inducing a tumor response in 33% of patients treated. Mitotane requires metabolic transformation for therapeutic action. Tumors may vary in their ability to metabolize mitotane and the ability of tumors to transform mitotane may predict the clinical response to the drug. Preliminary data show a possible correlation between metabolic activity of neoplastic adrenocortical tissue and response to mitotane. We have attempted to develop mitotane analogs with enhanced adrenalytic effect. Compared to mitotane, a di-chloro compound, the bromo-chloro and di-bromo analogs appear to have a greater effect. Future approaches to the treatment of adrenocortical carcinoma are likely to be based on blocking or reversing the biological mechanisms of tumorigenesis. Angiogenic and chemotactic mechanisms may play a role in adrenal tumor growth and inhibition of these mechanisms may result in inhibition of tumor growth. New mitotane analogs with greater adrenalytic potential could be a promising approach to developing more effective and selective therapies for adrenal cancer. Alternative approaches should attempt to suppress tumor growth by means of compounds with anti-angiogenic and anti-chemotactic activity.

  9. Supportive behaviors in adolescent romantic relationships moderate adrenocortical attunement.

    Science.gov (United States)

    Ha, Thao; Yeung, Ellen Wanheung; Rogers, Adam A; Poulsen, Franklin O; Kornienko, Olga; Granger, Douglas A

    2016-12-01

    This study investigated dyadic adrenocortical attunement within adolescent romantic relationships. An ethnically diverse sample (42% Latino) of adolescent heterosexual dating couples (N=91 dyads, Mage=16.5 years, SD=0.99) donated eight saliva samples (later assayed for cortisol) over the course of a 3-h laboratory session. Supportive behaviors were coded during a conflict and jealousy interaction task from video recordings, and participants completed pre-and-post task questionnaires. Parallel process latent growth models revealed a strong positive association between the couples' cortisol intercept, indicating that couples show attunement in initial levels of cortisol. Further, observed supportive behavior moderated the strength of the association between dyadic cortisol slopes. The results imply that low levels of supportive behavior predicted stronger adrenocortical attunement in the change in cortisol levels over time between adolescent romantic partners. These findings indicate that even early romantic relationships exhibit coordination of physiological activity. Findings raise the possibility that adrenocortical attunement may be a dyadic pathway through which the proximal social context of early romantic relationships is translated into risk or resilience in health and behavior.

  10. Imaging of Adrenal Masses with Emphasis on Adrenocortical Tumors

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    Anders Sundin

    2012-01-01

    Full Text Available Because of the more widespread and frequent use of cross-sectional techniques, mainly computed tomography (CT, an increasing number of adrenal tumors are detected as incidental findings (“incidentalomas”. These incidentaloma patients are much more frequent than those undergoing imaging because of symptoms related to adrenal disease. CT and magnetic resonance imaging (MRI are in most patients sufficient for characterization and follow-up of the incidentaloma. In a minor portion of patients, biochemical screening reveals a functional tumor and further diagnostic work-up and therapy need to be performed according to the type of hormonal overproduction. In oncological patients, especially when the morphological imaging criteria indicate an adrenal metastasis, biopsy of the lesion should be considered after pheochromocytoma is ruled out biochemically. In the minority of patients in whom CT and MRI fail to characterize the tumor and when time is of essence, functional imaging mainly by positron emission tomography (PET is available using various tracers. The most used PET tracer, [18F]fluoro-deoxy-glucose (18FDG, is able to differentiate benign from malignant adrenal tumors in many patients. 11C-metomidate (11C-MTO is a more specialized PET tracer that binds to the 11-beta-hydroxylase enzyme in the adrenal cortex and thus makes it possible to differ adrenal tumors (benign adrenocortical adenoma and adrenocortical cancer from those of non-adrenocortical origin.

  11. 类固醇生成因子1和DAX-1在肾上腺皮质肿瘤中的表达及临床意义%Expression of steroidogenic factor-1 and DAX-1 in human adrenocortical tumours

    Institute of Scientific and Technical Information of China (English)

    曹彩霞; 曾正陪; 童安莉; 卢琳; 陈适; 梁伟; 王永慧; 付春莉

    2012-01-01

    Objective To detect mRNA and protein expression of steroidogenic factor-1 ( SF-1 ) and DAX-1 in human adrenocortical tumors and normal adrenal cortex,and to investigate the effect of SF-1 and DAX-1 on the steroidogenesis and development of adrenocortical tumors.Methods Total RNA and protein was extracted from angiotensin Ⅱ unresponsive aldoterone-producing adenomas ( A Ⅱ -U-APA,n =12 ),angiotensin Ⅱ responsive aldoterone-producing adenomas ( AⅡ -R-APA,n =5 ),cortisol-producing adenomas ( CPA,n =10 ),adrenal nonfunctional adenomas ( NFA,n =10 ),aldosterone-producing carcinoma ( APC,n =2 ) and normal adrenal cortex ( NAC,n =8).To analyze gene expression of SF-1,DAX-1,ACTH receptor(ACTHR),and β-actin by real-time quantitative PCR in different tissues.The protein expression of SF-1,DAX-1,and β-actin in the same tissues by Western blot.To study the relationship of ACTHR,SF-1,and DAX-1 with clinical data in adrenocortical tumors.Results The expression of SF-1,DAX-1 mRNA and protein was different in NAC,AⅡ -U-APA,A Ⅱ -R- APA,APC,CPA,and NFA tissues [ relative expression of SF-1 mRNA:24.58±2.45,23.89±3.17,21.59±3.00,(38.75,44.16),14.17±2.80,and 36.38±3.50; DAX-1 mRNA:0.57±0.06,0.37±0.05,0.43±0.05,( 1.52,1.21 ),0.39 ±0.04,and 0.83 ±0.08 ; SF-1 protein:0.76 ±0.11,0.76 ±0.10,0.73 ±0.07,(1.24,1.40),0.55±0.04,and0.98±0.10; DAX-1 protein:0.65±0.14,0.39±0.13,0.43±0.14,(1.18,1.02),0.56±0.04,and 1.03±0.13 ; all P<0.05 or P<0.01 ].There was negative correlation by higher SF-1/DAX-1 ratio and tumor size in AⅡ -U-APA tissues.The mRNA and protein expression of SF-1 was lower in CPA and there was the positive correlation with tumor size.Conclusion SF-1 and DAX-1 might play a key role in the development of the adrenocortical tumorigenesis and steroidogenic tissues.%目的 探讨类固醇生成因子1(SF-1)和DAX-1在肾上腺皮质肿瘤中的表达及其临床意义.方法 应用实时荧光定量PCR检测39例肾上腺皮质肿瘤:包括对血

  12. Pediatric adrenocortical neoplasms: can imaging reliably discriminate adenomas from carcinomas?

    Energy Technology Data Exchange (ETDEWEB)

    Flynt, Kelsey A.; Dillman, Jonathan R.; Smith, Ethan A.; Strouse, Peter J. [University of Michigan Health System, Section of Pediatric Radiology, C. S. Mott Children' s Hospital, Department of Radiology, Ann Arbor, MI (United States); Davenport, Matthew S.; Caoili, Elaine M. [University of Michigan Health System, Division of Abdominal Imaging, Department of Radiology, Ann Arbor, MI (United States); Else, Tobias [University of Michigan Health System, Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, Ann Arbor, MI (United States)

    2015-08-15

    There is a paucity of literature describing and comparing the imaging features of adrenocortical adenomas and carcinomas in children and adolescents. To document the CT and MRI features of adrenocortical neoplasms in a pediatric population and to determine whether imaging findings (other than metastatic disease) can distinguish adenomas from carcinomas. We searched institutional medical records to identify pediatric patients with adrenocortical neoplasms. Pre-treatment CT and MRI examinations were reviewed by two radiologists in consensus, and pertinent imaging findings were documented. We also recorded relevant histopathological, demographic, clinical follow-up and survival data. We used the Student's t-test and Wilcoxon rank sum test to compare parametric and nonparametric continuous data, and the Fisher exact test to compare proportions. We used receiver operating characteristic (ROC) curve analyses to evaluate the diagnostic performances of tumor diameter and volume for discriminating carcinoma from adenoma. A P-value ≤0.05 was considered statistically significant. Among the adrenocortical lesions, 9 were adenomas, 15 were carcinomas, and 1 was of uncertain malignant potential. There were no differences in mean age, gender or sidedness between adenomas and carcinomas. Carcinomas were significantly larger than adenomas based on mean estimated volume (581 ml, range 16-2,101 vs. 54 ml, range 3-197 ml; P-value = 0.003; ROC area under the curve = 0.92) and mean maximum transverse plane diameter (9.9 cm, range 3.0-14.9 vs. 4.4 cm, range 1.9-8.2 cm; P-value = 0.0001; ROC area under the curve = 0.92). Carcinomas also were more heterogeneous than adenomas on post-contrast imaging (13/14 vs. 2/9; odds ratio [OR] = 45.5; P-value = 0.001). Six of 13 carcinomas and 1 of 8 adenomas contained calcification at CT (OR = 6.0; P-value = 0.17). Seven of 15 children with carcinomas exhibited metastatic disease at diagnosis, and three had inferior vena cava invasion. Median

  13. PRKACA: the catalytic subunit of protein kinase A and adrenocortical tumors

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    Annabel Sophie Berthon

    2015-05-01

    Full Text Available Cyclic-AMP (cAMP-dependent protein kinase (PKA is the main effector of cAMP signaling in all tissues. Inactivating mutations of the PRKAR1A gene, coding for the type 1A regulatory subunit of PKA, are responsible for Carney complex and primary pigmented nodular adrenocortical disease (PPNAD. PRKAR1A inactivation and PKA dysregulation have been implicated in various types of adrenocortical pathologies associated with ACTH-independent Cushing syndrome (AICS from PPNAD to adrenocortical adenomas and cancer, and other forms of bilateral adrenocortical hyperplasias (BAH. More recently, mutations of PRKACA, the gene coding for the catalytic subunit C alpha (Cα, were also identified in the pathogenesis of adrenocortical tumors. PRKACA copy number gain was found in the germline of several patients with cortisol-producing BAH, whereas the somatic Leu206Arg (c.617A>C recurrent PRKACA mutation was found in as many as half of all adrenocortical adenomas associated with AICS. In vitro analysis demonstrated that this mutation led to constitutive Cα activity, unregulated by its main partners, the PKA regulatory subunits. In this review, we summarize the current understanding of the involvement of PRKACA in adrenocortical tumorigenesis, and our understanding of PKA’s role in adrenocortical lesions. We also discuss potential therapeutic advances that can be made through targeting of PRKACA and the PKA pathway.

  14. Sex differences in adrenocortical structure and function. Pt. 11

    Energy Technology Data Exchange (ETDEWEB)

    Malendowicz, L.K.; Jachimowicz, B.

    1982-01-01

    Adrenal glands from orchectomized and ovariectomized rats, with and without replacement therapy, and also from intact controls of both sexes, were examined by autoradiography with /sup 3/H-thymidine. The labelling index after 1 or 2 nucleoside injections was higher in the zona glomerulosa of females than in male rats, while no differences were found in the fascicular and reticular zones. Orchiectomy increased the labelling index in the fascicular and reticular zones, an effect prevented by testosterone. Ovariectomy did not change the labelling index, while estradiol lowered it in the zona glomerulosa. Duration of the S phase was longer in the zona fasciculata cells of males than in females. Both orchiectomy and testosterone shortened this phase in cells of the zona fasciculata and zona reticularis. Ovariectomy prolonged the S phase in the zona fasciculata and shortened this time in the reticular zone, an effect reversed by estradiol. In the glomerular and fascicular zones, cell cycle time was longer in males than in females. Orchiectomy shortened this time in all adrenocortical zones, an effect reversed by testosterone. Ovariectomy shortened cell cycle time in the glomerular and reticular zones and prolonged it in the zona fasciculata; these effects were reversed by estradiol. Turnover rate in adrenocortical cells was markedly higher in females than in males, a difference due to testosterone which markedly decreased turnover rate.

  15. Hypertrophic obstructive cardiomyopathy in an infant with an adrenocortical tumor.

    Science.gov (United States)

    Hauser, Jakob; Riedl, Stefan; Michel-Behnke, Ina; Minkov, Milen; Perneczky, Eva; Horcher, Ernst

    2013-08-01

    Nonfamilial cardiomyopathies in childhood have been only sporadically ascribed to endocrine disorders. We report on a 4-month-old male infant presenting with Cushing's syndrome associated with excessive body weight (8.9 kg; >97th percentile) and features of virilization (Tanner stage 2 for pubic hair development). Abdominal sonography showed a large adrenal tumor. Echocardiography revealed myocardial hypertrophy with severe subaortic obstruction. Blood tests showed excessive androgen and cortisol serum levels with absent circadian rhythm as well as suppressed corticotropin. Urine catecholamine levels were within the normal range. Tumor resection with general anesthesia was performed after preparation with antihypertensive and anticongestive drug therapy. Continuous intravenous hydrocortisone substitution was started intraoperatively and subsequently tapered and switched to oral administration after 12 days. A gradual reduction in glucocorticoid substitution and its discontinuation after a total duration of 9 months were well tolerated. Histopathologic workup revealed an adrenocortical tumor of intermediate dignity. Postoperative tumor staging excluded both residual primary tumor and metastases. Both a normalization of body weight and myocardial mass were observed. The present article is, to our knowledge, the first to describe severe hypertrophic obstructive cardiomyopathy caused by an adrenocortical tumor and provides novel detailed data on postoperative glucocorticoid management.

  16. Glucocorticoid control of steroidogenesis in isolated rat adrenocortical cells.

    Science.gov (United States)

    Carsia, R V; Malamed, S

    1983-08-17

    The role of end-product glucocorticoids in the regulation of corticosteroidogenesis in isolated adrenocortical cells was investigated. Trypsin-isolated cells from male rat adrenal glands were incubated with or without corticotropin (ACTH) and with or without corticosterone. Endogenous corticosterone production was determined by radioimmunoassay at the end of incubation. Cessation of ACTH-induced corticosterone production was apparent after 2-4 h of incubation. The suppression occurred later with lower cell concentrations. Corticosterone production was partially restored after washing the suppressed cells. Supernatant fluid from suppressed cell suspensions also suppressed steroidogenesis of a fresh population of cells. However, the suppressing property of the supernatant fluid was abolished after the removal of corticosterone by charcoal-dextran treatment, suggesting that corticosterone or other steroids caused the suppression. Exogenous corticosterone induced suppression over a wide range of ACTH concentrations, but did not change the half-maximal steroidogenic concentration of ACTH, indicating that the suppression does not change the sensitivity of the cells to ACTH. Suppression occurred within 30-60 min after corticosterone had been added to the incubation medium either at the start of incubation or while steroidogenesis was in progress. Suppression varied directly with the concentration of exogenous corticosterone. These data indicate that glucocorticoids can directly and acutely suppress corticosteroidogenesis and thus control adrenocortical function in concert with other regulators such as ACTH and Ca2+.

  17. Cushing’s Syndrome in a Young Woman: A Rare Presentation of Adrenocortical Carcinoma

    Directory of Open Access Journals (Sweden)

    Nikhil Talwar, Manoj Andley, Bina Ravi, Ajay Kumar

    2008-01-01

    Full Text Available Cushing’s Syndrome is rarely caused by a malignant adrenal tumor. We report the case of a 24-year-oldfemale patient with Cushing’s syndrome caused by a functioning adrenocortical carcinoma and recoveredafter adrenalectomy.

  18. Cushing’s Syndrome in a Young Woman: A Rare Presentation of Adrenocortical Carcinoma

    OpenAIRE

    Nikhil Talwar, Manoj Andley, Bina Ravi, Ajay Kumar

    2008-01-01

    Cushing’s Syndrome is rarely caused by a malignant adrenal tumor. We report the case of a 24-year-oldfemale patient with Cushing’s syndrome caused by a functioning adrenocortical carcinoma and recoveredafter adrenalectomy.

  19. Effect of acupuncture on adrenocortical hormone production in rabbits with a central lesion

    Energy Technology Data Exchange (ETDEWEB)

    Liao, Y.Y.; Seto, K.; Saitoh, H.; Kawakami, M.

    A study was made of adrenocortical hormone production under electroacupuncture stimulation of the Tsu-San-Li locus in rabbits with a lesion in the fornix, stria terminalis, ventromedial nucleus or arcuate nucleus. In rabbits with a lesion in the stria terminalis or ventromedial nucleus, electroacupuncture stimulation of Tsu-San-Li resulted in no increase in phase 1 but an increase in phase 2 of adrenocortical hormone production. In rabbits with a lesion in the fornix or arcuate nucleus electroacupuncture stimulation of Tsu-San-Li was followed by increased adrenocortical hormone production in the both phases. These results show that the stria terminalis and the ventromedial nucleus play a major role in the augmentation of adrenocortical hormone production by electroacupuncture stimulation of Tsu-San-Li.

  20. A patient with adrenocortical carcinoma : Characterization of its biological activity and drug resistance profile

    NARCIS (Netherlands)

    Feller, N; Hoekman, K; Linn, SC; Verheul, HMW; Wolthers, BG; PoppSnijders, C; Pinedo, HM

    1997-01-01

    We describe a patient with a metastasized adrenocortical cancer who exhibited excessive production of both glucocorticoids and mineralocorticoids combined with suppressed androgen production, Unusual steroid metabolites found in the patient's urine have not been described previously in association w

  1. Analysis of circulating microRNAs in adrenocortical tumors.

    Science.gov (United States)

    Szabó, Diana Rita; Luconi, Michaela; Szabó, Peter M; Tóth, Miklós; Szücs, Nikolette; Horányi, János; Nagy, Zoltán; Mannelli, Massimo; Patócs, Attila; Rácz, Károly; Igaz, Peter

    2014-03-01

    Differential diagnosis of adrenocortical adenoma (ACA) and carcinoma is of pivotal clinical relevance, as the prognosis and clinical management of benign and malignant adrenocortical tumors (ACTs) is entirely different. Circulating microRNAs (miRNAs) are promising biomarker candidates of malignancy in several tumors; however, there are still numerous technical problems associated with their analysis. The objective of our study was to investigate circulating miRNAs in ACTs and to evaluate their potential applicability as biomarkers of malignancy. We have also addressed technical questions including the choice of profiling and reference gene used. A total of 25 preoperative plasma samples obtained from patients with ACAs and carcinomas were studied by microarray and quantitative real-time PCR. None of the three miRNAs (hsa-miR-192, hsa-mir-197 and hsa-miR-1281) found as differentially expressed in plasma samples in our microarray screening could be validated by quantitative real-time PCR. In contrast, of the selected eight miRNAs reported in the literature as differentially expressed in ACT tissues, five (hsa-miR-100, hsa-miR-181b, hsa-miR-184, hsa-miR-210 and hsa-miR-483-5p) showed a statistically significant overexpression in adrenocortical cancer vs adenoma when normalized on hsa-miR-16 as a reference gene. Receiver operator characteristic analysis of data revealed that the combination of dCThsa-miR-210 - dCThsa-miR-181b and dCThsa-miR-100/dCThsa-miR-181b showed the highest diagnostic accuracy (area under curve 0.87 and 0.85, respectively). In conclusion, we have found significant differences in expression of circulating miRNAs between ACAs and carcinomas, but their diagnostic accuracy is not yet high enough for clinical application. Further studies on larger cohorts of patients are needed to assess the diagnostic and prognostic potential application of circulating miRNA markers.

  2. Abdominal wall metastasis in scar after open resection of an adrenocortical carcinoma

    Directory of Open Access Journals (Sweden)

    Nikhil Gupta

    2011-12-01

    Full Text Available A 42-year-old man patient presented with progressively increasing, occasionally painful lump in the left upper and central abdomen. Investigations revealed well-defined capsulated left adrenocortical carcinoma. Tumor was resected successfully along with left kidney. Tumor recurred in the abdominal surgical scar 1.5 years after surgery. We are reporting this case because of rarity of metastatic recurrence of an adrenocortical carcinoma in the abdominal surgical scar 1.5 years after resection of primary tumor.

  3. Urinary Steroid Profiling for the Preoperative Identification of Adrenocortical Adenomas with Regression and Myelolipomatous Changes

    OpenAIRE

    Blanes, Alfredo; Perna, Victoria; Taylor, Norman; Dworakowska, Dorota; Schulte, Klaus-Martin; Salvador J. Diaz-Cano

    2014-01-01

    Background: Adrenocortical neoplasms are classically divided into adenomas (ACA) and carcinomas (ACC). Heterogeneous appearance and greater size are criteria to suggest malignancy, along with the urinary steroid profile (USP). The presence of regression and myelolipomatous changes in adenomas (ACA-RML) can contribute to confusion with ACC and its USP remains unknown. Objective: To evaluate the features of ACA-RML in comparison with other adrenocortical neoplasms. Design: We selected consecuti...

  4. MicroRNA Era: The Importance for Diagnosis and Prognosis of Adrenocortical Tumors

    Directory of Open Access Journals (Sweden)

    João Evangelista Bezerra

    2014-01-01

    Full Text Available MicroRNAs play an essential role in posttranscriptional regulation of gene expression. They are evolutionary conserved, small, noncoding, 19–22-nucleotide RNAs, whose abnormalities, such as up- or downregulated expression, have been associated with several neoplasms, including adrenocortical tumors. Expression levels of distinct microRNAs can distinguish benign from malignant adrenal tumors. This current review provides recent data on the miRNAs profile in benign and malignant adrenocortical tumors diagnosed in adult and pediatric patients.

  5. [11C]metomidate positron emission tomography of adrenocortical tumors in correlation with histopathological findings.

    Science.gov (United States)

    Hennings, Joakim; Lindhe, Orjan; Bergström, Mats; Långström, Bengt; Sundin, Anders; Hellman, Per

    2006-04-01

    Adrenal incidentalomas are common findings necessitating extensive laboratory work-up and repetitive radiological examinations. Positron emission tomography (PET) using (11)C-labeled metomidate (MTO) has previously been described as a tool for specific adrenocortical imaging. We evaluated 212 MTO-PET examinations in 173 patients to identify its role in the management of adrenal tumors. Seventy-five histopathological examinations from 73 patients were retrospectively analyzed. All examinations were performed at a referral center. Patients who were operated or biopsied due to adrenal tumors had histopathological diagnoses of adrenocortical adenoma (n = 26), adrenocortical cancer (ACC; n = 13), adrenocortical hyperplasia (n = 8), pheochromocytoma (n = 6), metastasis (n = 3), and tumors of nonadrenal origin (n = 19). The main outcome measures were statistical analyses and findings while scrutinizing images. The hypothesis that MTO-PET is of value in the management of adrenal tumors, especially incidentaloma, was stated before data collection. Sensitivity was 0.89 and specificity was 0.96 for MTO-PET in proving adrenocortical origin of the lesions. Pheochromocytomas, metastases to the adrenal gland, and nonadrenal masses were all MTO negative. PET measurements using standardized uptake values (SUV) in pathological adrenocortical tissue could differentiate lesions larger than 1-1.5 cm from normal adrenocortical tissue. SUV was higher in aldosterone-hypersecreting adenomas, and the SUV ratio between the tumor and the contralateral gland was significantly higher in all hormonally hypersecreting adenomas as well as in ACC. MTO-PET is a specific and sensitive method for diagnosing adrenocortical tumors. MTO-PET is useful in the imaging work-up of adrenal incidentalomas and may be beneficial for the examination of patients with primary aldosteronism or ACC.

  6. MicroRNAs as potential biomarkers in adrenocortical cancer: progress and challenges

    Directory of Open Access Journals (Sweden)

    Nadia eCHERRADI

    2016-01-01

    Full Text Available Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited therapeutic options. Over the last decade, pan-genomic analyses of genetic and epigenetic alterations and genome-wide expression profile studies allowed major advances in the understanding of the molecular genetics of adrenocortical carcinoma. Besides the well-known dysfunctional molecular pathways in adrenocortical tumors such as the IGF2 pathway, the Wnt pathway and TP53, high-throughput technologies enabled a more comprehensive genomic characterization of adrenocortical cancer. Integration of expression profile data with exome sequencing, SNP array analysis, methylation and microRNA profiling led to the identification of subgroups of malignant tumors with distinct molecular alterations and clinical outcomes. MicroRNAs post-transcriptionally silence their target gene expression either by degrading mRNA or by inhibiting translation. Although our knowledge of the contribution of deregulated microRNAs to the pathogenesis of adrenocortical carcinoma is still in its infancy, recent studies support their relevance in gene expression alterations in these tumors. Some microRNAs have been shown to carry potential diagnostic and prognostic values while others may be good candidates for therapeutic interventions. With the emergence of disease-specific blood-borne microRNAs signatures, analyses of small cohorts of patients with adrenocortical carcinoma suggest that circulating microRNAs represent promising non-invasive biomarkers of malignancy or recurrence. However, some technical challenges still remain, and most of the microRNAs reported in the literature have not yet been validated in sufficiently powered and longitudinal studies. In this review, we discuss the current knowledge regarding the deregulation of tumor-associated and circulating microRNAs in adrenocortical carcinoma patients, while emphasizing their potential significance in adrenocortical carcinoma pathogenic

  7. An endocrinologist's view on relative adrenocortical insufficiency in rheumatoid arthritis.

    Science.gov (United States)

    Imrich, Richard; Vlcek, Miroslav; Aldag, Jean C; Kerlik, Jana; Radikova, Zofia; Rovensky, Jozef; Vigas, Milan; Masi, Alfonse T

    2010-04-01

    The concept of relative adrenal insufficiency (RAI) has been originally introduced to describe a situation in which critically ill patients, without any prior risk or evidence for adrenal insufficiency, have total serum cortisol levels inadequate for the severity of patients' illness. The concept provided a framework for other disease states, in which higher than normal adrenal function could be expected, such as in chronic inflammation. An intense research in RAI field highlighted some new methodological aspects that significantly improved assessment of adrenal function in chronic illness. Measurement of salivary cortisol may provide additional information on locally available cortisol in target tissues. Low levels of dehydroepiandrosterone (DHEAS) for given age and gender were confirmed as a simple and reliable indicator of decreased adrenal function, even in subjects with normal baseline cortisol or normal corticotropin-stimulated cortisol response. Combined lower DHEAS and lower baseline cortisol levels could be an example of hypocompetence of adrenocortical function, yet clinically not apparent.

  8. Virilizing adrenocortical carcinoma advancing to central precocious puberty after surgery.

    Science.gov (United States)

    Kim, Min Sun; Yang, Eu Jeen; Cho, Dong Hyu; Hwang, Pyung Han; Lee, Dae-Yeol

    2015-05-01

    Adrenocortical carcinoma (ACC) in pediatric and adolescent patients is rare, and it is associated with various clinical symptoms. We introduce the case of an 8-year-old boy with ACC who presented with peripheral precocious puberty at his first visit. He displayed penis enlargement with pubic hair and facial acne. His serum adrenal androgen levels were elevated, and abdominal computed tomography revealed a right suprarenal mass. After complete surgical resection, the histological diagnosis was ACC. Two months after surgical removal of the mass, he subsequently developed central precocious puberty. He was treated with a gonadotropin-releasing hormone agonist to delay further pubertal progression. In patients with functioning ACC and surgical removal, clinical follow-up and hormonal marker examination for the secondary effects of excessive hormone secretion may be a useful option at least every 2 or 3 months after surgery.

  9. Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas.

    Science.gov (United States)

    Creemers, S G; van Koetsveld, P M; van Kemenade, F J; Papathomas, T G; Franssen, G J H; Dogan, F; Eekhoff, E M W; van der Valk, P; de Herder, W W; Janssen, J A M J L; Feelders, R A; Hofland, L J

    2016-09-01

    Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Discrimination of ACCs from adrenocortical adenomas (ACAs) is challenging on both imaging and histopathological grounds. High IGF2 expression is associated with malignancy, but shows large variability. In this study, we investigate whether specific methylation patterns of IGF2 regulatory regions could serve as a valuable biomarker in distinguishing ACCs from ACAs. Pyrosequencing was used to analyse methylation percentages in DMR0, DMR2, imprinting control region (ICR) (consisting of CTCF3 and CTCF6) and the H19 promoter. Expression of IGF2 and H19 mRNA was assessed by real-time quantitative PCR. Analyses were performed in 24 ACCs, 14 ACAs and 11 normal adrenals. Using receiver operating characteristic (ROC) analysis, we evaluated which regions showed the best predictive value for diagnosis of ACC and determined the diagnostic accuracy of these regions. In ACCs, the DMR0, CTCF3, CTCF6 and the H19 promoter were positively correlated with IGF2 mRNA expression (P<0.05). Methylation in the most discriminating regions distinguished ACCs from ACAs with a sensitivity of 96%, specificity of 100% and an area under the curve (AUC) of 0.997±0.005. Our findings were validated in an independent cohort of 9 ACCs and 13 ACAs, resulting in a sensitivity of 89% and a specificity of 92%. Thus, methylation patterns of IGF2 regulatory regions can discriminate ACCs from ACAs with high diagnostic accuracy. This proposed test may become the first objective diagnostic tool to assess malignancy in adrenal tumours and facilitate the choice of therapeutic strategies in this group of patients.

  10. Noninvasive monitoring of adrenocortical function in captive jaguars (Panthera onca).

    Science.gov (United States)

    Conforti, Valéria A; Morato, Ronaldo G; Augusto, Anderson M; de Oliveira e Sousa, Lúcio; de Avila, David M; Brown, Janine L; Reeves, Jerry J

    2012-01-01

    Jaguars are threatened with extinction throughout their range. A sustainable captive population can serve as a hedge against extinction, but only if they are healthy and reproduce. Understanding how jaguars respond to stressors may help improve the captive environment and enhance their wellbeing. Thus, our objectives were to: (1) conduct an adrenocorticotrophic hormone (ACTH) challenge to validate a cortisol radioimmunoassay (RIA) for noninvasive monitoring of adrenocortical function in jaguars; (2) investigate the relationship between fecal corticoid (FCM) and androgen metabolite (FAM) concentrations in males during the ACTH challenge; and (3) establish a range of physiological concentrations of FCMs for the proposed protocol. Seven jaguars (3 M, 4 F) received 500 IU/animal of ACTH. Pre- and post-ACTH fecal samples were assayed for corticoid (M and F) and androgen metabolites (M) by RIA. Concentrations of FCMs increased (P80.01) after ACTH injection (pre-ACTH: 0.90 ± 0.12 µg/g dry feces; post-ACTH: 2.55 ± 0.25 µg/g). Considering pre- and post-ACTH samples, FCM concentrations were higher (P80.01) in males (2.15 ± 0.20 µg/g) than in females (1.30 ± 0.20 µg/g), but the magnitude of the response to ACTH was comparable (P>0.05) between genders. After ACTH injection, FAMs increased in two (of 3) males; in one male, FCMs and FAMs were positively correlated (0.60; P80.01). Excretion of FCMs was assessed in 16 jaguars (7 M, 9 F) and found to be highly variable (range, 80.11-1.56 µg/g). In conclusion, this study presents a cortisol RIA for monitoring adrenocortical function in jaguars noninvasively. © 2011 Wiley Periodicals, Inc.

  11. Actual 10-year survivors following resection of adrenocortical carcinoma.

    Science.gov (United States)

    Tran, Thuy B; Postlewait, Lauren M; Maithel, Shishir K; Prescott, Jason D; Wang, Tracy S; Glenn, Jason; Phay, John E; Keplinger, Kara; Fields, Ryan C; Jin, Linda X; Weber, Sharon M; Salem, Ahmed; Sicklick, Jason K; Gad, Shady; Yopp, Adam C; Mansour, John C; Duh, Quan-Yang; Seiser, Natalie; Solorzano, Carmen C; Kiernan, Colleen M; Votanopoulos, Konstantinos I; Levine, Edward A; Hatzaras, Ioannis; Shenoy, Rivfka; Pawlik, Timothy M; Norton, Jeffrey A; Poultsides, George A

    2016-12-01

    Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options beyond surgical resection. The characteristics of actual long-term survivors following surgical resection for ACC have not been previously reported. Patients who underwent resection for ACC at one of 13 academic institutions participating in the US Adrenocortical Carcinoma Group from 1993 to 2014 were analyzed. Patients were stratified into four groups: early mortality (died within 2 years), late mortality (died within 2-5 years), actual 5-year survivor (survived at least 5 years), and actual 10-year survivor (survived at least 10 years). Patients with less than 5 years of follow-up were excluded. Among the 180 patients available for analysis, there were 49 actual 5-year survivors (27%) and 12 actual 10-year survivors (7%). Patients who experienced early mortality had higher rates of cortisol-secreting tumors, nodal metastasis, synchronous distant metastasis, and R1 or R2 resections (all P year survivors. Ten of twelve actual 10-year survivors were women, and of the seven 10-year survivors who experienced disease recurrence, five had undergone repeat surgery to resect the recurrence. Surgery for ACC can offer a 1 in 4 chance of actual 5-year survival and a 1 in 15 chance of actual 10-year survival. Long-term survival was often achieved with repeat resection for local or distant recurrence, further underscoring the important role of surgery in managing patients with ACC. J. Surg. Oncol. 2016;114:971-976. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  12. Modeling Steroidogenesis Disruption Using High-Throughput ...

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    Environmental chemicals can elicit endocrine disruption by altering steroid hormone biosynthesis and metabolism (steroidogenesis) causing adverse reproductive and developmental effects. Historically, a lack of assays resulted in few chemicals having been evaluated for effects on steroidogenesis. The steroidogenic pathway is a series of hydroxylation and dehydrogenation steps carried out by CYP450 and hydroxysteroid dehydrogenase enzymes, yet the only enzyme in the pathway for which a high-throughput screening (HTS) assay has been developed is aromatase (CYP19A1), responsible for the aromatization of androgens to estrogens. Recently, the ToxCast HTS program adapted the OECD validated H295R steroidogenesis assay using human adrenocortical carcinoma cells into a high-throughput model to quantitatively assess the concentration-dependent (0.003-100 µM) effects of chemicals on 10 steroid hormones including progestagens, androgens, estrogens and glucocorticoids. These results, in combination with two CYP19A1 inhibition assays, comprise a large dataset amenable to clustering approaches supporting the identification and characterization of putative mechanisms of action (pMOA) for steroidogenesis disruption. In total, 514 chemicals were tested in all CYP19A1 and steroidogenesis assays. 216 chemicals were identified as CYP19A1 inhibitors in at least one CYP19A1 assay. 208 of these chemicals also altered hormone levels in the H295R assay, suggesting 96% sensitivity in the

  13. Inhibin alpha-subunit (INHA expression in adrenocortical cancer is linked to genetic and epigenetic INHA promoter variation.

    Directory of Open Access Journals (Sweden)

    Johannes Hofland

    Full Text Available Adrenocortical carcinoma (ACC is a rare, but highly malignant tumor of unknown origin. Inhibin α-subunit (Inha knockout mice develop ACCs following gonadectomy. In man, INHA expression varies widely within ACC tissues and its circulating peptide inhibin pro-αC has been described as a novel tumor marker for ACC. We investigated whether genetic and epigenetic changes of the INHA gene in human ACC cause loss or variation of INHA expression. To this end, analyses of INHA sequence, promoter methylation and mRNA expression were performed in human adrenocortical tissues. Serum inhibin pro-αC levels were also measured in ACC patients. INHA genetic analysis in 37 unique ACCs revealed 10 novel, heterozygous rare variants. Of the 3 coding bases affected, one variant was synonymous and two were missense variants: S72F and S184F. The minor allele of rs11893842 at -124 bp was observed at a low frequency (24% in ACC samples and was associated with decreased INHA mRNA levels: 4.7±1.9 arbitrary units for AA, compared to 26±11 for AG/GG genotypes (P = 0.034. The methylation of four proximal INHA promoter CpGs was aberrantly increased in five ACCs (47.7±3.9%, compared to normal adrenals (18.4±0.6%, P = 0.0052, whereas the other 14 ACCs studied showed diminished promoter methylation (9.8±1.1%, P = 0.020. CpG methylation was inversely correlated to INHA mRNA levels in ACCs (r = -0.701, p = 0.0036, but not associated with serum inhibin pro-αC levels. In conclusion, aberrant methylation and common genetic variation in the INHA promoter occur in human ACCs and are associated with decreased INHA expression.

  14. Inhibin Alpha-Subunit (INHA) Expression in Adrenocortical Cancer Is Linked to Genetic and Epigenetic INHA Promoter Variation

    Science.gov (United States)

    Hofland, Johannes; Steenbergen, Jacobie; Voorsluijs, Jacoba M.; Verbiest, Michael M. P. J.; de Krijger, Ronald R.; Hofland, Leo J.; de Herder, Wouter W.; Uitterlinden, Andre G.; Feelders, Richard A.; de Jong, Frank H.

    2014-01-01

    Adrenocortical carcinoma (ACC) is a rare, but highly malignant tumor of unknown origin. Inhibin α-subunit (Inha) knockout mice develop ACCs following gonadectomy. In man, INHA expression varies widely within ACC tissues and its circulating peptide inhibin pro-αC has been described as a novel tumor marker for ACC. We investigated whether genetic and epigenetic changes of the INHA gene in human ACC cause loss or variation of INHA expression. To this end, analyses of INHA sequence, promoter methylation and mRNA expression were performed in human adrenocortical tissues. Serum inhibin pro-αC levels were also measured in ACC patients. INHA genetic analysis in 37 unique ACCs revealed 10 novel, heterozygous rare variants. Of the 3 coding bases affected, one variant was synonymous and two were missense variants: S72F and S184F. The minor allele of rs11893842 at −124 bp was observed at a low frequency (24%) in ACC samples and was associated with decreased INHA mRNA levels: 4.7±1.9 arbitrary units for AA, compared to 26±11 for AG/GG genotypes (P = 0.034). The methylation of four proximal INHA promoter CpGs was aberrantly increased in five ACCs (47.7±3.9%), compared to normal adrenals (18.4±0.6%, P = 0.0052), whereas the other 14 ACCs studied showed diminished promoter methylation (9.8±1.1%, P = 0.020). CpG methylation was inversely correlated to INHA mRNA levels in ACCs (r = −0.701, p = 0.0036), but not associated with serum inhibin pro-αC levels. In conclusion, aberrant methylation and common genetic variation in the INHA promoter occur in human ACCs and are associated with decreased INHA expression. PMID:25111790

  15. Adrenocortical responses to offspring-directed threats in two open-nesting birds.

    Science.gov (United States)

    Butler, Luke K; Bisson, Isabelle-Anne; Hayden, Timothy J; Wikelski, Martin; Romero, L Michael

    2009-07-01

    Dependent young are often easy targets for predators, so for many parent vertebrates, responding to offspring-directed threats is a fundamental part of reproduction. We tested the parental adrenocortical response of the endangered black-capped vireo (Vireo atricapilla) and the common white-eyed vireo (V. griseus) to acute and chronic threats to their offspring. Like many open-nesting birds, our study species experience high offspring mortality. Parents responded behaviorally to a predator decoy or human 1-2m from their nests, but, in contrast to similar studies of cavity-nesting birds, neither these acute threats nor chronic offspring-directed threats altered plasma corticosterone concentrations of parents. Although parents in this study showed no corticosterone response to offspring-directed threats, they always increased corticosterone concentrations in response to capture. To explain these results, we propose that parents perceive their risk of nest-associated death differently depending on nest type, with cavity-nesting adults perceiving greater risk to themselves than open-nesters that can readily detect and escape from offspring-directed threats. Our results agree with previous studies suggesting that the hypothalamic-pituitary-adrenal axis, a major physiological mechanism for coping with threats to survival, probably plays no role in coping with threats to offspring when risks to parents and offspring are not correlated. We extend that paradigm by demonstrating that nest style may influence how adults perceive the correlation between offspring-directed and self-directed threats.

  16. Hepatocyte growth factor/cMET pathway activation enhances cancer hallmarks in adrenocortical carcinoma

    Science.gov (United States)

    Phan, Liem M.; Fuentes-Mattei, Enrique; Wu, Weixin; Velazquez-Torres, Guermarie; Sircar, Kanishka; Wood, Christopher G.; Hai, Tao; Jimenez, Camilo; Cote, Gilbert J.; Ozsari, Levent; Hofmann, Marie-Claude; Zheng, Siyuan; Verhaak, Roeland; Pagliaro, Lance; Cortez, Maria Angelica; Lee, Mong-Hong; Yeung, Sai-Ching J.; Habra, Mouhammed Amir

    2015-01-01

    Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in ACC has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of ACC. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human ACC samples was positively associated with cancer-related biological processes including proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of ACC cells with exogenous HCG resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA-mediated knockdown or pharmacological inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in ACC growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer. PMID:26282167

  17. GATA4 is a critical regulator of gonadectomy-induced adrenocortical tumorigenesis in mice.

    Science.gov (United States)

    Krachulec, Justyna; Vetter, Melanie; Schrade, Anja; Löbs, Ann-Kathrin; Bielinska, Malgorzata; Cochran, Rebecca; Kyrönlahti, Antti; Pihlajoki, Marjut; Parviainen, Helka; Jay, Patrick Y; Heikinheimo, Markku; Wilson, David B

    2012-06-01

    In response to gonadectomy certain inbred mouse strains develop sex steroidogenic adrenocortical neoplasms. One of the hallmarks of neoplastic transformation is expression of GATA4, a transcription factor normally present in gonadal but not adrenal steroidogenic cells of the adult mouse. To show that GATA4 directly modulates adrenocortical tumorigenesis and is not merely a marker of gonadal-like differentiation in the neoplasms, we studied mice with germline or conditional loss-of-function mutations in the Gata4 gene. Germline Gata4 haploinsufficiency was associated with attenuated tumor growth and reduced expression of sex steroidogenic genes in the adrenal glands of ovariectomized B6D2F1 and B6AF1 mice. At 12 months after ovariectomy, wild-type B6D2F1 mice had biochemical and histological evidence of adrenocortical estrogen production, whereas Gata4(+/-) B6D2F1 mice did not. Germline Gata4 haploinsufficiency exacerbated the secondary phenotype of postovariectomy obesity in B6D2F1 mice, presumably by limiting ectopic estrogen production in the adrenal glands. Amhr2-cre-mediated deletion of floxed Gata4 (Gata4(F)) in nascent adrenocortical neoplasms of ovariectomized B6.129 mice reduced tumor growth and the expression of gonadal-like markers in a Gata4(F) dose-dependent manner. We conclude that GATA4 is a key modifier of gonadectomy-induced adrenocortical neoplasia, postovariectomy obesity, and sex steroidogenic cell differentiation.

  18. Partial KCNQ1OT1 hypomethylation: A disguised familial Beckwith–Wiedemann syndrome as a sporadic adrenocortical tumor

    Directory of Open Access Journals (Sweden)

    Dorra H'mida Ben-Brahim

    2015-03-01

    Full Text Available Beckwith–Wiedemann syndrome has a wide spectrum of complications such as embryonal tumors, namely adrenocortical tumor. Tumor predisposition is one of the most challenging manifestations of this syndrome. A 45-day old female with a family history of adrenocortical tumor presented with adrenocortical tumor. The case raised suspicion of a hereditary Beckwith–Wiedemann syndrome, therefore molecular analysis was undertaken. The results revealed partial KCNQ1OT1 hypomethylation in the infant's blood DNA which was associated with a complete loss of methylation in the infant's adrenocortical tumor tissue. It is unique for familial Beckwith–Wiedemann syndrome caused by KCNQ1OT1 partial hypomethylation to manifest solely through adrenocortical tumor. Incomplete penetrance and specific tissue mosaicism could provide explanations to this novel hereditary Beckwith–Wiedemann syndrome presentation.

  19. Percutaneous laser ablation of unresectable primary and metastatic adrenocortical carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Pacella, Claudio M. [Regina Apostolorum Hospital, Department of Diagnostic Imaging and Interventional Radiology, Via San Francesco 50, Albano Laziale, Rome 00041 (Italy)], E-mail: claudiomaurizio.pacella@fastwebnet.it; Stasi, Roberto; Bizzarri, Giancarlo; Pacella, Sara; Graziano, Filomena Maria; Guglielmi, Rinaldo; Papini, Enrico [Regina Apostolorum Hospital, Department of Diagnostic Imaging and Interventional Radiology, Via San Francesco 50, Albano Laziale, Rome 00041 (Italy)

    2008-04-15

    Purpose: To evaluate the feasibility, safety, and clinical benefits of percutaneous laser ablation (PLA) in patients with unresectable primary and metastatic adrenocortical carcinoma (ACC). Patients and methods: Four patients with hepatic metastases from ACC and a Cushing's syndrome underwent ultrasound-guided PLA. In one case the procedure was performed also on the primary tumor. Results: After three sessions of PLA, the primary tumor of 15 cm was ablated by 75%. After 1-4 (median 1) sessions of PLA, five liver metastases ranging from 2 to 5 cm were completely ablated, while the sixth tumor of 12 cm was ablated by 75%. There were no major complications. Treatment resulted in an improvement of performance status and a reduction of the daily dosage of mitotane in all patients. The three patients with liver metastases presented a marked decrease of 24-h urine cortisol levels, an improved control of hypertension and a mean weight loss of 2.8 kg. After a median follow-up after PLA of 27.0 months (range, 9-48 months), two patients have died of tumor progression, while two other patients remain alive and free of disease. Conclusions: Percutaneous laser ablation is a feasible, safe and well tolerated procedure for the palliative treatment of unresectable primary and metastatic ACC. Further study is required to evaluate the impact of PLA on survival.

  20. A Rare Case of Functioning Adrenocortical Oncocytoma Presenting as Cushing Syndrome

    Directory of Open Access Journals (Sweden)

    Nicola Tartaglia

    2016-01-01

    Full Text Available Functioning adrenocortical oncocytoma is very rare neoplasm. It is usually nonfunctional and benign and incidentally detected. Generally, these tumors originate in the kidneys, thyroid, parathyroid, and salivary or pituitary glands; they have also been reported in other sites including choroid plexus, respiratory tract, and larynx. Histologically, they are characterized by cells with eosinophilic granular cytoplasm and numerous packed mitochondria. We reported a case of a 44-year-old female who presented with Cushing syndrome for hypersecretion of cortisol due to adrenocortical oncocytoma. Magnetic resonance of abdomen revealed a right adrenal mass. Laparoscopic adrenalectomy was performed and the tumor was pathologically confirmed as benign adrenocortical oncocytoma. After surgical treatment, Cushing’s syndrome resolved.

  1. Cushing Syndrome in a 6-Month-Old Infant due to Adrenocortical Tumor

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    Volmar KeithE

    2009-09-01

    Full Text Available Cushing syndrome is rare in infancy and usually due to an adrenocortical tumor (ACT. We report an infant with Cushing syndrome due to adrenocortical carcinoma. The patient presented at six months of age with a three-month history of growth failure, rapid weight gain, acne, and irritability. Physical examination showed obesity, hypertension, and Cushingoid features. Biochemical evaluation showed very high serum cortisol, mildly elevated testosterone, and suppressed ACTH. Abdominal MRI revealed a heterogeneous right adrenal mass extending into the inferior vena cava. Evaluation for metastases was negative. The tumor was removed surgically en bloc. Pathologic examination demonstrated low mitotic rate, but capsular and vascular invasion. She received no adjuvant therapy. Her linear growth has improved and Cushingoid features resolved. Hormonal markers and quarterly PET scans have been negative for recurrence 24 months postoperatively. In conclusion, adrenocortical neoplasms in children are rare, but should be considered in the differential diagnosis of Cushing syndrome.

  2. Cushing Syndrome in a 6-Month-Old Infant due to Adrenocortical Tumor

    Directory of Open Access Journals (Sweden)

    Keith E. Volmar

    2009-01-01

    Full Text Available Cushing syndrome is rare in infancy and usually due to an adrenocortical tumor (ACT. We report an infant with Cushing syndrome due to adrenocortical carcinoma. The patient presented at six months of age with a three-month history of growth failure, rapid weight gain, acne, and irritability. Physical examination showed obesity, hypertension, and Cushingoid features. Biochemical evaluation showed very high serum cortisol, mildly elevated testosterone, and suppressed ACTH. Abdominal MRI revealed a heterogeneous right adrenal mass extending into the inferior vena cava. Evaluation for metastases was negative. The tumor was removed surgically en bloc. Pathologic examination demonstrated low mitotic rate, but capsular and vascular invasion. She received no adjuvant therapy. Her linear growth has improved and Cushingoid features resolved. Hormonal markers and quarterly PET scans have been negative for recurrence 24 months postoperatively. In conclusion, adrenocortical neoplasms in children are rare, but should be considered in the differential diagnosis of Cushing syndrome.

  3. Adrenocortical tumor in a cat secreting more than one type of corticosteroid

    Directory of Open Access Journals (Sweden)

    Simone Domit Guerios

    2015-11-01

    Full Text Available Case summary A 14-year-old, spayed female domestic shorthair cat was evaluated because of a right adrenal mass. The referring veterinarian had started treatment for hypokalemia and systemic arterial hypertension. During the initial evaluation the cat was alert and responsive, and serum potassium concentration was within the reference range. Serum concentrations of aldosterone and progesterone were increased. Atrophy of the contralateral adrenal and an exaggerated response of cortisol to stimulation with adrenocorticotropic hormone suggested hypersecretion of cortisol. Unilateral adrenalectomy was performed and recovery was uneventful. Histologic examination of the mass revealed an adrenocortical tumor. After surgery, clinical signs of hypercortisolism, hyperaldosteronism and hyperprogesteronism were no longer observed, and neither potassium supplementation nor antihypertensive treatment were needed. Relevance and novel information In cases with an adrenocortical tumor, clinicians should investigate whether the tumor hypersecretes glucocorticoids, mineralocorticoids, sex steroids or combinations of these. Hypersecretion of more than one adrenal hormone may occur in a cat with an adrenocortical tumor.

  4. Ectopic adrenocortical adenoma in the renal hilum: a case report and literature review.

    Science.gov (United States)

    Liu, Yang; Jiang, Yue-Feng; Wang, Ye-Lin; Cao, Hong-Yi; Wang, Liang; Xu, Hong-Tao; Li, Qing-Chang; Qiu, Xue-Shan; Wang, En-Hua

    2016-04-19

    Ectopic (accessory) adrenocortical tissue, also known as adrenal rests, is a developmental abnormality of the adrenal gland. The most common ectopic site is in close proximity to the adrenal glands and along the path of descent or migration of the gonads because of the close spatial relationship between the adrenocortical primordium and gonadal blastema during embryogenesis. Ectopic rests may undergo marked hyperplasia, and occasionally induce ectopic adrenocortical adenomas or carcinomas. A 27-year-old Chinese female patient who presented with amenorrhea of 3 months duration underwent computed tomography urography after ultrasound revealed a solitary mass in the left renal hilum. Histologically, the prominent eosinophilic tumor cells formed an alveolar- or acinar-like configuration. The immunohistochemical profile (alpha-inhibin+, Melan-A+, synaptophysin+) indicated the adrenocortical origin of the tumor, diagnosed as ectopic adrenocortical adenoma. The patient was alive with no tumor recurrence or metastasis at the 3-month follow-up examination. The unusual histological appearance of ectopic adrenocortical adenoma may result in its misdiagnosis as oncocytoma or clear cell renal cell carcinoma, especially if the specimen is limited. This case provides a reminder to pathologists to be aware of atypical cases of this benign tumor. Although uncommon, an ectopic adrenal lesion should be included in the differential diagnosis of tumors involving the renal hilum. A misdiagnosis of this benign condition as a malignant renal tumor may have severe consequences for the patient, including unnecessary radical nephrectomy. Preoperative biopsy and appropriate immunohistochemical staining will assist in determining the origin and nature of the tumor and in avoiding intraoperative uncertainty.

  5. Helsinki score-a novel model for prediction of metastases in adrenocortical carcinomas.

    Science.gov (United States)

    Pennanen, Mirkka; Heiskanen, Ilkka; Sane, Timo; Remes, Satu; Mustonen, Harri; Haglund, Caj; Arola, Johanna

    2015-03-01

    Histopathologic diagnosis of adrenocortical tumors is based on adverse features that indicate malignant potential. Proliferation index has served as a supplemental tool in assessing the malignant potential of adrenocortical tumors. None of the current histologic classification systems can sufficiently accurately predict tumors' metastatic potential. We studied 177 consecutive adult patients with primary adrenocortical tumors operated on at Helsinki University Central Hospital between 1990 and 2003, all patients with a minimum follow-up of 5 years. We determined for each tumor the Weiss score and the Weiss revisited score by Aubert. Proliferation index was measured by computer-assisted image analysis. Each of the 9 Weiss criteria and the proliferation index were then used to establish a scoring system to predict the metastatic potential of adrenocortical tumors. Use of stepwise regression analysis led us to propose a calculation: 3 × mitotic rate (>5/50 high-power fields) + 5 × presence of necrosis + proliferation index in the most proliferative area of the tumor. Using a cutoff value of 8.5, the new scoring system was able to diagnose metastatic adrenocortical carcinoma with 100% sensitivity (confidence interval [CI], 76.8%-100%) and 99.4% specificity (CI, 96.6%-100%). The corresponding sensitivity of the Weiss system was 100% (CI, 76.8%-100%), and specificity, 90.2% (CI, 84.6%-94.3%), with sensitivity of the Weiss revisited system at 100% (CI, 76.8%-100%) and specificity at 96.9% (CI, 93.0%-99.0%). The new Helsinki score thus was accurate in predicting the metastatic potential of adrenocortical tumors.

  6. Loss of sensitivity to ACTH of adrenocortical cells isolated from maturing domestic fowl.

    Science.gov (United States)

    Carsia, R V; Scanes, C G; Malamed, S

    1985-07-01

    Maturation of domestic fowl corticosteroidogenesis was evaluated using purified adrenocortical cells. Basal corticosterone production decreased steadily from 2 days to 26 weeks after hatching. However, maximally stimulated corticosterone production was not changed. In contrast, the half-maximal steroidogenic concentrations (ED50 values or effective doses for 50% maximal effect) of ACTH analogs increased approximately 40 times by 26 weeks, but the ED50 values of 8-bromo-cyclic AMP and pregnenolone were not changed. This suggests that adrenocortical cell sensitivity to ACTH decreases with maturation of the domestic fowl.

  7. Adrenocortical cancer (ACC) - literature overview and own experience.

    Science.gov (United States)

    Dworakowska, Dorota; Drabarek, Agata; Wenzel, Ingrid; Babińska, Anna; Świątkowska-Stodulska, Renata; Sworczak, Krzysztof

    2014-01-01

    Adrenocortical carcinoma (ACC) is a malignant endocrine tumour. The rarity of the disease has stymied therapeutic development. Age distribution shows two peaks: the first and fifth decades of life, with children and women more frequently affected. Although 60-70% of ACCs are biochemically found to overproduce hormones, it is not clinically apparent in many cases. If present, endocrine symptoms include signs of hypercortisolaemia, virilisation or gynaecomastia. ACC carries a poor prognosis, and a cure can be achieved only by complete surgical resection. Mitotane is used both as an adjuvant treatment and also in non-operative patients. The role of radio- and chemotherapy is still controversial. The post-operative disease free survival is low and oscillates around 30% due to high tumour recurrence rate. The diagnosis is based on tumour histological assessment with the use of the Weiss score, however urinary steroid profiling (if available) can serve to differentiate between ACC and other adrenal tumours. Conventional prognostic markers in ACC include stage and grade of disease, and, as currently reported, the presence of hypercortisolaemia. Molecular analysis has had a significant impact on the understanding of the pathogenetic mechanism of ACC development and the evaluation of prognostic and predictive markers, among which alterations of the IGF system, the Wnt pathway, p53 and molecules involved in cancer cell invasion properties and angiogenesis seem to be very promising. We here summarise our own experience related to the management of ACC and present a literature overview. We have not aimed to include a detailed summary of the molecular alterations biology described in ACC, as this has already been addressed in other papers.

  8. (18)F-labelled metomidate analogues as adrenocortical imaging agents.

    Science.gov (United States)

    Erlandsson, Maria; Karimi, Farhad; Lindhe, Orjan; Långström, Bengt

    2009-05-01

    Two- and one-step syntheses of (18)F-labelled analogues of metomidate, such as 2-[(18)F]fluoroethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (1), 2-[(18)F]fluoroethyl 1-[(1R)-1-(4-chlorophenyl)ethyl]-1H-imidazole-5-carboxylate (2), 2-[(18)F]fluoroethyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (3), 3-[(18)F]fluoropropyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (4) and 3-[(18)F]fluoropropyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (5) are presented. Analogues 1-5 were prepared by a two-step reaction sequence that started with the synthesis of either 2-[(18)F]fluoroethyl 4-methylbenzenesulfonate or 3-[(18)F]fluoropropyl 4-methylbenzenesulfonate. These were used as (18)F-alkylating agents in the second step, in which they reacted with the ammonium salt of a 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylic acid. One-step-labelling syntheses of 1, 2 and 5 were also explored. Analogues 1-4 were biologically validated by frozen-section autoradiography and organ distribution. Metabolite analysis was performed for 2 and 3. The radiochemical yield of the two-step synthesis was in the range of 10-29% and that of the one-step synthesis was 25-37%. Using microwave irradiation in the one-step synthesis of 1 and 2 increased the radiochemical yield to 46+/-3% and 79+/-30%, respectively. Both the frozen-section autoradiography and organ distribution results indicated that analogue 2 has a potential as an adrenocortical imaging agent, having the highest degree of specific adrenal binding and best ratio of adrenal to organ uptake among the compounds studied.

  9. THE CHARACTERISTICS OF ENDOGENOUS OUABAIN SECRETIONFROM CULTURED BOVINE ADRENOCORTICAL CELLS

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective To compare the characteristics of endogenous ouabain(EO) secretion with the other adrenocortical hormones and determine the effects of angiotensin Ⅰ (Ang Ⅰ ), and adrenocorticotrophin(ACTH) on the secretion of EO. Methods EO was measured by radioimmunoassay from primary cultured bovine adrenocotical cells (BAC). Results ①Ouabain was determined in the media of cultured BAC. Both EO and aldosterone secretion were decreased from the outer to inner layer of the cultured adrenal cortex, and the responses to Ang Ⅰ and ACTH were higher than that in the mid layer (P <0. 05) and inner layer (P <0. 01). Cortisol secretion was activated by Ang Ⅱ or ACTH was significantly higher in the mid layer and in the inner layer than that in the outer layer. ②The time-course experiment showed that the gradually rising amounts of aldosterone and cortisol could be determined dur ing the continuous incubation to 48h with or without Ang Ⅰ or ACTH. However, EO did not increase continuously af ter 24h of incubation in the basal secreting situation and after 12h of incubation in the stimulating situation by Ang Ⅱ or ACTH. ③There were obvious drops in aldosterone and cortisol secretion from 3rd day during a 21 day-period cell culture, but the peak secretion of ouabain was in 7th day. Conclusion It suggests that the secretory mechanism might be different between EO and aldosterone or cortisol. Also, Ang Ⅱ and ACTH might be involved in the regulation of EO secretion.

  10. Hair cortisol measurement in mitotane-treated adrenocortical cancer patients.

    Science.gov (United States)

    Manenschijn, L; Quinkler, M; van Rossum, E F C

    2014-04-01

    The only approved drug for the treatment of adrenocortical cancer (ACC) is mitotane. Mitotane is adrenolytic and therefore, hydrocortisone replacement therapy is necessary. Since mitotane increases cortisol binding globulin (CBG) and induces CYP3A4 activity, high doses of hydrocortisone are thought to be required. Evaluation of hydrocortisone therapy in mitotane-treated patients has been difficult since there is no good marker to evaluate hydrocortisone therapy. Measurement of cortisol in scalp hair is a novel method that offers the opportunity to measure long-term cortisol levels. Our aim was to evaluate whether hair cortisol measurements could be useful in evaluating recent hydrocortisone treatment in mitotane-treated ACC patients. Hair cortisol levels were measured in 15 mitotane-treated ACC patients on hydrocortisone substitution and 96 healthy individuals. Cortisol levels were measured in 3 cm hair segments, corresponding to a period of 3 months. Hair cortisol levels were higher in ACC patients compared to healthy individuals (pcortisol levels above the reference range. None of the patients had hair cortisol levels below normal. In contrast to hydrocortisone doses (β=0.03, p=0.93), hair cortisol levels were associated with BMI (β=0.53, p=0.042). There was no correlation between hair cortisol levels and hydrocortisone doses (β=0.41, p=0.13). Almost half of the ACC patients had high hair cortisol levels, suggesting long-term over-substitution of hydrocortisone in some of the patients, whereas none of the patients was under-substituted. Hair cortisol measurements might be useful in long-term monitoring hydrocortisone treatment in mitotane-treated ACC patients.

  11. The Application of a Highly Purified Rat Leydig Cell Assay as a Complement to the H295R Steroidogenesis Assay for the Evaluation of Toxicant Induced Alterations in Testosterone Production

    Data.gov (United States)

    U.S. Environmental Protection Agency — The greater dynamic range of testosterone production in a highly purified rat Leydig cell assay permitted the detection of chemical induced inhibition that was not...

  12. Sarcomatoid adrenocortical carcinoma : a comprehensive pathological, immunohistochemical, and targeted next-generation sequencing analysis

    NARCIS (Netherlands)

    Papathomas, Thomas G.; Duregon, Eleonora; Korpershoek, Esther; Restuccia, David F.; van Marion, Ronald; Cappellesso, Rocco; Sturm, Nathalie; Rossi, Giulio; Coli, Antonella; Zucchini, Nicola; Stoop, Hans; Oosterhuis, Wolter; Ventura, Laura; Volante, Marco; Fassina, Ambrogio; Dinjens, Winand N M; Papotti, Mauro; de Krijger, Ronald R.

    2016-01-01

    Adrenocortical carcinomas (ACCs) with sarcomatous areas represent an extremely rare type of highly aggressive malignancy of unknown molecular pathogenesis. The current study was planned to gain insight into its molecular genetics using a targeted next-generation sequencing approach and to explore

  13. Adrenocortical responses to repeated parachute jumping and subsequent h-CRH challenge in inexperienced healthy subjects.

    Science.gov (United States)

    Deinzer, R; Kirschbaum, C; Gresele, C; Hellhammer, D H

    1997-04-01

    The present study examined the adrenocortical response to 3 consecutive parachute jumps and a poststress h-CRH challenge. Fifteen participants in a parachute-jumping course took saliva samples for later cortisol analysis every 20 min throughout the day, when they accomplished their very first 3 parachute jumps and throughout a control day. The effects of an h-CRH challenge on salivary cortisol were assessed in the evening of the jumping day and on a control day. Parachute jumping induced 3 distinct highly significant adrenocortical responses. The respective cortisol increases for the first, second, and third jump were 39.4 +/- 26.5 nmol/1, 31.4 +/- 21.4 nmol/l, and 16.5 +/- 11.9 nmol/l. Cortisol responses to the first and second jump did not differ but the response to the third jump was significantly reduced [t(13) = 3.11; p = 0.008]. Two groups of subjects were identified, "decreasers," whose response decreased from one to the other jump, and "increasers," whose response remained unchanged or increased. The magnitude of the preceding cortisol response of decreasers exceeded that of increasers significantly by about 30 nmol. The mean adrenocortical effects of the poststress h-CRH challenge and the time-matched challenge on a control day did not differ although, in 4 subjects, the poststress adrenocortical response to h-CRH was completely suppressed.

  14. Urine steroid metabolomics as a novel diagnostic tool for early detection of recurrence in adrenocortical carcinoma

    NARCIS (Netherlands)

    Chortis, Vasileios; Bancos, Irina; Lang, Katharina; Hughes, Beverly A.; O'Neil, Donna M.; Taylor, Angela E.; Fassnacht, Martin; Bertherat, Jerome; Beuschlein, Felix; Quinkler, Marcus; Vassiliadi, Dimitri; Conall Dennedy, M; Mannelli, Massimo; Biehl, Michael; Arlt, Wiebke

    2015-01-01

    Introduction: Adrenocortical carcinoma (ACC) is an aggressive malignancy with a high rate of recurrence. Regular post-operative follow-up imaging is necessary, but associated with high radiation exposure and frequent diagnostic ambiguity. Urine steroid metabolomics has recently been introduced as a

  15. Adrenocortical stress responses influence an invasive vertebrate's fitness in an extreme environment.

    Science.gov (United States)

    Jessop, Tim S; Letnic, Mike; Webb, Jonathan K; Dempster, Tim

    2013-10-07

    Continued range expansion into physiologically challenging environments requires invasive species to maintain adaptive phenotypic performance. The adrenocortical stress response, governed in part by glucocorticoid hormones, influences physiological and behavioural responses of vertebrates to environmental stressors. However, any adaptive role of this response in invasive populations that are expanding into extreme environments is currently unclear. We experimentally manipulated the adrenocortical stress response of invasive cane toads (Rhinella marina) to investigate its effect on phenotypic performance and fitness at the species' range front in the Tanami Desert, Australia. Here, toads are vulnerable to overheating and dehydration during the annual hot-dry season and display elevated plasma corticosterone levels indicative of severe environmental stress. By comparing unmanipulated control toads with toads whose adrenocortical stress response was manipulated to increase acute physiological stress responsiveness, we found that control toads had significantly reduced daily evaporative water loss and higher survival relative to the experimental animals. The adrenocortical stress response hence appears essential in facilitating complex phenotypic performance and setting fitness trajectories of individuals from invasive species during range expansion.

  16. Emotional and Adrenocortical Regulation in Early Adolescence: Prediction by Attachment Security and Disorganization in Infancy

    Science.gov (United States)

    Spangler, Gottfried; Zimmermann, Peter

    2014-01-01

    The aim of the present study was to examine differences in emotion expression and emotion regulation in emotion-eliciting situations in early adolescence from a bio-psycho-social perspective, specifically investigating the influence of early mother-infant attachment and attachment disorganization on behavioural and adrenocortical responses. The…

  17. Mutational analyses of epidermal growth factor receptor and downstream pathways in adrenocortical carcinoma

    NARCIS (Netherlands)

    Hermsen, I.G.; Haak, H.R.; Krijger, R.R. de; Kerkhofs, T.M.; Feelders, R.A.; Herder, W.W. de; Wilmink, H.; Smit, J.W.A.; Gelderblom, H.; Miranda, N.F. de; Eijk, R. van; Wezel, T. van; Morreau, H.

    2013-01-01

    BACKGROUND: Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and limited therapeutic options. Mitotane is considered the standard first-line therapy with only 30% of the patients showing objective tumour response. Defining predictive factors for response is therefore of clinica

  18. Treatment with docetaxel and cisplatin in advanced adrenocortical carcinoma, a phase II study

    DEFF Research Database (Denmark)

    Urup, Thomas; Pawlak, W Z; Petersen, P M;

    2013-01-01

    Adrenocortical carcinoma (ACC) is a rare disease with a poor response to chemotherapy. Cisplatin is the most widely investigated drug in the treatment of ACC and in vitro studies have indicated activity of taxanes. The objectives of this study were to evaluate the efficacy and toxicity of cisplatin...

  19. Sarcomatoid adrenocortical carcinoma : a comprehensive pathological, immunohistochemical, and targeted next-generation sequencing analysis

    NARCIS (Netherlands)

    Papathomas, Thomas G.; Duregon, Eleonora; Korpershoek, Esther; Restuccia, David F.; van Marion, Ronald; Cappellesso, Rocco; Sturm, Nathalie; Rossi, Giulio; Coli, Antonella; Zucchini, Nicola; Stoop, Hans; Oosterhuis, Wolter; Ventura, Laura; Volante, Marco; Fassina, Ambrogio; Dinjens, Winand N M; Papotti, Mauro; de Krijger, Ronald R.

    2016-01-01

    Adrenocortical carcinomas (ACCs) with sarcomatous areas represent an extremely rare type of highly aggressive malignancy of unknown molecular pathogenesis. The current study was planned to gain insight into its molecular genetics using a targeted next-generation sequencing approach and to explore th

  20. Detection of adrenocortical autoantibodies in Addison's disease with a peroxidase-labelled protein A technique

    Directory of Open Access Journals (Sweden)

    R.C. Silva

    1998-09-01

    Full Text Available Adrenocortical autoantibodies (ACA, present in 60-80% of patients with idiopathic Addison's disease, are conventionally detected by indirect immunofluorescence (IIF on frozen sections of adrenal glands. The large-scale use of IIF is limited in part by the need for a fluorescence microscope and the fact that histological sections cannot be stored for long periods of time. To circumvent these restrictions we developed a novel peroxidase-labelled protein A (PLPA technique for the detection of ACA in patients with Addison's disease and compared the results with those obtained with the classical IIF assay. We studied serum samples from 90 healthy control subjects and 22 patients with Addison's disease, who had been clinically classified into two groups: idiopathic (N = 13 and granulomatous (N = 9. ACA-PLPA were detected in 10/22 (45% patients: 9/13 (69% with the idiopathic form and 1/9 (11% with the granulomatous form, whereas ACA-IIF were detected in 11/22 patients (50%: 10/13 (77% with the idiopathic form and 1/9 (11% with the granulomatous form. Twelve of the 13 idiopathic addisonians (92% were positive for either ACA-PLPA or ACA-IIF, but only 7 were positive by both methods. In contrast, none of 90 healthy subjects was found to be positive for ACA. Thus, our study shows that the PLPA-based technique is useful, has technical advantages over the IIF method (by not requiring the use of a fluorescence microscope and by permitting section storage for long periods of time. However, since it is only 60% concordant with the ACA-IIF method, it should be considered complementary instead of an alternative method to IIF for the detection of ACA in human sera.

  1. [18F]FETO for adrenocortical PET imaging: a pilot study in healthy volunteers.

    Science.gov (United States)

    Wadsak, Wolfgang; Mitterhauser, Markus; Rendl, Gundula; Schuetz, Matthias; Mien, Leonhard Key; Ettlinger, Dagmar E; Dudczak, Robert; Kletter, Kurt; Karanikas, Georgios

    2006-06-01

    Functional imaging of the adrenal cortex by means of PET may play an important clinical role. Recently, we presented the synthesis and first evaluation of a novel 11beta-hydroxylase inhibitor, [(18)F]FETO, in rats displaying high tracer accumulation in the adrenals. In this study, we aimed to investigate for the first time the potency of [(18)F]FETO as a PET tracer for the adrenal cortex in humans. An average preparation yielded 1-2 GBq of [(18)F]FETO ready to use. Ten healthy volunteers aged 24-57 years (five male and five female) were included in the study. After i.v. administration of 365 MBq [(18)F]FETO (246-391 MBq), dynamic images were acquired in 2D standard mode in 14 frames over 45 min. Afterwards, whole-body scanning was performed. In addition to visual interpretation, semi-quantitative analysis using standardised uptake values (SUVs) was conducted. [(18)F]FETO distribution was similar in all scanned volunteers. Visually, pronounced accumulation of [(18)F]FETO was found in the adrenals, whereas moderate uptake was observed-at least in some of the subjects-for liver, renal calices, gallbladder, stomach walls and pancreas. Kidney and bowels showed only faint uptake. Median SUVs for the right and left adrenal glands were 15.6 (10.0-28.6) and 15.7 (10.3-35.9), respectively. The reference tissue (liver) displayed a median SUV of 2.5 (2.2-4.6). [(18)F]FETO is a valuable tracer for adrenocortical PET imaging, combining the longer half-life of( 18)F with a high 11beta-hydroxylase selectivity. In accordance with our findings in rats, FETO PET revealed very high accumulation in the adrenal glands in healthy volunteers.

  2. PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease.

    Science.gov (United States)

    Bram, Zakariae; Louiset, Estelle; Ragazzon, Bruno; Renouf, Sylvie; Wils, Julien; Duparc, Céline; Boutelet, Isabelle; Rizk-Rabin, Marthe; Libé, Rossella; Young, Jacques; Carson, Dennis; Vantyghem, Marie-Christine; Szarek, Eva; Martinez, Antoine; Stratakis, Constantine A; Bertherat, Jérôme; Lefebvre, Hervé

    2016-09-22

    Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent hypercortisolism. The disease is primarily caused by germline mutations of the protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene, which induces constitutive activation of PKA in adrenocortical cells. Hypercortisolism is thought to result from PKA hyperactivity, but PPNAD tissues exhibit features of neuroendocrine differentiation, which may lead to stimulation of steroidogenesis by abnormally expressed neurotransmitters. We hypothesized that serotonin (5-HT) may participate in the pathophysiology of PPNAD-associated hypercortisolism. We show that PPNAD tissues overexpress the 5-HT synthesizing enzyme tryptophan hydroxylase type 2 (Tph2) and the serotonin receptors types 4, 6, and 7, leading to formation of an illicit stimulatory serotonergic loop whose pharmacological inhibition in vitro decreases cortisol production. In the human PPNAD cell line CAR47, the PKA inhibitor H-89 decreases 5-HT4 and 5-HT7 receptor expression. Moreover, in the human adrenocortical cell line H295R, inhibition of PRKAR1A expression increases the expression of Tph2 and 5-HT4/6/7 receptors, an effect that is blocked by H-89. These findings show that the serotonergic process observed in PPNAD tissues results from PKA activation by PRKAR1A mutations. They also suggest that Tph inhibitors may represent efficient treatments of hypercortisolism in patients with PPNAD.

  3. PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease

    Science.gov (United States)

    Bram, Zakariae; Louiset, Estelle; Renouf, Sylvie; Duparc, Céline; Boutelet, Isabelle; Rizk-Rabin, Marthe; Libé, Rossella; Young, Jacques; Carson, Dennis; Vantyghem, Marie-Christine; Szarek, Eva; Martinez, Antoine; Stratakis, Constantine A.; Bertherat, Jérôme

    2016-01-01

    Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent hypercortisolism. The disease is primarily caused by germline mutations of the protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene, which induces constitutive activation of PKA in adrenocortical cells. Hypercortisolism is thought to result from PKA hyperactivity, but PPNAD tissues exhibit features of neuroendocrine differentiation, which may lead to stimulation of steroidogenesis by abnormally expressed neurotransmitters. We hypothesized that serotonin (5-HT) may participate in the pathophysiology of PPNAD-associated hypercortisolism. We show that PPNAD tissues overexpress the 5-HT synthesizing enzyme tryptophan hydroxylase type 2 (Tph2) and the serotonin receptors types 4, 6, and 7, leading to formation of an illicit stimulatory serotonergic loop whose pharmacological inhibition in vitro decreases cortisol production. In the human PPNAD cell line CAR47, the PKA inhibitor H-89 decreases 5-HT4 and 5-HT7 receptor expression. Moreover, in the human adrenocortical cell line H295R, inhibition of PRKAR1A expression increases the expression of Tph2 and 5-HT4/6/7 receptors, an effect that is blocked by H-89. These findings show that the serotonergic process observed in PPNAD tissues results from PKA activation by PRKAR1A mutations. They also suggest that Tph inhibitors may represent efficient treatments of hypercortisolism in patients with PPNAD. PMID:27699247

  4. Clinical features, diagnosis, treatment and molecular studies in paediatric Cushing's syndrome due to primary nodular adrenocortical hyperplasia

    DEFF Research Database (Denmark)

    Storr, Helen L; Mitchell, J H; Swords, F M

    2004-01-01

    BACKGROUND: Primary nodular adrenocortical hyperplasia (PNAH) is a well recognized, but infrequently studied cause of paediatric Cushing's syndrome (CS). OBJECTIVE: To assess presentation, diagnosis, radiological imaging, treatment and molecular analysis of patients with childhood-onset CS due...

  5. Resposta adrenocortical em caninos tratados com betametasona e fludrocortisona por via auricular Canine adrenocortical response to otic betamethasone and fludrocortisone

    Directory of Open Access Journals (Sweden)

    Luiz Fernando Jantzen Gaspar

    1999-12-01

    Full Text Available Vinte e quatro caninos adultos hígidos, sem raça definida, machos e fêmeas, com peso e idade variados, foram divididos igualmente em grupo controle, betametasona, fludrocortisona, e receberam, por via auricular, 2ml diários das seguintes soluções: salina a 0,9%, fosfato dissódico de betametasona a 0,1% e acetato de fludrocortisona a 0,1%, respectivamente. Os animais foram submetidos a duas aplicações diárias de 0,5ml da solução correspondente em cada conduto auditivo, durante um período de 14 dias. Foram realizadas colheitas de sangue da jugular no 7º e 14º dias de tratamento e no 7º dia após o término dos tratamentos. Realizou-se a determinação dos níveis séricos de cortisol pré e pós-estímulo com ACTH. Os grupos betametasona e fludrocortisona apresentaram um decréscimo significativo (PTwenty four mature mixed-breed dogs, healthy, male and female, of several weights and ages were divided into control, betamethasone and fludrocortisone groups and received 2ml daily of these solutions: 0.9% saline solution, 0.1% betamethasone disodic phosphate and 0.1% fludrocortisone acetate, respectively. The dogs received, twice in day, 0.5ml of corresponding solution into each external ear canal for 14 days. During the treatments were realized collections of data on 7th and 14th day and in post-treatment (seven days later the end of treatments. In these times were obtained blood samples by jugular venopunction, for serologic determination of level serum cortisol pre- and post-ACTH. The pre- and post-ACTH cortisol concentrations of fludrocortisone and betamethasone groups reduced significantly (P<0.05 compared with control, during the experiment. Betamethasone and fludrocortisone by otic administration produce considerable effects in the adrenocortical function.

  6. Adrenocortical carcinoma with extension to the inferior vena cava and right atrium: 20-month-old girl with TP53 mutation

    Directory of Open Access Journals (Sweden)

    Terry L. Levin, MD

    2015-01-01

    Full Text Available A 20-month-old female presented with respiratory distress and a right adrenal mass extending into the inferior vena cava and right atrium. The mass was initially thought to be neuroblastoma. Pathology later revealed adrenocortical carcinoma. Inferior vena cava extension is far more common in adrenocortical carcinoma than neuroblastoma, and its presence should prompt clinical and laboratory evaluation for an adrenocortical tumor. The genetic findings in TP53 associated with this disease are discussed.

  7. Methylprednisolone Pulse Treatment of Graves´Ophthalmopathy is not associated with secondary Adrenocortical insufficiency

    DEFF Research Database (Denmark)

    Nygaard, Birte; Kristensen, Lars Østergaard

    2015-01-01

    treatment (500 mg i.v. per week for 6 weeks followed by 250 mg i.v. per week for an additional 6 weeks). Results: All patients included fulfilled the criteria of intact HPA axis function before and at cessation of methylprednisolone pulse treatment. Data are given as medians (with ranges). Before...... plasma ACTH was 4.2 pmol/l (4-16) and at cessation of therapy the corresponding value was 4.8 pmol/l (2-9; p = 0.27). Conclusion: Transient suppression of the HPA axis with secondary adrenocortical insufficiency does not seem to be a common phenomenon after intravenous methylprednisolone pulse therapy...... for GO. Therefore, routine precautions are not necessary. However, our results do not exclude that transient secondary adrenocortical insufficiency might occur occasionally. © 2015 European Thyroid Association Published by S. Karger AG, Basel...

  8. Shh signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages.

    Science.gov (United States)

    King, Peter; Paul, Alex; Laufer, Ed

    2009-12-15

    The adrenal cortex is a critical steroidogenic endocrine tissue, generated at least in part from the coelomic epithelium of the urogenital ridge. Neither the intercellular signals that regulate cortical development and maintenance nor the lineage relationships within the adrenal are well defined. We have explored adrenal Shh activity and found that Shh is expressed in relatively undifferentiated steroidogenic cells, which signal to the overlying capsule and subjacent nonsteroidogenic mesenchyme cells that we also find are progenitors of steroidogenic lineages. Shh-expressing cells also generate all steroidogenic cell types, but not nonsteroidogenic ones. Shh mutant adrenals have a thin capsule and small cortex. Our findings both support a novel dual lineage, Shh-independent and Shh-dependent, model of adrenocortical development, and identify distinct populations of adrenocortical progenitor and candidate stem cells.

  9. A morphometric analysis of adrenocortical actin localized by immunoelectron microscopy: the effect of adrenocorticotropin.

    Science.gov (United States)

    Loesser, K E; Malamed, S

    1987-10-01

    The localization of actin and the effect of ACTH on its concentration was examined in freshly isolated rat adrenocortical cells. Lowicryl K4M-embedded cells were used for the immunoelectron localization of actin; gold was used as a label for immunoreactive sites. Actin was at least 4 times as concentrated at the cortical cytoplasm as in the lipid droplets and at least 5 times as concentrated in the microvilli as in the lipid droplets. ACTH stimulation approximately doubled the concentration of actin in the cortical cytoplasm and increased by 50% the concentration of actin in the microvilli. The microvillar contribution to the cell surface area was 40% higher in ACTH-stimulated cells than it was in unstimulated cells. These results provide quantitative evidence suggesting that actin and the microvilli participate in steroid secretion by the adrenocortical cell.

  10. A genetic and molecular update on adrenocortical causes of Cushing syndrome.

    Science.gov (United States)

    Lodish, Maya; Stratakis, Constantine A

    2016-05-01

    Primary adrenal Cushing syndrome is the result of cortisol hypersecretion mainly by adenomas and, rarely, by bilateral micronodular or macronodular adrenocortical hyperplasia. cAMP-dependent protein kinase A (PKA) signalling is the major activator of cortisol secretion in the adrenal cortex. Many adenomas and hyperplasias associated with primary hypercortisolism carry somatic or germline mutations in genes that encode constituents of the cAMP-PKA pathway. In this Review, we discuss Cushing syndrome and its linkage to dysregulated cAMP-PKA signalling, with a focus on genetic findings in the past few years. In addition, we discuss the presence of germline inactivating mutations in ARMC5 in patients with primary bilateral macronodular adrenocortical hyperplasia. This finding has implications for genetic counselling of affected patients; hitherto, most patients with this form of adrenal hyperplasia and Cushing syndrome were thought to have a sporadic and not a familial disorder.

  11. Hidden diagnosis of multiple endocrine neoplasia-1 unraveled during workup of virilization caused by adrenocortical carcinoma

    Directory of Open Access Journals (Sweden)

    Sandeep Kharb

    2013-01-01

    Full Text Available Multiple endocrine neoplasia-1 (MEN1 is an autosomal dominant syndrome with classic triad of parathyroid hyperplasia, pancreatic neuroendocrine tumors, and pituitary adenomas. Other recognized manifestations include carcinoid, cutaneous or adrenocortical tumors. It is commonly presented with clinical features related to parathyroid, pancreas or pituitary lesions. Here, we have presented a case that had virilization and biochemical Cushing′s syndrome due to adrenocortical carcinoma as presenting feature of MEN1. Cushing′s syndrome in MEN1 is an extremely rare and usually late manifestation and most cases are due to corticotropin-producing pituitary adenomas. Although Cushing′s syndrome generally develops years after the more typical manifestations of MEN1 appear, it may be the primary manifestation of MEN1 syndrome particularly when related to adrenal adenoma or carcinoma.

  12. Aging of the rat adrenocortical cell: response to ACTH and cyclic AMP in vitro.

    Science.gov (United States)

    Malamed, S; Carsia, R V

    1983-03-01

    To study intrinsic age-related changes in adrenocortical steroid production, cells isolated from rats of different ages (3 to 24 months) were used. Acute (2 hour) corticosterone production in response to stimulation by adrenocorticotrophic hormone (ACTH) and adenosine 3':5'-cyclic monophosphate (cAMP) was measured by radioimmunoassay. With age, adrenocortical cells lose much of their ability to produce corticosterone in the absence or presence of ACTH or cAMP. The loss is progressive from 6 to 24 months of age. Analysis of the data suggests that from 6 to 12 months, an intracellular steroidogenic lesion develops; in addition there may be a loss in ACTH receptors on the plasma membrane. After 12 months these defects increase and are accompanied by a decrease in receptor sensitivity to ACTH.

  13. Adrenocortical responses to offspring-directed threats in two open-nesting birds

    OpenAIRE

    Butler, Luke K; Bisson, Isabelle-Anne; Hayden, Timothy J.; Wikelski, Martin; Romero, L. Michael

    2009-01-01

    Dependent young are often easy targets for predators, so for many parent vertebrates, responding to offspring-directed threats is a fundamental part of reproduction. We tested the parental adrenocortical response of the endangered black-capped vireo (Vireo atricapilla) and the common white-eyed vireo (Vireo griseus) to acute and chronic threats to their offspring. Like many open-nesting birds, our study species experience high offspring mortality. Parents responded behaviorally to a predator ...

  14. Effects of repeated restraint in Japanese quail genetically selected for contrasting adrenocortical responses.

    Science.gov (United States)

    Jones, R B; Satterlee, D G; Waddington, D; Cadd, G G

    2000-05-01

    Behavioral and adrenocortical responses to repeated mechanical restraint were compared in 28-day-old to 31-day-old male Japanese quail from two genetic lines divergently selected for reduced (low stress, LS) or exaggerated (high stress, HS) plasma corticosterone (C) responses to brief immobilization. Restraint in a metal crush cage for 5 min elicited immobility and silence in all the birds. Circulating C levels were considerably higher in quail of both lines following restraint than in the undisturbed controls of either line. As expected, both the behavioral and physiological effects were more pronounced in HS than in LS birds. Struggling increased with repeated restraint in HS and LS quail, thus suggesting behavioral habituation to the stressor in both lines. On the other hand, a line effect on the pattern of adrenocortical responses was revealed upon subtracting the change in plasma C concentrations from Day 1 to Day 4 in the undisturbed controls from the corresponding change in restrained birds. Thus, unlike LS quail, in which there were no detectable effects of repeated restraint, the adrenocortical responses of HS birds showed evidence of experience-dependent sensitization. Our results demonstrate the importance of the background genome in determining the patterns of the behavioral and adrenocortical responses elicited by repeated exposure to stressful stimulation. The present results and those of previous studies could be explained in one or both of two ways: that underlying fearfulness is lower in LS than HS quail or that they adopt active or passive coping strategies, respectively. Our findings may also have important implications for poultry welfare and productivity. @ 2000 Elsevier Science Inc.

  15. ACTH-Independent Cushing’s Syndrome with Bilateral Micronodular Adrenal Hyperplasia and Ectopic Adrenocortical Adenoma

    Science.gov (United States)

    Louiset, Estelle; Gobet, Françoise; Libé, Rossella; Horvath, Anelia; Renouf, Sylvie; Cariou, Juliette; Rothenbuhler, Anya; Bertherat, Jérôme; Clauser, Eric; Grise, Philippe; Stratakis, Constantine A.; Kuhn, Jean-Marc; Lefebvre, Hervé

    2010-01-01

    Context: Bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma are two rare causes of ACTH-independent Cushing’s syndrome. Objective: The aim of the study was to evaluate a 35-yr-old woman with ACTH-independent hypercortisolism associated with both micronodular adrenal hyperplasia and ectopic pararenal adrenocortical adenoma. Design and Setting: In vivo and in vitro studies were performed in a University Hospital Department and academic research laboratories. Intervention: Mutations of the PRKAR1A, PDE8B, and PDE11A genes were searched for in leukocytes and adrenocortical tissues. The ability of adrenal and adenoma tissues to synthesize cortisol was investigated by immunohistochemistry, quantitative PCR, and/or cell culture studies. Main Outcome Measure: Detection of 17α-hydroxylase and 21-hydroxylase immunoreactivities, quantification of CYP11B1 mRNA in adrenal and adenoma tissues, and measurement of cortisol levels in supernatants by radioimmunological assays were the main outcomes. Results: Histological examination of the adrenals revealed nonpigmented micronodular cortical hyperplasia associated with relative atrophy of internodular cortex. No genomic and/or somatic adrenal mutations of the PRKAR1A, PDE8B, and PDE11A genes were detected. 17α-Hydroxylase and 21-hydroxylase immunoreactivities as well as CYP11B1 mRNA were detected in adrenal and adenoma tissues. ACTH and dexamethasone activated cortisol secretion from adenoma cells. The stimulatory action of dexamethasone was mediated by a nongenomic effect involving the protein kinase A pathway. Conclusion: This case suggests that unknown molecular defects can favor both micronodular adrenal hyperplasia and ectopic adrenocortical adenoma associated with Cushing’s syndrome. PMID:19915020

  16. Acanthosis Nigricans Associated with an Adrenocortical Tumor in a Pediatric Patient

    Directory of Open Access Journals (Sweden)

    Elizabeth Isaacoff

    2013-01-01

    Full Text Available Malignant acanthosis nigricans (AN is a rare paraneoplastic syndrome seen primarily in adults with an underlying diagnosis of gastrointestinal adenocarcinoma. Malignant AN is characterized by hyperpigmentation and velvety hyperplasia of the epidermis. This condition is generally not associated with tumors in pediatric populations or in the adrenal gland. We present a case of malignant AN in a pediatric patient with a nonmalignant, functional adrenocortical tumor.

  17. Paediatric Nonfunctioning Adrenocortical Carcinoma with Extension up to Right-Side Heart: Cardiac Surgery Approach

    Directory of Open Access Journals (Sweden)

    Federica Iezzi

    2016-01-01

    Full Text Available Adrenocortical carcinoma is a rare malignancy. Due to late diagnosis and no adequate effective adjuvant treatment, prognosis remains poor. Only approximately 30% of these malignancies are confined to the adrenal gland when they are diagnosed, as these tumors tend to be found years after their genesis. Cardiac involvement of adrenal carcinoma is very rare. We report a rare case of a 7-year-old female with right adrenal cortical carcinoma, involving the right-side heart.

  18. [Effect of adaptogens on the activity of the pituitary-adrenocortical system in rats].

    Science.gov (United States)

    Filaretov, A A; Bogdanova, T S; Mitiushov, M I; Podvigina, T T; Srailova, G T

    1986-05-01

    Intraperitoneal injection of Panax ginseng C. A. Mey tincture, Polyscias filicifolia Bailey tincture, Panax ginseng tincture or Eleutherococcus Maxim extract to rats produced a rise in plasma corticosterone 1 hour after the treatment. Immobilization-induced rise in plasma corticosterone was increased by 7-day pretreatment with any agent. Thus, the adaptation effect of Panax ginseng C. A. Mey and Polyscias filicifolia Bailey is probably realized through the pituitary-adrenocortical system.

  19. Seasonal changes in adrenocortical responses to acute stress in Eurasian tree sparrow (Passer montanus) on the Tibetan Plateau: comparison with house sparrow (P. domesticus) in North America and with the migratory P. domesticus in Qinghai Province.

    Science.gov (United States)

    Li, Dongming; Wang, Gang; Wingfield, John C; Zhang, Zhi; Ding, Changqing; Lei, Fumin

    2008-08-01

    Seasonal modulation of the adrenocortical response to stress appears to be ubiquitous in arctic-breeding and temperate-zone-breeding birds, but has not been well investigated in alpine-breeding species at mid-latitude. We examined the adrenocortical response to acute stress (capture, handling and restraint) in populations of Eurasian tree sparrow (Passer montanus) among seasons and migratory house sparrow (P. domesticus bactrianus) in pre-breeding on the Qinghai-Xizang Plateau (the Tibetan Plateau). A population of house sparrow (Passer domesticus domesticus) was also sampled in lowland Phoenix, Arizona during breeding and wintering stages. In Eurasian tree sparrows, baseline corticosterone (CORT) does not differ among life history stages, but stress-induced CORT level (maximal CORT, total and corrected integrated CORT) is significantly higher in late breeding stage than those in early breeding and prebasic molt stages. In house sparrows, stress-induced CORT level does not differ between sites and life history stages, but baseline CORT is significantly lower in pre-breeding from Qinghai compared with those in breeding and wintering stages from Phoenix. Interestingly, both baseline CORT and maximal CORT do not differ between the populations of Eurasian tree sparrow and house sparrow in early/pre-breeding stage although tree sparrow is resident species whereas house sparrow is migratory in Qinghai. Our results suggest that the extreme environment of the Tibetan Plateau does not have significant effects on adrenocortical responses to acute stress in Eurasian tree sparrows and house sparrows, which may be a result of masking by human activities. These invasive human commensals may have a unique HPA axis response to different environments because they can take advantage of human food sources and shelter (i.e. buildings).

  20. Cerebellin in the rat adrenal gland: gene expression and effects of CER and [des-Ser1]CER on the secretion and growth of cultured adrenocortical cells.

    Science.gov (United States)

    Rucinski, Marcin; Albertin, Giovanna; Spinazzi, Raffaella; Ziolkowska, Agnieszka; Nussdorfer, Gastone G; Malendowicz, Ludwick K

    2005-03-01

    Cerebellin (CER) is a regulatory peptide, originally isolated from rat cerebellum, which derives from the cleavage of precerebellin (Cbln), three types of which (Cbln1-3) have been identified in humans and rats. CER is also expressed in several extra-cerebellar tissues, including adrenal gland, and evidence has been provided that CER exerts a modulatory action on human and rat adrenal gland. Hence, we have investigated the expression of Cbln1-3 mRNAs and CER protein-immunoreactivity (IR) in the various zones of rat adrenal glands, and the effects of CER and its metabolite [des-Ser(1)]CER (des-CER) on the secretion and growth of cultured rat adrenocortical cells. Reverse transcription-polymerase chain reaction showed high and low expression of Cbln2 mRNA in zona glomerulosa (ZG) and zona fasciculata-reticularis, respectively. Cbln1 was not expressed, and Cbln3 mRNA was detected only in ZG. No Cbln expression was found in adrenal medulla. Immunocytochemistry demonstrated the presence of CER-IR exclusively in the adrenal cortex, the reaction being more intense in ZG. As expected, ACTH (10(-8) M) markedly enhanced corticosterone secretion and lowered proliferation rate of cultured adrenocortical cells. CER was ineffective, while des-CER exerted an ACTH-like effect, but only at the lowest concentration (10(-10) M). Taken together, these findings allow us to conclude that CER is expressed in rat adrenal cortex, and to suggest that CER conversion to des-CER by endopeptidases is needed for CER to exert its autocrine-paracrine regulatory functions.

  1. Comparative CYP-dependent binding of the adrenocortical toxicants 3-methylsulfonyl-DDE and o,p'-DDD in Y-1 adrenal cells.

    Science.gov (United States)

    Hermansson, Veronica; Asp, Vendela; Bergman, Ake; Bergström, Ulrika; Brandt, Ingvar

    2007-11-01

    The environmental pollutant 3-MeSO(2)-DDE [2-(3-methylsulfonyl-4-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichloroethene] is an adrenocortical toxicant in mice, specifically in the glucocorticoid-producing zona fasciculata, due to a cytochrome P450 11B1 (CYP11B1)-catalysed bioactivation and formation of covalently bound protein adducts. o,p'-DDD [2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichloroethane] is toxic and inhibits steroidogenesis in the human adrenal cortex after bioactivation by unidentified CYPs, but does not exert any toxic effects on the mouse adrenal. As a step towards determining in vitro/in vivo relationships for the CYP-catalysed binding and toxicity of 3-MeSO(2)-DDE and o,p'-DDD, we have investigated the irreversible protein binding of these two toxicants in the murine adrenocortical cell line Y-1. The irreversible binding of 3-MeSO(2)-DDE previously demonstrated in vivo was successfully reproduced and could be inhibited by the CYP-inhibitors etomidate, ketoconazole and metyrapone. Surprisingly, o,p'-DDD reached similar levels of binding as 3-MeSO(2)-DDE. The binding of o,p'-DDD was sensitive to etomidate and ketoconazole, but not to metyrapone. Moreover, GSH depletion increased the binding of 3-MeSO(2)-DDE, but not of o,p'-DDD, indicating an important role of GSH conjugation in the detoxification of the 3-MeSO(2)-DDE-derived reactive metabolite. In addition, the specificity of CYP11B1 in activating 3-MeSO(2)-DDE was investigated using structurally analogous compounds. None of the analogues produced histopathological lesions in the mouse adrenal in vivo following a single i.p. injection of 100 mg/kg body weight, but two of the compounds were able to decrease the irreversible binding of 3-MeSO(2)-DDE to Y-1 cells. These results indicate that the bioactivation of 3-MeSO(2)-DDE by CYP11B1 is highly structure-dependent. In conclusion, both 3-MeSO(2)-DDE and o,p'-DDD bind irreversibly to Y-1 cells despite differences in binding and adrenotoxicity in mice

  2. Shen's Experience in Application of the Drugs for Tonifying the Kidney to Reduce and Withdraw Adrenocortical Hormone

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@Adrenocortical hormone (ACH) has antiinflammatory and antiallergic actions, changes stress state and controls the attack of some severe and obstinate diseases. The treatment of chronic diseases with ACH often leads to its dependence; especially oral administration of ACH for a long time is liable to inhibit the function of hypothalamus-pituitary-adrenocortical-thymic axis (HPAT), and results in the hypo-reservation of adrenal cortex. Hence, sudden ACH withdrawal or decrease often causes the disease recurrence, even adrenocortical crisis. Academician Shen Ziyin has a wealth of clinical experience in both the withdrawal and reduction of ACH and the keeping of therapeutical effectiveness to form his unique remedy in the application of drugs. Shen's rich experience is described as follows.

  3. A case of pediatric virilizing adrenocortical tumor resulting in hypothalamic-pituitary activation and central precocious puberty following surgical removal.

    Science.gov (United States)

    Miyoshi, Yoko; Oue, Takaharu; Oowari, Mitsugu; Soh, Hideki; Tachibana, Makiko; Kimura, Sadami; Kiyohara, Yuki; Yamada, Hiroyuki; Bessyo, Kazuhiko; Mushiake, Sotaro; Homma, Keiko; Hasegawa, Tomonobu; Sasano, Hironobu; Ozono, Keiichi

    2009-01-01

    We present a 6-year-old boy with a virilizing adrenocortical tumor who initially presented with peripheral precocious puberty. Development of facial acne, pubic hair and a growth spurt were noted at the age of five. A low-pitched voice as well as maturation of external genitalia was noted at the age of six. Both serum and urinary levels of adrenal androgens were elevated. Abdominal computed tomography revealed a large right suprarenal mass and he underwent surgical resection without any complications. The histological diagnosis was adrenocortical carcinoma according to the criteria of Weiss. Following surgical removal of the androgen-producing tumor, the patient subsequently developed hypothalamic-pituitary activation and demonstrated central precocious puberty. He was treated with a gonadotropin-releasing hormone agonist in order to delay further pubertal progression. Clinical follow-up of potential secondary effects of excess hormone secretion after removal is important in some pediatric patients with virilizing adrenocortical tumor.

  4. Effects of multiwalled carbon nanotubes and triclocarban on several eukaryotic cell lines: elucidating cytotoxicity, endocrine disruption, and reactive oxygen species generation.

    Science.gov (United States)

    Simon, Anne; Maletz, Sibylle X; Hollert, Henner; Schäffer, Andreas; Maes, Hanna M

    2014-01-01

    To date, only a few reports about studies on toxic effects of carbon nanotubes (CNT) are available, and their results are often controversial. Three different cell lines (rainbow trout liver cells (RTL-W1), human adrenocortical carcinoma cells (T47Dluc), and human adrenocarcinoma cells (H295R)) were exposed to multiwalled carbon nanotubes, the antimicrobial agent triclocarban (TCC) as well as the mixture of both substances in a concentration range of 3.13 to 50 mg CNT/L, 31.25 to 500 μg TCC/L, and 3.13 to 50 mg CNT/L + 1% TCC (percentage relative to carbon nanotubes concentration), respectively. Triclocarban is a high-production volume chemical that is widely used as an antimicrobial compound and is known for its toxicity, hydrophobicity, endocrine disruption, bioaccumulation potential, and environmental persistence. Carbon nanotubes are known to interact with hydrophobic organic compounds. Therefore, triclocarban was selected as a model substance to examine mixture toxicity in this study. The influence of multiwalled carbon nanotubes and triclocarban on various toxicological endpoints was specified: neither cytotoxicity nor endocrine disruption could be observed after exposure of the three cell lines to carbon nanotubes, but the nanomaterial caused intracellular generation of reactive oxygen species in all cell types. For TCC on the other hand, cell vitality of 80% could be observed at a concentration of 2.1 mg/L for treated RTL-W1 cells. A decrease of luciferase activity in the ER Calux assay at a triclocarban concentration of 125 μg/L and higher was observed. This effect was less pronounced when multiwalled carbon nanotubes were present in the medium. Taken together, these results demonstrate that multiwalled carbon nanotubes induce the production of reactive oxygen species in RTL-W1, T47Dluc, and H295R cells, reveal no cytotoxicity, and reduce the bioavailability and toxicity of the biocide triclocarban.

  5. Protein kinase A subunit expression is altered in Bloom syndrome fibroblasts and the BLM protein is increased in adrenocortical hyperplasias: inverse findings for BLM and PRKAR1A.

    Science.gov (United States)

    Heyerdahl, S L; Boikos, S; Horvath, A; Giatzakis, C; Bossis, I; Stratakis, C A

    2008-06-01

    Bloom syndrome is a genetic disorder associated with chromosomal instability and a predisposition to tumors that is caused by germline mutations of the BLM gene, a RecQ helicase. Benign adrenocortical tumors display a degree of chromosomal instability that is more significant than benign tumors of other tissues. Cortisol-producing hyperplasias, such as primary pigmented nodular adrenocortical disease (PPNAD), which has been associated with protein kinase A (PKA) abnormalities and/or PRKAR1A mutations, also show genomic instability. Another RecQ helicase, WRN, directly interacts with the PRKAR1B subunit of PKA. In this study, we have investigated the PRKAR1A expression in primary human Bloom syndrome cell lines with known BLM mutations and examined the BLM gene expression in PPNAD and other adrenal tumor tissues. PRKAR1A and other protein kinase A (PKA) subunits were expressed in Bloom syndrome cells and their level of expression differed by subunit and cell type. Overall, fibroblasts exhibited a significant decrease in protein expression of all PKA subunits except for PRKAR1A, a pattern that has been associated with neoplastic transformation in several cell types. The BLM protein was upregulated in PPNAD and other hyperplasias, compared to samples from normal adrenals and normal cortex, as well as samples from cortisol- and aldosterone-producing adenomas (in which BLM was largely absent). These data reveal an inverse relationship between BLM and PRKAR1A: BLM deficiency is associated with a relative excess of PRKAR1A in fibroblasts compared to other PKA subunits; and PRKAR1A deficiency is associated with increased BLM protein in adrenal hyperplasias.

  6. Investigation of N-cadherin/β-catenin expression in adrenocortical tumors.

    Science.gov (United States)

    Rubin, Beatrice; Regazzo, Daniela; Redaelli, Marco; Mucignat, Carla; Citton, Marilisa; Iacobone, Maurizio; Scaroni, Carla; Betterle, Corrado; Mantero, Franco; Fassina, Ambrogio; Pezzani, Raffaele; Boscaro, Marco

    2016-10-01

    β-catenin is a multifunctional protein; it is a key component of the Wnt signaling, and it plays a central role in cadherin-based adhesions. Cadherin loss promotes tumorigenesis by releasing membrane-bound β-catenin, hence stimulating Wnt signaling. Cadherins seem to be involved in tumor development, but these findings are limited in adrenocortical tumors (ACTs). The objective of this study was to evaluate alterations in key components of cadherin/catenin adhesion system and of Wnt pathway. This study included eight normal adrenal samples (NA) and 95 ACT: 24 adrenocortical carcinomas (ACCs) and 71 adrenocortical adenomas (ACAs). β-catenin mutations were evaluated by sequencing, and β-catenin and cadherin (E-cadherin and N-cadherin) expression was analyzed by quantitative reverse transcription PCR (qRT-PCR) and by immunohistochemistry (IHC). We identified 18 genetic alterations in β-catenin gene. qRT-PCR showed overexpression of β-catenin in 50 % of ACC (12/24) and in 48 % of ACA (21/44). IHC data were in accordance with qRT-PCR results: 47 % of ACC (7/15) and 33 % of ACA (11/33) showed increased cytoplasmic or nuclear β-catenin accumulation. N-cadherin downregulation has been found in 83 % of ACC (20/24) and in 59 % of ACA (26/44). Similar results were obtained by IHC: N-cadherin downregulation was observed in 100 % (15/15) of ACC and in 55 % (18/33) of ACA. β-catenin overexpression together with the aberrant expression of N-cadherin may play important role in ACT tumorigenesis. The study of differentially expressed genes (such as N-cadherin and β-catenin) may enhance our understanding of the biology of ACT and may contribute to the discovery of new diagnostic and prognostic tools.

  7. ROS mediated cytotoxicity of porcine adrenocortical cells induced by QdNOs derivatives in vitro.

    Science.gov (United States)

    Huang, Xian-Ju; Zhang, Hua-Hai; Wang, Xu; Huang, Ling-Li; Zhang, Ling-Yan; Yan, Cai-Xia; Liu, Yu; Yuan, Zong-Hui

    2010-05-14

    Quinoxaline 1,4-dioxides (QdNOs) derivatives, the potent synthetic antibacterial group used in food-producing animals, are assumed to have pro-oxidant properties. However, how oxidative stress mediated their adrenal toxicity is far from clear. The aim of this study was to assess the ability of three QdNOs, i.e. olaquindox (OLA), mequindox (MEQ), and cyadox (CYA), to produce reactive oxygen species (ROS) and oxidative cell damage in porcine adrenocortical cells. Multiple approaches such as cell activity assay, biochemical detectation, flow cytometry and fluorescent were used to study the integrated role of ROS homeostasis, mitochondrial redox metabolism and cell apoptosis as well as chemical stability of these drugs. The results showed that OLA and MEQ treatment evoked a significant dose and time-dependent cell damage in adrenocortical cells, well CYA displayed much less toxicity. As for the intracellular ROS production, OLA irritated a persistent and utmost release of ROS while MEQ made a similar but weaker reaction. CYA, however, had a short and unstable release of intracellular ROS. On the other hand, quinoxalinine-2-carboxylie acid (QCA), one of the metabolites of OLA and MEQ, did not cause any significant production of ROS and showed relatively lower toxicity than its parents. Moreover, an imbalance in the redox metabolism and mitochondrial membrane damage has been implicated in adrenal toxicity of QdNOs. ROS scavengers partially reversed QdNOs-induced mitochondrial damage, indicating that mitochondria may be a major target and critical for ROS-mediated cell death. In a word, these results suggested that ROS is a key mediator of QdNOs-induced cell death via mitochondria-dependent pathway in adrenocortical cells. The results provide a mechanism approach in understanding the characterize of adrenal damage caused by QdNOs in vitro, which would in turn, help in designing the appropriate therapeutic strategies of these kind of feed additives.

  8. The ARMC5 gene shows extensive genetic variance in primary macronodular adrenocortical hyperplasia

    Science.gov (United States)

    Correa, Ricardo; Zilbermint, Mihail; Berthon, Annabel; Espiard, Stephanie; Batsis, Maria; Papadakis, Georgios Z.; Xekouki, Paraskevi; Lodish, Maya B.; Bertherat, Jerome; Faucz, Fabio R.; Stratakis, Constantine A.

    2015-01-01

    Objective Primary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing’s syndrome (CS) that results in increased cortisol production and bilateral enlargement of the adrenal glands. Recent work showed that the disease may be caused by germline and somatic mutations in the ARMC5 gene, a likely tumor-suppressor gene (TSG). We investigated 20 different adrenal nodules from one patient with PMAH for ARMC5 somatic sequence changes. Design All of the nodules where obtained from a single patient who underwent bilateral adrenalectomy. DNA was extracted by standard protocols and the ARMC5 sequence was determined by the Sanger method. Results Sixteen of 20 adrenocortical nodules harbored, in addition to what appeared to be the germline mutation, a second somatic variant. The p.Trp476* sequence change was present in all 20 nodules, as well as in normal tissue from the adrenal capsule, identifying it as the germline defect; each of the 16 other variants were found in different nodules: 6 were frame shift, 4 were missense, 3 were nonsense, and 1 was a splice site variation. Allelic losses were confirmed in 2 of the nodules. Conclusion This is the most genetic variance of the ARMC5 gene ever described in a single patient with PMAH: each of 16 adrenocortical nodules had a second new, “private”, and -in most cases- completely inactivating ARMC5 defect, in addition to the germline mutation. The data support the notion that ARMC5 is a TSG that needs a second, somatic hit, to mediate tumorigenesis leading to polyclonal nodularity; however, the driver of this extensive genetic variance of the second ARMC5 allele in adrenocortical tissue in the context of a germline defect and PMAH remains a mystery. PMID:26162405

  9. Magnetic resonance imaging of adrenocortical adenomas in childhood: correlation with computed tomography and ultrasound

    Energy Technology Data Exchange (ETDEWEB)

    Hanson, J.A. [Department of Diagnostic Imaging, St. Bartholomew`s Hospital, London (United Kingdom); Weber, A. [Division of Paediatric Endocrinology, St. Bartholomew`s Hospital, London (United Kingdom); Reznek, R.H. [Department of Diagnostic Imaging, St. Bartholomew`s Hospital, London (United Kingdom); Cotterill, A.M. [Division of Paediatric Endocrinology, St. Bartholomew`s Hospital, London (United Kingdom); Ross, R.J.M. [Department of Endocrinology, St. Bartholomew`s Hospital, London (United Kingdom); Harris, R.J. [Department of Paediatrics, Royal London Hospital, London (United Kingdom); Armstrong, P. [Department of Diagnostic Imaging, St. Bartholomew`s Hospital, London (United Kingdom); Savage, M.O. [Division of Paediatric Endocrinology, St. Bartholomew`s Hospital, London (United Kingdom)

    1996-11-01

    There are few descriptions of the magnetic resonance (MR) appearance of hyperfunctioning adrenocortical tumours, particularly those occurring in childhood. We studied five patients, two girls and three boys, aged 6-14.3 years, presenting with clinical syndromes of adrenocortical hyperfunction. The diagnoses were Cushing`s syndrome (n = 2), virilisation (n = 2), and Conn`s syndrome (n = 1). Biochemical features suggested an adrenal lesion in each case. MR and ultrasound were performed in all five cases, with CT in four. Each patient had a functional adrenal tumour secreting either cortisol, androgens or aldosterone alone, or a combination of cortisol, androgens and oestradiol. The histological diagnosis was adenoma in four cases and tumour of indeterminate nature in one case. MR clearly showed the tumours (diameter 1.0-7.5 cm), all the lesions being of high signal intensity relative to liver on T2-weighted sequences. CT revealed an adrenal mass in each of the four patients scanned, three of which enhanced after intravenous contrast medium injection. The multiplanar imaging of MR allowed better distinction from adjacent structures and also demonstrated an unenlarged contralateral adrenal gland. In the patient with a 1-cm Conn`s adenoma the lesion was more easily seen on MR than CT. Ultrasound showed the four larger tumours but was unable to visualise the contralateral adrenal or the Conn`s adenoma. In conclusion, the MR appearances of four adrenocortical adenomas and one indeterminate tumour in children are described. MR has been found to be at least equal to CT in the detection of these tumours, with some possible advantages. Both techniques are superior to ultrasound. (orig.). With 4 figs.

  10. microRNAs as Potential Biomarkers in Adrenocortical Cancer: Progress and Challenges

    Science.gov (United States)

    Cherradi, Nadia

    2016-01-01

    Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis and limited therapeutic options. Over the last decade, pan-genomic analyses of genetic and epigenetic alterations and genome-wide expression profile studies allowed major advances in the understanding of the molecular genetics of ACC. Besides the well-known dysfunctional molecular pathways in adrenocortical tumors, such as the IGF2 pathway, the Wnt pathway, and TP53, high-throughput technologies enabled a more comprehensive genomic characterization of adrenocortical cancer. Integration of expression profile data with exome sequencing, SNP array analysis, methylation, and microRNA (miRNA) profiling led to the identification of subgroups of malignant tumors with distinct molecular alterations and clinical outcomes. miRNAs post-transcriptionally silence their target gene expression either by degrading mRNA or by inhibiting translation. Although our knowledge of the contribution of deregulated miRNAs to the pathogenesis of ACC is still in its infancy, recent studies support their relevance in gene expression alterations in these tumors. Some miRNAs have been shown to carry potential diagnostic and prognostic values, while others may be good candidates for therapeutic interventions. With the emergence of disease-specific blood-borne miRNAs signatures, analyses of small cohorts of patients with ACC suggest that circulating miRNAs represent promising non-invasive biomarkers of malignancy or recurrence. However, some technical challenges still remain, and most of the miRNAs reported in the literature have not yet been validated in sufficiently powered and longitudinal studies. In this review, we discuss the current knowledge regarding the deregulation of tumor-associated and circulating miRNAs in ACC patients, while emphasizing their potential significance in pathogenic pathways in light of recent insights into the role of miRNAs in shaping the tumor microenvironment. PMID:26834703

  11. Quantitative high-performance liquid chromatographic determination of delta 4-3-ketosteroids in adrenocortical extracts.

    Science.gov (United States)

    Ballerini, R; Chinol, M; Ghelardoni, M

    1980-05-30

    A high-performance liquid chromatographic method is described for the determination of seven steroids in adrenocortical extracts showing a delta 4-3-ketonic conjugated system. The seven steroids (cortisol, cortisone, 11-dehydrocorticosterone, corticosterone, 11-deoxycortisol, aldosterone and 11-deoxycorticosterone) were separated with a chloroform-methanol gradient on a 5-micron silica column and with a water-acetonitrile gradient on a 10-micron RP-8 column. Effluents were monitored by UV absorption at 242 nm. Quantitative analysis was performed by comparing peak areas, which are proportional to the amounts of the individual substances (external standard method). The method is rapid, sensitive, easy to perform and reproducible.

  12. Extension of adrenocortical carcinoma into the right atrium – echocardiographic diagnosis: A case report

    Directory of Open Access Journals (Sweden)

    Rozenman Yoseph

    2003-05-01

    Full Text Available Abstract Background Adrenocortical carcinoma is a rare, highly malignant tumor. Cardiac involvement of the tumor is very rare. Echocardiography facilitates the evaluation of the cardiac involvement of the tumor. Case Presentation We describe a patient with an adrenal tumor. Transthoracic echo showed its extension into the right atrium. Accordingly, a combined abdominal and cardiac operation was performed, monitored by transesophageal echocardiography. Conclusion This case highlights the importance of echocardiography in revealing the cardiac involvement by this tumor and in planning the operative procedure.

  13. The first laparoscopic resection of an aldosterone-secreting adrenocortical oncocytoma in a child

    Directory of Open Access Journals (Sweden)

    Melih Akin

    2014-09-01

    Full Text Available Oncocytomas of the adrenal cortex are usually benign and nonfunctional, consisting of oncocytes in which the cytoplasm becomes eosinophilic due to the accumulation of abnormal mitochondria. Oncocytomas can exist in many organs and are frequently found in the salivary gland, kidneys, thyroid gland, parathyroid gland, and hypophysis. Functioning oncocytomas are very rarely observed in children, and no more than ten cases have been reported in the literature. Here, we present the first report of laparoscopic excision of an aldosterone-secreting adrenocortical oncocytoma in a child.

  14. Neuropeptides and the hypothalamic-pituitary-adrenocortical (HPA) system: review of recent research strategies in depression.

    Science.gov (United States)

    Hatzinger, M

    2000-04-01

    Depressed patients show a variety of alterations in hypothalamic-pituitary-adrenocortical (HPA) system regulation which is reflected by increased pituitary-adrenocortical hormone secretion at baseline and a number of aberrant neuroendocrine function tests. The latter include the combined dexamethasone (DEX) suppression/corticotropin-releasing hormone (CRH) challenge test, in which CRH was able to override DEX induced suppression of ACTH and cortisol secretion. Whereas the abnormal HPA activation in these patients improved in parallel with clinical remission, persistent HPA dysregulation was associated with an increased risk of relapse. Moreover, healthy subjects at high genetic risk for depression also showed this phenomenon as a trait marker. In consequence, it has been concluded that HPA alteration and development as well as course of depression may be causally related. As evidenced from clinical and preclinical studies, underlying mechanisms of these abnormalities involve impairment of central corticosteroid receptor function which leads to enhanced activity of hypothalamic neurons synthesising and releasing vasopressin and CRH. These neuropeptides mediate not only neuroendocrine but also behavioural effects. Recent research provided evidence that CRH can induce depression-like symptoms in animals and that these signs are mediated through the CRH1 receptor subtype. Hence, therapeutical application of new compounds acting more specifically on the HPA system such as CRH1 receptor antagonists appear to be a promising approach for future treatment options of depression. In conclusion, research in neuroendocrinology provided new insights into the underlying pathophysiology of depression and, in consequence, may lead to the development of new therapeutic tools.

  15. Future directions in the diagnosis and medical treatment of adrenocortical carcinoma.

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    Creemers, S G; Hofland, L J; Korpershoek, E; Franssen, G J H; van Kemenade, F J; de Herder, W W; Feelders, R A

    2016-01-01

    Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. Discrimination between ACCs and adrenocortical adenomas (ACAs) remains challenging, with the current gold standard being the Weiss score, consisting of several histopathological characteristics. However, new markers like Ki67, a marker for proliferation, and the staining of reticulins are promising not only as it comes to identifying malignancy but also as prognostic markers in patients with ACC. Currently, surgery is still the only curative treatment for ACC. Mitotane, an adrenolytic drug, is used in the adjuvant setting and in case of metastatic or advanced disease. Patients with progressive disease are frequently treated with mitotane, alone or in combination with etoposide, doxorubicine and cisplatin. Radiotherapy is indicated in selected cases. The low response rates and high toxicity of the systemic therapies emphasize the need for markers that enable the identification of responders and non-responders. Consequently, research is focusing on predictive factors varying from the expression of DNA repair genes to clinical patient characteristics. Subgroups of ACC with different prognosis have been identified based on transcriptome characteristics. As a conclusion from large molecular studies, ACCs appear to harbor many abnormalities compared to ACAs. Altered pathways driving ACC pathogenesis include the IGF, TP53 and the Wnt signaling pathway, allowing these as new potential targets for medical therapy. However, despite efforts in preclinical and clinical studies investigating efficacy of targeting these pathways, most novel therapies appear to be effective in only a subset of patients with ACC. New treatment concepts are therefore urgently needed.

  16. A Rare Cause of Hypokalemia: Aldosterone-Secreting Adrenocortical Carcinoma Dear Editor,

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    Ethem Turgay Cerit

    2014-03-01

    Full Text Available Adrenocortical carcinoma (ACC is a rare malignancy accounting for 0.05-0.2% of all cancers (1. Determinants of prognosis are the stage of disease and completeness of resection(2. Approximately 60% of ACCs are hormonally active and glucocorticoids and/or androgens are most frequently over-secreted (2. Rapid development of signs and symptoms of Cushing’s syndrome is the most frequent presentation (3. Aldosterone-secreting ACC is extremely uncommon, comprising 0% to 7% of all functioning ACCs and presents with severe hypertension and profound hypokalemia (4. Here we report a case diagnosed as aldosterone producing adrenocortical carcinoma presented with severe hypokalemia and hypertension. A 32-year-old man referred to our instution because of pain and marked weakness especially in his lower extremities for 2 months. On admission his blood pressure was 180 mmHg systolic and 110 mmHg diastolic. Laboratory investigation revealed severe hypokalemia (2.6 mmol/l (normal: 3.5-5.5 mmol/l, elevated serum aldosterone (39.0 ng/dl (normal: 0.8-13 ng/dl with suppressed plasma renin activity (0.07 ng/ml/h. Serum sodium level was 142 mmol/l (normal: 135-146 mmol/l. Serum aldosterone level was not supressed (38.2 ng/dl after saline infusion test. Serum dehydroepiandrosterone sulfate (DHEA-SO4 was 150 mcg/dl (normal: 80-560, Δ4-androstenedione was 1.91 ng/ml (normal: 0.5-4.8 and total testosterone was 447.3 ng/dl (normal: 229.8-799.8 (Table 1. Suppressed renin levels, increased aldosterone levels with an aldosterone/renin ratio >30 were suggestive findings of aldosterone-producing adenoma of the adrenal gland or bilateral adrenal hyperplasia. Computed tomography demonstrated a large (4.6 cm left-sided adrenal tumour which is heterogeneous and has lobulated margin without a contrasting pattern of adenoma (Figure 1. 24-h urinary catecholamines and low-dose dexamethasone-suppressed plasma cortisol concentrations were all normal. At surgery, an adrenal mass (70

  17. Species differences in 3-methylsulphonyl-DDE bioactivation by adrenocortical tissue.

    Science.gov (United States)

    Lindström, Veronica; Brandt, Ingvar; Lindhe, Orjan

    2008-03-01

    The CYP11B1-activated adrenocortical toxicant 3-methylsulphonyl-DDE (3-MeSO2-DDE) is proposed as a lead compound for an improved chemotherapy for adrenocortical carcinoma. We compared the binding of 3-MeSO2-[14C]DDE in the adrenal cortex of four rodent species; hamster, guinea pig, mouse and rat, using a precision-cut adrenal slice culture system ex vivo. Localization and quantification of the bound radioactivity were carried out using light microscopy autoradiography and radioluminography. The results revealed major species differences since 3-MeSO2-[14C]DDE was extensively bound to the hamster adrenal tissue while the guinea pig adrenals were devoid of binding. A high binding in mouse adrenal cortex was confirmed while binding in rat adrenal cortex was very weak. The results support previous observations that metabolic activation of 3-MeSO2-DDE is highly species dependent. Since CYP11B1 could be expressed in tissues other than the adrenal cortex, final toxicological characterization should be carried out in a species that can bioactivate this compound.

  18. The Role of gsp Mutations on the Development of Adrenocortical Tumors and Adrenal Hyperplasia

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    Villares Fragoso, Maria Candida Barisson; Wanichi, Ingrid Quevedo; Cavalcante, Isadora Pontes; Mariani, Beatriz Marinho de Paula

    2016-01-01

    Somatic GNAS point mutations, commonly known as gsp mutations, are involved in the pathogenesis of McCune–Albright syndrome (MAS) and have also been described in autonomous hormone-producing tumors, such as somatotropinoma, corticotrophoma, thyroid cancer, ovarian and testicular Leydig cell tumors, and primary macronodular adrenocortical hyperplasia (PMAH) (1–3). The involvement of gsp mutations in adrenal tumors was first described by Lyons et al. Since then, several studies have detected the presence of gsp mutations in adrenal tumors, but none of them could explain its presence along or the mechanism that leads to tumor formation and hormone hypersecretion. As a result, the molecular pathogenesis of the majority of sporadic adrenocortical tumors remains unclear (3). PMAH has also been reported with gsp somatic mutations in a few cases. Fragoso et al. identified two distinct gsp somatic mutations affecting arginine residues on codon 201 of GNAS in a few patients with PMAH who lacked any features or manifestations of MAS. Followed by this discovery, other studies have continued looking for gsp mutations based on strong prior evidence demonstrating that increased cAMP signaling is sufficient for cell proliferation and cortisol production (2, 4). With consideration for the previously reported findings, we conjecture that although somatic activating mutations in GNAS are a rare molecular event, these mutations could probably be sufficient to induce the development of macronodule hyperplasia and variable cortisol secretion. In this manuscript, we revised the presence of gsp mutations associated with adrenal cortical tumors and hyperplasia. PMID:27512387

  19. Steroid control of steroidogenesis in isolated adrenocortical cells: molecular and species specificity.

    Science.gov (United States)

    Carsia, R V; Macdonald, G J; Malamed, S

    1983-06-01

    The molecular and species specificity of glucocorticoid suppression of corticosteroidogenesis was investigated in isolated adrenocortical cells. Trypsin-isolated cells from male rat, domestic fowl and bovine adrenal glands were incubated with or without steroidogenic agents and with or without steroids. Glucocorticoids were measured by radioimmunoassay or fluorometric assay after 1-2 h incubation. Glucocorticoids suppressed ACTH-induced steroidogenesis of isolated rat cells with the following relative potencies: corticosterone greater than cortisol = cortisone greater than dexamethasone. The mineralocorticoid, aldosterone did not affect steroidogenesis. Suppression by glucocorticoids was acute (within 1-2 h), and varied directly with the glucocorticoid concentration. Testosterone also suppressed ACTH-induced steroidogenesis. Glucocorticoid-type steroids have equivalent suppressive potencies, thus suggesting that these steroids may induce suppression at least partly by a common mechanism. Although corticosterone caused the greatest suppression, testosterone was more potent. The steroid specificity of suppression of cyclic AMP (cAMP)-induced and ACTH-induced steroidogenesis were similar, suggesting that suppression is not solely the result of interference with ACTH receptor function or the induction of adenylate cyclase activity. Exogenous glucocorticoids also suppressed ACTH-induced steroidogenesis of cells isolated from domestic fowl and beef adrenal glands, thus suggesting that this observed suppression may be a general mechanism of adrenocortical cell autoregulation.

  20. Isolated adrenocortical cells of the domestic fowl (Gallus domesticus): steroidogenic and ultrastructural properties.

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    Carsia, R V; Scanes, C G; Malamed, S

    1985-02-01

    Isolated adrenocortical cells from White Leghorn chickens (Gallus domesticus) were compared to those from rats (Rattus norvegicus). Cells were prepared from collagenase-dispersed adrenal glands of sexually mature male animals. Corticosterone was measured by radioimmunoassay after incubation for 2 h with steroidogenic agents. Of the four ACTH analogues used, three were 6-17 times more potent with rat cells than with fowl cells (potencies were indicated by half-maximal steroidogenic concentrations). However, 9-tryptophan (O-nitrophenylsulfenyl) ACTH was 8 times more potent with fowl cells than with rat cells, thus suggesting that ACTH receptor differences exist between the two cell types. In addition, cAMP analogues were 10 times more potent with rat cells than with fowl cells suggesting that fowl corticosteroidogenesis is less dependent on cAMP than is rat corticosteroidogenesis. At equal cell concentrations, rat cells secreted 20-40 times more corticosterone than did chicken cells when they were maximally stimulated. Although rat cells converted 8 times more pregnenolone to corticosterone than did fowl cells, the half-maximal steroidogenic concentration for pregnenolone-supported corticosterone synthesis was the same for both cell types (about 5 microM). This suggests that fowl cells have lower steroidogenic enzyme content rather than lower steroidogenic enzyme activity. An unusual feature seen in the isolated fowl adrenocortical cells was an abundance of intracellular filaments.

  1. Glucocorticoid- and androgen-secreting black adrenocortical adenomas: unique cause of corticotropin-independent Cushing syndrome.

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    Tanaka, Satoshi; Tanabe, Akiyo; Aiba, Motohiko; Hizuka, Naomi; Takano, Kazue; Zhang, Jun; Young, William F

    2011-01-01

    To describe the unique association of corticotropin-independent Cushing syndrome caused by cortisol- and androgen-secreting black adrenal cortical adenomas with myelolipomatous change. We report the clinical, laboratory, radiologic, and pathologic findings from 2 patients who presented with androgen excess and typical signs and symptoms of Cushing syndrome. Endocrine investigations showed high serum cortisol concentrations that lacked diurnal rhythm, undetectable plasma corticotropin concentrations, and absence of serum cortisol suppression after overnight dexamethasone suppression tests. Serum levels of adrenal androgens were elevated. Computed tomography of the abdomen revealed unilateral adrenal masses (largest lesional diameters 4.0 and 3.1 cm). On the basis of the plurihormonal hypersecretion and the imaging characteristics, adrenocortical carcinoma was considered as a possible diagnosis. However, histopathologic analysis in both patients revealed black adrenal cortical adenomas with myelolipomatous change. After surgery, adrenal androgens normalized, and the signs and symptoms of Cushing syndrome and androgen excess resolved. There was no evidence of recurrent disease at last follow-up. A unique form of corticotropin-independent Cushing syndrome is described: cortisol- and androgen-secreting black adrenal cortical adenomas with myelolipomatous change. Although most patients with corticotropin-independent Cushing syndrome associated with androgen excess prove to have adrenocortical carcinoma, the clinician should be aware of the possibility of benign, black adrenal adenomas in this clinical setting.

  2. Preliminary data concerning association of porphyria cutanea tarda and adrenocortical insufficiency. Report of two cases.

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    Pereţianu, D; Giurcăneanu, C; Deleanu, A

    1984-01-01

    The paper presents two cases in which clinical and laboratory investigations have revealed the simultaneous presence of porphyria cutanea tarda (PCT) and adrenocortical insufficiency (ACI). Whether this association is a coincidence, whether there is a common cause, or a "cause to effect" type relationship between the two entities is a question of debate. Without ignoring other possible causes (tuberculosis, hemochromatosis, autoimmunity, drugs) it is suggested that heme deficit consequent to inefficient protoporphyrin synthesis results in impaired steroidogenesis, due to decreased levels of adrenocortical hemoprotein enzymes, especially cytochrome P-450 dependent hydroxylases. Cytochrome P-450 has a well known sine-qua-non activity in steroid hydroxylations within steroid tissues, and a decrease in the levels of this heme-enzyme might be expected to result in impaired steroidogenesis. However, the association between PCT and ACI (whether pathogenic or not) is pathophysiologically characterized by the coexistence of a disease (PCT) in which the anatomo-clinical manifestations are determined by oxygen derived free radicals ( ODFR ), and a disease (ACI) which, among other consequences, presents a marked reduction in ODFR -scavenge capacity. The authors consider this supposition an attractive working hypothesis, suitable to further clinical laboratory direct testing.

  3. Adrenocortical function of Arctic-breeding glaucous gulls in relation to persistent organic pollutants.

    Science.gov (United States)

    Verboven, Nanette; Verreault, Jonathan; Letcher, Robert J; Gabrielsen, Geir W; Evans, Neil P

    2010-03-01

    Unpredictable changes in the environment stimulate the avian hypothalamo-pituitary-adrenal axis to produce corticosterone, which induces behavioural and metabolic changes that enhance survival in the face of adverse environmental conditions. In addition to profound environmental perturbations, such as severe weather conditions and unpredictable food shortages, many Arctic-breeding birds are also confronted with chronic exposure to persistent organic pollutants (POPs), some of which are known to disrupt endocrine processes. This study investigated the adrenocortical function of a top predator in the Arctic marine environment, the glaucous gull (Larus hyperboreus). High concentrations of organochlorines, brominated flame retardants and metabolically-derived products in blood plasma of incubating glaucous gulls were associated with high baseline corticosterone concentrations in both sexes and a reduced stress response in males. Contaminant-related changes in corticosterone concentration occurred over and above differences in body condition and seasonal variation. Chronically high corticosterone concentrations and/or a compromised adrenocortical response to stress can have negative effects on the health of an individual. The results of the present study suggest that exposure to POPs may increase the vulnerability of glaucous gulls to environmental stressors and thus could potentially compromise their ability to adapt to the rapidly changing environmental conditions associated with climate change that are currently seen in the Arctic.

  4. Acute effects of ACTH on dissociated adrenocortical cells: quantitative changes in mitochondria and lipid droplets.

    Science.gov (United States)

    Zoller, L C; Malamed, S

    1975-08-01

    To study the role of certain organelles in steroidogenesis, dissociated rat adrenocortical cells were incubated for two hours with ACTH at a concentration that induces a high level of steroid production. Sections of ACTH treated and untreated cells were photographed in the electron microscope, and morphometric analysis was undertaken to assess possible ACTH-induced changes in total cell volume, volume density and numerical denisty of lipid droplets and mitochondria. There was no change in total cell volume. Lipid droplet volume density and numerical density decreased. Mitochondrial volume density did not change, but numerical density increased. The decrease in lipid droplet volume density indicates a rapid depletion of cholesterol for steroid production. This depletion is almost entirely due to the disappearance of lipid droplets, rather than to an overall diminution in their size, as shown by the decrease in lipid droplet numerical density. The mitochondrial data suggest that the adrenocortical cell has an adedquate mitochondrial apparatus to respond to acute ACTH stimulation with increased steroid output without an increase inmitochondrial volume.

  5. Feminizing adrenocortical adenoma presenting as heterosexual precocious puberty: report of one case.

    Science.gov (United States)

    Hsiao, Hui-Pin; Chao, Mei-Chyn; Lin, Chao-Yu; Chen, Hsiu-Lin; Chen, Shiu-Lin; Chiou, Shyh-Shin; Chen, Bai-Hsiun

    2005-01-01

    We report on a case of a 2 2/12-year-old boy with heterosexual precocious puberty secondary to a feminizing adrenocortical adenoma. The boy, with no previous history of disease or treatment, presented with bilateral gynecomastia and pubic hair development (Tanner III breasts and Tanner II pubic hair). Plasma estradiol and testosterone were 410.9 pg/ml and 126.2 ng/dl respectively. Basal plasma LH and FSH levels were within the normal range. Bolus i.v. injection of GnRH showed unresponsiveness of LH and FSH. Abdominal echography and abdominal magnetic resonance imaging revealed a well-defined mass at the left suprarenal region (measuring 4.0 x 2.7 x 3.6 cm in size). After removal of the adrenal tumor, the estradiol and testosterone levels fell to normal in 2 weeks. The gynecomastia and pubic hair regressed with time. The pathology of the tumor showed compact pattern with polygonal cells containing moderate eosinophilic cytoplasm without mitotic figure. These findings were consistent with an adrenocortical adenoma secreting estradiol and testosterone as the cause of the patient's heterosexual precocious puberty.

  6. Genome-wide paternal uniparental disomy as a cause of Beckwith-Wiedemann syndrome associated with recurrent virilizing adrenocortical tumors.

    Science.gov (United States)

    Bertoin, F; Letouzé, E; Grignani, P; Patey, M; Rossignol, S; Libé, R; Pasqual, C; Lardière-Deguelte, S; Hoeffel-Fornes, C; Gaillard, D; Previderè, C; Delemer, B; Lalli, E

    2015-06-01

    Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by fetal macrosomia, macroglossia, and abdominal wall defects. BWS patients are at risk to develop Wilms tumor, neuroblastoma, hepatoblastoma, and adrenal tumors. A young woman with BWS features, but with inconclusive genetic evidence for the disease, came to clinical observation for signs of virilization at the age of 16 years. An adrenocortical tumor was diagnosed and surgically resected. The tumor underwent 2 local relapses that were also surgically treated. The patient was also operated to remove a breast fibroadenoma. SNP arrays were used to analyze chromosome abnormalities in normal and tumor samples from the patient and her parents. The patient presented genome-wide mosaic paternal uniparental disomy (patUPD) both in the adrenocortical and the breast tumors, with different degrees of loss of heterozygosity (LOH). The more recent relapses of the adrenocortical tumor showed a loss of part of chromosome 17p that was absent in the first tumor. Analysis of a skin biopsy sample also showed mosaic patUPD with partial LOH, while no LOH was detected in leukocyte DNA. This case shows that virilizing adrenocortical tumors may be a clinical feature of patients with BWS. The SNP array technology is useful to diagnose genome-wide patUPD mosaicism in BWS patients with an inconclusive molecular diagnosis and underlines the tumorigenic potential of the absence of the maternal genome combined with an excess of the paternal genome.

  7. Phase I trial of systemic intravenous infusion of interleukin-13-Pseudomonas exotoxin in patients with metastatic adrenocortical carcinoma.

    Science.gov (United States)

    Liu-Chittenden, Yi; Jain, Meenu; Kumar, Parag; Patel, Dhaval; Aufforth, Rachel; Neychev, Vladimir; Sadowski, Samira; Gara, Sudheer K; Joshi, Bharat H; Cottle-Delisle, Candice; Merkel, Roxanne; Yang, Lily; Miettinen, Markku; Puri, Raj K; Kebebew, Electron

    2015-07-01

    Adrenocortical carcinoma (ACC) is a rare but lethal malignancy without effective current therapy for metastatic disease. IL-13-PE is a recombinant cytotoxin consisting of human interleukin-13 (IL-13) and a truncated form of Pseudomonas exotoxin A (PE). The main objectives of this Phase I dose-escalation trial were to assess the maximum-tolerated dose (MTD), safety, and pharmacokinetics (PK) of IL-13-PE in patients with metastatic ACC. Eligible patients had confirmed IL-13 receptor alpha 2 (IL-13Rα2) expressions in their tumors. IL-13-PE at dose of 1-2 μg/kg was administered intravenously (IV) on day 1, 3, and 5 in a 4-week cycle. Six patients received 1 μg/kg and two patients received 2 μg/kg of IL-13-PE. Dose-limiting toxicity was observed at 2 μg/kg, at which patients exhibited thrombocytopenia and renal insufficiency without requiring dialysis. PK analysis demonstrated that at MTD, the mean maximum serum concentration (Cmax ) of IL-13-PE was 21.0 ng/mL, and the terminal half-life of IL-13-PE was 30-39 min. Two (25%) of the eight patients had baseline neutralizing antibodies against PE. Three (75%) of the remaining four tested patients developed neutralizing antibodies against IL-13-PE within 14-28 days of initial treatment. Of the five patients treated at MTD and assessed for response, one patient had stable disease for 5.5 months before disease progression; the others progressed within 1-2 months. In conclusion, systemic IV administration of IL-13-PE is safe at 1 μg/kg. All tested patients developed high levels of neutralizing antibodies during IL-13-PE treatment. Use of strategies for immunodepletion before IL-13-PE treatment should be considered in future trials.

  8. Persistent fever and weight loss due to an interleukin-6-producing adrenocortical oncocytoma in a girl--review of the literature.

    Science.gov (United States)

    Kawahara, Yuta; Morimoto, Akira; Onoue, Akinori; Kashii, Yoshifumi; Fukushima, Noriyoshi; Gunji, Yuji

    2014-08-01

    Adrenocortical oncocytomas are rarely reported, occur almost exclusively in adults, and are mostly nonfunctional. Here, we report an interleukin-6 (IL-6)-producing adrenocortical oncocytoma in an 11-year-old girl presenting with fever, body weight loss, and increased levels of inflammatory markers and serum IL-6. Imaging studies revealed a 4-cm mass in the left adrenal gland. After complete resection, laboratory findings returned to normal. Histology was consistent with adrenocortical oncocytoma, and the tumor cells stained positive for IL-6. IL-6-producing adrenocortical oncocytoma should be included in the differential diagnosis and imaging studies should be performed in patients presenting with persistent fever of unknown origin and high levels of inflammatory markers.

  9. Amplification of the Insulin-Like Growth Factor 1 Receptor Gene Is a Rare Event in Adrenocortical Adenocarcinomas: Searching for Potential Mechanisms of Overexpression

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    Tamaya Castro Ribeiro

    2014-01-01

    Full Text Available Context. IGF1R overexpression appears to be a prognostic biomarker of metastatic pediatric adrenocortical tumors. However, the molecular mechanisms that are implicated in its upregulation remain unknown. Aim. To investigate the potential mechanisms involved in IGF1R overexpression. Patients and Methods. We studied 64 adrenocortical tumors. IGF1R copy number variation was determined in all patients using MLPA and confirmed using real time PCR. In a subgroup of 32 patients, automatic sequencing was used to identify IGF1R allelic variants and the expression of microRNAs involved in IGF1R regulation by real time PCR. Results. IGF1R amplification was detected in an adrenocortical carcinoma that was diagnosed in a 46-year-old woman with Cushing’s syndrome and virilization. IGF1R overexpression was demonstrated in this case. In addition, gene amplification of other loci was identified in this adrenocortical malignant tumor, but no IGF1R copy number variation was evidenced in the remaining cases. Automatic sequencing revealed three known polymorphisms but they did not correlate with its expression. Expression of miR-100, miR-145, miR-375, and miR-126 did not correlate with IGF1R expression. Conclusion. We demonstrated amplification and overexpression of IGF1R gene in only one adrenocortical carcinoma, suggesting that these combined events are uncommon. In addition, IGF1R polymorphisms and abnormal microRNA expression did not correlate with IGF1R upregulation in adrenocortical tumors.

  10. A case report of adrenocortical carcinosarcoma with oncocytic and primitive neuroectodermal-like features.

    Science.gov (United States)

    Kao, Chia-Sui; Grignon, David J; Ulbright, Thomas M; Idrees, Muhammad T

    2013-09-01

    Adrenocortical carcinosarcomas are rare aggressive neoplasms; only a few have been reported to date, all with dismal prognosis. These were reported as having varying morphology. We have encountered a case of adrenal carcinosarcoma with an undifferentiated component bearing similarities to primitive neuroectodermal tumors and other areas of oncocytic differentiation. The 48-year-old woman patient presented with abdominal pain and unintended, excessive weight loss. Computed tomographic imaging revealed a tumor located adjacent to the liver and kidney necessitating a partial nephrectomy and hepatectomy. Histologically, the tumor exhibited malignant features. Melan-A, inhibin, calretinin, cytokeratin AE1/AE3, synaptophysin, and neuron-specific enolase were positive immunohistochemically. The patient developed metastasis within 2 months of surgery and is currently alive with disease after chemotherapy. Adrenal carcinosarcoma is a rare highly aggressive malignancy with a wide morphologic spectrum. Recognition of variant morphology and applying correct immunohistochemical studies will aid in reaching an accurate diagnosis.

  11. Primary bimorphic adrenocortical disease: cause of hypercortisolism in McCune-Albright syndrome.

    Science.gov (United States)

    Carney, J Aidan; Young, William F; Stratakis, Constantine A

    2011-09-01

    McCune-Albright syndrome (polyostotic fibrous dysplasia, café-au-lait skin spots, and precocious puberty) is a genetically mosaic disorder with populations of mutant and normal cells in affected organs. Cushing syndrome, a rare feature of the condition, usually affects infants and is the result of corticotropin-independent primary bilateral adrenal disease, usually interpreted as nodular adrenocortical hyperplasia. In this study of 9 patients with Cushing syndrome and McCune-Albright syndrome, light microscopy revealed a characteristic bimorphic pattern of diffuse and nodular hyperplasia and a distinctive form of cortical atrophy with apparent zona glomerulosa hyperplasia in 8 patients, all very young. The pattern could be explained by the presence of a mosaic distribution of mutant and normal cells in the adrenal glands. The findings are different from those in inherited or other forms of genetically caused Cushing syndrome. The ninth patient, aged 17 years, had an adrenal adenoma and diffuse cortical hyperplasia in each adrenal gland.

  12. Adrenocortical carcinoma presenting as varicocele and renal vein thrombosis: a case report

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    Horne John M

    2011-08-01

    Full Text Available Abstract Introduction Adrenocortical carcinomas are rare aggressive tumors. Their annual incidence is approximately one to two per million among the population of the United States of America. Patients with active endocrine tumors often present with Cushing's syndrome accompanied by virilizing features. Conversely, patients with non-functioning tumors may present with symptoms related to a mass-occupying lesion, such as abdominal pain and flank pain. Although varicoceles and acute kidney injuries are common problems in medicine, they are uncommon presentations of these rare tumors and easy to miss. We report a case of a large adrenocortical carcinoma that presented as testicular pain, varicocele, and acute kidney injury secondary to renal vein thrombosis. Case presentation A 54-year-old Caucasian man with a left-sided varicocele presented to our emergency department with lower abdominal pain and a decrease in urination. Four months previously, he had noticed pain and swelling in his left groin and had been diagnosed with left-sided varicocele. For one week, he began developing left-sided abdominal pain and decreased urination frequency, so he came to our emergency department for evaluation. His physical examination revealed a hard mass occupying the entire left side of his abdomen, crossing the midline, and extending to the pelvic brim. His blood tests showed acute kidney injury and mild anemia. Computed tomography of his abdomen showed a large retroperitoneal mass on the left side, displacing the left kidney inferiorly and the spleen superiorly with thoracic epidural compression. Thrombus was also identified in his left renal vein and inferior vena cava. Computed tomography of his chest showed bilateral pulmonary nodules. A computed tomography-guided abdominal mass biopsy was performed, and the diagnosis of adrenocortical carcinoma was made on the basis of pathology and immunohistochemistry. His hormonal evaluations were normal. His kidney

  13. Adrenocortical carcinoma: An extremely uncommon entity and the role of Immunohistochemistry in its diagnosis

    Science.gov (United States)

    Gogoi, G.; Baruah, Manash P; Borah, P.; Borgohain, M.

    2012-01-01

    Adrenocortcal carcinoma is an extremely uncommon entity with an incidence of two in one millionth population. Here we present a 60 year gentleman with pain in abdomen, nausea, and backache, and weight loss. Contrast enhanced computed tomography (CECT) abdomen revealed a heterogenous well defined mass measuring (15 × 10.3 × 13) cm3 on the left suprarenal region with central necrosis which extended medially up to the midline. Locally, the growth infiltrated the upper pole of left kidney. Initially, the differential diagnosis included that of renal cell carcinoma arising from upper pole of left kidney involving adrenal gland. The patient underwent left radical nephrectomy and left adrenalectomy. Histological evaluation could not differentiate it from of malignant pheochromocytoma, but immunohistochemistry confirmed it as adrenocortical carcinoma. This case highlights the crucial role of immunohistochemistry in establishing the diagnosis like tumors. PMID:23565434

  14. Adrenocortical carcinoma: An extremely uncommon entity and the role of Immunohistochemistry in its diagnosis

    Directory of Open Access Journals (Sweden)

    G Gogoi

    2012-01-01

    Full Text Available Adrenocortcal carcinoma is an extremely uncommon entity with an incidence of two in one millionth population. Here we present a 60 year gentleman with pain in abdomen, nausea, and backache, and weight loss. Contrast enhanced computed tomography (CECT abdomen revealed a heterogenous well defined mass measuring (15 × 10.3 × 13 cm 3 on the left suprarenal region with central necrosis which extended medially up to the midline. Locally, the growth infiltrated the upper pole of left kidney. Initially, the differential diagnosis included that of renal cell carcinoma arising from upper pole of left kidney involving adrenal gland. The patient underwent left radical nephrectomy and left adrenalectomy. Histological evaluation could not differentiate it from of malignant pheochromocytoma, but immunohistochemistry confirmed it as adrenocortical carcinoma. This case highlights the crucial role of immunohistochemistry in establishing the diagnosis like tumors.

  15. The peripheral cytoplasm of adrenocortical cells: zone-specific responses to ACTH.

    Science.gov (United States)

    Loesser, K E; Cain, L D; Malamed, S

    1994-05-01

    Differences in the cytoskeletal protein actin in cells from the zona glomerulosa and zona fasciculata would be of considerable interest because there is persuasive evidence that rat corticosteroids are secreted by mechanisms that are somewhat zone-specific. We have previously shown evidence that actin may be involved in steroid secretion, possibly in connection with changes in adrenocortical microvilli. However, the cells upon which the data were based were not separated according to zone of origin. Immunogold electron microscopy and morphometric procedures were used to determine whether ACTH-induced changes in the peripheral cytoplasm of isolated adrenocortical cells occur in both zona fasciculata and zona glomerulosa cells. Actin immunoreactivity was more concentrated in the cytoplasm adjacent to the plasma membrane (including the cytoplasm within the microvilli) than it was in the internal cytoplasm in cells from both zones (4-6 times more concentrated in zona glomerulosa cells and 3-6 times more concentrated in zona fasciculata cells). However, the mean aggregate microvillar surface length (microvillar index) of untreated zona fasciculata cells (previously reported (Loesser and Malamed, 1987)) was 23% greater than that of untreated zona glomerulosa cells. Although ACTH (at a maximal steroidogenic concentration) had no effect on the peripheral cytoplasmic actin concentration of zona glomerulosa cells, there was a 24% increase in the aggregate microvillar length. In contrast, in zona fasciculata cells, ACTH treatment was accompanied by an increase in peripheral cytoplasmic actin concentration of 58-64% and an increase in aggregate microvillar surface length of 40% (previously reported (Loesser and Malamed, 1987)), almost twice that for zona glomerulosa cells. The results suggest that ACTH-induced hormone release from zona fasciculata cells is mediated by increases in peripheral cytoplasmic actin and aggregate microvillar length; in zona glomerulosa cells such

  16. Adrenocortical activity and the Brazelton Neonatal Assessment Scale: moderating effects of the newborn's biomedical status.

    Science.gov (United States)

    Gunnar, M R; Isensee, J; Fust, L S

    1987-12-01

    The Brazelton Neonatal Behavioral Assessment Scale with Kansas Supplement (NBAS-K) was administered midway between feedings to 60 newborns who were between 32 and 122 hours old. 35 of the newborns were classified as extremely healthy and normal (Subgroup I), whereas 25 (Subgroup II) were characterized by slight perinatal problems including gestational age 36-37 weeks or 42+ weeks, and fetal distress during labor. All of the newborns were healthy enough to be cared for in a healthy newborn, Level I nursery. Immediately following administration of the NBAS-K, a blood sample was obtained for plasma cortisol determination. Correlations between behavioral responding on the NBAS-K and levels of plasma cortisol revealed few significant relations for the sample as a whole. When the 2 subgroups were examined separately, a number of significant relations emerged. Newborns in Subgroup I who were more competent in their motor control and state regulation capacities as assessed by Lester's Cluster Scores for the NBAS-K exhibited higher levels of plasma cortisol. In contrast, newborns in Subgroup II who exhibited a greater adrenocortical response to the examination showed more behaviors indicative of high behavioral arousal and distress. This pattern of relations for Subgroup II appeared to be mediated by the number of hours that had elapsed since delivery. As postpartum time increased, the strength of the association between adrenocortical activity and behavioral arousal/distress decreased for Subgroup II. A systems theory approach is used to interpret the difference in patterns of correlations found for the 2 subgroups.

  17. Adrenocortical response to low-dose ACTH test in female patients with rheumatoid arthritis.

    Science.gov (United States)

    Radikova, Zofia; Rovensky, Jozef; Vlcek, Miroslav; Penesova, Adela; Kerlik, Jana; Vigas, Milan; Imrich, Richard

    2008-12-01

    Alterations in adrenal steroid production have been suggested in females with rheumatoid arthritis (RA). The aim of the present study was to assess adrenocortical function in RA females. We examined 11 female RA patients (RA: age 30 +/- 2 years, BMI 21.0 +/- 0.7 kg/m(2)) and 10 matched healthy controls (C: age 31 +/- 1 years, BMI 21.6 +/- 0.6 kg/m(2)). Low-dose adrenocorticotropic hormone (ACTH) test (i.v. bolus of 1 microg synthetic ACTH) was performed at 10.00 h with blood sampling every 15 min for 90 min. Cortisol, 17-OH-progesterone (17OHP), androstenedione (ASD), and dehydroepiandrosterone (DHEA) were assayed in plasma. Baseline cortisol levels were higher in RA patients (RA: 385 +/- 38 versus C: 229 +/- 28 nmol/L, P= 0.007). In both study groups, ACTH administration increased all the four steroids measured (P < 0.001). Cortisol response to ACTH administration was diminished in RA patients when compared to controls (Delta(max): 284 +/- 24 in RA versus 424 +/- 31 nmol/L in C, P= 0.002). ACTH-induced maximal rise in plasma DHEA was significantly lower in RA patients when compared to controls (Delta(max): 2.59 +/- 0.68 in RA versus 5.57 +/- 1.25 ng/mL in C, P= 0.015). No significant between-groups differences were found in responses of ASD or 17OHP. The molar ratio of ASD:cortisol was significantly lower (P < 0.05) in RA patients at base line, but did not differ during ACTH test. After ACTH bolus, the cortisol:17OHP ratio decreased significantly in the RA group (P < 0.001), whereas there was no change in the control group. The present results show decreased secretion of cortisol and DHEA in RA patients in response to ACTH, suggesting a subtle HPA hypofunction at the adrenocortical level.

  18. Non-Invasive Measurement of Adrenocortical Activity in Blue-Fronted Parrots (Amazona aestiva, Linnaeus, 1758.

    Directory of Open Access Journals (Sweden)

    João C P Ferreira

    Full Text Available Parrots kept in zoos and private households often develop psychological and behavioural disorders. Despite knowing that such disorders have a multifactorial aetiology and that chronic stress is involved, little is known about their development mainly due to a poor understanding of the parrots' physiology and the lack of validated methods to measure stress in these species. In birds, blood corticosterone concentrations provide information about adrenocortical activity. However, blood sampling techniques are difficult, highly invasive and inappropriate to investigate stressful situations and welfare conditions. Thus, a non-invasive method to measure steroid hormones is critically needed. Aiming to perform a physiological validation of a cortisone enzyme immunoassay (EIA to measure glucocorticoid metabolites (GCM in droppings of 24 Blue-fronted parrots (Amazona aestiva, two experiments were designed. During the experiments all droppings were collected at 3-h intervals. Initially, birds were sampled for 24 h (experiment 1 and one week later assigned to four different treatments (experiment 2: Control (undisturbed, Saline (0.2 mL of 0.9% NaCl IM, Dexamethasone (1 mg/kg IM and Adrenocorticotropic hormone (ACTH; 25 IU IM. Treatments (always one week apart were applied to all animals in a cross-over study design. A daily rhythm pattern in GCM excretion was detected but there were no sex differences (first experiment. Saline and dexamethasone treatments had no effect on GCM (not different from control concentrations. Following ACTH injection, GCM concentration increased about 13.1-fold (median at the peak (after 3-9 h, and then dropped to pre-treatment concentrations. By a successful physiological validation, we demonstrated the suitability of the cortisone EIA to non-invasively monitor increased adrenocortical activity, and thus, stress in the Blue-fronted parrot. This method opens up new perspectives for investigating the connection between behavioural

  19. Relationship of Adrenocortical Function and TCM Syndrome Typing in Elderly Patients with Severe Sepsis

    Institute of Scientific and Technical Information of China (English)

    吴海云; 危成筠; 朱广卿; 许强; 张健; 王士雯

    2004-01-01

    Objective: To explore the relationship between TCM Syndrome typing and adrenocortical function in elderly patients with severe sepsis, and to see whether TCM Syndrome Differentiation can provide clinical clues in identifying relative adrenal insufficiency (RAI) in patients with severe sepsis. Methods: Six ty-one old patients with severe sepsis were classified into four types according to TCM Syndrome Differentiation: The severe invasion of toxic-heat type (Type SITH, n = 21 ); the Qi stagnation and blood stasis type ( Type QSBS, n = 11); the sudden depletion of Yang-Qi type ( Type SDYQ, n = 16); and the exhaustion of Qi-Yin type (Type EOQY, n = 13). The base-line level of plasma cortisol in patients of different types and their response to corticotropin stimulation were compared, which were also compared with those of 12 healthy elderly persons synchronously. Results: The base-line level of plasma cortisol was not significantly different between patients of different Syndrome types (P>0.05), but they were all sgnificantly higher than that in the healthy persons ( P<0.05). Compared with Type QSBS and Type EOQY, Type SITH and Type SDYQ showed less cortisol concentration increment after corticotropin stimulation ( P<0.05). RAI was more prevalent in patients of Type SITH and Type SDYQ than in patients of Type QSBS and Type EOQY (57% vs 25 %, P<0.01). Conclusion: In old patients with severe sepsis, different TCM Syndrome types are associated with different adrenocortical function status. TCM Syndrome differentiation can provide clinical clues in identifying old patients with severe sepsis who have also RAI.

  20. Non-invasive assessment of adrenocortical function in captive Nile crocodiles (Crocodylus niloticus).

    Science.gov (United States)

    Ganswindt, Stefanie B; Myburgh, Jan G; Cameron, Elissa Z; Ganswindt, Andre

    2014-11-01

    The occurrence of stress-inducing factors in captive crocodilians is a concern, since chronic stress can negatively affect animal health and reproduction, and hence production. Monitoring stress in wild crocodiles could also be beneficial for assessing the state of health in populations which are potentially threatened by environmental pollution. In both cases, a non-invasive approach to assess adrenocortical function as a measure of stress would be preferable, as animals are not disturbed during sample collection, and therefore sampling is feedback-free. So far, however, such a non-invasive method has not been established for any crocodilian species. As an initial step, we therefore examined the suitability of two enzyme-immunoassays, detecting faecal glucocorticoid metabolites (FGMs) with a 11β,21-diol-20-one and 5β-3α-ol-11-one structure, respectively, for monitoring stress-related physiological responses in captive Nile crocodiles (Crocodylus niloticus). An adrenocorticotropic hormone (ACTH) challenge was performed on 10 sub-adult crocodiles, resulting in an overall increase in serum corticosterone levels of 272% above the pre-injection levels 5h post-injection. Saline-treated control animals (n=8) showed an overall increase of 156% in serum corticosterone levels 5h post-administration. Faecal samples pre- and post-injection could be obtained from three of the six individually housed crocodiles, resulting in FGM concentrations 136-380% above pre-injection levels, always detected in the first sample collected post-treatment (7-15 days post-injection). FGM concentrations seem comparatively stable at ambient temperatures for up to 72 h post-defaecation. In conclusion, non-invasive hormone monitoring can be used for assessing adrenocortical function in captive Nile crocodiles based on FGM analysis.

  1. The aurora kinase inhibitor VX-680 shows anti-cancer effects in primary metastatic cells and the SW13 cell line.

    Science.gov (United States)

    Pezzani, Raffaele; Rubin, Beatrice; Bertazza, Loris; Redaelli, Marco; Barollo, Susi; Monticelli, Halenya; Baldini, Enke; Mian, Caterina; Mucignat, Carla; Scaroni, Carla; Mantero, Franco; Ulisse, Salvatore; Iacobone, Maurizio; Boscaro, Marco

    2016-10-01

    New therapeutic targets are needed to fight cancer. Aurora kinases (AK) were recently identified as vital key regulators of cell mitosis and have consequently been investigated as therapeutic targets in preclinical and clinical studies. Aurora kinase inhibitors (AKI) have been studied in many cancer types, but their potential capacity to limit or delay metastases has rarely been considered, and never in adrenal tissue. Given the lack of an effective pharmacological therapy for adrenal metastasis and adrenocortical carcinoma, we assessed AKI (VX-680, SNS314, ZM447439) in 2 cell lines (H295R and SW13 cells), 3 cell cultures of primary adrenocortical metastases (from lung cancer), and 4 primary adrenocortical tumor cell cultures. We also tested reversan, which is a P-gp inhibitor (a fundamental efflux pump that can extrude drugs), and we measured AK expression levels in 66 adrenocortical tumor tissue samples. Biomolecular and cellular tests were performed (such as MTT, thymidine assay, Wright's staining, cell cycle and apoptosis analysis, Western blot, qRT-PCR, and mutation analysis). Our results are the first to document AK overexpression in adrenocortical carcinoma as well as in H295R and SW13 cell lines, thus proving the efficacy of AKI against adrenal metastases and in the SW13 cancer cell model. We also demonstrated that reversan and AKI Vx-680 are useless in the H295R cell model, and therefore should not be considered as potential treatments for ACC. Serine/threonine AK inhibition, essentially with VX-680, could be a promising, specific therapeutic tool for eradicating metastases in adrenocortical tissue.

  2. Adrenocortical carcinoma

    Science.gov (United States)

    ... buffalo hump ) Flushed, rounded face with pudgy cheeks ( moon face ) Obesity Stunted growth ( short stature ) Virilization - the appearance of male characteristics, including increased body hair (especially on the face), pubic hair, acne , deepening ...

  3. Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome Combined With Adrenocortical Carcinoma on 18F-FDG PET/CT.

    Science.gov (United States)

    Guo, Xiuyu; Chen, Haojun; Fu, Hao; Wu, Hua

    2017-09-01

    Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is a recognized distinct phenotypic variant of multiple cutaneous and uterine leiomyomatosis. The present case reports an extremely rare case of HLRCC syndrome combined with adrenocortical carcinoma. The case suggests that HLRCC should be considered in any young patient with bulky uterine leiomyomas and renal cell cancer, and F-FDG PET/CT can help detect unexpected additional primary malignancy in a patient with known cancer.

  4. The adrenocortical response of greater sage grouse (Centrocercus urophasianus) to capture, ACTH injection, and confinement, as measured in fecal samples

    Science.gov (United States)

    Jankowski, M.D.; Wittwer, D.J.; Heisey, D.M.; Franson, J.C.; Hofmeister, E.K.

    2009-01-01

    Investigators of wildlife populations often utilize demographic indicators to understand the relationship between habitat characteristics and population viability. Assessments of corticosterone may enable earlier detection of populations at risk of decline because physiological adjustments to habitat disturbance occur before reproductive diminutions. Noninvasive methods to accomplish these assesments are important in species of concern, such as the greater sage grouse (GRSG). Therefore, we validated a radioimmunoassay that measures immunoreactive corticosterone metabolites (ICM) in fecal samples and used it to characterize the adrenocortical response of 15 GRSG exposed to capture, intravenous injection of 50 IU/kg adrenocorticotrophic hormone (ACTH) or saline, and 22 h of confinement. Those animals injected with ACTH exhibited a more sustained (P = 0.0139) and less variable (P = 0.0012) response than those injected with saline, indicating different levels of adrenocortical activity. We also found that potential field-collection protocols of fecal samples did not alter ICM concentrations: samples held at 4??C for up to 16 h contained similar levels of ICM as those frozen (-20??C) immediately. This study demonstrates a multiphasic adrenocortical response that varied with the level of stimulation and indicates that the assay used to measure this phenomenon is applicable for studies of wild GRSG. ?? 2009 by The University of Chicago. All rights reserved.

  5. Tissue mercury concentrations and adrenocortical responses of female big brown bats (Eptesicus fuscus) near a contaminated river.

    Science.gov (United States)

    Wada, Haruka; Yates, David E; Evers, David C; Taylor, Robert J; Hopkins, William A

    2010-10-01

    Much of the research on mercury (Hg) in wild vertebrates has focused on piscivores and other animals at high trophic levels. However, recent studies indicated that insectivorous terrestrial vertebrates may also be at risk. In the present study, we examined blood and fur Hg concentrations as well as the adrenocortical responses of insectivorous big brown bats (Eptesicus fuscus) near the Hg-contaminated South River, VA and a nearby reference area. Baseline glucocorticoids and adrenocortical responses to handling have been widely used to assess the influence of environmental stressors because plasma glucocorticoids rise in response to various physical, psychological, and physiological challenges. Female bats captured at the contaminated site had 2.6 times higher blood and fur Hg concentrations than those captured at the reference site (blood: 0.11 vs. 0.04 μg/g wet weight; fur: 28.0 vs. 10.9 μg/g fresh weight). Fur Hg concentrations at the contaminated site were higher than most wild omnivorous and carnivorous mammals reported in the literature. Although fur and blood Hg concentrations were tightly correlated, fur Hg concentrations averaged 260 times higher than concentrations in blood. This suggests that fur may be an important depuration route for bats, just as it is in other mammals. Despite the high Hg concentrations in bat tissue, we did not observe any site difference in adrenocortical responses. Our results suggest that the bats at the contaminated site were exposed to Hg concentrations below those causing adverse effects on their adrenal axis.

  6. Virilizing adrenocortical adenoma with Cushing's syndrome, thyroid papillary carcinoma and hypergastrinemia in a middle-aged woman.

    Science.gov (United States)

    Fukushima, Ayumi; Okada, Yosuke; Tanikawa, Takahisa; Kawahara, Chie; Misawa, Haruo; Kanda, Kazuko; Morita, Emiko; Sasano, Hironobu; Tanaka, Yoshiya

    2003-04-01

    We report a rare case of virilizing adrenocortical adenoma complicated with Cushing's syndrome, thyroid papillary carcinoma and hypergastrinemia. A 45-year-old woman had a history of amenorrhea for 10 years, hypertension for 8 years, and diabetes mellitus for 3 years. Physical examination showed a masculinized woman with severe hirsutism, male-like baldness, deep voice, acne in the precordia, and clitorism. Plasma testosterone, DHEA-S and urinary 17-KS were high, and plasma cortisol level was it at the upper limit of the normal range, but it did not show a diurnal rhythm nor was suppressed by 2 and 8 mg of dexamethasone. Abdominal CT scan showed a left adrenal tumor (4.5 cm in size). Adrenal scintigram revealed uptake of the tracer on the left side, and plasma cortisol concentration was high in a blood sample from the left adrenal vein. Left adrenalectomy was performed. Histopathological features of resected adrenal tumor were consistent with those of adrenocortical adenoma, consisting of tumor cells with eosinophilic compact cytoplasm. Immunohistochemical staining for steroidogenic enzymes showed reactivity for P450sec, 3 beta-HSD, P450c17, P450c21 and P450c11. Plasma testosterone and cortisol levels decreased to the normal range postoperatively. The patient was also found to have a papillary thyroid carcinoma and hypergastrinemia. Our patient is a rare case of virilizing adrenocortical adenoma associated with Cushing's syndrome, thyroid papillary carcinoma, and hypergastrinemia.

  7. Modulation of the adrenocortical response to acute stress with respect to brood value, reproductive success and survival in the Eurasian hoopoe.

    Science.gov (United States)

    Schmid, Baptiste; Tam-Dafond, Laura; Jenni-Eiermann, Susanne; Arlettaz, Raphaël; Schaub, Michael; Jenni, Lukas

    2013-09-01

    Reproducing parents face the difficult challenge of trading-off investment in current reproduction against presumed future survival and reproduction. Glucocorticoids are supposed to mediate this trade-off because the adrenocortical response to stress disrupts normal reproductive behaviour in favour of self-maintenance and own survival. According to the brood-value hypothesis, individuals with a low survival probability until the next reproductive season have to invest in current reproduction, a process driven by a down-regulation of their adrenocortical response. If the adrenocortical response to stress effectively mediates the trade-off between current reproduction versus future survival and reproduction, we expect a negative relationship with reproductive success and a positive correlation of the adrenocortical stress response with survival. We studied the relationship between corticosterone secretion in parents and their current brood value, reproductive success and survival in a short-lived multi-brooded bird, the Eurasian hoopoe Upupa epops. The adrenocortical response to acute handling stress was correlated with the brood value within the individual (first and second broods of the year) and between individuals. Birds breeding late in the season mounted a lower total corticosterone response to acute stress than birds breeding earlier, while females showed lower levels than males. We observed a negative relationship between the adrenocortical stress response and rearing success or fledging success in females, as predicted by the brood-value hypothesis. However, we could not evidence a clear link between the adrenocortical stress response and survival. Future research testing the brood-value hypothesis and trade-offs between current reproduction and future survival should also measure free corticosterone and carefully differentiate between cross-sectional (i.e. between-individual) and individual-based experimental studies.

  8. Adrenocortical tumors associated with the TP53 p.R337H germline mutation can be identified during child-care consultations.

    Science.gov (United States)

    Mastellaro, Maria J; Ribeiro, Raul C; Oliveira-Filho, Antônio G; Seidinger, Ana L; Cardinalli, Izilda A; Miranda, Eliana C M; Aguiar, Simone S; Brandalise, Silvia R; Yunes, José A; Barros-Filho, Antônio A

    2017-08-30

    To evaluate the clinical features associated with adrenocortical hormone overexpression and familial cancer profiling as potential markers for early detection of adrenocortical tumors in children from South and Southeast Brazil. The clinical manifestations and anthropometric measurements of 103 children diagnosed with adrenocortical tumors were analyzed. Between 1982 and 2011, 69 girls and 34 boys diagnosed with adrenocortical tumors were followed-up for a median time of 9.0 years (0-34 years). Signs of androgen overproduction alone (n=75) or associated with cortisol (n=18) were present in 90.3%. TP53 p.R337H mutation was found in 90.5% of patients. Stages I, II, III, and IV were observed in 45.6%, 27.2%, 19.4%, and 7.8% of patients, respectively. At diagnosis, there were no significant differences in height (p=0.92) and weight (p=0.22) among children with adrenocortical tumors, but children with virilization alone had significantly higher height-for-age Z-scores (0.92±1.4) than children with hypercortisolism alone or combined (-0.32±1.8; p=0.03). The five-year overall survival was 76.7% (SD±4.2). Patients with advanced-stage disease had a significantly worse prognosis than those with limited disease (pp.R337H carrier parents developed cancer, whereas none of the 55 non-carriers did. Signs of adrenocortical hormone overproduction appear early, even in cases with early-stage. These signs can be identified at the physical examination and anthropometric measurements. In southern Brazil, pediatric adrenocortical tumor is a sentinel cancer for detecting families with germline p.R337H mutation in TP53 gene. Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  9. ACTH-independent macronodular adrenocortical hyperplasia reveals prevalent aberrant in vivo and in vitro responses to hormonal stimuli and coupling of arginine-vasopressin type 1a receptor to 11 beta-hydroxylase

    NARCIS (Netherlands)

    Hofland, Johannes; Hofland, Leo J.; van Koetsveld, Peter M.; Steenbergen, Jacobie; de Herder, Wouter W.; van Eijck, Casper H.; de Krijger, Ronald R.; van Nederveen, Francien H.; van Aken, Maarten O.; de Groot, Johannes W.; Links, Thera P.; de Jong, Frank H.; Feelders, Richard A.

    2013-01-01

    Background: Adrenal Cushing's syndrome caused by ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) can be accompanied by aberrant responses to hormonal stimuli. We investigated the prevalence of adrenocortical reactions to these stimuli in a large cohort of AIMAH patients, both in viv

  10. Germline PRKACA amplification leads to Cushing syndrome caused by 3 adrenocortical pathologic phenotypes.

    Science.gov (United States)

    Carney, J Aidan; Lyssikatos, Charalampos; Lodish, Maya B; Stratakis, Constantine A

    2015-01-01

    We describe the pathology of 5 patients with germline PRKACA copy number gain and Cushing syndrome: 4 males and 1 female, aged 2 to 43 years, including a mother and son. Imaging showed normal or slightly enlarged adrenal glands in 4 patients and a unilateral mass in the fifth. Biochemically, the patients had corticotropin-independent hypercortisolism. Four underwent bilateral adrenalectomy; unilateral adrenalectomy was performed in the patient with the adrenal mass. Pathologically, 3 patients, including the 1 with the tumor (adenoma), had primary pigmented nodular adrenocortical disease with extranodular cortical atrophy and mild intracapsular and extracapsular extension of cortical cells. The other 2 patients had cortical hyperplasia and prominent capsular and extracapsular micronodular cortical hyperplasia. Immunoperoxidase staining revealed differences for synaptophysin, inhibin-A, and Ki-67 (nuclei) in the atrophic cortices (patients 1, 2, and 3) and hyperplastic cortices (patients 4 and 5) and for Ki-67 (nuclei) and vimentin in the extracortical nodules in the 2 groups of patients. β-Catenin stained the cell membrane, cytoplasm, and nuclei of the adenoma. The patients were well at follow-up (1-23 years); 24-hour urinary cortisol excretion was elevated in the patient who had unilateral adrenalectomy.

  11. Cytodiagnosis of myxoid adrenocortical carcinoma and role of immunocytochemistry to differentiate it from renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Santosh Kumar Mondal

    2014-01-01

    Full Text Available Adrenocortical carcinoma (ACC is a rare malignancy and cytodiagnosis of this tumor is not routinely encountered by a cytopathologist. Here, we report a case of ACC initially diagnosed by computed tomography (CT-guided fine needle aspiration cytology (FNAC with the help of immunocytochemistry. A 48-year-old lady presented with flank pain and abdominal mass for the last 6 months. A CT scan of her abdomen revealed a large mass arising from the upper part of the left kidney. CT-guided FNAC was performed. Cytologic smears showed pleomorphic large cells arranged discretely and in small aggregates against a myxoid background. The cells had a high nucleocytoplasmic ratio, anisonucleosis and conspicuous nucleoli. Based on cytomorphology, differential diagnoses of ACC and renal cell carcinoma (RCC were made. On immunocytochemistry, the tumor cells were synaptophysin, inhibin, vimentin and Melan-A positive but cytokeratin and epithelial membrane antigen negative. Thus, a cytodiagnosis of myxoid ACC was made and histopathologic examination was suggested. Subsequent histologic examination and immunohistochemistry proved the case to be myxoid ACC.

  12. Social crowding stress diminishes the pituitary-adrenocortical and hypothalamic histamine response to adrenergic stimulation.

    Science.gov (United States)

    Bugajski, J; Gadek-Michalska, A; Borycz, J

    1993-12-01

    Social stress of crowding almost totally reduced the rise in serum corticosterone elicited by intracerebroventricular administration of isoprenaline, a beta-adrenergic receptor agonist, after 3 and 7 day of crowding and substantially diminished that response after 14 and 21 days. Crowding stress totally abolished the increase in hypothalamic histamine induced by isoprenaline in control rats. Crowding also significantly diminished the increase in serum corticosterone evoked by clonidine, an alpha 2-adrenergic agonist, and abolished the clonidine-induced elevation in hypothalamic histamine levels. The stimulatory effect of phenylephrine, an alpha 1-adrenergic agonist, on corticosterone secretion was only moderately diminished in crowded rats. Neither phenylephrine nor crowding stress changed significantly the hypothalamic histamine levels. These results indicate that social stress of crowding considerably impairs the hypothalamic-pituitary-adrenocortical responsiveness to central beta- and alpha 2-adrenergic receptor stimulation. Crowding also abolishes the rise in hypothalamic histamine induced by beta- and alpha 2-adrenergic agonist, suggesting a role of hypothalamic histamine in the HPA adaptation to the social stress of crowding.

  13. Sex-specific associations between sleep problems and hypothalamic-pituitary-adrenocortical axis activity in children.

    Science.gov (United States)

    Pesonen, Anu-Katriina; Kajantie, Eero; Heinonen, Kati; Pyhälä, Riikka; Lahti, Jari; Jones, Alexander; Matthews, Karen A; Eriksson, Johan G; Strandberg, Timo; Räikkönen, Katri

    2012-02-01

    Sleep problems are associated with reduced physical and mental health. Altered function of the hypothalamic-pituitary-adrenocortical axis (HPAA) may be one underlying mechanism. We studied the associations between sleep problems and HPAA activity in children. A cross-sectional epidemiological cohort study. Salivary cortisol was sampled throughout one day at home and during the Trier Social Stress Test for Children (TSST-C) in clinic. Sleep disorders were measured with a parent-rated Sleep Disturbance Scale for Children, and sleep duration measured by actigraphy for one week. 284 (51% girls) 8-year-old children. Boys with sleep problems (≥ 85 th percentile in any of the sleep-wake transition, arousal, excessive daytime somnolence or sleep hyperhydrosis subscales) had lower diurnal salivary cortisol levels and salivary cortisol responses to TSST-C stress in comparison to boys without sleep problems. Girls with sleep problems (≥ 85 th percentile in disorders of initiating and maintaining sleep) displayed a higher overall level of salivary cortisol during the TSST-C. Salivary cortisol responses to stress were lower in boys and higher in girls with more than one sleep problem. Sleep problems in children are associated with altered HPAA function, after controlling for actual sleep quantity measured by actigraphy. Boys with sleep problems had lower HPAA activity and girls with sleep problems had higher HPAA activity, compared to children without sleep problems. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. Maternal prenatal licorice consumption alters hypothalamic-pituitary-adrenocortical axis function in children.

    Science.gov (United States)

    Räikkönen, Katri; Seckl, Jonathan R; Heinonen, Kati; Pyhälä, Riikka; Feldt, Kimmo; Jones, Alexander; Pesonen, Anu-Katriina; Phillips, David I W; Lahti, Jari; Järvenpää, Anna-Liisa; Eriksson, Johan G; Matthews, Karen A; Strandberg, Timo E; Kajantie, Eero

    2010-11-01

    Overexposure to glucocorticoids has been proposed as a mechanism by which prenatal adversity 'programs' the function of the hypothalamic-pituitary-adrenocortical axis (HPAA), thereby increasing the risk of adult diseases. Glycyrrhizin, a natural constituent of licorice, potently inhibits 11β-hydroxysteroid dehydrogenase type 2, the feto-placental barrier to the higher maternal cortisol levels. We studied if maternal consumption of glycyrrhizin in licorice associates with HPAA function in children. Diurnal salivary cortisol and salivary cortisol during the Trier Social Stress Test for Children (TSST-C) were measured in children (n=321, mean age=8.1, SD=0.3 years) whose mothers consumed varying levels of glycyrrhizin in licorice during pregnancy; exposure-level groups were labeled high (≥500 mg/week), moderate (250-499 mg/week) and zero-low (0-249 mg/week). In comparison to the zero-low exposure group, children in the high exposure group had 19.2% higher salivary cortisol awakening peak, 33.1% higher salivary cortisol awakening slope, 15.4% higher salivary cortisol awakening area under the curve (AUC), 30.8% higher baseline TSST-C salivary cortisol levels, and their salivary cortisol levels remained high throughout the TSST-C protocol (P-values HPAA function by overexposure to glucocorticoids. Copyright © 2010 Elsevier Ltd. All rights reserved.

  15. MAO A knockout attenuates adrenocortical response to various kinds of stress.

    Science.gov (United States)

    Popova, Nina K; Maslova, Larissa N; Morosova, Ekaterina A; Bulygina, Veta V; Seif, Isabelle

    2006-02-01

    The effect of a lack of the gene encoding monoamine oxidase A (MAO A) in transgenic Tg 8 mice on the corticosterone response to restraint, cold, water deprivation-induced, or social acute stress as well as chronic variable stress was studied. It was found that Tg 8 mice with genetic MAO A knockout and wild-type C3H/HeJ (C3H) strain showed similar plasma corticosterone resting level. MAO A knockout mice differed from C3H mice by attenuated response to restraint (60 min), cold (4 degrees C, 60 min), and water deprivation (48 h) as well as to a chronic (15 days) variable stress. No difference between Tg 8 and C3H strains in the response to psychosocial stress (encounters for 30 min of six previously isolated mice) has been found. ACTH administration to dexamethasone-pretreated mice produced a similar corticosterone effect in Tg 8 and C3H mice, indicating that the decreased stress response in MAO A-deficient mice was due rather to the central mechanisms regulating stress-induced ACTH release than to adrenocortical responsiveness to ACTH.

  16. Adrenocortical and behavioral attunement in parents with 1-year-old infants.

    Science.gov (United States)

    van Bakel, Hedwig J A; Riksen-Walraven, J Marianne

    2008-03-01

    Sethre-Hofstad et al. [2002, Psychoneuroendocrinology 27:731-747] found that behaviorally well-attuned or sensitive parents showed better physiological attunement with their 2- to 4-year-old toddlers' adrenocortical responses to a potentially challenging task than less sensitive parents. In the present study we aimed to replicate this finding in a sample of 83 parents with 15-month-old infants. Parental and infant cortisol responses were assessed using saliva samples collected before and 21 min after the child's confrontation with a stranger and a moving robot. Infant behaviors reflecting distress/uncertainty during the stranger-robot session were rated from videotape. Parental sensitivity was observed during a parent-infant teaching episode. Our findings replicate those of Sethre-Hofstad et al. [2002, Psychoneuroendocrinology 27:731-747] by showing correlated parent-infant cortisol responses for sensitive parents but not for less sensitive parents. Furthermore, sensitive parents cortisol responses were associated with their children's distress/uncertainty during the stranger-robot episode, whereas this was not true for less sensitive parents. Results indicate an important connection between behavior and physiology in parent-infant interactions that deserve more research.

  17. [Primary pigmented nodular adrenocortical disease as cause of Cushing's syndrome associated with Carney complex].

    Science.gov (United States)

    Dumić, Miroslav; Janjanin, Nevena; Uroić, Anita Spehar; Ille, Jasenka; Skegro, Mate; Kusec, Vesna; Marjanac, Igor; Matić, Toni; Jelasić, Drazen

    2006-01-01

    We report a 11-year-old girl and two 14-year-old boys with Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). In these patients, hypercortisolism is a consequence of autonomous cortisol secretion from adrenal glands and is ACTH-independent. Besides PPNAD, the girl had lentigines, spotty pigmentation on her bucal mucosa and lips and she also had schwannoma. One of the reported boys had prolactinoma. Considering this, those two patients fulfill the criteria for Carney complex which is a type of multiple endocrine neoplasia syndromes inherited in an autosomal dominant trait. The other boy had PPNAD but no other obvious signs of Carney complex were noticed. Family study didn't reveal any clinical or laboratory signs of Carney complex in our patients' first relatives. All of our patients underwent bilateral adrenalectomy (in one of the boys laparoscopic surgery was performed). Glucocorticoid and mineralocorticoid substitution has been started. Adrenal glands were macroscopically normal but pathohistological analysis confirmed the diagnosis of PPNAD.

  18. Adrenocortical carcinoma: a 15-year survival after complete resection and repeated resection. A retrospective study in a patient with an expected poor prognosis.

    Science.gov (United States)

    Orlando, Rocco; Pelizzo, Maria Rosa; Lirussi, Flavio

    2003-01-01

    Adrenocortical carcinoma is a rare but aggressive malignancy with metastases being present in 30-40% of cases at the time of diagnosis. A number of prognostic factors have been identified in patients with adrenocortical carcinoma, but criteria predicting survival are not uniform. We report the case of a 58-year-old man with a large, non-functioning and poorly-differentiated adrenocortical carcinoma who, according to current knowledge, was expected to have a short survival. On the contrary, the prompt diagnosis and curative resection of the primary tumour, together with two reoperations for local recurrences, allowed a 15-year survival and a good quality of life. A revision of both clinical and histological prognostic factors is therefore needed in patients with this type of malignancy.

  19. Effects of chloroquine on the adrenocortical function. II. Histological, histochemical and biochemical changes in the suprarenal gland of rats on long-term administration of chloroquine.

    Science.gov (United States)

    Grundmann, M; Bayer, A

    1976-01-01

    White female Wistar rats were used in order to study the influence of long-term oral application of 7-chloro-4-(4-diethylamino-1-methylbutylamino) quinoline (chloroquine) in doses of 30, 40 and 80 mg of base/kg upon the suprarenal gland. Histological, histochemical and biochemical findings give evidence of adrenocortical activation induced by chloroquine at all dose levels tested. The differences between the signs of adrenocortical activation as observed after the various doses were only those of quantity and time onset. The results indicate that the stimulation of the suprarenal cortex produced by repeated administration of chloroquine is not solely a manifestation of toxic action of chloroquine.

  20. Temperament moderates the influence of periadolescent social experience on behavior and adrenocortical activity in adult male rats.

    Science.gov (United States)

    Caruso, M J; McClintock, M K; Cavigelli, S A

    2014-08-01

    Adolescence is a period of significant behavioral and physiological maturation, particularly related to stress responses. Animal studies that have tested the influence of adolescent social experiences on stress-related behavioral and physiological development have led to complex results. We used a rodent model of neophobia to test the hypothesis that the influence of adolescent social experience on adult behavior and adrenocortical function is modulated by pre-adolescent temperament. Exploratory activity was assessed in 53 male Sprague-Dawley rats to classify temperament and then they were housed in one of the three conditions during postnatal days (PND) 28-46: (1) with familiar kin, (2) with novel social partners, or (3) individually with no social partners. Effects on adult adrenocortical function were evaluated from fecal samples collected while rats were individually-housed and exposed to a 1-hour novel social challenge during PND 110-114. Adolescent-housing with novel or no social partners led to reduced adult glucocorticoid production compared to adolescent-housing with familiar littermates. Additionally, highly-exploratory pre-weanling rats that were housed with novel social partners during adolescence exhibited increased exploratory behavior and a more rapid return to basal glucocorticoid production in adulthood compared to those housed with familiar or no social partners during adolescence and compared to low-exploratory rats exposed to novel social partners. In sum, relatively short-term adolescent social experiences can cause transient changes in temperament and potentially longer-term changes in recovery of glucocorticoid production in response to adult social challenges. Furthermore, early temperament may modulate the influence of adolescent experiences on adult behavioral and adrenocortical function.

  1. Temporal dynamic of adrenocortical and gonadal photo-responsiveness in male Japanese quail exposed to short days.

    Science.gov (United States)

    Dominchin, M F; Marin, R H; Palme, R; Busso, J M

    2014-10-01

    The study evaluated whether different short-term endocrine testicular and adrenocortical responses to short photoperiod exposure can persist over time and particularly when birds exhibit spontaneous cloacal gland recovery. At 11 wk of age, 33 male Japanese quail exposed to long photoperiod were switched to short photoperiod (8L:16D). Another group of males was kept under long photoperiod (n = 11; LD quail). After 5 wk of short photoperiod exposure, quail were classified as nonresponsive or responsive to short photoperiod, depending on whether the cloacal gland volume was above or below 1,000 mm(3) and with or without foam production, respectively. Since 11 wk of age and during a 20-wk period, droppings of all quail were collected to determine corticosterone and androgen metabolites (AM) by enzyme immunoassays. Cloacal gland volume was also determined weekly. Both short photoperiod nonresponsive (SD-NR) and responsive quail showed overall significantly lower (P quail that remained under long photoperiod (814.3 ± 24.1 ng/g). However, nonresponsive quail showed a significantly smaller reduction in their AM levels than their responsive counterparts. During the first 6 wk of short photoperiod exposure, SD-NR quail showed similar corticosterone metabolites values than LD quail. Corticosterone metabolite profiles changed from 7 wk of short photoperiod exposure onward, with photoperiodic differences (P SD-NR: 133.1 ± 15.5 > short photoperiod responsive: 61.6 ± 17.9 ng/g, respectively). Testicular and adrenocortical glands showed different degrees of activity associated with cloacal gland photoresponsiveness to short photoperiod manipulation. Our findings suggest long-term effects of short photoperiod, both in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenocortical axis activity of quail, including males that exhibited spontaneous cloacal gland recovery.

  2. The Contingency of Cocaine Administration Accounts for Structural and Functional Medial Prefrontal Deficits and Increased Adrenocortical Activation

    Science.gov (United States)

    Anderson, Rachel M.; Cosme, Caitlin V.; Glanz, Ryan M.; Miller, Mary C.; Romig-Martin, Sara A.; LaLumiere, Ryan T.

    2015-01-01

    The prelimbic region (PL) of the medial prefrontal cortex (mPFC) is implicated in the relapse of drug-seeking behavior. Optimal mPFC functioning relies on synaptic connections involving dendritic spines in pyramidal neurons, whereas prefrontal dysfunction resulting from elevated glucocorticoids, stress, aging, and mental illness are each linked to decreased apical dendritic branching and spine density in pyramidal neurons in these cortical fields. The fact that cocaine use induces activation of the stress-responsive hypothalamo-pituitary-adrenal axis raises the possibility that cocaine-related impairments in mPFC functioning may be manifested by similar changes in neuronal architecture in mPFC. Nevertheless, previous studies have generally identified increases, rather than decreases, in structural plasticity in mPFC after cocaine self-administration. Here, we use 3D imaging and analysis of dendritic spine morphometry to show that chronic cocaine self-administration leads to mild decreases of apical dendritic branching, prominent dendritic spine attrition in PL pyramidal neurons, and working memory deficits. Importantly, these impairments were largely accounted for in groups of rats that self-administered cocaine compared with yoked-cocaine- and saline-matched counterparts. Follow-up experiments failed to demonstrate any effects of either experimenter-administered cocaine or food self-administration on structural alterations in PL neurons. Finally, we verified that the cocaine self-administration group was distinguished by more protracted increases in adrenocortical activity compared with yoked-cocaine- and saline-matched controls. These studies suggest a mechanism whereby increased adrenocortical activity resulting from chronic cocaine self-administration may contribute to regressive prefrontal structural and functional plasticity. SIGNIFICANCE STATEMENT Stress, aging, and mental illness are each linked to decreased prefrontal plasticity. Here, we show that chronic

  3. Familial isolated primary pigmented nodular adrenocortical disease associated with a novel low penetrance PRKAR1A gene splice site mutation

    DEFF Research Database (Denmark)

    Storr, Helen L; Metherell, Louise A; Dias, Renuka

    2010-01-01

    Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating germline protein kinase A regulatory subunit type 1-alpha (PRKAR1A) mutations and loss of heterozygosity at the 17q22-24 locus in approximately 50% patients. PRKAR1A mutations are observed in both isolated PP...... PPNAD (iPPNAD) and Carney complex (CNC). Most mutations result in a functionally null-allele and exhibit high penetrance. We genotyped members of an extended family for a novel PRKAR1A mutation and undertook detailed phenotyping for CNC in the affected individuals....

  4. Salivary cortisol as an indicator of adrenocortical function in healthy infants, using massage therapy

    Directory of Open Access Journals (Sweden)

    Monalisa de Cássia Fogaça

    Full Text Available CONTEXT AND OBJECTIVE: The evaluation of adrenocortical function with the use of therapeutic massage has been little studied in Brazil. The purpose of this study was to evaluate the salivary cortisol levels before and after Shantala massage therapy on healthy infants. DESIGN AND SETTING: Prospective case series, in a public nursery, in São Paulo. METHODS: Saliva was obtained from 11 infants at the times of 8:00-9:00 a.m. and 4:00-5:00 p.m. in a nursery and 9:00-10:00 p.m. at home. They received a 15-minute therapeutic massage on two consecutive days, and saliva was collected before and after the massage. The procedure was repeated after a one-week interval. Cortisol values (intra-assay < 5%; inter-assay < 10% at different times of the day were compared by ANOVA. RESULTS: The mean cortisol values (nmol/l ± SD on the first day were: morning (M = 14.1 ± 5.7, afternoon (A = 8.3 ± 2.7, night (N = 3.3 ± 1.1; after two consecutive days of therapeutic massage: M = 22.3 ± 13.5, A = 13.4 ± 6.0, N = 5.8 ± 3.5; after a one-week interval: M = 15.8 ± 7.7, A = 14.3 ± 7.7, N = 3.4 ± 2.0. CONCLUSION: There was a modification in the salivary cortisol values following massage, thus reflecting possible adaptation of the hypothalamic-pituitary-adrenal axis.

  5. Expression of LIN28 and its regulatory microRNAs in adult adrenocortical cancer.

    Science.gov (United States)

    Faria, André M; Sbiera, Silviu; Ribeiro, Tamaya C; Soares, Iberê C; Mariani, Beatriz M P; Freire, Daniel S; de Sousa, Gabriela R V; Lerario, Antônio M; Ronchi, Cristina L; Deutschbein, Timo; Wakamatsu, Alda; Alves, Venancio A F; Zerbini, Maria Claudia N; Mendonca, Berenice B; Fragoso, Maria Candida B V; Latronico, Ana Claudia; Fassnacht, Martin; Almeida, Madson Q

    2015-04-01

    LIN28 control cells reprogramming and pluripotency mainly through miRNA regulation and has been overexpressed in many advanced cancers. In this study, we evaluated the prognostic role of LIN28 and its regulatory miRNAs in a large cohort of adrenocortical tumours (ACTs). LIN28 protein expression was assessed in 266 adults ACTs (78 adenomas and 188 carcinomas) from Brazil and Germany. LIN28A and LIN28B gene expression was analysed in 59 ACTs (31 adenomas and 28 carcinomas) and copy number variation in 39 ACTs. In addition, we determined the expression of let-7 family, mir-9, mir-30 and mir-125 in 28 carcinomas. LIN28A gene was overexpressed in aggressive ACCs when compared with adenomas and nonaggressive ACCs, but no LIN28A copy number variation was found in ACTs. Unexpectedly, weak LIN28 protein expression was significantly associated with reduced disease-free survival in ACC patients (P = 0·01), but for overall survival only a trend was detectable (P = 0·117). In the multivariate analysis, only Ki67 index ≥10% (HR 4·6, P = 0·000) and weak LIN28 protein expression (HR 2·0, P = 0·03) were independent predictors of recurrence in ACC patients. Interestingly, mir-9 expression, a negative LIN28A/B regulator, was significantly higher in aggressive than in nonaggressive ACCs [2076 (from 36 to 9307) vs 133·4 (from 2·4 to 5193); P = 0·011] and was highly associated with reduced overall (P = 0·01) and disease-free survival (P = 0·01). However, mir-9 prognostic role should be further evaluated in a larger cohort. Weak LIN28 protein expression was associated with recurrence in ACCs. Additionally, overexpression of mir-9, a negative LIN28A regulator, was associated with poor outcome. © 2014 John Wiley & Sons Ltd.

  6. Combined steroidogenic characters of fetal adrenal and Leydig cells in childhood adrenocortical carcinoma.

    Science.gov (United States)

    Fujisawa, Yasuko; Sakaguchi, Kimiyoshi; Ono, Hiroyuki; Yamaguchi, Rie; Kato, Fumiko; Kagami, Masayo; Fukami, Maki; Ogata, Tsutomu

    2016-05-01

    Although childhood adrenocortical carcinomas (c-ACCs) with a TP53 mutation are known to produce androgens, detailed steroidogenic characters have not been clarified. Here, we examined steroid metabolite profiles and expression patterns of steroidogenic genes in a c-ACC removed from the left adrenal position of a 2-year-old Brazilian boy with precocious puberty, using an atrophic left adrenal gland removed at the time of tumorectomy as a control. The c-ACC produced not only abundant dehydroepiandrosterone-sulfate but also a large amount of testosterone via the Δ5 pathway with Δ5-androstenediol rather than Δ4-androstenedione as the primary intermediate metabolite. Furthermore, the c-ACC was associated with elevated expressions of CYP11A1, CYP17A1, POR, HSD17B3, and SULT2A1, a low but similar expression of CYB5A, and reduced expressions of AKR1C3 (HSD17B5) and HSD3B2. Notably, a Leydig cell marker INSL3 was expressed at a low but detectable level in the c-ACC. Furthermore, molecular studies revealed a maternally inherited heterozygous germline TP53 mutation, and several post-zygotic genetic aberrations in the c-ACC including loss of paternally derived chromosome 17 with a wildtype TP53 and loss of maternally inherited chromosome 11 and resultant marked hyperexpression of paternally expressed growth promoting gene IGF2 and drastic hypoexpression of maternally expressed growth suppressing gene CDKN1C. These results imply the presence of combined steroidogenic properties of fetal adrenal and Leydig cells in this patient's c-ACC with a germline TP53 mutation and several postzygotic carcinogenic events.

  7. Fecal cortisol metabolite analysis for noninvasive monitoring of adrenocortical function in the cheetah (Acinonyx jubatus).

    Science.gov (United States)

    Terio, K A; Citino, S B; Brown, J L

    1999-12-01

    A radioimmunoassay was validated for quantifying excreted cortisol metabolites in cheetah (Acinonyx jubatus) feces. High-performance liquid chromatography analysis indicated that immunoreactivity was associated with a water-soluble metabolite in fecal extracts from males and females. None of the immunoreactivity corresponded with free cortisol or corticosterone but rather was associated with a more polar, unidentified metabolite. To determine the biologic relevance of excreted immunoreactive cortisol metabolites, cheetahs were exposed to a variety of situations anticipated to increase cortisol secretion. First, to assess acute changes in adrenal activity, adrenocorticotropic hormone (ACTH; 400 IU i.m.) was administered to two adult males and two adult females. Pre-ACTH baseline serum cortisol and fecal cortisol metabolite concentrations varied among individuals. Serum cortisol concentrations were elevated above baseline within 10 min of ACTH injection, followed by corresponding increases in fecal cortisol metabolite concentrations (690-4,194% above baseline) 48 hr later in three of four cheetahs. In the fourth cheetah, a smaller increase (334% above baseline) in fecal cortisol metabolite excretion was observed 96 hr after ACTH injection. Seven cheetah females also were subjected to a variety of potentially stressful manipulations, including immobilization, translocation, and introduction to a male to assess the ability of this technique to detect physiologic changes in adrenal activity. Increased fecal corticoid metabolite excretion was observed 24-72 hr after exposure to these exogenous stressors. Results indicate that adrenocortical activity can be monitored noninvasively in the cheetah through analysis of these metabolites. This technique could be valuable for evaluating, and thus optimizing, environmental and management conditions and for investigating the role of stress in disease pathogenesis and the usually poor reproductive performance of this species in

  8. Adrenocortical and adrenomedullary homologs in eight species of adult and developing teleosts: morphology, histology, and immunohistochemistry.

    Science.gov (United States)

    Grassi Milano, E; Basari, F; Chimenti, C

    1997-12-01

    Morphology, histology, and immunohistochemistry of the adrenocortical and adrenomedullary homologs (adrenal glands) of the following developing and adult teleosts were examined: Salmoniformes-Oncorhynchus mykiss (rainbow trout), Salmo trutta fario (brown trout), Coregonus lavaretus (white fish); Cyprinodontiformes-Gambusia affinis (mosquito fish). Perciformes-Dicentrarchus labrax (sea bass), Sparus aurata (sea bream), Diplodus sargus (white bream), Oblada melanura (saddled bream). The anatomical relationships of the gland with the renal system and venous vessels were also noted. In adults of all species steroidogenic and catecholaminergic chromaffin cells were found in the head kidney, which is pronephric in origin and subsequently transformed into a hematopoietic lymphatic organ. In Perciformes, chromaffin cells are distributed around the anterior and posterior cardinal veins and ducts of Cuvier; in Salmoniformes, around the posterior cardinal veins and in the hematopoietic tissue; and in G. affinis, around the ducts of Cuvier and posterior cardinal veins, while a few are visible also around the sinus venosus. In Perciformes and Salmoniformes, numerous chromaffin cells are also present in the posterior kidney, derived from the opisthonephros, in contact with the caudal vein. Steroidogenic cells are always confined to the head kidney. During development chromaffin and steroidogenic cells appear early after hatching in the pronephric kidney, at the level of the ducts of Cuvier and of the cephalic part of the posterior cardinal veins. Later, chromaffin cells in Perciformes reach the anterior cardinal veins, and subsequently, in both Perciformes and Salmoniformes, they reach the developing posterior kidney. Their localization along the posterior kidney is still in progress about 4 months after hatching and is completed about a year after hatching. These findings support the concept that the structure of the adrenal gland in teleosts is intermediate between that of the

  9. ADH-1 in the treatment of metastatic adrenocortical carcinoma--case report.

    Science.gov (United States)

    Yarom, Nirit; Stewart, David; Avruch, Leonard; Malik, Rajesh; Wells, Julie; Jonker, Derek J

    2011-11-01

    Adrenocortical Carcinoma (ACC) is rare with an annual incidence of 0.5-2 cases per million worldwide. Some ACC tumors over express N-cadherin, which correlates with metastatic potential. ADH-1 (Exherin™) is a competitive inhibitor of N-cadherin, resulting in rapid onset of tumor vascular angiolysis and apoptosis in preclinical models. Targeting N-cadherin may cause direct anti-tumor and anti-vascular effects. We report a case of ACC with benefit from ADH-1 therapy. A 24 year old woman with an N-cadherin expressing metastatic ACC was treated on a phase I trial and treated with ADH-1 subsequently received additional doses through a special access program. The patient presented with cushingoid features from cortisol over-secretion and was diagnosed with metastatic ACC in January 2003. Tumor progression followed treatment with a combination of doxorubicin, cisplatin and mitotane. In October 2003, as a part of a phase I clinical trial she was treated with as a single dose of ADH-1 at 150 mg/m(2). This resulted in transient normalization of cortisol, tumor necrosis on CT imaging, and reduction in tumor perfusion on DCE-MRI. Following progression on several additional lines of chemotherapy, she was again treated with ADH-1 under a Special Access Program (SAP). After 33 weekly doses (22 with 150 mg/m(2) and 11 with 300 mg/m(2)) radiographic tumor progression was demonstrated and treatment discontinued. She survived 40 months with metastatic disease, dying 12 months after her last dose of ADH-1. This observation merits consideration for prospectively evaluating the efficacy of ADH-1 in patients with cortisol secreting ACC that over express N-cadherin.

  10. Vincristine, cisplatin, teniposide, and cyclophosphamide combination in the treatment of recurrent or metastatic adrenocortical cancer.

    Science.gov (United States)

    Khan, Tanweera S; Sundin, Anders; Juhlin, Claes; Wilander, Erik; Oberg, Kjell; Eriksson, Barbro

    2004-01-01

    The efficacy and tolerability of a combination of vincristine, cisplatin, teniposide, and cyclophosphamide (OPEC) in 11 patients (median age, 45 yr) with recurrent and/or metastatic adrenocortical cancer (ACC) (seven functional and four nonfunctional) were evaluated. All patients received this regimen after the failure of streptozocin and o,p'-DDD (SO) combination therapy. The regimen comprised cyclophosphamide, 600 mg/m2, and vincristine, 1.5 mg/m2, maximum dose 2.0 mg (d 1); cisplatin, 100 mg/m2 (d 2) and teniposide, 150 mg/m2 (d 4). Cycles were repeated every 4 wk. One to eight cycles (median, six cycles) of OPEC were administered to each patient. The median duration of treatment was 6 mo. The overall 2-yr survival rate was 82% and the median survival since diagnosis was 44 mo while it was 21 mo since start of OPEC therapy. Responses were obtained in nine patients: partial response in two patients, and stable disease in seven patients. The median duration of response was 6.75 mo. A total of 60 cycles of chemotherapy were given to all patients; grade 1-2 toxicity occurred in 57 cycles, while grade 3 toxicity was observed only in two cycles, according to NCI's Common Toxicity Criteria. We conclude that the OPEC regimen may be considered in recurrent or metastatic ACC as a second-line medical treatment. However, the combination is accompanied by considerable side effects and dose modifications are necessary in order to be able to recommend the treatment. This regimen needs further evaluation compared with SO therapy preferably in a randomized multicenter trial.

  11. Contralateral adrenal suppression on adrenocortical scintigraphy provides good evidence showing subclinical cortisol overproduction from unilateral adenomas.

    Science.gov (United States)

    Katabami, Takuyuki; Ishii, Satoshi; Obi, Ryusei; Asai, Shiko; Tanaka, Yasushi

    2016-12-30

    Unilateral and/or predominant uptake on adrenocortical scintigraphy (ACS) may be related to autonomous cortisol overproduction in patients with subclinical Cushing's syndrome (SCS). However, there is no information regarding whether increased tracer uptake on the tumor side or decreased uptake on the contralateral side on ACS is more greatly associated with inappropriate cortisol production. Therefore, we evaluated the relationship between quantitative (131)I-6β-iodomethyl-norcholesterol ((131)I-NP-59) uptake in both adrenal glands and parameters of autonomic cortisol secretion and attempted to set a cut off for SCS detection. The study included 90 patients with unilateral adrenal adenoma who fulfilled strict criteria. The diagnosis of SCS was based on serum cortisol ≥3.0 μg/dL after 1-mg dexamethasone suppression test (DST) with at least 1 other hypothalamus-pituitary-adrenal axis function abnormality. Twenty-two (27.7%) subjects were diagnosed with SCS. The uptake rate on the affected side in the SCS group was comparable to that in the non-functioning adenoma group. In contrast, the uptake rate on the contralateral side was lower and the laterality ratio significantly higher in the SCS group. The two ACS indices were correlated with serum cortisol levels after a 1-mg DST, but uptake on the tumor side was not. Tumor size was also important for the functional statuses of adrenal tumors and NP-59 imaging patterns. The best cut-off point for the laterality ratio to detect SCS was 3.07. These results clearly indicate that contralateral adrenal suppression in ACS is good evidence showing subclinical cortisol overproduction.

  12. Regulation of Adrenal Aldosterone Production by Serine Protease Prostasin

    Directory of Open Access Journals (Sweden)

    Takehiro Ko

    2010-01-01

    Full Text Available A serine protease prostasin has been demonstrated to have a pivotal role in the activation of the epithelial sodium channel. Systemic administration of adenovirus carrying human prostasin gene in rats resulted in an increase in plasma prostasin and aldosterone levels. However, the mechanism by which the elevation of prostasin levels in the systemic circulation stimulated the plasma aldosterone levels remains unknown. Therefore, we examined if prostasin increases the aldosterone synthesis in a human adrenocortical cell line (H295R cells. Luciferase assay using CYP11B2 promoter revealed that prostasin significantly increased the transcriptional activity of CYP11B2. Prostasin significantly increased both CYP11B2 mRNA expression and aldosterone production in a dose-dependent manner. Surprisingly, treatment with camostat mesilate, a potent prostasin inhibitor, had no effect on the aldosterone synthesis by prostasin and also a protease-dead mutant of prostasin significantly stimulated the aldosterone production. A T-type/L-type calcium channel blocker and a protein kinase C (PKC inhibitor significantly reduced the aldosterone synthesis by prostasin. Our findings suggest a stimulatory effect of prostasin on the aldosterone synthesis by adrenal gland through the nonproteolytic action and indicate a new role of prostasin in the systemic circulation.

  13. In vitro steroid profiling system for the evaluation of endocrine disruptors.

    Science.gov (United States)

    Nakano, Yosuke; Yamashita, Toshiyuki; Okuno, Masashi; Fukusaki, Eiichiro; Bamba, Takeshi

    2016-09-01

    Endocrine disruptors (ED) are chemicals that affect various aspects of the endocrine system, often leading to the inhibition of steroidogenesis. Current chemical safety policies that restrict human exposure to such chemicals describe often time-consuming and costly methods for the evaluation of ED effects. We aimed to develop an effective tool for accurate phenotypic chemical toxicology studies. We developed an in vitro ED evaluation system using gas chromatography/mass spectrometry (GC/MS/MS) methods for metabolomic analysis of multi-marker profiles. Accounting for sample preparation and GC/MS/MS conditions, we established a screening method that allowed the simultaneous analysis of 17 steroids with good reproducibility and a linear calibration curve. Moreover, we applied the developed system to H295R human adrenocortical cells exposed to forskolin and prochloraz in accordance with the Organization for Economic Cooperation and Development (OECD) guidelines and observed dose-dependent variations in steroid profiles. While the OECD guidelines include only testosterone and 17β-estradiol, our system enabled a comprehensive and highly sensitive analysis of steroid profile alteration due to ED exposure. The application of our ED evaluation screen could be economical and provide novel insights into the hazards of ED exposure to the endocrine system.

  14. First Case Report of a Sporadic Adrenocortical Carcinoma With Gastric Metastasis and a Synchronous Gastrointestinal Stromal Tumor of the Stomach.

    Science.gov (United States)

    Kovecsi, Attila; Jung, Ioan; Bara, Tivadar; Bara, Tivadar; Azamfirei, Leonard; Kovacs, Zsolt; Gurzu, Simona

    2015-09-01

    Adrenocortical carcinoma is a rare tumor with high aggresivity that can associate systemic metastases. A 71-year-old man was hospitalized for gastric cancer. The abdominal computed tomography also revealed a tumor above the right kidney. Total gastrectomy and right adrenalectomy were performed. The encapsulated tumor of the adrenal gland weighed 560 grams and presented diffuse tumor architecture under microscope, with capsular, sinusoidal, and vascular invasion. The large tumor cells had a polygonal shape, with slight basophilic, eosinophilic, or vacuolated cytoplasm, pleomorphic nuclei, and a high mitotic rate. In the stomach, the protruded tumor was covered by normal mucosa; under microscope, the tumor cells were observed only in the submucosal layer. In primary adrenal tumor and gastric metastasis the tumor cells were marked by vimentin, inhibin, synaptophysin, neuron-specific enolase, and calretinin. Based on these criteria, the diagnosis of adrenocortical carcinoma (ACC) with gastric metastasis and no lymph node metastases was established. A synchronous 10 × 10-mm-sized gastrointestinal stromal tumor (GIST) of the stomach, without mitoses, was also identified. So far, as we know, this is the 15th case of ever reported synchronous/metachronous sporadic ACCs; the ACC-related gastric metastases either synchronous ACC and GIST, has not been reported in the literature previously.

  15. Prenatal Maternal Stress Predicts Methylation of Genes Regulating the Hypothalamic-Pituitary-Adrenocortical System in Mothers and Newborns in the Democratic Republic of Congo

    Science.gov (United States)

    Kertes, Darlene A.; Kamin, Hayley S.; Hughes, David A.; Rodney, Nicole C.; Bhatt, Samarth; Mulligan, Connie J.

    2016-01-01

    Exposure to stress early in life permanently shapes activity of the hypothalamic-pituitary-adrenocortical (HPA) axis and the brain. Prenatally, glucocorticoids pass through the placenta to the fetus with postnatal impacts on brain development, birth weight (BW), and HPA axis functioning. Little is known about the biological mechanisms by which…

  16. Preproorexin and orexin receptors are expressed in cortisol-secreting adrenocortical adenomas, and orexins stimulate in vitro cortisol secretion and growth of tumor cells.

    Science.gov (United States)

    Spinazzi, R; Rucinski, M; Neri, G; Malendowicz, L K; Nussdorfer, G G

    2005-06-01

    Orexins A and B are hypothalamic peptides that originate from the proteolytic cleavage of preproorexin and act through two subtypes of receptors, named OX1-R and OX2-R. OX1-R almost exclusively binds orexin-A, whereas OX2-R is nonselective for both orexins. We previously found that orexin-A, via the OX1-R, stimulates cortisol secretion from dispersed human adrenocortical cells. In this study, we demonstrate that six of eight cortisol-secreting adenomas expressed preproorexin mRNA, and seven of 10 adenomas contained measurable amounts of orexin-A but not orexin-B. Normal adrenal cortexes neither expressed preproorexin nor contained orexins. All adenomas expressed OX1-R and OX2-R mRNAs, and real-time PCR showed that the expression of both receptors was up-regulated in adenomas, compared with normal adrenal cortex. Orexin-A concentration-dependently raised basal cortisol secretion from freshly dispersed normal and adenomatous cells, minimal and maximal effective concentrations being 10(-10) and 10(-8) m, and the peptide efficacy (percent increase elicited by 10(-8) m orexin-A) was significantly higher in adenomas than in the normal adrenal cortex. Orexin-B was ineffective, thereby indicating that orexin secretagogue action is mediated by the OX1-R. In contrast, both orexins (10(-8) m) raised the proliferative activity of cultured normal and adenomatous cells, suggesting that this effect is mediated by OX2-R or both receptor subtypes. Collectively, our findings allow us to conclude that the orexin system is overexpressed in cortisol-secreting adenomas and suggest that orexin-A may act as an autocrine-paracrine regulator of the secretory activity and growth of some of these adrenal tumors.

  17. Identification of a novel putative interaction partner of the nucleoporin ALADIN

    Directory of Open Access Journals (Sweden)

    Ramona Jühlen

    2016-11-01

    Full Text Available It has been shown that the nucleoporin ALADIN plays a significant role in the redox homeostasis of the cell, but its function in steroidogenesis contributing to adrenal atrophy in triple A syndrome remains largely unknown. In an attempt to identify new interaction partners of ALADIN, co-immunoprecipitation followed by proteome analysis was conducted in different expression models using the human adrenocortical tumour cell line NCI-H295R. Our results suggest an interaction of ALADIN with the microsomal protein PGRMC2. PGRMC2 is shown to be activity regulator of CYP P450 enzymes and, therefore, to be a possible target for adrenal dysregulation in triple A syndrome. We show that there is a sexual dimorphism regarding the expression of Pgrmc2 in adrenals and gonads of wild-type (WT and Aaas knock-out (KO mice. Female Aaas KO mice are sterile due to delayed oocyte maturation and meiotic spindle assembly. A participation in meiotic spindle assembly confirms the recently investigated involvement of ALADIN in mitosis and emphasises an interaction with PGRMC2 which is a regulator of the cell cycle. By identification of a novel interaction partner of ALADIN, we provide novel aspects for future research of the function of ALADIN during cell cycle and for new insights into the pathogenesis of triple A syndrome.

  18. MicroRNA expression patterns in adrenocortical carcinoma variants and clinical pathologic correlations.

    Science.gov (United States)

    Duregon, Eleonora; Rapa, Ida; Votta, Arianna; Giorcelli, Jessica; Daffara, Fulvia; Terzolo, Massimo; Scagliotti, Giorgio V; Volante, Marco; Papotti, Mauro

    2014-08-01

    Several microRNAs (miRNAs) were shown to be deregulated in adrenocortical carcinoma (ACC) as compared with adenoma, but a detailed assessment of their expression in its histologic variants and correlation with clinicopathologic characteristics has not been performed, so far. Our aim was to assess the expression of 5 selected miRNAs (IGF2 gene-related miR-483-3p and 5p and hypoxia-induced miR-210, miR-195, and miR-1974) in a series of 51 ACCs (35 classical, 6 myxoid, and 10 oncocytic) as compared with clinical and pathologic features and immunohistochemical expression of prognostic markers, including steroidogenic factor 1, p53, β-catenin, and glucose transporter 1. Oncocytic carcinomas had a reduced expression of miR-483-3p (P = .0325), miR-483-5p (P = .0175), and miR-210 (P = .0366), as compared with other histotypes. Overexpression of miR-210 was associated with the presence of necrosis (P = .0035), high Ki-67 index (P = .0013), and high glucose transporter 1 expression (P = .0043), whereas an inverse correlation with mitotic rate was observed in cases with high miR-493-3p (P = .0191) and miR-1974 (P = .0017) expression. High miR-1974 was also associated with low Ki-67 (P = .0312) and European Network for the Study of Adrenal Tumors stage (P = .0082) and negative p53 (P = .0013). At univariate analysis myxoid/classic histotype (P = .026), high miR-210 (P = .0465), high steroidogenic factor 1 protein (P = .0017), high Ki-67 (P = .0066), and high mitotic index (P = .0006) were significantly associated the shorter overall survival, the latter being the sole independent prognostic factor at multivariate analysis (P = .017). In conclusion, (a) miR-483-3p, miR-483-5p, and miR-210 are differentially expressed in ACC variants, and (b) high miR-210 is associated with clinicopathologic parameters of aggressiveness and a poor prognosis.

  19. {sup 18}F-Labelled metomidate analogues as adrenocortical imaging agents

    Energy Technology Data Exchange (ETDEWEB)

    Erlandsson, Maria; Karimi, Farhad [Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, S-751 23 Uppsala (Sweden); Lindhe, Orjan [Uppsala Imanet, GE Healthcare, Box 967, S-751 09 Uppsala (Sweden); Langstroem, Bengt [Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, S-751 23 Uppsala (Sweden)], E-mail: bengt.langstrom@biorg.uu.se

    2009-05-15

    Introduction: Two- and one-step syntheses of {sup 18}F-labelled analogues of metomidate, such as 2-[{sup 18}F]fluoroethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (1), 2-[{sup 18}F]fluoroethyl 1-[(1R)-1-(4-chlorophenyl)ethyl]-1H-imidazole-5-carboxylate (2), 2-[{sup 18}F]fluoroethyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (3), 3-[{sup 18}F]fluoropropyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (4) and 3-[{sup 18}F]fluoropropyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (5) are presented. Methods: Analogues 1-5 were prepared by a two-step reaction sequence that started with the synthesis of either 2-[{sup 18}F]fluoroethyl 4-methylbenzenesulfonate or 3-[{sup 18}F]fluoropropyl 4-methylbenzenesulfonate. These were used as {sup 18}F-alkylating agents in the second step, in which they reacted with the ammonium salt of a 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylic acid. One-step-labelling syntheses of 1, 2 and 5 were also explored. Analogues 1-4 were biologically validated by frozen-section autoradiography and organ distribution. Metabolite analysis was performed for 2 and 3. Results: The radiochemical yield of the two-step synthesis was in the range of 10-29% and that of the one-step synthesis was 25-37%. Using microwave irradiation in the one-step synthesis of 1 and 2 increased the radiochemical yield to 46{+-}3% and 79{+-}30%, respectively. Conclusion: Both the frozen-section autoradiography and organ distribution results indicated that analogue 2 has a potential as an adrenocortical imaging agent, having the highest degree of specific adrenal binding and best ratio of adrenal to organ uptake among the compounds studied.

  20. Single Nucleotide Polymorphism Microarray Analysis in Cortisol-Secreting Adrenocortical Adenomas Identifies New Candidate Genes and Pathways

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    Cristina L. Ronchi

    2012-03-01

    Full Text Available The genetic mechanisms underlying adrenocortical tumor development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays (Affymetrix SNP 6.0 to detect copy number alterations (CNAs and copy-neutral losses of heterozygosity (cnLOH in 15 cortisol-secreting adrenocortical adenomas with matched blood samples. We focused on microalterations aiming to discover new candidate genes involved in early tumorigenesis and/or autonomous cortisol secretion. We identified 962 CNAs with a median of 18 CNAs per sample. Half of them involved noncoding regions, 89% were less than 100 kb, and 28% were found in at least two samples. The most frequently gained regions were 5p15.33, 6q16.1, 7p22.3-22.2, 8q24.3, 9q34.2-34.3, 11p15.5, 11q11, 12q12, 16q24.3, 20p11.1-20q21.11, and Xq28 (≥20% of cases, most of them being identified in the same three adenomas. These regions contained among others genes like NOTCH1, CYP11B2, HRAS, and IGF2. Recurrent losses were less common and smaller than gains, being mostly localized at 1p, 6q, and 11q. Pathway analysis revealed that Notch signaling was the most frequently altered. We identified 46 recurrent CNAs that each affected a single gene (31 gains and 15 losses, including genes involved in steroidogenesis (CYP11B1 or tumorigenesis (CTNNB1, EPHA7, SGK1, STIL, FHIT. Finally, 20 small cnLOH in four cases affecting 15 known genes were found. Our findings provide the first high-resolution genome-wide view of chromosomal changes in cortisol-secreting adenomas and identify novel candidate genes, such as HRAS, EPHA7, and SGK1. Furthermore, they implicate that the Notch1 signaling pathway might be involved in the molecular pathogenesis of adrenocortical tumors.

  1. Inhibition of aromatase activity by methyl sulfonyl PCB metabolites in primary culture of human mammary fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Berg, M. van den; Heneweer, M.; Geest, M. de; Sanderson, T. [Inst. for Risk Assessment Sciences and Utrecht Univ. (Netherlands); Jong, P. de [St. Antonius Hospital, Nieuwegein (Netherlands); Bergman, A. [Stockholm Univ., Stockholm (Sweden)

    2004-09-15

    results that were obtained when using the human adrenocorticocarcinoma cell line H295R. Previous studies proved these cells to be a suitable tool for studying inhibitory effects of xenobiotics on aromatase activity. The aim of this study was to investigate effects on aromatase by MeSO{sub 2}-PCB exposure and elucidate a possible mechanism of action.

  2. Assessment of adrenocortical activity by non-invasive measurement of faecal cortisol metabolites in dromedary camels (Camelus dromedarius).

    Science.gov (United States)

    Sid-Ahmed, Omer-Elfaroug; Sanhouri, Ahmed; Elwaseela, Badr-Eldin; Fadllalah, Imad; Mohammed, Galal-Eldin Elazhari; Möstl, Erich

    2013-08-01

    The aim of this study was to determine whether glucocorticoid production could be monitored non-invasively in dromedary camels by measuring faecal cortisol metabolites (FCMs). Five Sudanese dromedaries, two males and three females, were injected with a synthetic adrenocorticotropic hormone (ACTH) analogue. Blood samples were collected pre- and post-ACTH injection. Faeces were sampled after spontaneous defecation for five consecutive days (2 days before and 3 days after ACTH injection). Baseline plasma cortisol values ranged from 0.6 to 10.8 ng/ml in males and from 1.1 to 16.6 ng/ml in females, while peak values after ACTH injection were 10.9-41.9 in males and 10-42.2 ng/ml in females. Peak blood cortisol values were reached between 1.5 and 2.0 h after ACTH injection. The concentration of FCMs increased after ACTH injection in the faeces of both sexes, although steroid levels peaked earlier in males [24 h; (286.7-2,559.7 ng/g faeces)] than in females [36-48 h; (1,182.6-5,169.1 ng/g faeces)], reflecting increases of 3.1-8.3- and 4.3-8-fold above baseline levels. To detect chromatographic patterns of immunoreactive FCMs, faecal samples with high FCM concentrations from both sexes were pooled and subjected to reverse phase high performance liquid chromatography (RP-HPLC). RP-HPLC analysis revealed sex differences in the polarity of FCMs, with females showing more polar FCMs than males. We concluded that stimulation of adrenocortical activity by ACTH injection resulted in a measurable increase in blood cortisol that was reliably paralleled by increases in FCM levels. Thus, measurement of FCMs is a powerful tool for monitoring the adrenocortical responses of dromedaries to stressors in field conditions.

  3. Adrenal incidentalomas showing unilateral concordant visualization by adrenocortical scintigraphy. Comparison with adenomas in Cushing's syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Tani, Atsushi; Nakajo, Masayuki; Tsuchimochi, Shinsaku; Nakabeppu, Yoshiaki; Umanodan, Tomokazu [Kagoshima Univ. (Japan). Faculty of Medicine

    2000-06-01

    An adrenocortical adenoma causing Cushing's syndrome (Cushing's adenoma) produces a unilateral concordant visualization (UCV) imaging pattern in which the adenoma is only visualized on radioiodocholesterol adrenocortical scintigraphy. But because this imaging pattern is also noted in some patients with adrenal incidentalomas, we examined whether the UCV-incidentaloma was essentially identical with Cushing's adenoma and would develop Cushing's syndrome. The subjects were 9 patients with UCV-incidentalomas (mean size, 30 mm; range, 20-45 mm) and 6 patients with Cushing's adenomas (mean size, 28 mm; range, 25-35 mm). Endocrinological evaluations showed several abnormalities including blunted diurnal rhythm of plasma cortisol within the normal range, low plasma ACTH and/or high 24-hr urinary 17-OHCS levels in 8 of 9 patients with UCV-incidentalomas, but these abnormalities did not meet the diagnostic criteria of Cushing's syndrome. Adrenal uptake of the tracer in the patients with UCV-incidentalomas was not statistically different from that in the patients with Cushing's adenomas and had no relationship with hormonal values in either patient group. Tumor size on CT correlated with the levels of 24-hr urinary 17-OHCS (r=0.75, p=0.02) and plasma cortisol at 7:00 (r=0.82, p=0.007) in the patients with UCV-incidentalomas, but not in the patients with Cushing's adenomas. Although 3 UCV-incidentalomas increased slightly in size, none of 9 patients with UCV-incidentalomas has developed Cushing's syndrome for 4 to 52 months. These results suggest that the UCV-incidentaloma may be essentially different from the Cushing's adenoma and unlikely to develop Cushing's syndrome. (author)

  4. Validation of a Fecal Glucocorticoid Assay to Assess Adrenocortical Activity in Meerkats Using Physiological and Biological Stimuli.

    Directory of Open Access Journals (Sweden)

    Ines Braga Goncalves

    Full Text Available In mammals, glucocorticoid (i.e. GC levels have been associated with specific life-history stages and transitions, reproductive strategies, and a plethora of behaviors. Assessment of adrenocortical activity via measurement of glucocorticoid metabolites in feces (FGCM has greatly facilitated data collection from wild animals, due to its non-invasive nature, and thus has become an established tool in behavioral ecology and conservation biology. The aim of our study was to validate a fecal glucocorticoid assay for assessing adrenocortical activity in meerkats (Suricata suricatta, by comparing the suitability of three GC enzyme immunoassays (corticosterone, 11β-hydroxyetiocholanolone and 11oxo-etiocholanolone in detecting FGCM increases in adult males and females following a pharmacological challenge with adrenocorticotropic hormone (ACTH and biological stimuli. In addition, we investigated the time course characterizing FGCM excretion, the effect of age, sex and time of day on FGCM levels and assessed the potential effects of soil contamination (sand on FGCM patterns. Our results show that the group specific 11β-hydroxyetiocholanolone assay was most sensitive to FGCM alterations, detecting significant and most distinctive elevations in FGCM levels around 25 h after ACTH administration. We found no age and sex differences in basal FGCM or on peak response levels to ACTH, but a marked diurnal pattern, with FGCM levels being substantially higher in the morning than later during the day. Soil contamination did not significantly affect FGCM patterns. Our results emphasize the importance of conducting assay validations to characterize species-specific endocrine excretion patterns, a crucial step to all animal endocrinology studies using a non-invasive approach.

  5. CLINICOPATHOLOGICAL AND IMMUNOHISTOCHEMISTRY BASED DIAGNOSIS OF A RARE VIRILIZING ADRENOCORTICAL ADENO MA IN A 13 MONTH OLD MALE CHILD: A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Ramani

    2013-01-01

    Full Text Available ABSRACT: Adrenocortical tumors are rare in childhood and ado lescence. They account for 0.2% of pediatric tumors. Adrenal tumors that exclusively secrete androgens are rare. We here report a case of 13 month old male child with androgen sec reting right adrenal gland tumor. The child presented with frontal baldness, acne, pubic hair and enlarged penis. This case is presented because of its rarity.

  6. Adrenocortical function and reserve in children treated for acute lymphoblastic leukemia; Czynnosc i rezerwa korowo-nadnerczowa u dzieci po leczeniu ostrej bialaczki limfoblastycznej

    Energy Technology Data Exchange (ETDEWEB)

    Pawlaczyk, B.; Malecka, E.H.; Krause, W. [Instytut Pediatrii, Akademia Medyczna, Poznan (Poland)

    1993-12-31

    Serum cortisol and 17 OHS, 17 KS and DHA levels in 24-hour urine were determined in 30 children (22 girls and boys) 0.5 to 4 years after completion of therapy (radio- and chemotherapy) for acute lymphoblastic leukemia (ALL). Serum cortisol after Syncthen (adrenocortical reserve) was determined in 15 girls and 4 boys. The results show that therapy for ALL depresses glucocorticosteroid synthesis; however, it does not disturb the adrenal reserve or androgenesis. (author) 15 refs, 6 tabs

  7. 34. Effect and the Possible Mediated Pathway of Cortisol Secretion in Adrenocortical Cells Induced by Lead and Cadmium in Vitro

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To understand the direct effect on the secretion of adreno-cortical cells induced by lead and cadmium and the possible mediated pathway. Methods: The adrenocortical cells of male guinea pigs were dispersed and primarily cultured, then the cells were incubated wich cadmiun chloride and lead acetate in dosage as 0,6.25, 12.5, 25, 50, 100 μmol/L respectively for different periods (30, 60, 120 and 240 minutes). The cortisol levels in culture medium and cellular cAMP concentration were measured with RIA. Results: Under the existence of ACTH, the levels of cortisol secreted from the cultured cells were showed significantly declined in dose-dependent manner when the cells were treated in 6.25-100μmol/L CdCl2 for 30 to 240 minutes. There would be an interaction for cortisol secretion between the dose of CdCl2 and the incubatal period. Nevertheless, it seemed to have no obvious linear relation in the alterations of cortisol secretion after 12.5~100μmol/L PbAc incubated for 30~240 minutes. It appeared to have a tendency of dual-phase response in a manner of inhibiting the cortisol secretion in low dose (lower than 25μmol/L) and stimulating the secretion function in high dose (50 and 100μmol/L). The cAMP level was presented a remarkably decrease after 6.25~100 μmol/L CdCl2 incubated with the cells. It was proved that the cAMP level had does-effect relations with the CdCl2 dose. PbAc appeared not only dual response with the tendency of cAMP inhibition in low dose and activating to raise in high dose but also dose-effect relationship. Conclusion: CdCl2 could directly inhibit the secretion of cortisol. PbAc is also of the toxic effect on the cortisol secretion with the characteristic of dual-response as inhibition in early phase and low dose while induction to raising in high dose. cAMP, as an important second messenger, play a role in synthesis and secretion of adrenocorticoids. The toxic effects on steroids secretion induced by cadmium and lead were

  8. Detecting Adreno-Cortical Activity in Gorillas: A Comparison of Faecal Glucocorticoid Measures Using RIA Versus EIA

    Directory of Open Access Journals (Sweden)

    J.B. Nizeyi

    2011-04-01

    Full Text Available The conservation community is concerned that the remnants of highly endangered Mountain gorilla are being exposed to enormous stressors in their habitat but no assay has been validated to monitor stress markers in their fecal medium. Non specific ICN Corticosterone RIA and Munro Cortisol EIA were validated for measurement of free-ranging Mountain gorilla Faecal Glucocorticoids Metabolites (FGM to non-invasively detect effect of environmental stressors on the adrenocortical activity in gorillas. Parallelism and quantitative recovery of FGM showed that the RIA and EIA can reliably measure corticoid metabolites in this medium. High Performance Liquid Chromatography confirmed presence of FGM in faecal extracts. Peak immunoreactive metabolites constituting 35.43% of FGM measured by the RIA co-eluted with maximum corticosterone radioactivity, the EIA measured multiple immunoreactive peak metabolites which were less polar than the cortisol, corticosterone and DOC standard hormones. For Lowland gorilla, peak FGM eluted at fractions 27 and 53 under the 100% Isocratic gradient (San Diago protocol, and 20-80% Methanol gradient (National Zoo protocol respectively; while peak FGM eluted at fraction 8 and 47 in Mountain gorilla under 100% Isocratic and 20-80% Methanol gradients respectively. After injection of Lowland gorilla with long acting Adrenal Cortico-trophic Hormone (ACTH gel (150U Acthar Gel, urinary cortisol increased by 5-fold (p<0.05 within the first 6 h and then decreased to original values by 24 h. FGM were significantly elevated (p<0.05 between 72 and 96 h (RIA and between 48 and 120 h (EIA and there after decreased towards the pre-ACTH levels. Both assays detected a 2-fold increase in FGM 48 h post ACTH. Mean pre-ACTH and post- ACTH FGM amounts measured by RIA were 36 times (p<0.05 more than those measured by the EIA. For field application FGM were measure from three free-ranging Mountain gorilla individuals before and after chasing the

  9. Adrenocortical Production Is Associated with Higher Levels of Luteinizing Hormone in Nonobese Women with Polycystic Ovary Syndrome

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    Luciana Tock

    2014-01-01

    Full Text Available Objective. Insulin resistance (IR and ovarian and adrenal hyperandrogenism are a common finding in women with polycystic ovary syndrome (PCOS. The aim of the present study was to access possible differences in insulin resistance, gonadotropins, and androgens production in obese and nonobese PCOS women. Study Design. We studied 37 PCOS women (16 nonobese and 21 obese and 18 nonobese controls. Fasting glucose, insulin, androgens, and gonadotropins levels were determined. Salivary cortisol was measured basal and in the morning after dexamethasone (DEX 0.25 mg. Results. Nonobese PCOS women showed higher basal salivary cortisol and serum dehydroepiandrosterone sulfate and luteinizing hormone (LH levels than controls and obese PCOS. These hormones levels did not differ between the obese and control groups. After DEX administration no differences were found between the three groups. In PCOS women, salivary cortisol levels showed negative correlation with BMI (r=-0.52; P=0.001 and insulin (r=-0.47; P=0.003 and positive correlation with LH (r=0.40; P=0.016. Conclusion. Our results show an increased adrenocortical production in nonobese PCOS women, not related to IR and associated with a normal hypothalamic-pituitary-adrenal suppression. Higher LH levels might be involved in this event.

  10. Amplification of 9q34 in childhood adrenocortical tumors: a specific feature unrelated to ethnic origin or living conditions

    Directory of Open Access Journals (Sweden)

    Figueiredo B.C.

    2000-01-01

    Full Text Available Adrenocortical tumors (ACT in children under 15 years of age exhibit some clinical and biological features distinct from ACT in adults. Cell proliferation, hypertrophy and cell death in adrenal cortex during the last months of gestation and the immediate postnatal period seem to be critical for the origin of ACT in children. Studies with large numbers of patients with childhood ACT have indicated a median age at diagnosis of about 4 years. In our institution, the median age was 3 years and 5 months, while the median age for first signs and symptoms was 2 years and 5 months (N = 72. Using the comparative genomic hybridization technique, we have reported a high frequency of 9q34 amplification in adenomas and carcinomas. This finding has been confirmed more recently by investigators in England. The lower socioeconomic status, the distinctive ethnic groups and all the regional differences in Southern Brazil in relation to patients in England indicate that these differences are not important to determine 9q34 amplification. Candidate amplified genes mapped to this locus are currently being investigated and Southern blot results obtained so far have discarded amplification of the abl oncogene. Amplification of 9q34 has not been found to be related to tumor size, staging, or malignant histopathological features, nor does it seem to be responsible for the higher incidence of ACT observed in Southern Brazil, but could be related to an ACT from embryonic origin.

  11. The use of immunohistochemical expression of SF-1 and EMA in distinguishing adrenocortical tumors from renal neoplasms.

    Science.gov (United States)

    Enriquez, Miriam L; Lal, Priti; Ziober, Amy; Wang, Liping; Tomaszewski, John E; Bing, Zhanyong

    2012-03-01

    Steroidogenic factor -1 (SF-1) is an orphan member of the nuclear hormone receptor superfamily, and is considered to play an important role in the differentiation of steroidogenic tissues. In this study, we compared the immunohistochemical stains of SF-1 and epithelial membrane antigen (EMA) in non-neoplastic adrenal tissue, and adrenal and renal tumors using tissue microarrays (TMAs). The adrenal tissue array included 19 cases of normal adrenal cortex, 22 cases of adrenal adenoma, and 20 cases of adrenal cortical carcinoma. The renal tissue array included 20 cases of each of the following types of renal cell carcinoma: clear cell, papillary, and chromophobe. In addition, 20 cases of renal oncocytoma were also included in the study. SF-1 showed positive staining in all cases (100%) of normal adrenal cortex and adrenal cortical adenoma, and in 18 (90%) cases of adrenocortical carcinoma. In renal tumors, SF-1 showed negative stains in all of oncocytoma, papillary, and chromophobe renal cell carcinoma. Only 3 out of 20 cases of clear cell renal cell carcinoma showed weak positivity in approximately 10% of tumor cells. EMA stained positively in 85%, 95%, 100%, and 95% of clear cell, papillary, chromophobe renal cell carcinomas, and oncocytomas, respectively. EMA was completely negative in the adrenal TMAs. In conclusion, SF-1 and EMA may be helpful in the differentiation of adrenal tumors from renal tumors in difficult cases.

  12. Higher levels of physical activity are associated with lower hypothalamic-pituitary-adrenocortical axis reactivity to psychosocial stress in children.

    Science.gov (United States)

    Martikainen, Silja; Pesonen, Anu-Katriina; Lahti, Jari; Heinonen, Kati; Feldt, Kimmo; Pyhälä, Riikka; Tammelin, Tuija; Kajantie, Eero; Eriksson, Johan G; Strandberg, Timo E; Räikkönen, Katri

    2013-04-01

    Children who undertake more physical activity (PA) not only have more optimal physical health but also enjoy better mental health. However, the pathways by which PA affects well-being remain unclear. To address this question, we examined whether objectively measured daytime PA was associated with diurnal hypothalamic-pituitary-adrenocortical axis (HPAA) activity and HPAA responses to psychosocial stress. We conducted a cross-sectional study in a birth cohort in Helsinki, Finland. We studied 258 8-year-old children. PA was assessed with wrist-worn accelerometers. Overall PA and percentage of time spent in vigorous PA (VPA) were categorized by sex into thirds. Salivary cortisol was measured diurnally and in response to the Trier Social Stress Test for Children. The children in different PA groups did not show differences in diurnal salivary cortisol (P > .10 for overall PA and VPA). Children with the highest levels of overall PA or VPA showed no, or only small, increases over time in salivary cortisol after stress (P = .10 and P =.03 for time in analyses of PA and VPA, respectively), whereas children belonging to the lowest and intermediate thirds showed significant increases over time in salivary cortisol after stress (P ≤ .002 for time in the analyses of overall PA and VPA). These results suggest that children with lower levels of daytime PA have higher HPAA activity in response to stress. These findings may offer insight into the pathways of PA on physical and mental well-being.

  13. Adrenocortical and Adipose Responses to High-Altitude-Induced, Long-Term Hypoxia in the Ovine Fetus

    Directory of Open Access Journals (Sweden)

    Dean A. Myers

    2012-01-01

    Full Text Available By late gestation, the maturing hypothalamo-pituitary-adrenal (HPA axis aids the fetus in responding to stress. Hypoxia represents a significant threat to the fetus accompanying situations such as preeclampsia, smoking, high altitude, and preterm labor. We developed a model of high-altitude (3,820 m, long-term hypoxia (LTH in pregnant sheep. We describe the impact of LTH on the fetal HPA axis at the level of the hypothalamic paraventricular nucleus (PVN, anterior pituitary corticotrope, and adrenal cortex. At the PVN and anterior pituitary, the responses to LTH are consistent with hypoxia being a potent activator of the HPA axis and potentially maladaptive, while the adrenocortical response to LTH appears to be primarily adaptive. We discuss mechanisms involved in the delicate balance between these seemingly opposing responses that preserve the normal ontogenic rise in fetal plasma cortisol essential for organ maturation and in this species, birth. Further, we examine the response to, and ramifications of, an acute secondary stressor in the LTH fetus. We provide an integrative model on the potential role of adipose in modulating these responses to LTH. Integration of these adaptive responses to LTH plays a key role in promoting normal fetal growth and development under conditions of a chronic stress.

  14. A Novel PRKAR1A Mutation Identified in a Patient with Isolated Primary Pigmented Nodular Adrenocortical Disease

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    Sira Korpaisarn

    2017-08-01

    Full Text Available Primary pigmented nodular adrenocortical disease (PPNAD is a rare cause of Cushing syndrome, especially the isolated form without Carney complex, associated with germline mutations in PRKAR1A, the protein kinase A regulatory subunit type 1 alpha gene. We report a 31-year-old female who presented with secondary amenorrhea, cushingoid appearance, and hypertension without Carney complex. Biochemical laboratory examinations confirmed the ACTH-independent adrenal Cushing syndrome with negative Liddle test. A small right adrenal adenoma of 0.8 cm was shown on computed tomography while magnetic resonance imaging revealed nodularity of both adrenal glands. The histological report confirmed PPNAD using laparoscopic right adrenalectomy, and subsequent left adrenalectomy was performed 6 months later. She had inherited heterozygosity of a novel germline mutation of the PRKAR1A gene (g.114213T>G or c.709-5T>G. This splice site mutation results in exon 8 skipping. Her father carrying the same mutation had no clinical features of either PPNAD or Carney complex. This novel PRKAR1A gene mutation, c.709-5T>G, is reported here for the first time manifesting as an incomplete clinical expression of the isolated form of PPNAD and being inherited with low penetrance unlike other inherited mutations of the Carney complex which have a penetrance of almost 100%.

  15. Low vigorous physical activity is associated with increased adrenocortical reactivity to psychosocial stress in students with high stress perceptions.

    Science.gov (United States)

    Gerber, Markus; Ludyga, Sebastian; Mücke, Manuel; Colledge, Flora; Brand, Serge; Pühse, Uwe

    2017-06-01

    The pathways by which physical activity impacts on participants' health are still not fully understood. The purpose of the present study was to go beyond existing research by combining methods from survey-based and experimental stress research, and by examining whether the potential of vigorous physical activity (VPA) to attenuate physiological and psychological stress responses is moderated by participants' subjective stress perception. The sample consisted of 42 undergraduate students (M=21.2±2.2 years, 52% women). Participants self-reported their stress and wore an accelerometer device for seven consecutive days. To examine differences in the adrenocortical, autonomic and psychological stress reactivity, salivary free cortisol, heart rate, state anxiety, mood and calmness were assessed prior to, during and after the Trier Social Stress Test (TSST). The cut-offs of the American College of Sports Medicine (ACSM) were used to distinguish between students below/above current VPA recommendations. High levels of perceived stress combined with VPA levels below the ACSM's standards (strategy to increase physiological and psychological stress resilience. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Worsening central sarcopenia and increasing intra-abdominal fat correlate with decreased survival in patients with adrenocortical carcinoma.

    Science.gov (United States)

    Miller, Barbra S; Ignatoski, Kathleen M; Daignault, Stephanie; Lindland, Ceit; Doherty, Megan; Gauger, Paul G; Hammer, Gary D; Wang, Stewart C; Doherty, Gerard M

    2012-07-01

    Accurate prediction of survival from adrenocortical carcinoma (ACC) is difficult and current staging models are unreliable. Central sarcopenia as part of the cachexia syndrome is a marker of frailty and predicts mortality. This study seeks to confirm that psoas muscle density (PMD), lean psoas muscle area (LPMA), lumbar skeletal muscle index (LSMI), and intra-abdominal (IA) or subcutaneous fat (SC) can be used in combination to more accurately predict survival in ACC patients. PMD, LPMA, IA, and SC fat were measured on serial CT scans of patients with ACC. Clinical outcome was correlated with quantitative data from patients with ACC and analyzed. A linear regression model was used to describe the relationship between PMD, LPMA, LSMI, IA, and SC fat, time to recurrence, and length of survival according to tumor stage. One hundred twenty-five ACC patients (94 females) were treated from 2005 to 2011. Significant morphometric predictors of survival include PMD, LPMA, and IA fat (p ≤ 0.0001, ≤ 0.0024, increase in LPMA confers an 8 % lower hazard of death. LSMI does not change significantly between stages (p = 0.3196). Decreased PMD, LPMA, and increased IA fat suggest decreased survival in ACC patients and correlate with traditional staging systems. A more precise prediction of survival may be achieved when staging systems and morphometric measures are used in combination. Serial measurements of morphometric data are possible. The rate of change of these variables over time may be more important than the absolute value.

  17. Phytoestrogens in menopausal supplements induce ER-dependent cell proliferation and overcome breast cancer treatment in an in vitro breast cancer model.

    Science.gov (United States)

    van Duursen, Majorie B M; Smeets, Evelien E J W; Rijk, Jeroen C W; Nijmeijer, Sandra M; van den Berg, Martin

    2013-06-01

    Breast cancer treatment by the aromatase inhibitor Letrozole (LET) or Selective Estrogen Receptor Modulator Tamoxifen (TAM) can result in the onset of menopausal symptoms. Women often try to relieve these symptoms by taking menopausal supplements containing high levels of phytoestrogens. However, little is known about the potential interaction between these supplements and breast cancer treatment, especially aromatase inhibitors. In this study, interaction of phytoestrogens with the estrogen receptor alpha and TAM action was determined in an ER-reporter gene assay (BG1Luc4E2 cells) and human breast epithelial tumor cells (MCF-7). Potential interactions with aromatase activity and LET were determined in human adrenocorticocarcinoma H295R cells. We also used the previously described H295R/MCF-7 co-culture model to study interactions with steroidogenesis and tumor cell proliferation. In this model, genistein (GEN), 8-prenylnaringenin (8PN) and four commercially available menopausal supplements all induced ER-dependent tumor cell proliferation, which could not be prevented by physiologically relevant LET and 4OH-TAM concentrations. Differences in relative effect potencies between the H295R/MCF-7 co-culture model and ER-activation in BG1Luc4E2 cells, were due to the effects of the phytoestrogens on steroidogenesis. All tested supplements and GEN induced aromatase activity, while 8PN was a strong aromatase inhibitor. Steroidogenic profiles upon GEN and 8PN exposure indicated a strong inhibitory effect on steroidogenesis in H295R cells and H295R/MCF-7 co-cultures. Based on our in vitro data we suggest that menopausal supplement intake during breast cancer treatment should better be avoided, at least until more certainty regarding the safety of supplemental use in breast cancer patients can be provided.

  18. Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors

    Energy Technology Data Exchange (ETDEWEB)

    Gicquel, C.; Schneid, H.; Le Bouc, Y. [Hopital Trousseau, Paris (France); Bertagna, X.; Francillard-Leblond, M.; Luton, J.P.; Girard, F. [Hopital Cochin, Paris (France)

    1994-06-01

    Little is known about the pathophysiology of sporadic adrenocortical tumors in adults. Because loss of heterozygosity at the 11p15 locus has been described in childhood tumors, particularly in adrenocortical tumors associated with the Beckwith-Wiedemann syndrome, and because insulin-like growth factor-II (IGF-II) is a crucial regulator of fetal adrenal growth, the authors looked for structural analysis at the 11p15 locus and IGF-II gene expression in 23 sporadic adrenocortical adult tumors: 6 carcinomas (5 with Cushing`s syndrome and 1 nonsecreting) and 17 benign adenomas (13 with Cushing`s syndrome, 1 pure androgen secreting, and 3 nonsecreting). Twenty-one patients were informative at the 11p15 locus, and six (four carcinomas and two adenomas) of them (28.5%) exhibited 11p15 structural abnormalities in tumor DNA (five, a uniparental disomy and one, a mosaicism). In a single case that could be further studied, a paternal isodisomy was observed. Very high IGF-II mRNA contents were detected in seven tumors (30%; 5 of the 6 carcinomas and 2 of the 17 adenomas). They were particularly found in tumors with uniparental disomy at the 11p15 locus. Overall, a strong correlation existed between IGF-II mRNA contents and DNA demethylation at the IGF-II locus. These data show that genetic alterations involving the 11p15 locus were highly frequent in malignant tumors, but found only in rare adenomas. These results in combination with evidence for overexpression of IGF-II from the 11p15.5 locus suggest that abnormalities in structure and/or expression of the IGF-II gene play a role as a late event of a multistep process of tumorigenesis. 58 refs., 6 figs., 4 tabs.

  19. Adrenocortical Carcinoma (Report of 9 Cases)%肾上腺皮质癌9例报告

    Institute of Scientific and Technical Information of China (English)

    罗兵锋; 曾甫清; 梁铸林; 魏卓; 郭钜; 蒋国松

    2011-01-01

    Objective: To study the methods of diagnosis and treatment of adrenocortical carcinoma.Methods:Clinical data of 9 cases of adrenocortical carcinoma were retrospectively analyzed, including 7men and 2 women,whose average were 39 years old,from 5 months to 63 years old.Radiologic evaluations were performed in all cases,including ultra-sound and CT scan.Endocrinological evaluation performed in 9 patients, hormonally active tumor diagnosed were 2 of them, which usually showed typical clinical features such as Cushings syndrome and primary aldosteronism.In other 7 patients,their tumors were described as non-functional.Results: All case underwent complete resection.The pathologically,there was 2 cases of stage I ,4 of stage Ⅱ ,3 of stage m and 1 of stage Ⅳ.The mean survival time was 30 months after the follow up from 4 months to 60 months,1 patient died of pulmonary metastasis after operation 26 months later and the remaining 7 cases were still alive.Conclusions:Adrenal cortical carcinoma is a rare malignant neoplasm with poor prognosis,surgical operation is the best way for patients,chemotherapy and radiotherapy could be assisted and useful.Early diagnosis and management could increase the survival rate.%目的:探讨肾上腺皮质癌的诊断和治疗方法.方法:回顾性分析9例肾上腺皮质癌患者的临床资料,其中男7例,女2例.年龄5个月~63岁,平均39岁.术前全部行B超及CT检查,有内分泌异常者2例,分别为Cushing syndrome及原发性醛固酮增多症.无内分泌异常者7例.结果:手术完整切除9例.术后病理检查:I期1例;Ⅱ期4例;Ⅲ期3例;IV期1例.随访4~60个月,平均生存30个月,1例因肺部转移而术后26个月死亡,1例失去随访,其余7例均存活至今.结论:肾上腺皮质癌恶性程度较高,预后较差,根治性切除是治疗肾上腺皮质癌最有效的方法.化疗及放疗可作为术后辅助治疗.早期诊断和早期治疗可提高患者生存率.

  20. Adjuvant Radiation Therapy Improves Local Control After Surgical Resection in Patients With Localized Adrenocortical Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Sabolch, Aaron [Department of Radiation Oncology, University of Michigan Hospital and Health Systems, Ann Arbor, Mchigan (United States); Else, Tobias [Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Hospital and Health Systems, Ann Arbor, Mchigan (United States); Griffith, Kent A. [Center for Cancer Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Mchigan (United States); Ben-Josef, Edgar [Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Williams, Andrew [University of Michigan Medical School, Ann Arbor, Mchigan (United States); Miller, Barbra S. [Division of Endocrine Surgery, Department of General Surgery, University of Michigan Hospital and Health Systems, Ann Arbor, Mchigan (United States); Worden, Francis [Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Hospital and Health Systems, Ann Arbor, Mchigan (United States); Hammer, Gary D. [Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Hospital and Health Systems, Ann Arbor, Mchigan (United States); Jolly, Shruti, E-mail: shrutij@med.umich.edu [Department of Radiation Oncology, University of Michigan Hospital and Health Systems, Ann Arbor, Mchigan (United States)

    2015-06-01

    Purpose: Adrenocortical carcinoma (ACC) is a rare malignancy known for high rates of local recurrence, though the benefit of postoperative radiation therapy (RT) has not been established. In this study of grossly resected ACC, we compare local control of patients treated with surgery followed by adjuvant RT to a matched cohort treated with surgery alone. Methods and Materials: We retrospectively identified patients with localized disease who underwent R0 or R1 resection followed by adjuvant RT. Only patients treated with RT at our institution were included. Matching to surgical controls was on the basis of stage, surgical margin status, tumor grade, and adjuvant mitotane. Results: From 1991 to 2011, 360 ACC patients were evaluated for ACC at the University of Michigan (Ann Arbor, MI). Twenty patients with localized disease received postoperative adjuvant RT. These were matched to 20 controls. There were no statistically significant differences between the groups with regard to stage, margins, grade, or mitotane. Median RT dose was 55 Gy (range, 45-60 Gy). Median follow-up was 34 months. Local recurrence occurred in 1 patient treated with RT, compared with 12 patients not treated with RT (P=.0005; hazard ratio [HR] 12.59; 95% confidence interval [CI] 1.62-97.88). However, recurrence-free survival was no different between the groups (P=.17; HR 1.52; 95% CI 0.67-3.45). Overall survival was also not significantly different (P=.13; HR 1.97; 95% CI 0.57-6.77), with 4 deaths in the RT group compared with 9 in the control group. Conclusions: Postoperative RT significantly improved local control compared with the use of surgery alone in this case-matched cohort analysis of grossly resected ACC patients. Although this retrospective series represents the largest study to date on adjuvant RT for ACC, its findings need to be prospectively confirmed.

  1. Activation in the hypothalamic-pituitary-adrenocortical axis and sympathetic nervous system in women with carpal tunnel syndrome.

    Science.gov (United States)

    Fernández-de-Las-Peñas, César; Díaz-Rodríguez, Lourdes; Salom-Moreno, Jaime; Galiano-Castillo, Noelia; Valverde-Herreros, Lis; Martínez-Martín, Javier; Pareja, Juan A

    2014-08-01

    The aim of this study is to investigate the differences in salivary cortisol (hypothalamic-pituitary-adrenocortical [HPA] axis), α-amylase activity (sympathetic nervous system [SNS]), and immunoglobulin A (IgA; immune system) concentrations between women with carpal tunnel syndrome (CTS) and healthy women. A cross-sectional study. Activation of HPA, SNS, and immune system in CTS has not been clearly determined. One hundred two women (age: 45 ± 7 years) with electrodiagnostic and clinical diagnosis of CTS and 102 matched healthy women. The intensity of the pain was assessed with a Numerical Pain Rating Scale (0-10), and disability was determined with Boston Carpal Tunnel Questionnaire. Salivary cortisol concentration, α-amylase activity, salivary flow rate, and IgA concentration were collected from nonstimulated saliva. Women with CTS exhibited lower salivary flow rate (P  0.2) were found between groups as a total. Women with severe CTS exhibited lower salivary flow rate (P < 0.001), higher α-amylase activity (P = 0.002), and higher cortisol concentration (P = 0.03) than healthy women and than those with minimal/moderate CTS (P < 0.05). Within women with CTS, significant positive associations between α-amylase activity and the intensity of pain were found: the highest the level of pain, the higher the α-amylase activity, i.e., higher SNS activation. These results suggest that women with severe CTS exhibit changes in activation in the HPA axis and SNS but not in the humoral immune system. Activation of the SNS was associated with the intensity of pain. Future studies are needed to elucidate the direction of this relationship. Wiley Periodicals, Inc.

  2. The kappa-opioid receptor is involved in the stimulating effect of nicotine on adrenocortical activity but not in nicotine induced anxiety.

    Science.gov (United States)

    Marco, Eva Maria; Llorente, Ricardo; Pérez-Alvarez, Laura; Moreno, Enrique; Guaza, Carmen; Viveros, Maria Paz

    2005-09-01

    The kappa (kappa) opioid system appears to interact with nicotine in the modulation of locomotion and addiction related processes. In this study we have investigated the possible implication of the kappa-opioid system in the effects of nicotine on anxiety and adrenocortical activity. In two different experiments, we analysed the possible interaction between nicotine (0.5 mg/kg i.p.) and either the kappa-opioid receptor antagonist nor-binaltorphimine (5 mg/kg i.p.) or the kappa-opioid receptor agonist U50,488H (1 mg/kg s.c.). Behavioural and endocrine experiments were performed in different groups of animals. Animals were exposed to the holeboard immediately followed by the plus-maze. Serum corticosterone levels were determined by radioimmunoassay. Nicotine induced an anxiogenic-like effect in the plus-maze and a significant decrease of holeboard activity. The anxiogenic-like effect in the plus-maze was not modified by any of the kappa-opioid receptor ligands. Nicotine also induced a significant increase in the corticosterone levels, and the kappa antagonist, which did not exert any effect per se, antagonised this effect. The kappa-agonist U50,488H induced a significant increase in corticosterone concentration when administered alone. We provide the first evidence for the involvement of the kappa-opioid receptor in the stimulatory effect of nicotine on adrenocortical activity.

  3. Comparison of beclomethasone dipropionate (2 and 3 mg) and prednisolone sodium phosphate enemas (30 mg) in the treatment of ulcerative proctitis. An adrenocortical approach.

    Science.gov (United States)

    Mulder, C J; Endert, E; van der Heide, H; Houthoff, H J; Wiersinga, W; Wiltink, E H; Tytgat, G N

    1989-08-01

    Twenty-three patients with attacks of distal ulcerative colitis were treated randomly with either 2 or 3 mg of topically administered beclomethasone dipropionate (BDP) or 30 mg of prednisolone sodium phosphate (PP). The effect of the steroid enemas on adrenocortical function was assessed by ACTH tests, which were performed before and after treatment. Endoscopic, clinical and histological scores were comparable in the three treatment groups in this pilot trial. Fasting cortisol in the PP group decreased significantly from 0.47 +/- 0.12 mumol/l before to 0.22 +/- 0.14 mumol/l (P less than 0.05) after therapy; in the BDP group no significant changes were found. Urinary cortisol excretion in the PP group was not detectable after therapy; in the BDP group no changes were found. It is concluded that in the topical treatment of ulcerative colitis, BDP may be preferable to PP because it exerts a promising anti-inflammatory action without affecting adrenocortical function.

  4. Direct evaluation of adrenocortical function by measurement of adrenal percent uptake of sup 131 I-6. beta. -iodomethyl-19-norcholesterol using single photon emission computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Ishimura, Junji (Hyogo Coll. of Medicine, Nishinomiya (Japan))

    1990-12-01

    In 55 patients (110 adrenal glands) with suspected adrenocortical abnormalities, I assessed the clinical usefulness of adrenal percent uptake of {sup 131}I-6{beta}-iodomethyl-19-norcholesterol (NCL-6-{sup 131}I) by single photon emission computed tomography (SPECT). The percent uptake of NCL-6-{sup 131}I in 6 hyperfunctioning glands of patients with the final diagnosis of Cushing's syndrome (2.62{+-}1.13(SD)%) was significantly (p<0.01) higher than that in 10 glands of patients with the final diagnosis of adenoma of primary aldosteronism (1.16{+-}0.09(SD)%). Moreover, the percent uptake of NCL-6-{sup 131}I in adrenal glands with hyperfunctioning lesions was significantly (p<0.01) higher than those in 10 contralateral normal glands of primary aldosteronism (0.55{+-}0.23(SD)%), 30 right glands (0.57{+-}0.24(SD)%) and 30 left glands (0.53{+-}0.22(SD)%) of essential hypertension with normally functioning adrenal cortices. The adrenal percent uptake of NCL-6-{sup 131}I in 24 glands with hypofunctioning adrenal cortices, including 4 glands suppressed by adenomas of Cushing's syndrome, was below the detectable limit. The data presented above show that the adrenocortical function can be evaluated directly based on measurement of adrenal percent uptake of NCL-6-{sup 131}I using SPECT. (author).

  5. Effects of in ovo exposure of Imazalil and Atrazine on sexual differentiation in chick gonads

    Energy Technology Data Exchange (ETDEWEB)

    Yamashita, J.; Ikeda, M. [Univ. of Shizuoka, Shizuoka (Japan); Matsushita, S.; Iwasawa, T.; Ikeya, M. [Shizuoka Swine and Poultry Experiment Station, Kikugawa (Japan)

    2004-09-15

    numerous anti-fungal chemicals. These chemicals have shown to reversibly (although not necessarily competitively) inhibit aromatase activity in human placental microsomes. It is reported that imazalil and difenoconazole inhibit aromatase activity in human adrenocortical carcinoma cell line H295R. Atrazine is the most commonly used herbicide in the word. There are several reports about the adverse effects of atrazine exposure. Atrazine induced hermaphroditism in African clawed frogs and demasculinized the larynx in male frogs. Plasma testosterone concentration in male frogs was decreased by atrazine exposure, and plasma estradiol concentration in rats was increased by atrazine exposure. Atrazine also increased aromatase activity in human adrenocortical carcinoma cell line H295R by inducing aromatase mRNA. In this study, the effects of in ovo exposure to an aromatase-inhibiting chemical (imazalil) and an aromatase-activating chemical (atrazine) on the sexual differentiation of chick gonad were investigated.

  6. Impact of {sup 18}F-FDG PET/CT on the management of adrenocortical carcinoma: analysis of 106 patients

    Energy Technology Data Exchange (ETDEWEB)

    Takeuchi, Satoshi; Macapinlac, Homer A.; Chuang, Hubert H. [The University of Texas MD Anderson Cancer Center, Department of Nuclear Medicine, Houston, TX (United States); Balachandran, Aparna [The University of Texas MD Anderson Cancer Center, Department of Diagnostic Radiology, Houston, TX (United States); Habra, Mouhammed Amir [The University of Texas MD Anderson Cancer Center, Department of Endocrine Neoplasia and Hormonal Disorders, Houston, TX (United States); Phan, Alexandria T. [The University of Texas MD Anderson Cancer Center, Department of Gastrointestinal Medical Oncology, Houston, TX (United States); Bassett, Roland L. [The University of Texas MD Anderson Cancer Center, Department of Biostatistics, Houston, TX (United States)

    2014-11-15

    Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. Limited data are available about on value of {sup 18}F-FDG PET/CT in ACC. We evaluated the impact of PET/CT on the management of ACC. We performed a retrospective review in patients with ACC who had undergone PET/CT. The impact of PET/CT on the management plan was evaluated by comparing the findings on PET/CT to the findings on contrast-enhanced CT. The sensitivity, specificity, and accuracy of each form of imaging were calculated. The correlations between PET/CT parameters, including maximum standardized uptake value (SUV{sub max}), total lesion glycolysis, and decline in SUV{sub max} after chemotherapy, and clinical outcome were evaluated. Included in the analysis were 106 patients with 180 PET/CT scans. Of the 106 patients, 7 underwent PET/CT only for initial staging, 84 underwent PET/CT only for restaging, and 15 underwent PET/CT for both initial staging and restaging. PET/CT changed the management plan in 1 of 22 patients (5 %) at initial staging and 9 of 99 patients (9 %) at restaging. In 5 of the patients in whom PET/CT changed the management plan, PET/CT showed response to chemotherapy but contrast-enhanced CT showed stable disease. Sensitivity, specificity, and accuracy were 100 %, 100 %, and 100 % for PET/CT at initial staging; 92.6 %, 100 %, and 96.4 % for CT at initial staging; 98.4 %, 100 %, and 99.5 % for PET/CT at restaging; and 96.8 %, 98.6 %, and 98.0 % for CT at restaging, respectively. No PET/CT parameters were associated with survival at either initial diagnosis or recurrence. PET/CT findings could substantially change the management plan in a small proportion of patients with ACC. Although lesion detection was similar between PET/CT and CT, PET/CT may be preferred for chemotherapeutic response assessment because it may predict response before anatomic changes are detected on CT. (orig.)

  7. Lower birth weight and attenuated adrenocortical response to ACTH in offspring from sows that orally received cortisol during gestation.

    Science.gov (United States)

    Kranendonk, Godelieve; Hopster, Hans; Fillerup, Maaike; Ekkel, E Dinand; Mulder, Eduard J H; Wiegant, Victor M; Taverne, Marcel A M

    2006-03-01

    Prenatal stress is known to affect several offspring characteristics, but its effects depend among other factors on the period of gestation in which it is applied. In the present study, oral administration of hydrocortisone-acetate (HCA) was used to elevate cortisol concentrations in pregnant sows to levels also observed after psychological stress. HCA was administered during three different periods of gestation (115 days in pigs): period 1: 21-50 (P1, n = 10), period 2: 51-80 (P2, n = 10) and period 3: 81-110 (P3, n = 10) days after insemination. Control sows (n = 11) received vehicle from 21-110 days after insemination. When P1-, P2- and P3-sows did not receive HCA, they also received vehicle. During gestation, weekly saliva samples were taken from the sows to determine salivary cortisol concentrations. Treatment effects on sow, litter and piglet characteristics were determined. In addition, two female piglets per litter were subjected to an ACTH-challenge test at 6 weeks of age to determine the adrenocortical response to ACTH. Pigs were slaughtered at 6 months of age and slaughter weight, back fat thickness and percentage of lean meat were analysed. During the period of treatment with HCA, salivary cortisol concentrations were increased in P1-, P2- and P3-sows compared to control sows (P 0.30), but pooled HCA-litters had a higher percentage of live born piglets (P Gestation length did not differ among treatment groups (P = 0.21), but did affect treatment effects on birth weight. Overall, HCA-piglets weighed less at birth, and remained lighter until weaning (P < 0.05). The salivary cortisol concentrations after i.m. injection of ACTH (2.5 IU/kg) were lower in P1- and P3-piglets compared to control piglets. At slaughter, HCA-treatment indirectly decreased lean meat percentage and increased back fat thickness. In conclusion, elevated peripheral cortisol concentrations in pregnant sows affect both litter characteristics and piglet physiology, the latter depending on

  8. The effect of road and sea transport on inflammatory, adrenocortical, metabolic and behavioural responses of weanling heifers

    Directory of Open Access Journals (Sweden)

    Murray Margaret

    2010-07-01

    Full Text Available Abstract The objective was to investigate the effect of transport on inflammatory, adrenocortical, metabolic and behavioural responses of weanling heifers transported from Ireland to Spain. Background At the end of the grazing season, 60 Charolais × beef heifers (mean live weight 245, s.e. 4.3 kg and mean weaning age 219, s.e. 4.9 days were abruptly weaned from their dams on day 0. The animals were assigned by live weight to two treatments, transport (T (n = 40 (mean 246, s.e. 5.4 kg and control (C (n = 20 (mean 247, s.e. 7.2 kg on day 0. The T animals were transported from Ireland to France on a roll-on roll-off ferry at a stocking density of 0.93 m2/animal and then by road for 9 h to a French lairage while C animals remained in Ireland and were not transported. On arrival at the French lairage (d 2, 20 T animals were unloaded (ULT and rested for 12 h in the French lairage and 20 animals rested (RT on the transporter. All animals had access to hay and water. After the rest period, the ULT animals were re-loaded. The subsequent journey by road from France to Spain was 9 h travel, 7 h rest (on the transporter and a further 7 h travel by road. All T animals were blood sampled prior to transport (day (d 0; baseline, on arrival in the French lairage (d 2, after 12 h rest in the French lairage (d 2, on arrival at the feedlot in Spain (d 4 and on d 6, d 8, d 10 and d 34. Control animals were blood sampled at the same times as T animals. Results ULT and RT animals had lower (P 0.05 in plasma protein concentration between RT and ULT animals from day 2 to d 34. Plasma concentrations of urea were higher (P Conclusion It is concluded that, within the conditions of the present study, the performance of the animals that remained on the transporter during the 12 h lairage period in France was not different post-transport from the transported animals that were unloaded and lairaged in France.

  9. [{sup 18}F]FETO for adrenocortical PET imaging: a pilot study in healthy volunteers

    Energy Technology Data Exchange (ETDEWEB)

    Wadsak, Wolfgang [Medical University of Vienna, Department of Nuclear Medicine, Vienna (Austria); University of Vienna, Department of Inorganic Chemistry, Vienna (Austria); Mitterhauser, Markus [Medical University of Vienna, Department of Nuclear Medicine, Vienna (Austria); University of Vienna, Department of Pharmaceutical Technology and Biopharmaceutics, Vienna (Austria); Hospital Pharmacy of the General Hospital of Vienna, Vienna (Austria); Rendl, Gundula; Schuetz, Matthias; Ettlinger, Dagmar E.; Kletter, Kurt; Karanikas, Georgios [Medical University of Vienna, Department of Nuclear Medicine, Vienna (Austria); Mien, Leonhard K. [Medical University of Vienna, Department of Nuclear Medicine, Vienna (Austria); University of Vienna, Department of Pharmaceutical Technology and Biopharmaceutics, Vienna (Austria); Medical University of Vienna, Department of Psychiatry, Vienna (Austria); Dudczak, Robert [Medical University of Vienna, Department of Nuclear Medicine, Vienna (Austria); Ludwig-Boltzmann-Institute for Nuclear Medicine, Vienna (Austria)

    2006-06-15

    Functional imaging of the adrenal cortex by means of PET may play an important clinical role. Recently, we presented the synthesis and first evaluation of a novel 11{beta}-hydroxylase inhibitor, [{sup 18}F]FETO, in rats displaying high tracer accumulation in the adrenals. In this study, we aimed to investigate for the first time the potency of [{sup 18}F]FETO as a PET tracer for the adrenal cortex in humans. An average preparation yielded 1-2 GBq of [{sup 18}F]FETO ready to use. Ten healthy volunteers aged 24-57 years (five male and five female) were included in the study. After i.v. administration of 365 MBq [{sup 18}F]FETO (246-391 MBq), dynamic images were acquired in 2D standard mode in 14 frames over 45 min. Afterwards, whole-body scanning was performed. In addition to visual interpretation, semi-quantitative analysis using standardised uptake values (SUVs) was conducted. [{sup 18}F]FETO distribution was similar in all scanned volunteers. Visually, pronounced accumulation of [{sup 18}F]FETO was found in the adrenals, whereas moderate uptake was observed - at least in some of the subjects - for liver, renal calices, gallbladder, stomach walls and pancreas. Kidney and bowels showed only faint uptake. Median SUVs for the right and left adrenal glands were 15.6 (10.0-28.6) and 15.7 (10.3-35.9), respectively. The reference tissue (liver) displayed a median SUV of 2.5 (2.2-4.6). (orig.)

  10. In vivo and in vitro evaluation of [{sup 18}F]FETO with respect to the adrenocortical and GABAergic system in rats

    Energy Technology Data Exchange (ETDEWEB)

    Mitterhauser, Markus [Department of Nuclear Medicine, AKH Wien, University of Vienna, Waehringer Guertel 18-20, 1090, Vienna (Austria); Department of Pharmaceutic Technology and Biopharmaceutics, University of Vienna (Austria); Hospital Pharmacy of the General Hospital of Vienna (Austria); Wadsak, Wolfgang [Department of Nuclear Medicine, AKH Wien, University of Vienna, Waehringer Guertel 18-20, 1090, Vienna (Austria); Department of Inorganic Chemistry, University of Vienna (Austria); Ludwig-Boltzmann-Institute for Nuclear Medicine, Vienna (Austria); Wabnegger, Leila; Sieghart, Werner [Institute for Brain Research, University of Vienna (Austria); Viernstein, Helmut [Department of Pharmaceutic Technology and Biopharmaceutics, University of Vienna (Austria); Kletter, Kurt [Department of Nuclear Medicine, AKH Wien, University of Vienna, Waehringer Guertel 18-20, 1090, Vienna (Austria); Dudczak, Robert [Department of Nuclear Medicine, AKH Wien, University of Vienna, Waehringer Guertel 18-20, 1090, Vienna (Austria)

    2003-10-01

    11{beta}-Hydroxylase (CYP11B1, P450{sub 11{beta}}) plays an important role in the biosynthesis of cortisol and aldosterone and has been shown to be a good target for the in vivo imaging of adrenocortical incidentalomas in nuclear medicine. [{sup 11}C]Metomidate (MTO), a potent inhibitor of this enzyme, is used for positron emission tomography (PET) imaging of adrenocortical pathology. The synthesis of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid 2-[{sup 18}F]fluoroethylester (FETO), a close analogue to MTO and etomidate (ETO), has been presented recently, and the present investigation aimed to characterise the in vivo distribution of FETO. Since ETO is a well-known anaesthetic drug acting via the GABAergic system, the interaction of FETO with GABA{sub A} receptors was also evaluated. Eighteen male Sprague-Dawley rats were injected with 1.73-3.06 MBq of FETO into a tail vein after venodilatation in a 40 C water bath. Rats were sacrificed by exsanguination from the abdominal aorta under deep ether anaesthesia after 10 (n=6), 30 (n=6) or 60 min (n=6); organs were removed, weighed and counted. For binding experiments, rat cerebellar membranes were incubated for 90 min at 4 C in TC-50 buffer, 150 mM NaCl and 2 nM of [{sup 3}H]flunitrazepam in the absence or presence of 10 {mu}M diazepam or various concentrations of ETO, MTO and FETO. In vivo evaluation evinced very high uptake in the adrenal glands (7.52%{+-}1.19% ID/g at 30 min), followed by lung (1.18%{+-}0.19% ID/g, 10 min), liver (0.59%{+-}0.13% ID/g, 10 min) and duodenum (0.7%{+-}0.29% ID/g, 60 min). No defluorination nor fluoroethyl-ester cleavage was observed. When brain regions were compared with the thalamus (the reference region), highest relative uptake was seen in the cortex (2.34), followed by ''rest brain'' (2.13) and cerebellum (1.96). FETO and ETO were able to increase the binding of [{sup 3}H]flunitrazepam with similar potencies and to a comparable extent. It is concluded

  11. Endocrine effects of real-life mixtures of persistent organic pollutants (POP) in experimental models and wild fish.

    Science.gov (United States)

    Berg, Vidar; Kraugerud, Marianne; Nourizadeh-Lillabadi, Rasoul; Olsvik, Pål A; Skåre, Janneche U; Alestrøm, Peter; Ropstad, Erik; Zimmer, Karin Elisabeth; Lyche, Jan L

    2016-01-01

    A series of studies have assessed the occurrence, levels, and potential adverse effects of persistent organic pollutants (POP) in fish from Lake Mjøsa. In this lake, high levels of various POP were detected in biota. Fish from the nearby Lake Losna contain background levels of POP and served as reference (controls) in these studies. Significantly higher prevalence of mycobacteriosis and pathological changes were documented in burbot (Lota lota) from Mjøsa compared to burbot from Losna. Further, transcriptional profiling identified changes in gene expression in burbot from Mjøsa compared to burbot from Losna associated with drug metabolism enzymes and oxidative stress. POP extracted from burbot liver oil from the two lakes was used to expose zebrafish (Danio rerio) during two consecutive generations. During both generations, POP mixtures from both lakes increased the rate of mortality, induced earlier onset of puberty, and skewed sex ratio toward males. However, opposite effects on weight gain were found in exposure groups compared to controls during the two generations. Exposure to POP from both lakes was associated with suppression of ovarian follicle development. Analyses of genome-wide transcription profiling identified functional networks of genes associated with weight homeostasis, steroid hormone functions, and insulin signaling. In human cell studies using adrenocortical H295R and primary porcine theca and granulosa cells, exposure to lake extracts from both populations modulated steroid hormone production with significant difference from controls. The results suggest that POP from both lakes may possess the potential to induce endocrine disruption and may adversely affect health in wild fish.

  12. Assessment of the potential of polyphenols as a CYP17 inhibitor free of adverse corticosteroid elevation.

    Science.gov (United States)

    Lin, Chun-Ju; Cheng, Li-Chuan; Lin, Tsu-Chun Emma; Wang, Chien-Jen; Li, Lih-Ann

    2014-08-01

    Inhibition of 17α-hydroxylase/17,20-lyase (CYP17), which dictates the proceeding of androgen biosynthesis, is recommended as an effective treatment for androgen-dependent diseases. However, androgen depletion by selective CYP17 inhibition is accompanied with corticosteroid elevation, which increases risk of cardiovascular diseases. In this study, we evaluated the likelihood of polyphenols as a CYP17 inhibitor without cardiovascular complications. All examined polyphenols significantly inhibited CYP17 in human adrenocortical H295R cells, but their effects on androgen and cortisol biosynthesis were diverse. Resveratrol was the most potent CYP17 inhibitor with an approximate IC50 of 4 μM, and the inhibition might weigh on the 17α-hydroxylase activity more than the 17,20-lyase activity. Resveratrol also inhibited 21α-hydroxylase (CYP21) essential for corticosteroid biosynthesis but to a lesser extent, thus preventing the occurrence of cortisol elevation following CYP17 blockade. Although transcriptional down-regulation was important for α-naphthoflavone-mediated CYP17 inhibition, resveratrol inhibited CYP17 and CYP21 mainly at the level of enzyme activity rather than enzyme abundance and cytochrome P450 electron transfer. Daidzein also inhibited CYP17 and CYP21 although less potent than resveratrol. Daidzein was the only polyphenol showing inhibition of 3β-hydroxysteroid dehydrogenase type II (3βHSD2). The exceptional 3βHSD2 inhibition led to dehydroepiandrosterone accumulation alongside daidzein-caused androgen biosynthetic impairment. In contrast, androgen and cortisol secretion was increased or remained normal under α-naphthoflavone and β-naphthoflavone treatments, suggesting that CYP17 inhibition was counteracted by increased substrate generation. α-naphthoflavone and β-naphthoflavone also enhanced the formation of cortisol from 17-hydroxyprogesterone and testosterone from androstenedione. Our findings suggest a potential application of resveratrol in

  13. 儿童肾上腺皮质肿瘤的临床特征%Clinical characters of childhood adrenocortical tumors

    Institute of Scientific and Technical Information of China (English)

    陈秋莉; 苏喆; 李燕虹; 马华梅; 陈红珊; 杜敏联; 古玉芬

    2010-01-01

    目的 分析儿童肾上腺皮质肿瘤的临床特征,提高对本病诊断的认识以及判别能力.方法 回顾分析广州中山大学附属第一医院31例儿童肾上腺皮质肿瘤患儿的症状、实验室检查、影像学检查等.结果 腺瘤16例,腺癌15例.诊断时平均年龄(4.49±3.51)岁,男女比例为1:1.4.12例呈单纯外周性性早熟表现,4例单纯库欣综合征表现,10例兼有二者表现,5例无内分泌异常症状.92.3%患儿睾酮升高.B超和CT诊断分别仅12.5%、20.8%与病理符合.结论 儿童肾上腺皮质肿瘤以外周性性早熟及雄激素升高表现多见.影像学检查无法准确定性,最后诊断须综合临床表现、实验室检查、影像学和病理结果.%Objective To analyze the clinical characters of childhood adrenocortical tumors, and to enhance the knowledge of diagnosis of this disease. Methods A retrospective analysis of clinical characters,laboratory tests,and imaging findings in 31 cases of childhood adrenocortical tumors was carried out. Results 16 cases of adenoma and 15 cases of carcinoma were included. The average age was (4.49±3.51) years old, and 67.7% of the patients were younger than 5 years old. The ratio of male to female was 1.0: 1.4. 12 patients presented only precocious sexual development, 4 patients presented only Cushing syndrome, 10 patients showed sexual precocity combined with Cushing syndrome, and 5 patients did not have any endocrine abnormalities. Raised testosterone level in 92.3% of these patients was the most common finding in laboratory tests. Only 12.5% of ultrasound images and 20.8% of CT images were consistent with pathologic diagnosis. Conclusions The clinical manifestations of adrenocortical tumors in childhood are precocious sexual development, Cushing's syndrome, or nonfunctional. The common laboratory findings are elevation of sex hormone and disorder of cortisol circadian rhythm. Precocious sexual development and elevation of androgens are more

  14. Effect of noise exposure (85 dB ) on testicular adrenocortical steroidogenic key enzymes, acid and alkaline phosphatase activities of sex organs in mature albino rats

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Changes in the activities of △5-3β-hydroysteroid dehydrogenase (HSD) in testis and adrenal gland, 17β-hydroxysteroid dehydrogenase in testis, acid and alkaline phosphatase in testis, prostate and seminal vesicle were observed in noise exposed mature rats at the intensity of 85 dB for 8 h/day for 45 days. The results indicated that noise exposed group showed a significant diminution in the activities of androgenic key enzymes △5-3β and 17β-HSD, acid phosphatase in testis, prostate and seminal vesicle. There was a significant elevation in the activities of adrenal △5-3β-HSD, alkaline phosphatase in testis and other accessory sex organ in noise exposed group. Gonadosomatic, prostatosomatic and seminal vesiculo-somatic indexes were decreased significantly in noise exposed group. Therefore, it is evident that noise exposure at 85dB exerts a deleterious effect on testicular and adrenocortical activities.

  15. Bilateral adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1 (MEN1 and a novel mutation in the MEN1 gene

    Directory of Open Access Journals (Sweden)

    Kamakari Smaragda

    2011-01-01

    Full Text Available Abstract The incidence of adrenal involvement in MEN1 syndrome has been reported between 9 and 45%, while the incidence of adrenocortical carcinoma (ACC in MEN1 patients has been reported between 2.6 and 6%. In the literature data only unilateral development of ACCs in MEN1 patients has been reported. We report a 31 years-old female MEN1-patient, in whom hyperplasia of the parathyroid glands, prolactinoma, non functioning pancreatic endocrine carcinoma and functioning bilateral adrenal carcinomas were diagnosed. Interestingly, a not previously described in the literature data, novel germline mutation (p.E45V in exon 2 of MEN1 gene, was detected. The association of exon 2 mutation of the MEN1 gene with bilateral adrenal carcinomas in MEN1 syndrome, should be further investigated.

  16. Regulation of steroidogenesis in a primary pigmented nodular adrenocortical disease-associated adenoma leading to virilization and subclinical Cushing’s syndrome

    Science.gov (United States)

    Hofland, Johannes; de Herder, Wouter W; Derks, Lieke; Hofland, Leo J; van Koetsveld, Peter M; de Krijger, Ronald R; van Nederveen, Francien H; Horvath, Anelia; Stratakis, Constantine A; de Jong, Frank H; Feelders, Richard A

    2014-01-01

    Context Primary pigmented nodular adrenocortical disease (PPNAD) can lead to steroid hormone overproduction. Mutations in the cAMP protein kinase A regulatory subunit type 1A (PRKAR1A) are causative of PPNAD. Steroidogenesis in PPNAD can be modified through a local glucocorticoid feed-forward loop. Objective Investigation of regulation of steroidogenesis in a case of PPNAD with virilization. Materials and methods A 33-year-old woman presented with primary infertility due to hyperandrogenism. Elevated levels of testosterone and subclinical ACTH-independent Cushing’s syndrome led to the discovery of an adrenal tumor, which was diagnosed as PPNAD. In vivo evaluation of aberrantly expressed hormone receptors showed no steroid response to known stimuli. Genetic analysis revealed a PRKAR1A protein-truncating Q28X mutation. After adrenalectomy, steroid levels normalized. Tumor cells were cultured and steroidogenic responses to ACTH and dexamethasone were measured and compared with those in normal adrenal and adrenocortical carcinoma cells. Expression levels of 17β-hydroxysteroid dehydrogenase (17β-HSD) types 3 and 5 and steroid receptors were quantified in PPNAD, normal adrenal, and adrenal adenoma tissues. Results Isolated PPNAD cells, analogous to normal adrenal cells, showed both increased steroidogenic enzyme expression and steroid secretion in response to ACTH. Dexamethasone did not affect steroid production in the investigated types of adrenal cells. 17β-HSD type 5 was expressed at a higher level in the PPNAD-associated adenoma compared with control adrenal tissue. Conclusion PPNAD-associated adenomas can cause virilization and infertility by adrenal androgen overproduction. This may be due to steroidogenic control mechanisms that differ from those described for PPNAD without large adenomas. PMID:23065993

  17. Effects of Nutrition Relevant Mixtures of Phytoestrogens on Steroidogenesis, Aromatase, Estrogen, and Androgen Activity

    DEFF Research Database (Denmark)

    Taxvig, Camilla; Engell-Kofoed, Anders Elleby; Sonne-Hansen, Katrine;

    2010-01-01

    Phytoestrogens (PEs) are naturally occurring plant components produced in a large range of plants. They can induce biologic responses in vertebrates by mimicking or modulating the action or production of endogenous hormones. This study examined mixtures of 12 food relevant PEs for effects...... on steroid hormone production, aromatase activity, estrogenic activity, and for interaction with the androgen receptor. The results show that a mixture of all tested PEs increased estradiol production and decreased testosterone production in H295R human adrenal corticocarcinoma cells, indicating an induced...... aromatase activity. Furthermore, exposure of the H295R cells to isoflavonoids caused a decrease in testosterone production, and various mixtures of PEs significantly stimulated MCF-7 human breast adenocarcinoma cell growth and induced aromatase activity in JEG-3 choriocarcinoma cells. The estrogenic effect...

  18. Separation, isolation and stereochemical assignment of imazalil enantiomers and their quantitation in an in vitro toxicity test

    DEFF Research Database (Denmark)

    Casas, Mònica Escolà; Kretschmann, Andreas Christopher; Andernach, Lars;

    2016-01-01

    A simple method for the separation of the enantiomers of the fungicide imazalil was developed. Racemic imazalil was separated into its enantiomers with an enantiomeric purity of 99% using HPLC-UV with an enantioselective column (permethylated cyclodextrin) operated in reversed phase mode (water w...... fractions in samples from an in vitro test on effects on human steroidogenesis (H295R steroidogenesis assay). The quantification verified the stability of the enantiomers of imazalil during the in vitro tests....

  19. Ecological factors affecting the adrenocortical response to stress in chestnut-collared and McCown's longspurs (Calcarius ornatus, Calcarius mccownii).

    Science.gov (United States)

    Lynn, Sharon E; Hunt, Kathleen E; Wingfield, John C

    2003-01-01

    Secretion of the steroid hormone corticosterone (CORT) in response to perturbations results in behavior patterns that can maximize survival. Three commonly cited hypotheses suggest that during breeding, there are advantages associated with suppressed (CORT) secretion in (1) the sex that is most important for parental care, (2) individuals in good body condition, and (3) species with a short breeding season and limited renesting opportunities. We addressed these hypotheses in two midlatitude breeders, chestnut-collared and McCown's longspurs, by assessing CORT secretion over a 1-h period of handling. These species have congeners that are exclusively arctic breeders, and this provides a unique opportunity to assess adrenocortical responsiveness both within a phylogenetic framework and across environmental variables. In both species, males and females showed similar CORT secretion patterns in response to handling, and body condition was unrelated to CORT secretion. Additionally, although these midlatitude breeders have more opportunities to attempt a renest than their arctic congeners, their hormonal response to stress was similar to that reported for their arctic congeners. We suggest that an attenuated stress response may relate to the severity of the breeding environment and a low likelihood of successful renesting, since these variables are common to both arctic and grassland habitats.

  20. Degranulation of mast cells located in median eminence in response to compound 48/80 evokes adrenocortical secretion via histamine and CRF in dogs.

    Science.gov (United States)

    Matsumoto, Itsuro; Inoue, Yasuhisa; Tsuchiya, Katsuhiko; Shimada, Toshio; Aikawa, Tadaomi

    2004-10-01

    The effect of intracerebroventricular infusion of compound 48/80 (C48/80), a mast cell secretagogue, on adrenal cortisol secretion was investigated in dogs under pentobarbital sodium anesthesia. A marked increase in adrenal cortisol secretion was elicited by C48/80 along with a concomitant increase in the plasma levels of cortisol and immunoreactive ACTH, but neither arterial blood pressure and heart rate nor the plasma histamine level altered significantly. Pretreatment with either anti-CRF antiserum or pyrilamine maleate (H(1) histamine-receptor antagonist) significantly attenuated the C48/80-evoked increase in cortisol secretion, but pretreatment with metiamide (H(2)-receptor antagonist) significantly potentiated it. Significant attenuation of the C48/80-evoked increase in cortisol also occurred in dogs given ketotifen, a mast cell stabilizing drug, before pharmacologic challenge. In the pars tuberalis and median eminence (ME), mast cells were highly concentrated in close association with the primary plexus of the hypophysial portal system. Degranulated mast cells were extensively found in the ME of C48/80-treated animals. These results suggest that mast cells located in these regions liberated histamine within the brain as a result of degranulation induced by C48/80 and that this led to activation of the hypothalamic-pituitary-adrenocortical axis.

  1. miRNA-200c mediates mono-butyl phthalate-disrupted steroidogenesis by targeting vimentin in Leydig tumor cells and murine adrenocortical tumor cells.

    Science.gov (United States)

    Lu, Hongchao; Zhang, Chang; Hu, Yanhui; Qin, Heng; Gu, Aihua; Li, Yuan; Zhang, Lulu; Li, Zhong; Wang, Yubang

    2016-01-22

    The reproductive toxicity of plasticizer di-n-butyl phthalate (DBP) and its active metabolite monobutyl phthalate (MBP) has been demonstrated in rodents. The objective of this study was to explore roles of vimentin and miRNA-200c in steroidogenesis interfered by MBP. Mouse Leydig tumor cells (MLTC-1) and murine adrenocortical tumor cells (Y1) were employed and exposed to various levels of MBP (10(-7), 10(-6), 10(-5) and 10(-4)M). Steroid hormone production was increased significantly when MLTC-1 and Y1 cells were exposed to MBP at 10(-7)M. Additionally, vimentin and steroidogenic acute regulatory protein (StAR) expressions were upregulated at the same dose. It was found that MBP increased the steroidogenesis by facilitating the cholesterol transfer process by vimentin. In contrast, miRNA-200c expression was depressed at doses of MBP (10(-7)M) in both cells. Moreover, vimentin expression and progesterone production were increased in both MLTC-1 and Y1 cells after miRNA-200c expression was artificially inhibited. These results strongly suggested that MBP raised steroid hormone synthesis via upregulated vimentin by miRNA-200c.

  2. Behavioral Abnormality Induced by Enhanced Hypothalamo-Pituitary-Adrenocortical Axis Activity under Dietary Zinc Deficiency and Its Usefulness as a Model

    Science.gov (United States)

    Takeda, Atsushi; Tamano, Haruna; Nishio, Ryusuke; Murakami, Taku

    2016-01-01

    Dietary zinc deficiency increases glucocorticoid secretion from the adrenal cortex via enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activity and induces neuropsychological symptoms, i.e., behavioral abnormality. Behavioral abnormality is due to the increase in glucocorticoid secretion rather than disturbance of brain zinc homeostasis, which occurs after the increase in glucocorticoid secretion. A major target of glucocorticoids is the hippocampus and their actions are often associated with disturbance of glutamatergic neurotransmission, which may be linked to behavioral abnormality, such as depressive symptoms and aggressive behavior under zinc deficiency. Glucocorticoid-mediated disturbance of glutamatergic neurotransmission in the hippocampus is also involved in the pathophysiology of, not only psychiatric disorders, such as depression, but also neurodegenerative disorders, e.g., Alzheimer’s disease. The evidence suggests that zinc-deficient animals are models for behavioral and psychological symptoms of dementia (BPSD), as well as depression. To understand validity to apply zinc-deficient animals as a behavioral abnormality model, this paper deals with the effect of antidepressive drugs and herbal medicines on hippocampal dysfunctions and behavioral abnormality, which are induced by enhanced HPA axis activity under dietary zinc deficiency. PMID:27438830

  3. Behavioral Abnormality Induced by Enhanced Hypothalamo-Pituitary-Adrenocortical Axis Activity under Dietary Zinc Deficiency and Its Usefulness as a Model

    Directory of Open Access Journals (Sweden)

    Atsushi Takeda

    2016-07-01

    Full Text Available Dietary zinc deficiency increases glucocorticoid secretion from the adrenal cortex via enhanced hypothalamo-pituitary-adrenocortical (HPA axis activity and induces neuropsychological symptoms, i.e., behavioral abnormality. Behavioral abnormality is due to the increase in glucocorticoid secretion rather than disturbance of brain zinc homeostasis, which occurs after the increase in glucocorticoid secretion. A major target of glucocorticoids is the hippocampus and their actions are often associated with disturbance of glutamatergic neurotransmission, which may be linked to behavioral abnormality, such as depressive symptoms and aggressive behavior under zinc deficiency. Glucocorticoid-mediated disturbance of glutamatergic neurotransmission in the hippocampus is also involved in the pathophysiology of, not only psychiatric disorders, such as depression, but also neurodegenerative disorders, e.g., Alzheimer’s disease. The evidence suggests that zinc-deficient animals are models for behavioral and psychological symptoms of dementia (BPSD, as well as depression. To understand validity to apply zinc-deficient animals as a behavioral abnormality model, this paper deals with the effect of antidepressive drugs and herbal medicines on hippocampal dysfunctions and behavioral abnormality, which are induced by enhanced HPA axis activity under dietary zinc deficiency.

  4. Cerebellin and des-cerebellin exert ACTH-like effects on corticosterone secretion and the intracellular signaling pathway gene expression in cultured rat adrenocortical cells--DNA microarray and QPCR studies.

    Science.gov (United States)

    Rucinski, Marcin; Ziolkowska, Agnieszka; Szyszka, Marta; Malendowicz, Ludwik K

    2009-04-01

    Precerebellins (Cbln) belong to the C1q/TNF superfamily of secreted proteins which have diverse functions. They are abundantly expressed in the cerebellum, however, three of them are also expressed in the rat adrenal gland. All members of the Cbln family form homomeric and heteromeric complexes with each other in vitro and it was suggested that such complexes play a crucial role in normal development of the cerebellum. The aim of our study was to investigate whether Cbln1-derived peptides, cerebellin (CER) and des-Ser1-cerebellin (desCER) are involved in regulating biological functions of rat adrenocortical cells. In the primary culture of rat adrenocortical cells, 24 h exposure to CER or desCER notably stimulated corticosterone output and inhibited proliferative activity and similar effects were evoked by ACTH. To study gene transcript regulation by CER, desCER and ACTH, we applied Oligo GEArray DNA Microarray: Rat Signal Transduction Pathway Finder. In relation to the control culture, 13 of the 113 transcripts present on the array were differentially expressed. These transcripts were either up- or down-regulated by ACTH and/or CER or desCER treatment. Validation of DNA Microarray data by QPCR revealed that only 5 of 13 genes studied were differentially expressed. Of those genes, Fos and Icam1 were up-regulated and Egr1 was down-regulated by ACTH, CER and desCER. The remaining two genes, Fasn (insulin signaling pathway) and Hspb1 (HSP27) (stress signaling pathway), were regulated only by CER and desCER, but not by ACTH. Thus, both CER and desCER have effects similar to and different from corticotrophin on the intracellular signaling pathway gene expression in cultured rat adrenocortical cells.

  5. Virilizing Adrenocortical Carcinoma Invading the Right Atrium with Histological High-Grade Malignancy and p53 Mutation in a 3-Year-Old Child: Indication of Post Operative Adjuvant Chemotherapy

    OpenAIRE

    Nagasaki, Keisuke; Horikawa, Reiko; Nagaishi, Jun-ichi; Honna, Toshiro; Sekiguchi, Akihiko; Tsunematsu, Yukiko; Tanaka, Toshiaki

    2004-01-01

    We present a 3-yr-old girl with a virilizing adrenocortical carcinoma invading into the right atrium with histological high-grade malignancy and p53 mutation. Development of facial acne and pubic hair were noted at 3 yr and 2 mo. The levels of androgens were high. Diurnal variation in ACTH and cortisol were absent. Abdominal computed tomography revealed a large right suprarenal mass, with extension into the inferior vena cava and right atrium. Based on the diagnosis of a right virilizing adre...

  6. 肾上腺皮质嗜酸细胞瘤临床病理观察%Adrenocortical oncocytoma.a clinicopathologic observation

    Institute of Scientific and Technical Information of China (English)

    余挽澜; 余晓; 管域

    2013-01-01

    Objective to evaluate the adrenocortical oncocytoma clinicopathologic features and differential diagnosis. Methods histopathologic features and immunohistochemical findings of the tumor were observed and discussed with review of the literatures. Results The tumors with well capsule,aspect greyish brown and greyish yellow were located in the adrenal cortex.Hemorrhage and necrosis were not seen.Microscoppically,the majority of tumor cells were diffusly distributed in solid,the others were arranged in cord and glandular patterns.With some lymphocytes infiltrated the cells were separated by fibrous conective tissue septu.Vascular sinusoids were abundant. Immunohistochemistry:This group of 4 cases,tumor cells Mart-1,Inhibin-α,Calretin,Vimentin were positive in 4cases,Syn in 2 cases,CD56 and P53 in 3 cases,CgA,S-100 4 cases were negative. Conclusion the rare adrenocortical oncocytoma may be associated with functional changes. By combination the morphology and immunohistochemistry adrenocontical oncocytoma may be a high-risk tips cortical tumors.%  目的探讨肾上腺皮质嗜酸细胞瘤的临床病理特点及鉴别诊断。方法对4例肾上腺皮质嗜酸细胞瘤患者的组织病理学及免疫组化结果进行观察分析,结合文献进行讨论。结果肿瘤均位于肾上腺皮质内,包膜完整,切面灰褐色及灰黄色,无出血及坏死灶。光镜下瘤细胞大部分呈弥散实性分布,小部分呈梁索及腺泡状排列。肿瘤细胞间有纤细的纤维间隔,其中有少量的淋巴细胞集聚;血管血窦丰富。免疫组化:本组4例,肿瘤细胞黑色素瘤抗原-1(Mart-1)、抑制素α抗体(Inhibin-α)、波形蛋白(VIM)4例阳性、突触素(Syn)2例阳性,CD56及p533例阳性,嗜铬素A(CgA)、S-1004例均呈阴性。结论肾上腺皮质嗜酸细胞瘤少见,可伴有功能改变,其形态和免疫组化提示可能为一种高危性皮质肿瘤。

  7. Adiponectin and adiponectin receptor system in the rat adrenal gland: ontogenetic and physiologic regulation, and its involvement in regulating adrenocortical growth and steroidogenesis.

    Science.gov (United States)

    Paschke, Lukasz; Zemleduch, Tomasz; Rucinski, Marcin; Ziolkowska, Agnieszka; Szyszka, Marta; Malendowicz, Ludwik K

    2010-09-01

    Adiponectin (ADN) is a regulatory peptide secreted mostly by adipose tissue and acting via two receptors: AdipoR1 and AdipoR2. Our aim was to investigate expression of adiponectin system genes in the rat adrenal gland as well as its ontogenetic and physiological control. Furthermore, we examined the effects of acute and prolonged activation of HPA axis on ADN system in adipose tissue. By means of QPCR, ADN and AdipoR1 expression was demonstrated in rat adrenal cortex both at mRNA and protein levels, while AdipoR2 could only be detected at mRNA levels. ADN expression level was significantly upregulated in a developing and regenerating adrenal cortex. Globular domain of adiponectin at 10(-9) M stimulated corticosterone output and BrdU incorporation by cultured rat adrenocortical cells. Moreover, both acute (ACTH and ether stress) and prolonged (ACTH) adrenal stimulation resulted in lowered ADN levels, while expression of AdipoR1 and AdipoR2 was upregulated by the acute treatment. Depending on its site of origin, visceral (VAT) or subcutaneous (SAT) adipose tissue responded differently to alterations in HPA axis. VAT expression of ADN and its receptors remained almost unchanged by experimental manipulations. In SAT, on the other hand, expression of ADN and AdipoR2 was markedly increased by ACTH treatment and stress, while dexamethasone suppressed ADN and AdipoR1 mRNA levels. The results of this study provide new evidence for direct and indirect interactions between adipokines and HPA axis.

  8. Adrenocortical hormone in the treatment of pediatric epilepsy%肾上腺皮质激素在儿科癫(痫)中的应用

    Institute of Scientific and Technical Information of China (English)

    钟建民

    2013-01-01

    肾上腺皮质激素在癫(痫)治疗中的应用已有70多年的历史,主要用于癫(痫)性脑病的治疗.肾上腺皮质激素已成为婴儿痉挛症和癫(痫)性失语的一线治疗.对于婴儿痉挛症多采用单药治疗,癫(痫)性失语则常与抗癫(疴)药物联合应用,但其确切的作用机制尚未完全阐明.在应用肾上腺皮质激素治疗儿童癫(痫)时,应特别注意其不良反应的发生并进行风险效益评估.%Adrenocortical hormone (ACH) has been used in the treatment of the epilepsies,especially for epileptic encephalopathy,for over 70 years.ACH is clearly established as fast line treatment of infantile spasm and the Landau-Kleffner syndrome.This is typically as monotherapy in infantile spasm,but often in conjunction with anti-epileptic drugs in Landau-Kleffner syndrome,though the mechanism of ACH for epilepsies is not clear.However,in view of these potential adverse side effects,the use of ACH in the treatment of the epilepsies in children must be determined on a risk-benefit basis.

  9. Activation of the baboon fetal hypothalamic-pituitary-adrenocortical axis at midgestation by estrogen-induced changes in placental corticosteroid metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Pepe, G.J.; Waddell, B.J.; Albrecht, E.D. (Eastern Virginia Medical School, Norfolk (USA))

    1990-12-01

    We have hypothesized that the change in placental cortisol (F)-cortisone (E) metabolism induced by estrogen late in gestation is important to activation of the baboon fetal hypothalamic-pituitary-adrenocortical axis, culminating in the ontogenesis of de novo F secretion by the fetal adrenal. The present study tested this hypothesis in vivo by comparing the proportion of F in the fetus derived via maternal and fetal production on day 100 (n = 7; term = day 184) and day 165 (n = 4) in untreated baboons and on day 100 in baboons (n = 9) in which 50-mg pellets of androstenedione were implanted sc in the mother in increasing numbers (i.e. two on day 70, four on day 78, six on day 86, and eight on day 94) to increase placental estrogen production. Maternal, uterine, and umbilical venous samples were collected during constant maternal infusion (120 min) of (3H)F/(14C)E, endogenous and radiolabeled F/E content was determined, and corticosteroid dynamics were quantified. The MCR and peripheral interconversion of F and E as well as the production rate of F were unaltered in the mother. However, at midgestation, androstenedione increased (P less than 0.05) estrogen by 62% and altered transuterofeto placental F-E metabolism from preferential reduction of E to preferential oxidation of F, a pattern similar to that at term. In untreated baboons, on day 100 none of the F in the fetus was due to fetal production, whereas by day 165, 49 +/- 6% was of fetal origin. In animals treated with androstenedione at midgestation, 22 +/- 4% of fetal F was derived de novo within the fetus. Thus, production of F by the fetus was negligible on day 100, increased near term in association with an increase in transplacental oxidation of F to E, and was induced at midgestation in baboons in which placental F-E metabolism was altered by an increase in estrogen production.

  10. Impact of Neonatal Screening and Surveillance for the TP53 R337H Mutation on Early Detection of Childhood Adrenocortical Tumors

    Science.gov (United States)

    Custódio, Gislaine; Parise, Guilherme A.; Kiesel Filho, Nilton; Komechen, Heloisa; Sabbaga, Cesar C.; Rosati, Roberto; Grisa, Leila; Parise, Ivy Z.S.; Pianovski, Mara A.D.; Fiori, Carmem M.C.M.; Ledesma, Jorge A.; Barbosa, José Renato S.; Figueiredo, Francisco R.O.; Sade, Elis R.; Ibañez, Humberto; Arram, Sohaila B.I.; Stinghen, Sérvio T.; Mengarelli, Luciano R.; Figueiredo, Mirna M.O.; Carvalho, Danilo C.; Avilla, Sylvio G.A.; Woiski, Thiago D.; Poncio, Lisiane C.; Lima, Geneci F.R.; Pontarolo, Roberto; Lalli, Enzo; Zhou, Yinmei; Zambetti, Gerard P.; Ribeiro, Raul C.; Figueiredo, Bonald C.

    2013-01-01

    Purpose The incidence of pediatric adrenocortical tumors (ACTs) is remarkably high in southern Brazil, where more than 90% of patients carry the germline TP53 mutation R337H. We assessed the impact of early detection of this mutation and of surveillance of carriers. Patients and Methods Free newborn screening was offered at all hospitals in the state of Paraná. Parents of positive newborns were tested, and relatives in the carrier line were offered screening. Positive newborns and their relatives age < 15 years were offered surveillance (periodic clinical, laboratory, and ultrasound evaluations). ACTs detected by imaging were surgically resected. Results Of 180,000 newborns offered screening, 171,649 were screened, and 461 (0.27%) were carriers. As of April 2012, ACTs had been diagnosed in 11 of these carriers but in only two neonatally screened noncarriers (P < .001); six patient cases were identified among 228 carrier relatives age < 15 years (total, 19 ACTs). Surveillance participants included 347 (49.6%) of 699 carriers. Tumors were smaller in surveillance participants (P < .001) and more advanced in nonparticipants (four with stage III disease; two deaths). Neonatally screened carriers also had neuroblastoma (n = 1), glioblastoma multiforme (n = 1), choroid plexus carcinoma (n = 2), and Burkitt lymphoma (n = 1). Cancer histories and pedigrees were obtained for 353 families that included 1,704 identified carriers. ACTs were the most frequent cancer among carrier children (n = 48). Conclusion These findings establish the prevalence of the TP53 R337H mutation in Paraná state and the penetrance of ACTs among carriers. Importantly, screening and surveillance of heterozygous carriers are effective in detecting ACTs when readily curable. PMID:23733769

  11. Phytoestrogens in menopausal supplements induce ER-dependent cell proliferation and overcome breast cancer treatment in an in vitro breast cancer model

    Energy Technology Data Exchange (ETDEWEB)

    Duursen, Majorie B.M. van, E-mail: M.vanDuursen@uu.nl [Endocrine Toxicology, Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 104, PO Box 80177, 3508 TD, Utrecht (Netherlands); Smeets, Evelien E.J.W. [Endocrine Toxicology, Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 104, PO Box 80177, 3508 TD, Utrecht (Netherlands); Rijk, Jeroen C.W. [RIKILT - Institute for Food Safety, Wageningen UR, P.O. Box 230, 6700 AE, Wageningen (Netherlands); Nijmeijer, Sandra M.; Berg, Martin van den [Endocrine Toxicology, Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 104, PO Box 80177, 3508 TD, Utrecht (Netherlands)

    2013-06-01

    Breast cancer treatment by the aromatase inhibitor Letrozole (LET) or Selective Estrogen Receptor Modulator Tamoxifen (TAM) can result in the onset of menopausal symptoms. Women often try to relieve these symptoms by taking menopausal supplements containing high levels of phytoestrogens. However, little is known about the potential interaction between these supplements and breast cancer treatment, especially aromatase inhibitors. In this study, interaction of phytoestrogens with the estrogen receptor alpha and TAM action was determined in an ER-reporter gene assay (BG1Luc4E2 cells) and human breast epithelial tumor cells (MCF-7). Potential interactions with aromatase activity and LET were determined in human adrenocorticocarcinoma H295R cells. We also used the previously described H295R/MCF-7 co-culture model to study interactions with steroidogenesis and tumor cell proliferation. In this model, genistein (GEN), 8-prenylnaringenin (8PN) and four commercially available menopausal supplements all induced ER-dependent tumor cell proliferation, which could not be prevented by physiologically relevant LET and 4OH-TAM concentrations. Differences in relative effect potencies between the H295R/MCF-7 co-culture model and ER-activation in BG1Luc4E2 cells, were due to the effects of the phytoestrogens on steroidogenesis. All tested supplements and GEN induced aromatase activity, while 8PN was a strong aromatase inhibitor. Steroidogenic profiles upon GEN and 8PN exposure indicated a strong inhibitory effect on steroidogenesis in H295R cells and H295R/MCF-7 co-cultures. Based on our in vitro data we suggest that menopausal supplement intake during breast cancer treatment should better be avoided, at least until more certainty regarding the safety of supplemental use in breast cancer patients can be provided. - Highlights: • Supplements containing phytoestrogens are commonly used by women with breast cancer. • Phytoestrogens alter steroidogenesis in a co-culture breast

  12. Virilizing Adrenocortical Carcinoma Invading the Right Atrium with Histological High-Grade Malignancy and p53 Mutation in a 3-Year-Old Child: Indication of Post Operative Adjuvant Chemotherapy.

    Science.gov (United States)

    Nagasaki, Keisuke; Horikawa, Reiko; Nagaishi, Jun-Ichi; Honna, Toshiro; Sekiguchi, Akihiko; Tsunematsu, Yukiko; Tanaka, Toshiaki

    2004-01-01

    We present a 3-yr-old girl with a virilizing adrenocortical carcinoma invading into the right atrium with histological high-grade malignancy and p53 mutation. Development of facial acne and pubic hair were noted at 3 yr and 2 mo. The levels of androgens were high. Diurnal variation in ACTH and cortisol were absent. Abdominal computed tomography revealed a large right suprarenal mass, with extension into the inferior vena cava and right atrium. Based on the diagnosis of a right virilizing adrenocortical tumor with Cushing syndrome, surgery was performed by a combined thoracoabdominal approach with the patient on cardiopulmonary bypass. The tumor was 7 × 5.5 × 3.5 cm in size, and weighed 95 g. The histological diagnosis was adrenocartical carcinoma with high-grade malignancy according to the category of Weiss. A heterozygous mutation of the p53 tumor-suppressor gene (codon 248 CGC→TGG) was found. We did not perform adjuvant chemotherapy because of radical resection on macroscopic observation and no metastasis in radiological findings. Five months after the surgery, her chest X ray and computed tomography revealed multiple lung metastases and a single liver metastasis. In this type of patient with histological high-grade malignancy and p53 mutations, postoperative adjuvant chemotherapy is indicated even if macroscopic total surgical removal had been performed.

  13. Habituation of adult Magellanic penguins to human visitation as expressed through behavior and corticosterone secretion.

    Science.gov (United States)

    Walker, Brian G; Boersma, P Dee; Wingfield, John C

    2006-02-01

    Ecotourism is increasing worldwide; hence, it is important to know how wildlife are affected behaviorally and physiologically by human visitation. We studied the effects of human visitation on the Magellanic Penguins (Spheniscus magellanicus) at Punta Tombo, Argentina, by monitoring changes in defensive head turns and plasma corticosterone (a hormone secreted in response to stress) for penguins with and without a history of tourist visitation. Habituation to human visitation was rapid. In penguins with no previous exposure to tourists, the number of defensive head turns and level of plasma corticosterone decreased significantly within 5 days of one 15-minute visit/day. Penguins living in tourist-visited and undisturbed areas secreted more corticosterone when captured and restrained than penguins visited by a person. Penguins in tourist areas, however did not show as strong a corticosterone response to capture and restraint as did penguins in areas without tourists. This difference was due to a decreased capability of the adrenocortical tissue to secrete corticosterone in tourist-visited birds. Although our data show no direct negative effects of tourism on Magellanic Penguins at Punta Tombo, consequences of a modification of physiological capabilities (e.g., adrenocortical function) may not become apparent until much later in life. The physiological differences between tourist-visited and undisturbed groups of Magellanic Penguins emphasize the importance of monitoring the effects of anthropogenic disturbances on wildlife at multiple levels.

  14. Contribution of the TP53 R337H mutation to the cancer burden in southern Brazil: Insights from the study of 55 families of children with adrenocortical tumors.

    Science.gov (United States)

    Mastellaro, Maria J; Seidinger, Ana L; Kang, Guolian; Abrahão, Renata; Miranda, Eliana C M; Pounds, Stanley B; Cardinalli, Izilda A; Aguiar, Simone S; Figueiredo, Bonald C; Rodriguez-Galindo, Carlos; Brandalise, Silvia R; Yunes, José A; Barros-Filho, Antônio de A; Ribeiro, Raul C

    2017-08-15

    The tumor protein p53 (TP53) arginine-to-histidine mutation at codon 337 (R337H) predisposes children to adrenocortical tumors (ACTs) and, rarely, to other childhood tumors, but its impact on adult cancer remains undetermined. The objective of this study was to investigate the frequency and types of cancer in relatives of children with ACT who carry the TP53 R337H mutation. TP53 R337H testing was offered to relatives of probands with ACT. The parental lineage segregating the R337H mutation was identified in all families. The frequency and distribution of cancer types were compared according to R337H status. The authors' data also were compared with those publicly available for children with TP53 mutations other than R337H. The mean and median follow-up times for the probands with ACT were 11.2 years and 9.7 years (range, 3-32 years), respectively. During this time, cancer was diagnosed in 12 of 81 first-degree relatives (14.8%) carrying the R337H mutation but in only 1 of 94 noncarriers (1.1%; P = .0022). At age 45 years, the cumulative risk of cancer was 21% (95% confidence interval, 5%-33%) in carriers and 2% (95% confidence interval, 0%-4%) in noncarriers (P = .008). The frequency of cancer was higher in the R337H segregating lineages than in the nonsegregating lineages (249 of 1410 vs 66 of 984 individuals; P cancer were the most common types. TP53 R337H carriers have a lifelong predisposition to cancer with a bimodal age distribution: 1 peak, represented by ACT, occurs in the first decade of life, and another peak of diverse cancer types occurs in the fifth decade. The current findings have implications for genetic counseling and surveillance of R337H carriers. Cancer 2017;123:3150-58. © 2017 American Cancer Society. © 2017 American Cancer Society.

  15. In vitro effects of selected brominated flame retardants on the adreno cortical enzyme (CYP17). A novel endocrine mechanism of action?

    Energy Technology Data Exchange (ETDEWEB)

    Fernandez Canton, R.; Sanderson, T.; Nijmeijer, S.; Berg, M. van den [Utrecht Univ. (NL). Inst. for Risk Assessment Sciences (IRAS); Berkman, Aa. [Stockholm Univ. (Sweden). Dept. of Environmental Chemistry and Analytical Chemistry

    2004-09-15

    investigated for its relationship with anti-obesity, anti-tumor, anti-aging and anti-cancer effects. In these experiments we used the human adrenocortical carcinoma cell line (H295R cell line) to assess possible effects of these BFRs on CYP17 activity.

  16. Urocortin 1, urocortin 3/stresscopin, and corticotropin-releasing factor receptors in human adrenal and its disorders.

    Science.gov (United States)

    Fukuda, Tsuyoshi; Takahashi, Kazuhiro; Suzuki, Takashi; Saruta, Masayuki; Watanabe, Mika; Nakata, Taisuke; Sasano, Hironobu

    2005-08-01

    Urocortin 1 (Ucn1) and urocortin 3 (Ucn3)/stresscopin are new members of the corticotropin-releasing factor (CRF) neuropeptide family. Ucn1 binds to both CRF type 1 (CRF1) and type 2 receptors (CRF2), whereas Ucn3 is a specific agonist for CRF2. Recently, direct involvement of the locally synthesized CRF family in adrenocortical function has been proposed. We examined in situ expression of Ucn and CRF receptors in nonpathological human adrenal gland and its disorders using immunohistochemistry and mRNA in situ hybridization. Ucn immunoreactivity was localized in the cortex and medulla of nonpathological adrenal glands. Ucn1 immunoreactivity was marked in the medulla, whereas Ucn3 was immunostained mostly in the cortex. Both CRF type 1 and CRF2 were expressed in the cortex, particularly in the zonae fasciculata and reticularis but very weakly or undetectably in the medulla. Immunohistochemistry in serial tissue sections with mirror images revealed that both Ucn3 and CRF2 were colocalized in more than 85% of the adrenocortical cells. mRNA in situ hybridization confirmed these findings above. In fetal adrenals, Ucn and CRF receptors were expressed in both fetal and definitive zones of the cortex. Ucn and CRF receptors were all expressed in the tumor cells of pheochromocytomas, adrenocortical adenomas, and carcinomas, but its positivity was less than that in nonpathological adrenal glands, suggesting that Ucn1, Ucn3, and CRF receptors were down-regulated in these adrenal neoplasms. Ucn1, Ucn3, and CRF receptors are all expressed in human adrenal cortex and medulla and may play important roles in physiological adrenal functions.

  17. Phialophora richardsiae infection in humans.

    Science.gov (United States)

    Pitrak, D L; Koneman, E W; Estupinan, R C; Jackson, J

    1988-01-01

    Phialophora richardsiae infection in humans is rare. The first human isolate was recovered from a patient with a phaeomycotic cyst in 1968. Since 1975 seven other cases have appeared in the world literature, and an additional case is reported here. The mean age of these nine patients was 61.4 years. Two patients had diabetes mellitus, one had diabetes mellitus and disseminated adrenocortical carcinoma, and one had a myeloproliferative disorder. The mode of acquisition was presumed to be inoculation with contaminated plant material, but a history consistent with an inoculation injury was obtained in only four patients and a retained splinter was found in the lesion of only one patient. Infection with P. richardsiae was not associated with systemic symptoms or signs. Six patients presented with a single subcutaneous cystic granulomatous lesion. One patient had chronic dacryocystitis. More extensive or invasive disease occurred in two patients, both with an ultimately fatal underlying neoplastic process. A specific etiologic diagnosis was made by culture of purulent material obtained by excisional biopsy in six patients, incision and drainage in one patient, aspiration in one, and spontaneous drainage in one. Subcutaneous nodules were cured with surgical excision. There is insufficient information concerning antifungal therapy to recommend its use.

  18. Cushing’s Syndrome Secondary to isolated Micronodular Adrenocortical Disease (iMAD) associated with Rapid Onset Weight Gain and Negative Abdominal MRI Findings in a 3 year old Male

    Science.gov (United States)

    Henry, Rohan K.; Keil, Margaret F.; Stratakis, Constantine A.; Fechner, Patricia Y.

    2011-01-01

    Cushing’s syndrome (CS) is uncommon in childhood. CS may be either dependent or independent of adrenocorticotrophic hormone (ACTH). ACTH independent micronodular adrenocortical (MAD) disease may present in the second to third decade of life or between ages 2–3years. It may occur in isolation, or as a part of the Carney complex and it represents an elusive entity to diagnose. We present a 3 year 7 month old boy with isolated MAD (iMAD). Abdominal CT revealed prominent mildly lobulated anteromedial margin of adrenals with nodular appearance. Cardiac echo, thyroid and testicular ultrasounds performed as a work up for Carney complex were normal. Bilateral adrenalectomy confirmed MAD as the cause of CS. We present the history’ and identification of a unique case of iMAD. PMID:20662336

  19. Cytochrome P450-catalyzed binding of 3-methylsulfonyl-DDE and o,p'-DDD in human adrenal zona fasciculata/reticularis.

    Science.gov (United States)

    Lindhe, Orjan; Skogseid, Britt; Brandt, Ingvar

    2002-03-01

    3-Methylsulfonyl-2,2'-bis(4-chlorophenyl)-1,1'-dichloroethene (MeSO(2)-DDE) is a potent, tissue-specific toxicant that induces necrosis of the adrenal zona fasciculata following a local CYP11B1-catalyzed activation to a reactive intermediate in mice. Autoradiography was used to examine CYP11B1-catalyzed binding of MeSO(2)-[(14)C]DDE and the adrenocorticolytic drug 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichlorethane; (o,p'-[(14)C]DDD, Mitotane, Lysodren) in human adrenal tissue slice culture. Both compounds gave rise to a selective binding in the one sample of normal adrenal zona fasciculata/reticularis, leaving zona glomerulosa and the adrenal medulla devoid of binding. Addition of the CYP11B1 selective inhibitor metyrapone (50 microM) reduced MeSO(2)-[(14)C]DDE binding below the detection limit, whereas o,p'-[(14)C]DDD binding was reduced only by 42%. Selective binding of MeSO(2)-[(14)C]DDE and o,p'-[(14)C]DDD was also observed in an aldosterone-producing adrenocortical carcinoma and in a nonfunctional adrenocortical hyperplasia. Exposure of slices from the normal adrenal cortex to MeSO(2)-DDE (25 microM) resulted in an increased accumulation of 11-deoxycorticosterone, 11-deoxycortisol and androstenedione in the medium, and exposure to o,p'-DDD (25 microM) did not alter the steroid secretion pattern. No histological changes were found in either MeSO(2)-DDE- or o,p'-DDD-exposed slices, compared with nonexposed slices. We suggest that MeSO(2)-DDE might act as a potent adrenocorticolytic agent in humans. Further studies are needed to establish the usefulness of MeSO(2)-DDE as a possible alternative for the treatment of adrenocortical hypersecretion and tumor growth.

  20. Flavonoids exhibit diverse effects on CYP11B1 expression and cortisol synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Li-Chuan; Li, Lih-Ann, E-mail: lihann@nhri.org.tw

    2012-02-01

    CYP11B1 catalyzes the final step of cortisol biosynthesis. The effects of flavonoids on transcriptional expression and enzyme activity of CYP11B1 were investigated using the human adrenocortical H295R cell model. All tested nonhydroxylated flavones including 3′,4′-dimethoxyflavone, α-naphthoflavone, and β-naphthoflavone upregulated CYP11B1 expression and cortisol production, whereas apigenin and quercetin exhibited potent cytotoxicity and CYP11B1 repression at high concentrations. Nonhydroxylated flavones stimulated CYP11B1-catalyzed cortisol formation at transcriptional level. Resveratrol increased endogenous and substrate-supported cortisol production like nonhydroxylated flavones tested, but it had no effect on CYP11B1 gene expression and enzyme activity. Resveratrol appeared to alter cortisol biosynthesis at an earlier step. The Ad5 element situated in the − 121/− 106 region was required for basal and flavone-induced CYP11B1 expression. Overexpression of COUP-TFI did not improve the responsiveness of Ad5 to nonhydroxylated flavones. Although COUP-TFI overexpression increased CYP11B1 and CYP11B2 promoter activation, its effect was not mediated through the common Ad5 element. Treating cells with PD98059 (a flavone-type MEK1 inhibitor) increased CYP11B1 promoter activity, but not involving ERK signaling because phosphorylation of ERK1/2 remained unvarying throughout the course of treatment. Likewise, AhR was not responsible for the CYP11B1-modulating effects of flavonoids because inconsistency with their effects on AhR activation. 3′,4′-dimethoxyflavone and 8-Br-cAMP additively activated CYP11B1 promoter activity. H-89 reduced 3′,4′-dimethoxyflavone-induced CYP11B1 promoter activation but to a lesser extent as compared to its inhibition on cAMP-induced transactivation. Our data suggest that constant exposure to nonhydroxylated flavones raises a potential risk of high basal and cAMP-induced cortisol synthesis in consequence of increased CYP11B1

  1. Temporal and spatial distribution of mast cells and steroidogenic enzymes in the human fetal adrenal.

    Science.gov (United States)

    Naccache, Alexandre; Louiset, Estelle; Duparc, Céline; Laquerrière, Annie; Patrier, Sophie; Renouf, Sylvie; Gomez-Sanchez, Celso E; Mukai, Kuniaki; Lefebvre, Hervé; Castanet, Mireille

    2016-10-15

    Mast cells are present in the human adult adrenal with a potential role in the regulation of aldosterone secretion in both normal cortex and adrenocortical adenomas. We have investigated the human developing adrenal gland for the presence of mast cells in parallel with steroidogenic enzymes profile and serotonin signaling pathway. RT-QPCR and immunohistochemical studies were performed on adrenals at 16-41 weeks of gestation (WG). Tryptase-immunopositive mast cells were found from 18 WG in the adrenal subcapsular layer, close to 3βHSD- and CYP11B2-immunoreactive cells, firstly detected at 18 and 24 WG, respectively. Tryptophan hydroxylase and serotonin receptor type 4 expression increased at 30 WG before the CYP11B2 expression surge. In addition, HDL and LDL cholesterol receptors were expressed in the subcapsular zone from 24 WG. Altogether, our findings suggest the implication of mast cells and serotonin in the establishment of the mineralocorticoid synthesizing pathway during fetal adrenal development.

  2. Controlled Cohort Study of Serum Gonadal and Adrenocortical Steroid Levels in Males Prior to Onset of Rheumatoid Arthritis (pre-RA: A Comparison to pre-RA Females and Sex Differences among the Study Groups

    Directory of Open Access Journals (Sweden)

    Alfonse T. Masi

    2013-01-01

    Full Text Available Serum testosterone levels are generally reported to be lower in male rheumatoid arthritis (RA patients, but it is not determined if a deficiency may occur before clinical onset of disease (pre-RA. Lower testosterone levels were recently reported in males many years before RA onset but were predictive only of rheumatoid factor (RF—negative disease. A preceding prospective study did not reveal androgenic-anabolic hormone association with risk of RA in men or women. This cohort study of males analyzed baseline serum levels of gonadal and adrenocortical steroids, luteinizing hormone, and prolactin in 18 pre-RA versus 72 matched non-RA control (CN subjects. Findings in males were compared to those in female pre-RA and CN subjects in the same cohort, and sex differences were analyzed. Steroidal and hormonal levels, including total testosterone, were similar between male study groups. In females, mean (±SE serum androstenedione (nmol/L was slightly (P=0.048 lower in 36 pre-RA (6.7 ± 0.36 than 144 CN (7.6 ± 0.22. With the exception of 3 partial correlations of hormonal variables observed to differ between pre-RA versus CN subjects, the patterns were similar overall. However, partial correlations of hormonal variables differed frequently by sex, both within and between study groups.

  3. The relevance of chemical interactions with CYP17 enzyme activity: Assessment using a novel in vitro assay

    Energy Technology Data Exchange (ETDEWEB)

    Roelofs, Maarke J.E., E-mail: m.j.e.roelofs@uu.nl [Endocrine Toxicology Research Group, Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.177, NL-3508 TD Utrecht (Netherlands); Center for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Piersma, Aldert H. [Endocrine Toxicology Research Group, Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.177, NL-3508 TD Utrecht (Netherlands); Center for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Berg, Martin van den; Duursen, Majorie B.M. van [Endocrine Toxicology Research Group, Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.177, NL-3508 TD Utrecht (Netherlands)

    2013-05-01

    The steroidogenic cytochrome P450 17 (CYP17) enzyme produces dehydroepiandrosterone (DHEA), which is the most abundant circulating endogenous sex steroid precursor. DHEA plays a key role in e.g. sexual functioning and development. To date, no rapid screening assay for effects on CYP17 is available. In this study, a novel assay using porcine adrenal cortex microsomes (PACMs) was described. Effects of twenty-eight suggested endocrine disrupting compounds (EDCs) on CYP17 activity were compared with effects in the US EPA validated H295R (human adrenocorticocarcinoma cell line) steroidogenesis assay. In the PACM assay DHEA production was higher compared with the H295R assay (4.4 versus 2.2 nmol/h/mg protein). To determine the additional value of a CYP17 assay, all compounds were also tested for interaction with CYP19 (aromatase) using human placental microsomes (HPMs) and H295R cells. 62.5% of the compounds showed enzyme inhibition in at least one of the microsomal assays. Only the cAMP inducer forskolin induced CYP17 activity, while CYP19 was induced by four test compounds in the H295R assay. These effects remained unnoticed in the PACM and HPM assays. Diethylstilbestrol and tetrabromobisphenol A inhibited CYP17 but not CYP19 activity, indicating different mechanisms for the inhibition of these enzymes. From our results it becomes apparent that CYP17 can be a target for EDCs and that this interaction differs from interactions with CYP19. Our data strongly suggest that research attention should focus on validating a specific assay for CYP17 activity, such as the PACM assay, that can be included in the EDC screening battery. - Highlights: ► DHEA, produced by CYP17, plays a key role in sexual functioning and development. ► No rapid screening assay for effects on CYP17 is available yet. ► A novel assay using porcine adrenal cortex microsomes (PACMs) was described. ► Endocrine disrupting compounds (EDCs) targeting CYP17 interact differently with CYP19. ► A

  4. Expression of adrenomedullin 2/intermedin in human adrenal tumors and attached non-neoplastic adrenal tissues.

    Science.gov (United States)

    Morimoto, Ryo; Satoh, Fumitoshi; Murakami, Osamu; Hirose, Takuo; Totsune, Kazuhito; Imai, Yutaka; Arai, Yoichi; Suzuki, Takashi; Sasano, Hironobu; Ito, Sadayoshi; Takahashi, Kazuhiro

    2008-07-01

    Adrenomedullin 2/intermedin (AM2/IMD) is a new member of calcitonin/calcitonin gene-related peptide family. AM is expressed in various tumors including adrenocortical tumors and modulates tumor growth. The AM2/IMD expression has not been studied, however, in adrenal tumors. The expression of AM2/IMD and AM was therefore studied in human adrenal tumors and attached non-neoplastic adrenal tissues by immunocytochemistry (ICC). Immunoreactive (IR)-AM2/IMD was measured by RIA. Furthermore, the expression of AM2/IMD and its receptor components, calcitonin receptor-like receptor (CRLR), and receptor activity-modifying proteins (RAMPs) 1, 2, and 3 mRNA in these tissues was studied by reverse transcription PCR (RT-PCR). ICC showed that AM2/IMD and AM immunoreactivities were localized in adrenocortical tumors and pheochromocytomas. AM2/IMD and AM immunoreactivities were detected in medulla of attached non-neoplastic tissues, while the degree of immunoreactivity for AM2/IMD and AM in cortices of attached adrenals was relatively weak or undetectable. RIA detected IR-AM2/IMD in adrenal tumors (0.414+/-0.12 to 0.786+/-0.27 pmol/g wet weight, mean+/-S.E.M.) and attached adrenal tissues (0.397+/-0.052 pmol/g wet weight). Reverse-phase high-performance liquid chromatography showed one broad peak eluted in the similar position to synthetic AM2/IMD with several minor peaks. RT-PCR showed expression of AM2/IMD, CRLR, and RAMP1, RAMP2, and RAMP3 mRNA in tissues of adrenal tumors and attached adrenal glands. In conclusion, AM2/IMD is expressed in human adrenal tumors and attached non-neoplastic adrenal tissues and may play (patho-)physiological roles in normal and neoplastic adrenals as an autocrine/paracrine regulator.

  5. 大鼠肾上腺皮质细胞原代培养分离与鉴定%Isolation and identification of rat adrenocortical cells in primary culture

    Institute of Scientific and Technical Information of China (English)

    刘天乙; 杨波; 赵亮; 邓文宏; 赵凯亮; 王卫星

    2013-01-01

    目的 体外培养大鼠肾上腺皮质细胞原代细胞,并为临床实验提供对照和补充.方法 采用胶原酶Ⅱ、透明质酸酶消化法分离Wistar大鼠的肾上腺皮质细胞,在不同离心转速下离心后分为三组(A组1200r/min、B组1500r/min和C组1800r/min);分离出的细胞于全料培养基恒温培养;采用免疫组织化学法、培养基上清皮质酮水平测定及电镜下观察细胞形态分别鉴定.结果 三组中B组培养得到肾上腺皮质细胞较多,A、C组得到正常的皮质细胞较少;光镜下培养的肾上腺皮质细胞呈梭形、胞体较大、有少量突起,3β-羟内固醇脱氢酶特异性染色后胞质内可见大量棕黄色甲蜡沉淀;培养3d后换液,取培养基上清测定皮质酮水平特异性增高.结论 通过皮质酮水平测定、光镜和电镜下细胞形态观察及特异酶染色鉴定,本实验培养的细胞为原代大鼠肾上腺皮质细胞,该方法 培养出的肾上腺皮质细胞为肾上腺体外实验研究提供了技术基础.%Objective To culture the primary rat adrenal cortical cells in vitro and provide comparison and supplement for clinical experiment. Methods The adrenocortical cells of Wistar rats were dispersed by collagenase-hyaluronidase digestion. According to the different centrifugal speed, the cells were divided into 3 groups:group A( 1200 r/min ),group B( 1500 r/min )and group C( 1800 r/min ). All the isolated cells were cultured under a constant temperature; Immunohistochemical method, determination of corticosterone levels and electron microscope were used to identify the cells. Results In all three groups,the adrenocortical cell count of group B was more than that of the group A and C. The cultured adrenal cortical cell was spindle with a big body and a small amount of protrusions under the light microscope. After the specific staining of 3β-hydroxysteroid dehydrogenase( 3β-HSD ),a large number of brown-yellow precipitates of formazan were

  6. Effect of a high-fat--high-fructose diet, stress and cinnamon on central expression of genes related to immune system, hypothalamic-pituitary-adrenocortical axis function and cerebral plasticity in rats.

    Science.gov (United States)

    Marissal-Arvy, Nathalie; Batandier, Cécile; Dallennes, Julien; Canini, Frédéric; Poulet, Laurent; Couturier, Karine; Hininger-Favier, Isabelle; Moisan, Marie-Pierre; Roussel, Anne-Marie; Mormède, Pierre

    2014-04-14

    The intake of a high-fat/high-fructose (HF/HFr) diet is described to be deleterious to cognitive performances, possibly via the induction of inflammatory factors. An excess of glucocorticoids is also known to exert negative effects on cerebral plasticity. In the present study, we assessed the effects of an unbalanced diet on circulating and central markers of inflammation and glucocorticoid activity, as well as their reversal by dietary cinnamon (CN) supplementation. A group of male Wistar rats were subjected to an immune challenge with acute lipopolysaccharide under a HF/HFr or a standard diet. Another group of Wistar rats were fed either a HF/HFr or a control diet for 12 weeks, with or without CN supplementation, and with or without restraint stress (Str) application before being killed. We evaluated the effects of such regimens on inflammation parameters in the periphery and brain and on the expression of actors of brain plasticity. To assess hypothalamic-pituitary-adrenocortical axis activity, we measured the plasma concentrations of corticosterone and the expression of central corticotrophin-releasing hormone, mineralocorticoid receptor, glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase. We found that the HF/HFr diet induced the expression of cytokines in the brain, but only after an immune challenge. Furthermore, we observed the negative effects of Str on the plasma concentrations of corticosterone and neuroplasticity markers in rats fed the control diet but not in those fed the HF/HFr diet. Additionally, we found that CN supplementation exerted beneficial effects under the control diet, but that its effects were blunted or even reversed under the HF/HFr diet. CN supplementation could be beneficial under a standard diet. [corrected].

  7. The adrenal gland and the patient with pulmonary tuberculosis infected with human immunodeficiency virus

    Directory of Open Access Journals (Sweden)

    Ifedayo Adeola Odeniyi

    2017-01-01

    Full Text Available Background: The adrenal gland is not spared from the involvement by tuberculosis. One of the recognized causes of adrenal insufficiency (AI is tuberculosis. AI, mostly at the subclinical level, is common in persons with pulmonary tuberculosis (PTB infection, occurring in about 23% of patients. Coinfection with PTB and human immunodeficiency virus (HIV may compromise adrenocortical function and produce significant adrenocortical insufficiency. Objective: To determine if coinfection with tuberculosis and HIV have a compound effect on adrenocortical function in persons with HIV and PTB coinfection. Materials and Methods: Persons with sputum-positive PTB, treatment naive, who met our inclusion criteria, were selected. All the recruited patients were screened for HIV and those positive for HIV infection had confirmatory test. A baseline blood samples for cortisol, fasting plasma glucose, full blood count, and electrolytes were collected between 8.00 h and 9.00 h immediately before administration of adrenocorticotropic hormone (ACTH. The persons received an intravenous bolus injection of 1 μg ACTH (Alliance Pharmaceuticals Ltd., Chippenham, Wiltshire SN15 2BB and blood sample was drawn for cortisol level at 30 min. Results: Forty-four people with PTB infection and forty people with PTB and HIV coinfection met the inclusion criteria of the study. The adrenal response to 1 μg ACTH stimulation in participants with PTB and PTB and HIV coinfection showed that the mean basal cortisol level in the 2 groups was not statistically significant; however, 30-min post-ACTH stimulation cortisol level was 630.84 ± 372.17 and 980.36 ± 344.82 nmol/L (P < 0.001 and increment was 367.79 ± 334.87 and 740.77 ± 317.97 nmol/L (P < 0.001, respectively. Fourteen persons (31.8% with PTB has subnormal adrenal response to ACTH stimulation while only 2 (5% persons with PTB and HIV coinfection has subnormal response. Conclusion: AI, at subclinical level, was less frequent in

  8. Effects of nutrition relevant mixtures of phytoestrogens on steroidogenesis, aromatase, estrogen, and androgen activity.

    Science.gov (United States)

    Taxvig, Camilla; Elleby, Anders; Sonne-Hansen, Katrine; Bonefeld-Jørgensen, Eva C; Vinggaard, Anne Marie; Lykkesfeldt, Anne E; Nellemann, Christine

    2010-01-01

    Phytoestrogens (PEs) are naturally occurring plant components produced in a large range of plants. They can induce biologic responses in vertebrates by mimicking or modulating the action or production of endogenous hormones. This study examined mixtures of 12 food relevant PEs for effects on steroid hormone production, aromatase activity, estrogenic activity, and for interaction with the androgen receptor. The results show that a mixture of all tested PEs increased estradiol production and decreased testosterone production in H295R human adrenal corticocarcinoma cells, indicating an induced aromatase activity. Furthermore, exposure of the H295R cells to isoflavonoids caused a decrease in testosterone production, and various mixtures of PEs significantly stimulated MCF-7 human breast adenocarcinoma cell growth and induced aromatase activity in JEG-3 choriocarcinoma cells. The estrogenic effect in the MCF7 cells of the isoflavonoid mixture and coumestrol was supported by an observed increase in progesterone receptor protein expression as well as a decreased ERalpha expression. Overall, the results support that nutrition-relevant concentrations of PEs both alone and in mixtures possess various endocrine disrupting effects, all of which need to be considered when assessing the effects on human health.

  9. Aberrant gonadotropin-releasing hormone receptor (GnRHR) expression and its regulation of CYP11B2 expression and aldosterone production in adrenal aldosterone-producing adenoma (APA).

    Science.gov (United States)

    Nakamura, Yasuhiro; Hattangady, Namita G; Ye, Ping; Satoh, Fumitoshi; Morimoto, Ryo; Ito-Saito, Takako; Sugawara, Akira; Ohba, Koji; Takahashi, Kazuhiro; Rainey, William E; Sasano, Hironobu

    2014-03-25

    Aberrant expression of gonadotropin-releasing hormone receptor (GnRHR) has been reported in human adrenal tissues including aldosterone-producing adenoma (APA). However, the details of its expression and functional role in adrenals are still not clear. In this study, quantitative RT-PCR analysis revealed the mean level of GnRHR mRNA was significantly higher in APAs than in human normal adrenal (NA) (P=0.004). GnRHR protein expression was detected in human NA and neoplastic adrenal tissues. In H295R cells transfected with GnRHR, treatment with GnRH resulted in a concentration-dependent increase in CYP11B2 reporter activity. Chronic activation of GnRHR with GnRH (100nM), in a cell line with doxycycline-inducible GnRHR (H295R-TR/GnRHR), increased CYP11B2 expression and aldosterone production. These agonistic effects were inhibited by blockers for the calcium signaling pathway, KN93 and calmidazolium. These results suggest GnRH, through heterotopic expression of its receptor, may be a potential regulator of CYP11B2 expression levels in some cases of APA. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. CT 引导下经皮射频消融治疗肾上腺皮质腺瘤库欣综合征%CT-guided percutaneous radiofrequency ablation for adrenocortical adenoma with Cushing's syndrome

    Institute of Scientific and Technical Information of China (English)

    屈峰; 查振雷; 周科峰; 连惠波; 张古田; 汪维; 兰厚金; 甘卫东; 郭宏骞

    2015-01-01

    目的:评价CT引导下经皮射频消融( radiofrequency ablation ,RFA)治疗肾上腺皮质腺瘤库欣综合征( Cushing's syndrome )的可行性、安全性、疗效和不良反应。方法自2009年1月至2013年12月,采用CT引导下射频消融治疗肾上腺皮质腺瘤库欣综合征患者24例,共24个肿瘤。平均肿瘤直径(2.1±0.7)(1.1~3.9)cm。采用CT实时扫描引导下进行射频消融。术后1周复查增强CT扫描,肿瘤病灶无强化定义为消融成功。术后随访血清皮质醇及促肾上腺皮质激素较术前明显改善,且症状改善定义为临床治愈。射频消融术后肿瘤病灶穿刺活检取病理明确诊断。结果24例手术均获成功,无中转开放。术中患者出现血压波动,未发生高血压危象,6例术后出现腰部轻微疼痛。术后1周CT增强扫描显示24个肿瘤完全消融。24例平均随访18(3~36)个月,血清皮质醇及促肾上腺皮质激素基本恢复到正常水平,库欣综合征相关症状也逐渐改善,随访过程中未见肿瘤复发。病理活检结果均为肾上腺皮质腺瘤。所有患者均无严重并发症发生。结论 CT引导下RFA治疗具有库欣综合征的肾上腺皮质腺瘤是一种安全可行、有效、并发症少的微创治疗方法。%Objective To evaluate the feasibility , safety, therapeutic effects and adverse reactions of CT-guided radiofrequency ablation (RFA)for adrenocortical adenoma with Cushing's syndrome.Methods From Jan.2009 to Dec.2013, 24 patients with 24 tumors diagnosed as adrenocortical adenoma with Cushing's syn-drome received CT-guided percutaneous RFA.The average tumor size was(2.1 ±0.7)cm(ranging from 1.1 to 3.9 cm) .RFA was performed under real-time computed tomography guidance .Technical success was defined as disappearance of tumor enhancement on contrast CT imaging 1 week after RFA .Clinical success was defined as improvement in serum cortisol, adreno

  11. Alpha-human atrial natriuretic polypeptide (. cap alpha. -hANP) specific binding sites in bovine adrenal gland

    Energy Technology Data Exchange (ETDEWEB)

    Higuchi, K.; Nawata, H.; Kato, K.I.; Ibayashi, H.; Matsuo, H.

    1986-06-13

    The effects of synthetic ..cap alpha..-human atrial natriuretic polypeptide (..cap alpha..-hANP) on steroidogenesis in bovine adrenocortical cells in primary monolayer culture were investigated. ..cap alpha..-hANP did not inhibit basal aldosterone secretion. ..cap alpha..-hANP induced a significant dose-dependent inhibition of basal levels of cortisol and dehydroepiandrosterone (DHEA) secretion and also of aCTH (10/sup -8/M)-stimulated increases in aldosterone, cortisol and DHEA secretion. Visualization of (/sup 125/I) ..cap alpha..-hANP binding sites in bovine adrenal gland by an in vitro autoradiographic technique demonstrated that these sites were highly localized in the adrenal cortex, especially the zona glomerulosa. These results suggest that the adrenal cortex may be a target organ for direct receptor-mediated actions of ..cap alpha..-hANP.

  12. Transposition of pedicled adrenal gland for the treatment of adrenocortical and medullary hyperplasia%带蒂肾上腺背部皮下移位术治疗肾上腺皮髓质增生

    Institute of Scientific and Technical Information of China (English)

    孟庆军; 赵高贤; 徐培元; 白悦心; 张卫星; 魏金星

    2009-01-01

    DA和VMA、血钾和Ald均恢复正常;4例血压、17-OH和17-KS仍偏高,再行对侧肾上腺移位或切除后,恢复正常. 结论 带蒂肾上腺背部皮下移位术是治疗肾上腺皮髓质增生的有效方法.%Objective To investigate the clinical efficacy of pedicled adrenal transposition for the treatment of adrenocortical and medullary hyperplasia, Methods Twenty cases of adrenal hyperpla-sia (6 men and 14 women; mean age,36 years ) had history of hypertension from 0.5 to 5 years. Of all cases, 15 had centripetal obesity and purple striae, 2 had weakness and polyuria, 3 had durative hypertension. Serum potassium and aldosterone were increased in 4 and 3 cases, respectively. Urinary 17-OH and 17-KS were increased in 15 cases. Epinepgrine, norepinephrine and dopamine increased in 3 cases, VMA increased in 4 cases. CT scan and MRI revealed adrenal diffuse enlargement with in-creased thickness or nodules in 18 and 3 cases, respectively, 131I-MIBG scan showed positive in 3 ca-ses. Preoperative diagnoses were Cushing's syndrome in 11 cases, hyperaldosteronism in 2 cases, pheochromocytoma in 1 case, adrenomedullary hyperplasia in 2 cases, Cushing's syndrome-cate-cholamine syndrome in 4 cases. All cases were treated with transposition of pedicled adrenal gland into the subcutaneous tissues. Results All operations were successful. The average operation time was 120 min, the average blood loss was 40 ml and the average hospital stay was 10 d. No obvious surgical complications occurred. Pathological studies of all the cases revealed the coexistence of adrenocortical and medullary hyperplasia. Seventeen cases were followed up for 0.5-8 years. Thirteen cases had no symptom and normal biochemical results. Four cases still had hypertension and abnormal biochemical results. They were recovered after adrenal operation of the ther side. Conclusion Transposition of pedicled adrenal gland could be an available option to treat patients with adrenocortical and medullary

  13. Identification of a novel TP53 germline mutation in one child with adrenocortical carcinoma%肾上腺皮质癌患儿TP53基因的一个新生殖系突变

    Institute of Scientific and Technical Information of China (English)

    司锘; 孙淼; 卢超霞; 刘彦山; 齐展; 杨威; 赵秀丽; 张学

    2009-01-01

    Objective To detect the germline TP53 gene mutation in a child with pediatric adrenocortical carcinoma (ADCC) in order to provide genetic diagnosis and counseling. Methods Genomic DNA was extracted from peripheral blood from a girl with ADCC and her parents. All TP53 exons and their flanking intronic sequences were PCR-amplified and subjected to automatic DNA sequencing. Results Direct sequencing of PCR products revealed a heterozygous G insertion between nucleotide 522 and 523 (c.522-523insG) in TP53 exon 5. This novel mutation is predicted to result in a frame shift at codon 175, producing a new reading frame ending in a stop at position 6 (p.R175AfsX6). The same heterozygous mutation was also found in her father, but not in her mother. Conclusion A novel germline mutation in the TP53 gene has been identified in one case with pediatric ADCC.%目的 研究1例肾上腺皮质癌患儿TP53基因突变情况,为该病的基因诊断与遗传咨询提供依据.方法 提取1例肾上腺皮质癌患儿及父母外周血基因组DNA,针对TP53基因设计特异性引物,采用聚合酶链式反应(PCR)扩增基因的全部编码及侧翼序列,对扩增产物进行直接测序.结果 PCR结合DNA测序发现患者TP53基因第5外显子存在异常:第522与523位核苷酸间插入一个鸟嘌呤(c.522-523insG),导致P53蛋白DNA结合域第175位密码子由精氨酸(R)变为丙氨酸(A),并从突变位置起发生移码,产生移码突变(p.R175AfsX6).患者父亲带有相同的突变,而母亲未发现此突变.结论 TP53基因p.R175AfsX6生殖系突变是导致该例患者肾上腺皮质癌的特异突变.

  14. Assessment of the relationship between melatonin, hormones of the pituitary-ovarian, -thyroid and -adrenocortical axes, and osteoprotegerin and its ligand sRANKL in girls with anorexia nervosa

    Directory of Open Access Journals (Sweden)

    Zofia Ostrowska

    2013-05-01

    Full Text Available Background: It has been suggested that disturbances in melatonin (MEL secretion might play a role in osteoporosis development in females with anorexia nervosa (AN. It might be hypothesized that changes in the levels of hormones of the pituitary-ovarian, -thyroid and -adrenocortical axes might mediate the potential relationship between MEL and bone tissue.Aim: We investigated whether a relationship existed between MEL and LH, FSH-E2, TSH-FT3, FT4 and ACTH-cortisol axes in girls with AN. We also aimed to establish whether such a relationship might adversely affect the balance of the OPG/sRANKL system.Material/Methods: Eighty-six girls with AN and 21 healthy subjects aged 12.6 to 18.2 years participated in the study. The serum levels of hormones as well as OPG and sRANKL were determined by radioimmunoassay (RIA, immunoradiometric assay (IRMA or enzyme-linked immunosorbent assay (ELISA methods.Discussion: Our study participants with AN showed a significant reduction in body mass and body mass index (BMI, a decrease in LH, E2 and FT3 concentrations, increased MEL concentration at 02.00 hours and increased amplitude between its nocturnal and morning levels (Δ MEL2.00/9.00 as well as an increase in cortisol concentration. These changes were associated with a significant increase of OPG and sRANKL levels and a decrease in the OPG/sRANKL ratio. BMI values correlated positively with LH, FSH, E2, FT3 and the OPG/sRANKL ratio while the correlation between BMI and cortisol was negative. Δ MEL2.00/9.00 correlated positively with cortisol and negatively with LH, FSH, E2, FT3 concentrations and the OPG/sRANKL ratio. A positive correlation was observed between LH, E2 and the OPG/sRANKL ratio as well as between cortisol and sRANKL while the correlation between LH and OPG as well as between cortisol and the OPG/sRANKL ratio was negative. E2 and LH were shown to be significant and independent predictors of Δ MEL2.00/9.00. LH turned out to be a

  15. Late recurrent adrenocortical carcinoma presenting radiologically as ...

    African Journals Online (AJOL)

    A. Beltagy

    2016-07-01

    Jul 1, 2016 ... Official journal of the Pan African Urological Surgeon's Association ... symptoms and signs of hormonal excess [3–5]. ... On high power examination, the vast majority of the cells are polygonal with abundant eosinophilic ...

  16. Current management options for recurrent adrenocortical carcinoma

    Directory of Open Access Journals (Sweden)

    Glover AR

    2013-06-01

    Full Text Available Anthony R Glover,1 Julian C Y Ip,1 Jing Ting Zhao,1 Patsy S H Soon,1,4 Bruce G Robinson,1,3 Stan B Sidhu1,2 1Kolling Institute of Medical Research, Cancer Genetics Laboratory, 2Endocrine Surgical Unit, 3Department of Endocrinology, Royal North Shore Hospital and University of Sydney, St Leonards, 4Department of Surgery, Bankstown Hospital and University of New South Wales, Bankstown, NSW, Australia Abstract: Adrenal cortical carcinoma (ACC is a rare cancer that poses a number of management challenges due to the limited number of effective systemic treatments. Complete surgical resection offers the best chance of long-term survival. However, despite complete resection, ACC is associated with high recurrence rates. This review will discuss the management of recurrent ACC in adults following complete surgical resection. Management should take place in a specialist center and treatment decisions must consider the individual tumor biology of each case of recurrence. Given the fact that ACC commonly recurs, management to prevent recurrence should be considered from initial diagnosis with the use of adjuvant mitotane. Close follow up with clinical examination and imaging is important for early detection of recurrent disease. Locoregional recurrence may be isolated, and repeat surgical resection should be considered along with mitotane. The use of radiotherapy in ACC remains controversial. Systemic recurrence most often involves liver, pulmonary, and bone metastasis and is usually managed with mitotane, with or without combination chemotherapy. There is a limited role for surgical resection in systemic recurrence in selected patients. In all patients with recurrent disease, control of excessive hormone production is an important part of management. Despite intensive management of recurrent ACC, treatment failure is common and the use of clinical trials and novel treatment is an important part of management. Keywords: recurrence, surgery, chemotherapy, mitotane, treatment

  17. Fluoxetine and its active metabolite norfluoxetine disrupt estrogen synthesis in a co-culture model of the feto-placental unit.

    Science.gov (United States)

    Hudon Thibeault, Andrée-Anne; Laurent, Laetitia; Vo Duy, Sung; Sauvé, Sébastien; Caron, Patrick; Guillemette, Chantal; Sanderson, J Thomas; Vaillancourt, Cathy

    2017-02-15

    The effects of fluoxetine, one of the most prescribed selective serotonin-reuptake inhibitors (SSRIs) during pregnancy, and its active metabolite norfluoxetine were studied on placental aromatase (CYP19) and feto-placental steroidogenesis. Fluoxetine did not alter estrogen secretion in co-culture of fetal-like adrenocortical (H295R) and trophoblast-like (BeWo) cells used as a model of the feto-placental unit, although it induced CYP19 activity, apparently mediated by the serotonin (5-HT)2A receptor/PKC signaling pathway. Norfluoxetine decreased estrogen secretion in the feto-placental co-culture and competitively inhibited catalytic CYP19 activity in BeWo cells. Decreased serotonin transporter (SERT) activity in the co-culture was comparable to 17β-estradiol treatment of BeWo cells. This work shows that the complex interaction of fluoxetine and norfluoxetine with placental estrogen production, involves 5-HT-dependent and -independent mechanisms. Considering the crucial role of estrogens during pregnancy, our results raise concern about the impact of SSRI treatment on placental function and fetal health. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Effect of "rose essential oil" inhalation on stress-induced skin-barrier disruption in rats and humans.

    Science.gov (United States)

    Fukada, Mika; Kano, Eri; Miyoshi, Michio; Komaki, Ryoichi; Watanabe, Tatsuo

    2012-05-01

    In stressed animals, several brain regions (e.g., hypothalamic paraventricular nucleus [PVN]) exhibit neuronal activation, which increases plasma adrenocorticotropic hormone (ACTH) and glucocorticoids. We previously reported that so-called "green odor" inhibits stress-induced activation of the hypothalamo-pituitary-adrenocortical axis (HPA axis) and thereby prevents the chronic stress-induced disruption of the skin barrier. Here, we investigated whether rose essential oil, another sedative odorant, inhibits the stress-induced 1) increases in PVN neuronal activity in rats and plasma glucocorticoids (corticosterone [CORT] in rats and cortisol in humans) and 2) skin-barrier disruption in rats and humans. The results showed that in rats subjected to acute restraint stress, rose essential oil inhalation significantly inhibited the increase in plasma CORT and reduced the increases in the number of c-Fos-positive cells in PVN. Inhalation of rose essential oil significantly inhibited the following effects of chronic stress: 1) the elevation of transepidermal water loss (TEWL), an index of the disruption of skin-barrier function, in both rats and humans and 2) the increase in the salivary concentration of cortisol in humans. These results suggest that in rats and humans, chronic stress-induced disruption of the skin barrier can be limited or prevented by rose essential oil inhalation, possibly through its inhibitory effect on the HPA axis.

  19. The rapid tapering glucocorticoids replacement perioperatively on adrenocortical adenoma related Cushing's syndrome:a prospective study%围手术期激素快速撤退疗法对于肾上腺皮质腺瘤所致库欣综合征的临床治疗效果观察

    Institute of Scientific and Technical Information of China (English)

    徐烈雨; 廉建坡; 陈东宁; 祝宇; 赵菊平; 吴瑜璇; 沈周俊; 宁光

    2015-01-01

    Objective To prospectively investigate the safety of rapid tapering glucocorticoids supplementation periopera-tively for the treatment of Cushing's syndrome caused by adrenocortical adenoma.Methods A total of 38 patients with adre-nocortical adenoma caused Cushing's syndrome were enrolled,who were treated during Feb.2010 and Jan.2013.Of all pa-tients,18 received novel rapid tapering regimen (group A),and the other 20 were supplied with conventional tapering dose (group B).The regimen of group A was reduced fast till the maintenance within 4 days,while it was gradually decreased within nearly 2 weeks.Results The rapid tapering regimen could significantly reduce the duration of hospital stay from (8.25 ± 1?28) d in conventional group to (5.83 ± 0.75)d of group A (P<0.01).With similar curative effects achieved,it could also help to shorten the cortisol withdrawal duration,which was (8.70 ± 3.89) for group A and (10.22 ± 3.07) months for group B.The difference was significant (P<0.05).Conclusions The rapid cortisol tapering perioperatively is safe,effective and ben-eficial for patients with Cushing's Syndrome caused by adrenocortical adenoma undergoing adrenalectomy.%目的 探讨围手术期激素提前撤退对于ACT H-非依赖型库欣综合征患者的治疗效果,重点研究该疗法是否能够满足术后患者激素需要量及其治疗效果.方法 本试验收集2010年2月至2013年1月瑞金医院收治的38例肾上腺皮质腺瘤所致库欣综合征患者,其中18例围手术期给予激素快速撤退补充治疗,另外20例则给予传统激素补充方案,收集患者术前、术后及随访临床资料并研究.结果 两组患者治疗方案术前、术后总体预后相似,但围手术期激素快速撤退疗法能够明显降低患者术后住院天数[(5.83 ± 0.75)] vs.(8.25 ± 1.28)d,P<0.01],同时能够缩减激素完全时间[(8.70 ± 3.89)vs.(10.22 ± 3.07)月,P<0.05 ].结论 肾上腺皮质腺瘤所致库欣综合征围手术期给

  20. Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311).

    Science.gov (United States)

    Qiao, Jennifer X; Wang, Tammy C; Adam, Leonard P; Chen, Alice Ye A; Taylor, David S; Yang, Richard Z; Zhuang, Shaobin; Sleph, Paul G; Li, Julia P; Li, Danshi; Yin, Xiaohong; Chang, Ming; Chen, Xue-Qing; Shen, Hong; Li, Jianqing; Smith, Daniel; Wu, Dauh-Rurng; Leith, Leslie; Harikrishnan, Lalgudi S; Kamau, Muthoni G; Miller, Michael M; Bilder, Donna; Rampulla, Richard; Li, Yi-Xin; Xu, Carrie; Lawrence, R Michael; Poss, Michael A; Levesque, Paul; Gordon, David A; Huang, Christine S; Finlay, Heather J; Wexler, Ruth R; Salvati, Mark E

    2015-11-25

    Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.

  1. Human See, Human Do.

    Science.gov (United States)

    Tomasello, Michael

    1997-01-01

    A human demonstrator showed human children and captive chimpanzees how to drag food or toys closer using a rakelike tool. One side of the rake was less efficient than the other for dragging. Chimps tried to reproduce results rather than methods while children imitated and used the more efficient rake side. Concludes that imitation leads to…

  2. In vitro and in vivo screening of azole fungicides for antiandrogenic effects

    DEFF Research Database (Denmark)

    Taxvig, Camilla; Vinggaard, Anne; Hass, Ulla

    and antiandrogenic effects both in vitro and in vivo. Two other azole fungicides, tebuconazole and epoxiconazole, have now been investigated for antiandrogenic effects in vitro and in vivo as well. The fungicides were screened in two well-established cell assays, including testing for agonistic and antagonistic...... effects on AR in transfected CHO cells, using an AR reporter gene assay. The compounds were also analyzed for effects on steroidogenesis in H295R cells, a human adrenocorticocarcinoma cell line, used to detect effects on steroid production. In vitro tebuconazole and epoxiconazole proved to be antagonists...... signs of feminization of the male offspring were investigated. Tebuconazole caused an increase in testicular 17alfa-hydroxyprogesterone and progesterone levels, and a decrease in testosterone levels in male fetuses. Epoxiconazole had no effect on any of the mesured hormonelevels. Furthermore...

  3. More Human than Human.

    Science.gov (United States)

    Lawrence, David

    2017-07-01

    Within the literature surrounding nonhuman animals on the one hand and cognitively disabled humans on the other, there is much discussion of where beings that do not satisfy the criteria for personhood fit in our moral deliberations. In the future, we may face a different but related problem: that we might create (or cause the creation of) beings that not only satisfy but exceed these criteria. The question becomes whether these are minimal criteria, or hierarchical, such that those who fulfill them to greater degree should be afforded greater consideration. This article questions the validity and necessity of drawing divisions among beings that satisfy the minimum requirements for personhood; considering how future beings-intelligent androids, synthezoids, even alternate-substrate sentiences-might fit alongside the "baseline" human. I ask whether these alternate beings ought to be considered different to us, and why this may or may not matter in terms of a notion of "human community." The film Blade Runner, concerned in large part with humanity and its key synthezoid antagonist Roy Batty, forms a framing touchstone for my discussion. Batty is stronger, faster, more resilient, and more intelligent than Homo sapiens. His exploits, far beyond the capability of normal humans, are contrasted with his frailty and transient lifespan, his aesthetic appreciation of the sights he has seen, and his burgeoning empathy. Not for nothing does his creator within the mythos term him "more human than human."

  4. Expression of the human apolipoprotein E gene suppresses steroidogenesis in mouse Y1 adrenal cells

    Energy Technology Data Exchange (ETDEWEB)

    Reyland, M.E.; Forgez, P.; Prack, M.M.; Williams, D.L. (State Univ. of New York, Stony Brook (United States)); Gwynne, J.T. (Univ. of North Carolina, Chapel Hill (United States))

    1991-03-15

    The lipid transport protein, apolipoprotein E (apoE), is expressed in many peripheral tissues in vivo including the adrenal gland and testes. To investigate the role of apoE in adrenal cholesterol homeostasis, the authors have expressed a human apoE genomic clone in the Y1 mouse adrenocortical cell line. Y1 cells do not express endogenous apoE mRNA or protein. Expression of apoE in Y1 cells resulted in a dramatic decrease in basal steroidogenesis; secretion of fluorogenic steroid was reduced 7- to {gt}100-fold relative to Y1 parent cells. Addition of 5-cholesten-3{beta},25-idol failed to overcome the suppression of steroidogenesis in these cells. Cholesterol esterification under basal conditions, as measured by the production of cholesteryl ({sup 14}C)oleate, was similar in the Y1 parent and the apoE-transfected cell lines. Upon incubation with adrenocorticotropin or dibutyryl cAMP, production of cholesteryl ({sup 14}C)oleate decreased 5-fold in the Y1 parent cells but was unchanged in the apoE-transfected cell lines. These results suggest that apoE may be an important modulator of cholesterol utilization and steroidogenesis in adrenal cells.

  5. Regulation of endocrine-disrupting chemicals: critical overview and deficiencies in toxicology and risk assessment for human health.

    Science.gov (United States)

    Harvey, Philip W; Everett, David J

    2006-03-01

    Regulation of endocrine-disrupting chemicals is reviewed in terms of hazard assessment (regulatory toxicology) and risk assessment. The current range of regulatory general toxicology protocols can detect endocrine toxicity, but specific endocrine toxicology tests are required to confirm mechanisms (e.g. oestrogenic, anti-androgenic). Strategies for validating new endocrine toxicology protocols and approaches to data assessment are discussed, and deficiencies in regulatory toxicology testing (e.g. lack of adrenocortical function assessment) identified. Recent evidence of a role of prolactin in human breast cancer also highlights deficiencies in regulatory evaluation. Actual human exposure to chemicals and the high-exposure example of chemicals in body-care cosmetics is reviewed with reference to evidence that common ingredients (e.g. parabens, cyclosiloxanes) are oestrogenic. The hypothesis and epidemiology concerning chemical exposure from body-care cosmetics (moisturizers, lotions, sun screens, deodorants) and breast cancer in women is reviewed, applying Bradford-Hill criteria for association and causality, and research requirements are identified.

  6. Effects of 12 beticolins, Cercospora beticola toxins, on proliferation of ras-transformed adrenocortical cell%真菌Cercospora beticola的12种毒素贝第高林对癌基因ras转导的肾上腺细胞生长的作用

    Institute of Scientific and Technical Information of China (English)

    丁国庆; Gabrielle MAUME; Hanan OSMAN; Martine PADIEU; Marie-Louise MILAT; Claude HUMBERT; Jean-Pierre BLEIN; Bernard F MAUME

    2001-01-01

    AIM: To explore different effects of 12 beticolins, Cercospora beticola toxins, on ras-transformed adrenocortical cell growth inhibition and their functional mechanism.METHODS: Beticolin-induced inhibition was measured with survival cell number determined by an automated photocolorimetric method. The penetration of beticolin was examined by confocal microscopy. Ras protein determined by Lowry method were separated by 14 % SDS-PAGE and electroblotted to Immobilon-P transfer membrane and detected with pan-Ras (Ab-3) monoclonal antibody. The Ca2+ chelation by beticolin was investigated using a calcium ionophore. RESULTS: Cell growth inhibition was found dose- and time-dependently at submicromolar level for beticolin-1, -2, and -13 (IC50 ≤250 nmol/L) and for beticolin-0, 6, and-11 (400 nmol/L < IC50 ≤ 500 nmol/L ). The inhibition by beticolin-1 was immediate, independent of cell culture step and not reversible for 3-day treatment. Beticolin-3 and -4 were slightly active (1 μmol/L < IC50 ≤ 2μmol/L) and beticolin-7, -9, -12, and -5 were inactive at micromolar level. The beticolin-induced cell growth inhibition was correlated with the hydrophobicity of these compounds. Beticolin-1 fluorescence in RTAC cells was detected by confocal microscopy whereas beticolin-3 and -12 were not even after a 24 h incubation period.Beticolin-1-induced cell growth inhibition was partially reverted by calcium ionophore suggesting a role of intracellular Ca2 + chelation by beticolin-1 on cell growth inhibition. Furthermore, beticolin-1 blocked up Ras p21 translocation to membrane and induced accumulation of Ras in the cytosol as an inactive form by different ways.

  7. Human Development, Human Evolution.

    Science.gov (United States)

    Smillie, David

    One of the truly remarkable events in human evolution is the unprecedented increase in the size of the brain of "Homo" over a brief span of 2 million years. It would appear that some significant selective pressure or opportunity presented itself to this branch of the hominid line and caused a rapid increase in the brain, introducing a…

  8. Models of stress in nonhuman primates and their relevance for human psychopathology and endocrine dysfunction.

    Science.gov (United States)

    Meyer, Jerrold S; Hamel, Amanda F

    2014-01-01

    Stressful life events have been linked to the onset of severe psychopathology and endocrine dysfunction in many patients. Moreover, vulnerability to the later development of such disorders can be increased by stress or adversity during development (e.g., childhood neglect, abuse, or trauma). This review discusses the methodological features and results of various models of stress in nonhuman primates in the context of their potential relevance for human psychopathology and endocrine dysfunction, particularly mood disorders and dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system. Such models have typically examined the effects of stress on the animals' behavior, endocrine function (primarily the HPA and hypothalamic-pituitary-gonadal systems), and, in some cases, immune status. Manipulations such as relocation and/or removal of an animal from its current social group or, alternatively, formation of a new social group can have adverse effects on all of these outcome measures that may be either transient or more persistent depending on the species, sex, and other experimental conditions. Social primates may also experience significant stress associated with their rank in the group's dominance hierarchy. Finally, stress during prenatal development or during the early postnatal period may have long-lasting neurobiological and endocrine effects that manifest in an altered ability to cope behaviorally and physiologically with later challenges. Whereas early exposure to severe stress usually results in deficient coping abilities, certain kinds of milder stressors can promote subsequent resilience in the animal. We conclude that studies of stress in nonhuman primates can model many features of stress exposure in human populations and that such studies can play a valuable role in helping to elucidate the mechanisms underlying the role of stress in human psychopathology and endocrine dysfunction.

  9. Human rights

    NARCIS (Netherlands)

    Gaay Fortman, B. de

    2006-01-01

    Human rights reflect a determined effort to protect the dignity of each and every human being against abuse of power. This endeavour is as old as human history. What is relatively new is the international venture for the protection of human dignity through internationally accepted legal standards an

  10. Human Rights, Human Needs, Human Development, Human Security

    OpenAIRE

    Gasper, Des

    2009-01-01

    Human rights, human development and human security form increasingly important, partly interconnected, partly competitive and misunderstood ethical and policy discourses. Each tries to humanize a pre-existing and unavoidable major discourse of everyday life, policy and politics; each has emerged within the United Nations world; each relies implicitly on a conceptualisation of human need; each has specific strengths. Yet mutual communication, understanding and co-operation are deficient, espec...

  11. Human Technology and Human Affects

    DEFF Research Database (Denmark)

    Fausing, Bent

    2009-01-01

    Human Technology and Human Affects  This year Samsung introduced a mobile phone with "Soul". It was made with a human touch and included itself a magical touch. Which function does technology and affects get in everyday aesthetics like this, its images and interactions included this presentation ...... often mentioned post-human condition....

  12. Human microbiomics

    OpenAIRE

    Rajendhran, J.; P. Gunasekaran

    2010-01-01

    The sequencing of the human genome has driven the study of human biology in a significant way and enabled the genome-wide study to elucidate the molecular basis of complex human diseases. Recently, the role of microbiota on human physiology and health has received much attention. The influence of gut microbiome (the collective genomes of the gut microbiota) in obesity has been demonstrated, which may pave the way for new prophylactic and therapeutic strategies such as bacteriotherapy. The sig...

  13. Human Smuggling

    NARCIS (Netherlands)

    Siegel - Rozenblit, Dina; Zaitch, Damian

    2014-01-01

    Human smuggling is based on a consensus between smuggler, smuggled, and his/her family (which usually guarantees or effectuates payment). However, unauthorized immigrants are violating immigration laws and human smugglers are profiting from enabling illegal immigration. Both human smuggling and its

  14. When is high-Ca+ microdomain required for mitochondrial Ca+ uptake?

    Science.gov (United States)

    Spät, A; Fülöp, L; Koncz, P; Szanda, G

    2009-01-01

    Ca(2+) release from IP(3)-sensitive stores in the endoplasmic reticulum (ER) induced by Ca(2+)-mobilizing agonists generates high-Ca(2+) microdomains between ER vesicles and neighbouring mitochondria. Here we present a model that describes when such microdomains are required and when submicromolar [Ca(2+)] is sufficient for mitochondrial Ca(2+) uptake. Mitochondrial Ca(2+) uptake rate in angiotensin II-stimulated H295R adrenocortical cells correlates with the proximity between ER vesicles and the mitochondrion, reflecting the uptake promoting effect of high-Ca(2+) peri-mitochondrial microdomains. Silencing or inhibition of p38 mitogen-activated protein kinase (MAPK) or inhibition of the novel isoforms of protein kinase C enhances mitochondrial Ca(2+) uptake and abolishes the positive correlation between Ca(2+) uptake and ER-mitochondrion proximity. Inhibition of protein phosphatases attenuates mitochondrial Ca(2+) uptake and also abolishes its positive correlation with ER-mitochondrion proximity. We postulate that during IP(3)-induced Ca(2+) release, Ca(2+) uptake is confined to ER-close mitochondria, because of the simultaneous activation of the protein kinases. Attenuation of Ca(2+) uptake prevents Ca(2+) overload of mitochondria and thus protects the cell against apoptosis. On the other hand, all the mitochondria accumulate Ca(2+) at a non-inhibited rate during physiological Ca(2+) influx through the plasma membrane. Membrane potential is higher in ER-distant mitochondria, providing a bigger driving force for Ca(2+) uptake. Our model explains why comparable mitochondrial Ca(2+) signals are formed in response to K(+) and angiotensin II (equipotent in respect to global cytosolic Ca(2+) signals), although only the latter generates high-Ca(2+) microdomains.

  15. Human Rights/Human Needs.

    Science.gov (United States)

    Canning, Cynthia

    1978-01-01

    The faculty of Holy Names High School developed an interdisciplinary human rights program with school-wide activities focusing on three selected themes: the United Nations Universal Declaration of Human Rights, in conjunction with Human Rights Week; Food; and Women. This article outlines major program activities. (SJL)

  16. Digital Humanities

    DEFF Research Database (Denmark)

    Brügger, Niels

    2016-01-01

    the humanities for decades, starting with research fields such as humanities computing or computational linguistics in the 1950s, and later new media studies and internet studies. The historical development of digital humanities has been characterized by a focus on three successive, but co-existing types......Digital humanities is an umbrella term for theories, methodologies, and practices related to humanities scholarship that use the digital computer as an integrated and essential part of its research and teaching activities. The computer can be used for establishing, finding, collecting......, and preserving material to study, as an object of study in its own right, as an analytical tool, or for collaborating, and for disseminating results. The term "digital humanities" was coined around 2001, and gained currency within academia in the following years. However, computers had been used within...

  17. Human Rights, Human Needs, Human Development, Human Security - Relationships between four international human discourses.

    NARCIS (Netherlands)

    D.R. Gasper (Des)

    2007-01-01

    markdownabstractAbstract: Human rights, human development and human security form increasingly important, partly interconnected, partly competitive and misunderstood ethical and policy discourses. Each tries to humanize a pre-existing and unavoidable major discourse of everyday life, policy and

  18. Acute stress alters auditory selective attention in humans independent of HPA: a study of evoked potentials.

    Directory of Open Access Journals (Sweden)

    Ludger Elling

    Full Text Available BACKGROUND: Acute stress is a stereotypical, but multimodal response to a present or imminent challenge overcharging an organism. Among the different branches of this multimodal response, the consequences of glucocorticoid secretion have been extensively investigated, mostly in connection with long-term memory (LTM. However, stress responses comprise other endocrine signaling and altered neuronal activity wholly independent of pituitary regulation. To date, knowledge of the impact of such "paracorticoidal" stress responses on higher cognitive functions is scarce. We investigated the impact of an ecological stressor on the ability to direct selective attention using event-related potentials in humans. Based on research in rodents, we assumed that a stress-induced imbalance of catecholaminergic transmission would impair this ability. METHODOLOGY/PRINCIPAL FINDINGS: The stressor consisted of a single cold pressor test. Auditory negative difference (Nd and mismatch negativity (MMN were recorded in a tonal dichotic listening task. A time series of such tasks confirmed an increased distractibility occurring 4-7 minutes after onset of the stressor as reflected by an attenuated Nd. Salivary cortisol began to rise 8-11 minutes after onset when no further modulations in the event-related potentials (ERP occurred, thus precluding a causal relationship. This effect may be attributed to a stress-induced activation of mesofrontal dopaminergic projections. It may also be attributed to an activation of noradrenergic projections. Known characteristics of the modulation of ERP by different stress-related ligands were used for further disambiguation of causality. The conjuncture of an attenuated Nd and an increased MMN might be interpreted as indicating a dopaminergic influence. The selective effect on the late portion of the Nd provides another tentative clue for this. CONCLUSIONS/SIGNIFICANCE: Prior studies have deliberately tracked the adrenocortical influence

  19. Human Rights and Human Nature

    Directory of Open Access Journals (Sweden)

    Vittorio Possenti

    2013-11-01

    Full Text Available There seems to be two different versions of human rights in Western tradition: say Rationalistic and Christian; the former adopted in revolutionary France, the latter highly developed in Renaissance Spain. Current relativistic criticisms attempt to deny the universality of human rights alleging that this theory has been created in Western countries or it has no strong justification, and therefore cannot have universal approach; but this objection can be dismissed with an alternative justification of human rights.

  20. Human kapital

    DEFF Research Database (Denmark)

    Grosen, Anders; Nielsen, Peder Harbjerg

    2007-01-01

    finansiel og human kapital. Den traditionelle rådgivnings snævre synsvinkel kan føre til forkerte investeringsråd. Der skal derfor opfordres til, at de finansielle virksomheder i tilrettelæggelsen af deres rådgivning af private kunder systematisk inddrager den humane kapitals størrelse og karakteristika i...

  1. Human trichuriasis

    DEFF Research Database (Denmark)

    Betson, Martha; Søe, Martin Jensen; Nejsum, Peter

    2015-01-01

    Human trichuriasis is a neglected tropical disease which affects hundreds of millions of people worldwide and is particularly prevalent among children living in areas where sanitation is poor. This review examines the current knowledge on the taxonomy, genetics and phylogeography of human Trichuris...

  2. Think Human

    DEFF Research Database (Denmark)

    Nielsen, Charlotte Marie Bisgaard

    2013-01-01

    years' campaigns suggests that the theory of communication underlying the campaign has its basis in mechanical action rather than in human communication. The practice of 'Communication design' is investigated in relation to this metaphorical 'machine thinking' model of communication and contrasted...... with the human-centered theory of communication advocated by integrationism....

  3. Human evolution

    DEFF Research Database (Denmark)

    Llamas, Bastien; Willerslev, Eske; Orlando, Ludovic Antoine Alexandre

    2017-01-01

    , and true population genomic studies of Bronze Age populations. Among the emerging areas of aDNA research, the analysis of past epigenomes is set to provide more new insights into human adaptation and disease susceptibility through time. Starting as a mere curiosity, ancient human genetics has become...

  4. Think Human

    DEFF Research Database (Denmark)

    Nielsen, Charlotte Marie Bisgaard

    2013-01-01

    years' campaigns suggests that the theory of communication underlying the campaign has its basis in mechanical action rather than in human communication. The practice of 'Communication design' is investigated in relation to this metaphorical 'machine thinking' model of communication and contrasted...... with the human-centered theory of communication advocated by integrationism....

  5. Teaching humanism.

    Science.gov (United States)

    Stern, David T; Cohen, Jordan J; Bruder, Ann; Packer, Barbara; Sole, Allison

    2008-01-01

    As the "passion that animates authentic professionalism," humanism must be infused into medical education and clinical care as a central feature of medicine's professionalism movement. In this article, we discuss a current definition of humanism in medicine. We will also provide detailed descriptions of educational programs intended to promote humanism at a number of medical schools in the United States (and beyond) and identify the key factors that make these programs effective. Common elements of programs that effectively teach humanism include: (1) opportunities for students to gain perspective in the lives of patients; (2) structured time for reflection on those experiences; and (3) focused mentoring to ensure that these events convert to positive, formative learning experiences. By describing educational experiences that both promote and sustain humanism in doctors, we hope to stimulate the thinking of other medical educators and to disseminate the impact of these innovative educational programs to help the profession meet its obligation to provide the public with humanistic physicians.

  6. Human recombinant factor VIIa may improve heat intolerance in mice by attenuating hypothalamic neuronal apoptosis and damage.

    Science.gov (United States)

    Hsu, Chuan-Chih; Chen, Sheng-Hsien; Lin, Cheng-Hsien; Yung, Ming-Chi

    2014-10-01

    Intolerance to heat exposure is believed to be associated with hypothalamo-pituitary-adrenocortical (HPA) axis impairment [reflected by decreases in blood concentrations of both adrenocorticotrophic-hormone (ACTH) and corticosterone]. The purpose of this study was to determine the effect of human recombinant factor VIIa (rfVIIa) on heat intolerance, HPA axis impairment, and hypothalamic inflammation, ischemic and oxidative damage, and apoptosis in mice under heat stress. Immediately after heat stress (41.2 °C for 1 h), mice were treated with vehicle (1 mL/kg of body weight) or rfVIIa (65-270 µg/kg of body weight) and then returned to room temperature (26 °C). Mice still alive on day 4 of heat exposure were considered survivors. Cellular ischemia markers (e.g., glutamate, lactate-to-pyruvate ratio), oxidative damage markers (e.g., nitric oxide metabolite, hydroxyl radials), and pro-inflammatory cytokines (e.g., interleukin-6, interleukin-1β, tumor necrosis factor-α) in hypothalamus were determined. In addition, blood concentrations of both ACTH and corticosterone were measured. Hypothalamic cell damage was assessed by determing the neuronal damage scores, whereas the hypothalamic cell apoptosis was determined by assessing the numbers of cells stained with terminal deoxynucleotidyl transferase-mediated αUTP nick-end labeling, caspase-3-positive cells, and platelet endothelial cell adhesion molecula-1-positive cells in hypothalamus. Compared with vehicle-treated heated mice, rfVIIa-treated heated mice had significantly higher fractional survival (8/10 vs 1/10), lesser thermoregulatory deficit (34.1 vs 24.8 °C), lesser extents of ischemic, oxidative, and inflammatory markers in hypothalamus, lesser neuronal damage scores and apoptosis in hypothalamus, and lesser HPA axis impairment. Human recombinant factor VIIa appears to exert a protective effect against heatstroke by attenuating hypothalamic cell apoptosis (due to ischemic, inflammatory, and oxidative damage

  7. 白芍提取物对嗅球损毁抑郁模型大鼠行为学及下丘脑-垂体-肾上腺轴的影响%Influences of Extract of Peony Radix Alba on Behavior and Hypothalamic-pituitary-adrenocortical Axis in Depressive Rats Model with Damaged Olfactory Bulb

    Institute of Scientific and Technical Information of China (English)

    王景霞; 张建军; 苗春平; 刘妍; 林清; 陈振振

    2011-01-01

    Objective: To investigate the influences of extract from Peony Radix Alba on the behavioral and hypothalamic-pituitary-adrenocortical (HPA) axis changes in rats with damaged olfactory bulb (DOB). Method: The tests of open-field and step-down passive avoidance were used to observe the behaviors of rats.Radioimmunoassay (RIA) was used to analyze the level of corticotropin releasing hormone (CRH) in hypothalamus, adrenocorticotropic hormone (ACTH) in pituitary gland and cortisol (CORT) in serum of rats with DOB. Result: The rats had a characteristic hyperactivity in the test of "open-field" and learning deficits in stepdown passive avoidance ( P < 0. 05 ), and their levels of CRH, ACTH and CORT increased significantly ( P < 0. 05). The extract of Peony Radix Alba at the dose of 70,35 mg·kg-1 corrected the behavioral changes (P < 0. 05 ) and decreased the levels of CRH, ACTH and CORT ( P < 0. 05). Conclusion: The extract of Peony Radix Alba can correct behavioral changes in rats with DOB, and its regulating effect on HPA axis is one of the mechanisms for treating depression.%目的:研究白芍提取物对嗅球损毁抑郁模型大鼠行为学及下丘脑一垂体.肾上腺(HPA)轴的影响.方法:将嗅球损毁大鼠随机分为对照组、模型组、阳性药氟西汀2.5 mg·kg-1组以及白芍提取物70,35,17.5 mg·kg-1组,采用敞箱法、跳台法观察嗅球损毁大鼠的行为变化,间时用放免法分析白芍提取物对嗅球损毁大鼠下丘脑促肾上腺皮质激素释放素(CRH)、垂体促肾上腺皮质激素(ACTH)和血清皮质酮(CORT)含量的影响.结果:大鼠嗅球损毁后敞箱行为出现明显变化,水平运动和垂直运动显著增加,白芍提取物中、高剂量组可显著降低大鼠水平运动和垂直运动的得分;跳台试验中,造模后大鼠训练期和测试期的错误次数显著增加,自芍提取物中、高剂量组能显著降低嗅球损毁大鼠训练期和测试期的触电次数;嗅球损毁大

  8. Human Computation

    CERN Document Server

    CERN. Geneva

    2008-01-01

    What if people could play computer games and accomplish work without even realizing it? What if billions of people collaborated to solve important problems for humanity or generate training data for computers? My work aims at a general paradigm for doing exactly that: utilizing human processing power to solve computational problems in a distributed manner. In particular, I focus on harnessing human time and energy for addressing problems that computers cannot yet solve. Although computers have advanced dramatically in many respects over the last 50 years, they still do not possess the basic conceptual intelligence or perceptual capabilities...

  9. Practicing Humanities

    DEFF Research Database (Denmark)

    Gimmler, Antje

    2016-01-01

    In contemporary societies, the humanities are under constant pressure and have to justify their existence. In the ongoing debates, Humboldt’s ideals of ‘Bildung’ and ‘pure science’ are often used to justify the unique function of the humanities of ensuring free research and contributing to a vital...... philosophy. Contrary to Humboldt’s idea that the non-practical is the most practical in the long run, philosophical pragmatism recommends to the humanities to situate knowledge in practices and apply knowledge to practices....

  10. Evaluation of adrenocortical function in Florida manatees (Trichechus manatus latirostris).

    Science.gov (United States)

    Tripp, Kathleen M; Verstegen, John P; Deutsch, Charles J; Bonde, Robert K; de Wit, Martine; Manire, Charles A; Gaspard, Joseph; Harr, Kendal E

    2011-01-01

    The study objectives were to determine the predominant manatee glucocorticoid; validate assays to measure this glucocorticoid and adrenocorticotropic hormone (ACTH); determine diagnostic thresholds to distinguish physiological vs. pathological concentrations; identify differences associated with sex, age class, female reproductive status, capture time, and lactate; and determine the best methods for manatee biologists and clinicians to diagnose stress. Cortisol is the predominant manatee glucocorticoid. IMMULITE 1000 assays for cortisol and ACTH were validated. Precision yielded intra- and inter-assay coefficients of variation for serum cortisol: ≤23.5 and ≤16.7%; and ACTH: ≤6.9 and ≤8.5%. Accuracy resulted in a mean adjusted R(2)≥0.87 for serum cortisol and ≥0.96 for ACTH. Assay analytical sensitivities for cortisol (0.1 µg/dl) and ACTH (10.0 pg/ml) were verified. Methods were highly correlated with another IMMULITE 1000 for serum cortisol (r=0.97) and ACTH (r=0.98). There was no significant variation in cortisol or ACTH with sex or age class and no correlation with female progesterone concentrations. Cortisol concentrations were highest in unhealthy manatees, chronically stressed by disease or injury. ACTH was greatest in healthy free-ranging or short-term rehabilitating individuals, peracutely stressed by capture and handling. Cortisol concentrations ≥1.0 µg/dl were diagnostic of chronic stress; ACTH concentrations ≥87.5 pg/ml were diagnostic of peracute stress. In healthy long-term captive manatees, cortisol (0.4±0.2 µg/dl) and ACTH (47.7±15.9 pg/ml) concentrations were lower than healthy free-ranging, short-term rehabilitated or unhealthy manatees. Capture time was not significantly correlated with cortisol; ACTH correlation was borderline significant. Cortisol and ACTH were positively correlated with lactate.

  11. Adrenocortical Carcinoma: False Positive in an I-123 Metaiodobenzylguanidine Scan

    Energy Technology Data Exchange (ETDEWEB)

    Rey, Cristina Rodriguez; Candil, Aida Ortega; Galvan, Eliseo Vano; Martin, Maria Nieves Cabrera; Delgado, Jose Luis Carreras [Clinico San Carlos Hospital, Madrid (Spain)

    2016-06-15

    A 55-year-old man with a personal his history of left pheochromocytoma 2 years previously presented with an abdominal ultrasound showed a large left upper quadrant solid mass (calipers), with heterogeneous echogenicity and central cystic degeneration areas or necrosis. F-18 Fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT was performed as ACC was suspected. ACC is an uncommon malignant neoplasm of unknown cause; however, smoking and oral contraceptives may be risk factors. Patients usually present with advanced-stage disease and have poor prognosis, with a 2-year recurrence rate that ranges form 73 to 86 %. An MIBG scan was performed after injection of 185 MBq of I-123 MIBG intravenously. Single photon emission tomography (SPECT)/CT scan showed abnormal isotope accumulation in the tumor region. The patient underwent total resection of the tumor. The histology was of ACC, with areas of necrosis and cystic areas, so the result of the MIBG scan was a false positive. Authors divided false-positive MIBG studies into three categories. The first category is neuroendocrine lesions other than pheochromocytomas (tumors of the APUD series). the second category consists in adrenal lesions other than pheochromocytomas (adenomas, ACC) the reasons for this abnormal uptake are unclear. The third category consists of tracer uptake adjacent to the adrenal due to abnormalities in the route of excretion.

  12. Human Toxicity

    DEFF Research Database (Denmark)

    Jolliet, Olivier; Fantke, Peter

    2015-01-01

    This chapter reviews the human toxicological impacts of chemicals and how to assess these impacts in life cycle impact assessment (LCIA), in order to identify key processes and pollutants. The complete cause-effect pathway – from emissions of toxic substances up to damages on human health...... on characterisation factors means that results should by default be reported and interpreted in log scales when comparing scenarios or substance contribution! We conclude by outlining future trends in human toxicity modelling for LCIA, with promising developments for (a) better estimates of degradation halflives, (b......) the inclusion of ionization of chemicals in human exposure including bioaccumulation, (c) metal speciation, (d) spatialised models to differentiate the variability associated with spatialisation from the uncertainty, and (e) the assessment of chemical exposure via consumer products and occupational settings...

  13. Human Toxicity

    DEFF Research Database (Denmark)

    Jolliet, Olivier; Fantke, Peter

    2015-01-01

    . The first section of this chapter outlines the complete cause-effect pathway, from emissions of toxic substances to intake by the population up to damages in terms of human health effects. Section 2 outlines the framework for assessing human toxicity in LCIA. Section 3 discusses the contributing substances......This chapter reviews the human toxicological impacts of chemicals and how to assess these impacts in life cycle impact assessment (LCIA), in order to identify key processes and pollutants. The complete cause-effect pathway – from emissions of toxic substances up to damages on human health...... – demonstrates the importance to account for both outdoor and indoor exposure, including consumer products. Analysing the variations in intake fraction (the fraction of the emitted or applied chemical that is taken in by the consumer and the general population), effect factor and characterisation factor across...

  14. Human influences

    NARCIS (Netherlands)

    Lanen, van H.A.J.; Kasparek, L.; Novicky, O.; Querner, E.P.; Fendeková, M.; Kupczyk, E.

    2004-01-01

    Human activities can cause drought, which was not previously reported (man-induced hydrological drought). Groundwater abstractions for domestic and industrial use are a well-known example of such an environmental change

  15. Human phantom

    CERN Multimedia

    CERN PhotoLab

    1973-01-01

    This human phantom has been received by CERN on loan from the State Committee of the USSR for the Utilization of Atomic Energy. It is used by the Health Physics Group to study personel radiation doses near the accelerators.

  16. Human expunction

    Science.gov (United States)

    Klee, Robert

    2017-10-01

    Thomas Nagel in `The Absurd' (Nagel 1971) mentions the future expunction of the human species as a `metaphor' for our ability to see our lives from the outside, which he claims is one source of our sense of life's absurdity. I argue that the future expunction (not to be confused with extinction) of everything human - indeed of everything biological in a terran sense - is not a mere metaphor but a physical certainty under the laws of nature. The causal processes by which human expunction will take place are presented in some empirical detail, so that philosophers cannot dismiss it as merely speculative. I also argue that appeals to anthropic principles or to forms of mystical cosmology are of no plausible avail in the face of human expunction under the laws of physics.

  17. Human babesiosis.

    Science.gov (United States)

    Rożej-Bielicka, Wioletta; Stypułkowska-Misiurewicz, Hanna; Gołąb, Elżbieta

    2015-01-01

    Babesiosis is an emerging parasitic, anthropo-zoonotic tick-borne disease, seldom diagnosed in humans. Caused by Protozoa, Babesia (also called Piroplasma) intraerytrocytic piriform microorganism. Infection of vertebrates is transmitted by ticks. Out of more than 100 Babesia species/genotypes described so far, only some were diagnosed in infected humans, mostly B. microti, B. divergens and B. venatorum (Babesia sp. EU1). Infection in humans is often asymptomatic or mild but is of a particular risk for asplenic individuals, those with congenital or acquired immunodeficiencies, and elderly. Infections transmitted with blood and blood products raise concerns in hemotherapy. Epidemiological situation of babesiosis varies around the world. In Europe, no increase in the number of cases was reported, but in the USA its prevalence is increasing and extension of endemic areas is observed. The aim of this publication is to describe the problems connected with the current epidemiological situation, diagnosis and treatment of human babesiosis with regard to clinical status of patients.

  18. Human energy

    OpenAIRE

    2010-01-01

    In the midst of big-oil record profits and growing debate on global warming, the Chevron Corporation launched its “Human Energy” public relations campaign. In television commercials and print advertisements, Chevron portrays itself as a compassionate entity striving to solve the planet’s energy crisis. Yet, the first term in this corporate oxymoron misleadingly reframes the significance of the second, suggesting that the corporation has a renewed focus. In depicting Chevron as a green/human o...

  19. Human Echolocation

    OpenAIRE

    Teng, Santani

    2013-01-01

    The use of active natural echolocation as a mobility aid for blind humans has received increased scientific and popular attention in recent years (Engber, 2006; Kreiser, 2006; NPR, 2011), in part due to a focus on several blind individuals who have developed remarkable expertise. However, perhaps surprisingly, the history of empirical human echolocation research is not much younger than the era of echolocation research (cf. Griffin, 1958). Nevertheless, compared to its bat and cetacean count...

  20. Human ehrlichiosis

    Directory of Open Access Journals (Sweden)

    Đokić Milomir

    2006-01-01

    Full Text Available Background. Human ehrlichiosis is a newly recognized disease. It is a tick-borne disease caused by several bacterial species of the genhus Erlichia. These are small gram-negative pleomorphic cocci, that are obligatory intracellular bacteria. Tick Ixodes is the principle vector in Europe, and Amblyomma americanum in the United States. Bacterial organisms replicate in a tick, and are transmited from infected cells in a vector to the blood cells of animals or humans. Human ehrlichiosis is a name for a group of diseases caused by different species of Ehrlichia. One of them is the disease named human monocytic ehrlichiosis, caused by Ehrlichia chaffeensis, and the other is a human granulocytic ehrlichiosis caused by Anaplasma phagocytophilia. Case report. We reported a 23-year-old patient admitted for the clinical treatment with the symptoms of high febrility (above 40 °C, headache, vomiting, general weakness and exhaustion, but without data on a tick bite. The patient was treated with trimetoprim-sulfamethoxazole for a week when Ehrlichia chaffeensis was confirmed by the immunofluoroscence test, and the therapy contimed with doxacyclin. Conclusion. Human ehrlichiosis is also present in our country, so this disease should be considered everyday, especially in infectology practice.

  1. [Human influenza].

    Science.gov (United States)

    Stock, Ingo

    2006-10-01

    Human influenza is one of the most common human infectious diseases, contributing to approximately one million deaths every year. In Germany, each year between 5.000 and 20.000 individuals die from severe influenza infections. In several countries, the morbidity and mortality of influenza is greatly underestimated. This is reflected by general low immunization rates. The emergence of avian influenza against the background of the scenario of a human influenza pandemic has revived public interest in the disease. According to the World Health Organisation, it is only the question on the beginning of a new influenza pandemic. The virus type of the new pandemic is still uncertain and it is also unclear, if a pandemic spread of the virus may be prevented by consistent controlling of avian influenza.

  2. [Humanized childbirth].

    Science.gov (United States)

    Kuo, Su-Chen

    2005-06-01

    Childbirth is a major event in a family. The expectant parent's perception of the childbirth experience influences his or her development as a parent. Making childbirth a positive and satisfying experience for women is the responsibility of health care providers. Women want to have physical and emotional privacy during labor and delivery, and to experience both in a friendly, comfortable environment. For women expected to undergo normal deliveries, humanized childbirth is one accessible approach. This article explores the definition and evolution of humanized childbirth and the care practice that it involves. It also explores birth plans and birth experiences, and the improvements necessary to routine labor practices to enable women to participate in decision making about their childbirth experiences. The author emphasizes that when health-care providers recognize the value of humanized childbirth and make changes accordingly, the dignity of women's childbirth experiences will be enhanced.

  3. Beyond Humanisms

    Directory of Open Access Journals (Sweden)

    Capurro, Rafael

    2012-01-01

    Full Text Available In the first part of this paper a short history of Western humanisms (Socrates, Pico della Mirandola, Descartes, Kant is presented. As far as these humanisms rest on a fixation of the ‘humanum’ they are metaphysical, although they might radically differ from each other. The second part deals with the present debate on trans- and posthumanism in the context of some breath-taking developments in science and technology.Angeletics, a theory of messengers and messages, intends to give an answer to the leading question of this paper, namely: ‘what does it mean to go beyond humanisms?’ The conclusion exposes briefly an ethics of hospitality and care from an angeletic perspective.

  4. Human Rights, Human Needs, Human Development, Human Security : Relationships between four international 'human' discourses

    NARCIS (Netherlands)

    D.R. Gasper (Des)

    2007-01-01

    textabstractHuman rights, human development and human security form increasingly important, partly interconnected, partly competitive and misunderstood ethical and policy discourses. Each tries to humanize a pre-existing and unavoidable major discourse of everyday life, policy and politics; each

  5. Nothing Human

    Science.gov (United States)

    Wharram, C. C.

    2014-01-01

    In this essay C. C. Wharram argues that Terence's concept of translation as a form of "contamination" anticipates recent developments in philosophy, ecology, and translation studies. Placing these divergent fields of inquiry into dialogue enables us read Terence's well-known statement "I am a human being--I deem nothing…

  6. Human Trafficking

    Science.gov (United States)

    Wilson, David McKay

    2011-01-01

    The shadowy, criminal nature of human trafficking makes evaluating its nature and scope difficult. The U.S. State Department and anti-trafficking groups estimate that worldwide some 27 million people are caught in a form of forced servitude today. Public awareness of modern-day slavery is gaining momentum thanks to new abolitionist efforts. Among…

  7. Human waste

    NARCIS (Netherlands)

    Amin, Md Nurul; Kroeze, Carolien; Strokal, Maryna

    2017-01-01

    Many people practice open defecation in south Asia. As a result, lot of human waste containing nutrients such as nitrogen (N) and phosphorus (P) enter rivers. Rivers transport these nutrients to coastal waters, resulting in marine pollution. This source of nutrient pollution is, however, ignored in

  8. Nothing Human

    Science.gov (United States)

    Wharram, C. C.

    2014-01-01

    In this essay C. C. Wharram argues that Terence's concept of translation as a form of "contamination" anticipates recent developments in philosophy, ecology, and translation studies. Placing these divergent fields of inquiry into dialogue enables us read Terence's well-known statement "I am a human being--I deem nothing…

  9. Practicing Humanities

    DEFF Research Database (Denmark)

    Gimmler, Antje

    2016-01-01

    and self-reflective democracy. Contemporary humanities have adopted a new orientation towards practices, and it is not clear how this fits with the ideals of ‘Bildung’ and ‘pure science’. A possible theoretical framework for this orientation towards practices could be found in John Dewey’s pragmatic...

  10. 芍药内酯苷对嗅球切除抑郁模型大鼠行为学以及下丘脑-垂体-肾上腺轴功能的影响%Effect of albiflorin on behavior and hypothalamic-pituitary-adrenocortical axis in olfactory bulbectomized rats

    Institute of Scientific and Technical Information of China (English)

    陈岚; 龚正华; 薛瑞; 张亭亭; 李云峰; 洪浩; 张有志

    2014-01-01

    目的:探讨芍药内酯苷(Alb)的抗抑郁作用及其对下丘脑-垂体-肾上腺轴(HPA)功能的影响。方法采用切除大鼠嗅球制备抑郁模型,恢复14 d后每天2次给予盐酸丙咪嗪(IMI)5.0 mg·kg -1,Alb 2.5,5.0和10.0 mg·kg -1,连续给药14 d。开场实验检测大鼠的酶联免疫法检测血清中皮质酮(CO RT)及促肾上腺皮质激素(ACTH)含量;Western蛋白质印迹法检测海马糖皮质激素受体(GR)表达水平。结果与假手术组相比,嗅球切除模型组大鼠运动距离、运动时间和运动速度均显著增加(P<0.01);给药7 d 后,Alb 10.0 mg·kg -1显著降低嗅球切除大鼠运动时间、速度和距离(P<0.05);给药14 d 后,Alb 5.0和10.0 mg·kg -1均可以显著降低嗅球切除大鼠运动时间、速度和距离(P<0.05)。嗅球切除模型组大鼠血清CORT和ACTH 水平显著升高(P<0.01),海马 GR 表达下降(P<0.01),给予 Alb 2.5,5.0和10.0 mg·kg -1可显著降低嗅球切除大鼠血清CORT和ACTH水平(P<0.05);Western蛋白质印迹法结果表明,Alb 5.0和10.0 mg·kg -1可增加海马GR的表达(P<0.05)。结论芍药内酯苷对嗅球切除模型大鼠具有明确的抗抑郁行为效应,其抗抑郁作用机制可能与抑制H PA功能亢进有关。%OBJECTIVE Toexploretheantidepressanteffectsofalbiflorinandtheinvolvementof hypothalamic-pituitary-adrenocortical (HPA) axis function in its antidepressant potency.METHODS Two weeks after the olfactory bulbectomized (OB)surgery,albiflorin (2.5 ,5.0 ,10.0 mg·kg -1 ,ig) and imipramine 5.0 mg·kg -1 (ig)were given to rats twice a day for 14 d.The open-field test was con-ducted to evaluate the move ment distance,move ment ti me and velocity of olfactory bulbecto mized rats and sham-operated rats.The serum levels of corticosterone(CORT)and adrenocorticotropic hormone (ACTH)in rats were measured by the

  11. Human Rights in the Humanities

    Science.gov (United States)

    Harpham, Geoffrey

    2012-01-01

    Human rights are rapidly entering the academic curriculum, with programs appearing all over the country--including at Duke, Harvard, Northeastern, and Stanford Universities; the Massachusetts Institute of Technology; the Universities of Chicago, of Connecticut, of California at Berkeley, and of Minnesota; and Trinity College. Most of these…

  12. Human Rights in the Humanities

    Science.gov (United States)

    Harpham, Geoffrey

    2012-01-01

    Human rights are rapidly entering the academic curriculum, with programs appearing all over the country--including at Duke, Harvard, Northeastern, and Stanford Universities; the Massachusetts Institute of Technology; the Universities of Chicago, of Connecticut, of California at Berkeley, and of Minnesota; and Trinity College. Most of these…

  13. Digital Humanities

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørn

    2015-01-01

    Artiklen præsenterer først nogle generelle problemstillinger omkring Digital Humanities (DH) med det formål at undersøge dem nærmere i relation til konkrete eksempler på forskellige digitaliseringsmåder og ændringer i dokumentproduktion. I en nærmere afgrænsning vælger artiklen den tendens i DH...

  14. Human paleoneurology

    CERN Document Server

    2015-01-01

    The book presents an integrative review of paleoneurology, the study of endocranial morphology in fossil species. The main focus is on showing how computed methods can be used to support advances in evolutionary neuroanatomy, paleoanthropology and archaeology and how they have contributed to creating a completely new perspective in cognitive neuroscience. Moreover, thanks to its multidisciplinary approach, the book addresses students and researchers approaching human paleoneurology from different angles and for different purposes, such as biologists, physicians, anthropologists, archaeologists

  15. Digital Humanities

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørn

    2015-01-01

    Artiklen præsenterer først nogle generelle problemstillinger omkring Digital Humanities (DH) med det formål at undersøge dem nærmere i relation til konkrete eksempler på forskellige digitaliseringsmåder og ændringer i dokumentproduktion. I en nærmere afgrænsning vælger artiklen den tendens i DH...

  16. Human universe

    CERN Document Server

    Cox, Brian

    2014-01-01

    Human life is a staggeringly strange thing. On the surface of a ball of rock falling around a nuclear fireball in the blackness of a vacuum the laws of nature conspired to create a naked ape that can look up at the stars and wonder where it came from. What is a human being? Objectively, nothing of consequence. Particles of dust in an infinite arena, present for an instant in eternity. Clumps of atoms in a universe with more galaxies than people. And yet a human being is necessary for the question itself to exist, and the presence of a question in the universe - any question - is the most wonderful thing. Questions require minds, and minds bring meaning. What is meaning? I don't know, except that the universe and every pointless speck inside it means something to me. I am astonished by the existence of a single atom, and find my civilisation to be an outrageous imprint on reality. I don't understand it. Nobody does, but it makes me smile. This book asks questions about our origins, our destiny, and our place i...

  17. Human Capital, (Human) Capabilities and Higher Education

    Science.gov (United States)

    Le Grange, L.

    2011-01-01

    In this article I initiate a debate into the (de)merits of human capital theory and human capability theory and discuss implications of the debate for higher education. Human capital theory holds that economic growth depends on investment in education and that economic growth is the basis for improving the quality of human life. Human capable…

  18. Human Capital, (Human) Capabilities and Higher Education

    Science.gov (United States)

    Le Grange, L.

    2011-01-01

    In this article I initiate a debate into the (de)merits of human capital theory and human capability theory and discuss implications of the debate for higher education. Human capital theory holds that economic growth depends on investment in education and that economic growth is the basis for improving the quality of human life. Human capable…

  19. Humanizing Architecture

    DEFF Research Database (Denmark)

    Toft, Tanya Søndergaard

    2015-01-01

    The article proposes the urban digital gallery as an opportunity to explore the relationship between ‘human’ and ‘technology,’ through the programming of media architecture. It takes a curatorial perspective when proposing an ontological shift from considering media facades as visual spectacles...... agency and a sense of being by way of dematerializing architecture. This is achieved by way of programming the symbolic to provide new emotional realizations and situations of enlightenment in the public audience. This reflects a greater potential to humanize the digital in media architecture....

  20. Human steroidogenesis

    DEFF Research Database (Denmark)

    Andersen, Claus Y; Ezcurra, Diego

    2014-01-01

    steroid concentrations cause alterations in endometrial development, affecting oocyte viability in assisted reproductive technology. Furthermore, it has been proposed that elevated progesterone levels have a negative effect on the reproductive outcome of COS. This may arise from an asynchrony between...... reviews current knowledge of the regulation of progesterone in the human ovary during the follicular phase and highlights areas where knowledge remains limited. In this review, we provide in-depth information outlining the regulation and function of gonadotropins in the complicated area of steroidogenesis...

  1. Humanizing Architecture

    DEFF Research Database (Denmark)

    Toft, Tanya Søndergaard

    2015-01-01

    The article proposes the urban digital gallery as an opportunity to explore the relationship between ‘human’ and ‘technology,’ through the programming of media architecture. It takes a curatorial perspective when proposing an ontological shift from considering media facades as visual spectacles...... agency and a sense of being by way of dematerializing architecture. This is achieved by way of programming the symbolic to provide new emotional realizations and situations of enlightenment in the public audience. This reflects a greater potential to humanize the digital in media architecture....

  2. Human Toxocariasis

    Directory of Open Access Journals (Sweden)

    Mehmet Burak Selek

    2013-09-01

    Full Text Available Human toxocariasis is an parasitic infection caused by the ingestion of larvae of dog nematode Toxocara canis and less frequently of cat nematode T.cati. Toxocara eggs, shed to environment by infected dogs' and cats' droppings, become infective by embryonation. Humans, particularly children, can be infected by accidentally ingesting embryonated Toxocara eggs. Larvae hatch in the small intestine, penetrate the intestinal wall and migrate to other parts of body via the bloodstream. It is generally a benign, asymptomatic, and self-limiting disease, although migrating larvae can cause damage to tissues and organs, especially brain involvement can cause severe morbidity. The two main clinical presentations of toxocariasis are visceral larva migrans (VLM (a systemic disease caused by larval migration through major organs and ocular larva migrans (OLM (a disease limited to the eyes and optic nerves. There are also two less-severe syndromes which have recently been described, one mainly in children (covert toxocariasis and the other mainly in adults (common toxocariasis. Diagnosis is usually made by clinical signs/symptoms, epidemiological background of the patient and the use of immunological methods (ELISA or western-blot. On the other hand definitive diagnosis is much more challenging, since it requires the demonstration of larvae via biopsy or autopsy. Most cases of toxocariasis clear up without any treatment. VLM is primarily treated with antihelmintic drugs, such as; albendazole or mebendazole. Treatment of OLM is more difficult and usually consists of measures to prevent progressive damage to the eye like steroids. Laser photocoagulation and cryoretinopexy may also be used to treat severe cases. Since eradicating T.canis infection is difficult due to the complexity of its life cycle, prevention of toxocariasis is always preferred. Toxocara eggs have a strong protective layer which makes the eggs able to survive in the environment for months or

  3. How similar are high latitude and high altitude habitats? A review and a preliminary study of the adrenocortical response to stress in birds of the Qinghai-Tibetan Plateau%高海拔和高纬度生境的相似性:综述以及青藏高原鸟类肾上腺皮质激素对应激反应的初步研究

    Institute of Scientific and Technical Information of China (English)

    MatthewI.RICHARDSON; IgnacioT.MOORE; KiranK.SONMA; LEIFu-Min; JohnC.WINGFIELD

    2003-01-01

    Arctic and alpine biomes are frequently considered the same in introductory textbooks, conservation planning and even in the primary literature. Both alpine and arctic biomes are treeless expanses with low amounts of grass- and forb-based primary productivity, and simplified food webs. Furthermore, with the possible exception of tropical alpine habitats, both environments are highly seasonal. Few studies, however, have made a critical comparison of these superficially similar environments. They have some significant differences, including energy regimes, proximity to refugia and scale of the habitat. If the environments are the same, our hypothesis is that birds inhabiting them will exhibit similar responses to unpredictable stressors. Conversely, if these habitats are sufficiently different, then responses to acute stress should be attuned to the local environment and not be the same. A preliminary study was conducted to compare the adrenocortical responses of selected avian species breeding on the Tibetan Plateau of Central China with published data of birds inhabiting the arctic tundra ecosystem. Two species of snowfinch, Onychostruthus taczanowskii and Pyrgilauda ruficollis, are regarded as high altitude specialists and show typical increases in plasma levels of corticosterone following a standardized stress of capture, handling and restraint. However, neither showed any seasonal variation in adrenocortical response to stress, unlike many arctic specialists. This study suggests that avian species living in alpine and arctic environments may have hormonal responses tailored to the ecological challenges presented by their environment[Acta Zoologica Sinica 49(1):1-19,2003].%在介绍性教科书、保护计划甚至基础著作中,常常将北极区和高山生物群系等同看待.高山和北极区生物群系无树的广阔区域,草本和非禾本科草本植物的初级生产力总量低,食物网单一.此外,除热带高山生境可能有例外,该两种

  4. NATO Human View Architecture and Human Networks

    Science.gov (United States)

    Handley, Holly A. H.; Houston, Nancy P.

    2010-01-01

    The NATO Human View is a system architectural viewpoint that focuses on the human as part of a system. Its purpose is to capture the human requirements and to inform on how the human impacts the system design. The viewpoint contains seven static models that include different aspects of the human element, such as roles, tasks, constraints, training and metrics. It also includes a Human Dynamics component to perform simulations of the human system under design. One of the static models, termed Human Networks, focuses on the human-to-human communication patterns that occur as a result of ad hoc or deliberate team formation, especially teams distributed across space and time. Parameters of human teams that effect system performance can be captured in this model. Human centered aspects of networks, such as differences in operational tempo (sense of urgency), priorities (common goal), and team history (knowledge of the other team members), can be incorporated. The information captured in the Human Network static model can then be included in the Human Dynamics component so that the impact of distributed teams is represented in the simulation. As the NATO militaries transform to a more networked force, the Human View architecture is an important tool that can be used to make recommendations on the proper mix of technological innovations and human interactions.

  5. Expression of the IGF and the aromatase/estrogen receptor systems in human adrenal tissues from early infancy to late puberty: implications for the development of adrenarche.

    Science.gov (United States)

    Belgorosky, Alicia; Baquedano, María Sonia; Guercio, Gabriela; Rivarola, Marco A

    2009-03-01

    Adrenarche is a process of postnatal sexual maturation occurring in higher primates, in which there is an increase in the secretion of adrenal androgens. It is the consequence of a process of postnatal organogenesis characterized by the development of a new zone in the adrenal cortex, the zona reticularis (ZR). The mechanism of this phenomenon remains poorly understood, suggesting that it might be a multifactorial event. A relationship between circulating IGF-I, insulin sensitivity, and adrenal androgens has been postulated. Boys and girls have different patterns of changes in insulin sensitivity at puberty, perhaps secondary to differences in the estrogen milieu. Estrogen effects may also play a role in premature adrenarche. Peripheral or local IGF-1 actions could regulate adrenal progenitor cell proliferation and migration. Since adrenal progenitor cells as well as IGF-I and the IGF-R1 are located in the outer zone of the adrenal cortex during childhood and adolescence, this peripheral cell layer, below the capsule, may contain undifferentiated progenitor cells. Therefore, the IGF-R1 signaling pathway might positively modulate the proliferation and migration of adrenal progenitor cell to stimulate the development of adrenal zones, including ZR. However, no evidence of a direct action of IGF-I on ZR was found. In addition, a role for estrogens in the ontogenesis of ZR is suggested by the presence of aromatase (CYP19) in the subcapsular zona glomerulosa and in the adrenal medulla. Estrogens produced locally could act on ZR by interacting with estrogen receptor beta (ERbeta), but not alpha, and membrane estrogen receptor GPR-30. An estradiol-induced increase in DHEA/cortisol ratio was indeed seen in cultures of adrenocortical cells from post-adrenarche adrenals. In summary, several lines of evidence point to the action of multiple factors, such as local adrenal maturational changes and peripheral metabolic signals, on postnatal human adrenal gland ZR formation.

  6. Two simple cleanup methods combined with LC-MS/MS for quantification of steroid hormones in in vivo and in vitro assays

    DEFF Research Database (Denmark)

    Weisser, Johan Juhl; Hansen, Cecilie Hurup; Poulsen, Rikke

    2016-01-01

    . The in vitro assay was validated by exposing H295R cells to prochloraz for inhibiting steroid hormone secretion and by exposing cells to forskolin for inducing steroid hormone secretion. The developed method fulfills the recommendations for the H295R assay suggested by the OECD. Furthermore, a simple off......-line SPE methodology was developed for the necessary clean-up of in vivo assays. Samples, such as gonad tissue, plasma and serum, are complex biological matrixes, and the SPE methodology was optimized to remove salts and proteins prior to elution of target analytes. At the same time, lipophilic compounds...... of steroid hormones in plasma, testes, and H295R cell medium corresponded well with previous studies. The off-line SPE method was validated using spiked charcoal-stripped serum. Method recovery, accuracy, precision and robustness were all good. Instrument sensitivity was in the range of 55-530 pg/mL (LLOQ)....

  7. Mutations of the p53 gene in human functional adrenal neoplasms

    Energy Technology Data Exchange (ETDEWEB)

    Shiu-Ru Lin; Yau-Jiunn Lee; Juei-Hsiung Tsai [Kaohsiung Medical College, Taiwan (China)

    1994-02-01

    To clarify gene alterations in functional human adrenal tumors, the authors performed molecular analysis for p53 abnormalities in 23 cases with adrenal neoplasms. The immunohistochemical study with anti-p53 monoclonal antibody pAb1801 demonstrated that 10 of 23 (43.5%) cases overexpressed p53 protein in the tumor cells. Using a polymerase chain reaction-single strand conformation polymorphism study, 5 of 6 (83.3%) pheochromocytoma tissues (1 malignant and 5 benign) and 11 of 15 (73.3%) adrenocortical adenomas (2 with Cushing`s syndrome and 13 with primary aldosteronism, all benign) showed an apparent electrophoretic mobility shift between the tumor and its paired adjacent normal adrenal tissue. Such differences were detected in exon 4 (12 cases), exon 5 (2 cases), and exon 7 (3 cases). The types of these mutations in exon 4 were a substitution from threonine (ACC) to isoleucine (ATC) at codon 102 in 5 cases, from glutamine (CAG) to histidine (CAC) at codon 104 in 1 case, from glycine (GGG) to alanine (CGG) at codon 117 in 1 case, from glutamate (GAG) to glutamine (CAG) at codon 68 in 1 case, and single base changes resulting in a premature stop codon at codon 100 in 2 cases. A 2-basepair deletion at codon 175 in exon 5 resulting in a frame shift was identified in 1 case. A single point mutation was identified, resulting in the substitution of glutamine (CAG) for arginine (CGG) at codon 248 of exon 7 in 1 case. A single basepair deletion at codon 249 resulted in a frame shift in 2 cases. There was 1 case with malignant pheochromocytoma that combined a single point mutation in exon 4 and a single base deletion in exon 7. Only 2 of 23 cases showed a loss of a normal allele encoding in the p53 gene. Northern blot analysis with 1.8-kilobase p53 cDNA revealed that p53 mRNA was overexpressed in 6 cases. The results indicate that high frequencies of p53 gene mutation, especially in exon 4, exist in functional adrenal tumors. 39 refs., 6 figs., 4 tabs.

  8. [Human papillomaviruses].

    Science.gov (United States)

    Gross, G

    2003-10-01

    Human papillomaviruses (HPV) infect exclusively the basal cells of the skin and of mucosal epithelia adjacent to the skin such as the mouth, the upper respiratory tract, the lower genital tract and the anal canal. HPV does not lead to a viremia. Basically there are three different types of HPV infection: Clinically visible lesions, subclinical HPV infections and latent HPV infections. Distinct HPV types induce morphologically and prognostically different clinical pictures. The most common HPV associated benign tumor of the skin is the common wart. Infections of the urogenitoanal tract with specific HPV-types are recognised as the most frequent sexually transmitted viral infections. So-called "high-risk" HPV-types (HPV16, 18 and others) are regarded by the world health organisation as important risk-factors for the development of genital cancer (mainly cervical cancer), anal cancer and upper respiratory tract cancer in both genders. Antiviral substances with a specific anti-HPV effect are so far unknown. Conventional therapies of benign skin warts and of mucosal warts are mainly nonspecific. They comprise tissue-destroying therapies such as electrocautery, cryotherapy and laser. In addition cytotoxic substances such as podophyllotoxin and systemic therapy with retinoids are in use. Systemically and topically administered immunotherapies represent a new approach for treatment. Both interferons and particularly the recently developed imiquimod, an interferon-alpha and cytokine-inductor lead to better results and are better tolerated then conventional therapies. HPV-specific vaccines have been developed in the last 5 years and will be used in future for prevention and treatment of benign and malignant HPV-associated tumors of the genitoanal tract in both sexes.

  9. Human Development Report 1991: Financing Human Development

    OpenAIRE

    United Nations Development Programme, UNDP

    1991-01-01

    Lack of political commitment rather than financial resources is often the real barrier to human development. This is the main conclusion of Human Development Report 1991 - the second in a series of annual reports on the subject.

  10. The golden triangle of human dignity: human security, human development and human rights

    NARCIS (Netherlands)

    Gaay Fortman, B. de

    2004-01-01

    The success or failure of processes of democratization cannot be detached from processes of development related to the aspirations of people at the grassroots. Human rights, in a more theoretical terminology, require human development in order to enhance human security.

  11. Human-machine interactions

    Science.gov (United States)

    Forsythe, J. Chris; Xavier, Patrick G.; Abbott, Robert G.; Brannon, Nathan G.; Bernard, Michael L.; Speed, Ann E.

    2009-04-28

    Digital technology utilizing a cognitive model based on human naturalistic decision-making processes, including pattern recognition and episodic memory, can reduce the dependency of human-machine interactions on the abilities of a human user and can enable a machine to more closely emulate human-like responses. Such a cognitive model can enable digital technology to use cognitive capacities fundamental to human-like communication and cooperation to interact with humans.

  12. In vitro bioassay investigations of the endocrine disrupting potential of steviol glycosides and their metabolite steviol, components of the natural sweetener Stevia.

    Science.gov (United States)

    Shannon, Maeve; Rehfeld, Anders; Frizzell, Caroline; Livingstone, Christina; McGonagle, Caoimhe; Skakkebaek, Niels E; Wielogórska, Ewa; Connolly, Lisa

    2016-05-15

    The food industry is moving towards the use of natural sweeteners such as those produced by Stevia rebaudiana due to the number of health and safety concerns surrounding artificial sweeteners. Despite the fact that these sweeteners are natural; they cannot be assumed safe. Steviol glycosides have a steroidal structure and therefore may have the potential to act as an endocrine disruptor in the body. Reporter gene assays (RGAs), H295R steroidogenesis assay and Ca(2+) fluorimetry based assays using human sperm cells have been used to assess the endocrine disrupting potential of two steviol glycosides: stevioside and rebaudioside A, and their metabolite steviol. A decrease in transcriptional activity of the progestagen receptor was seen following treatment with 25,000 ng/ml steviol in the presence of progesterone (157 ng/ml) resulting in a 31% decrease in progestagen response (p=<0.01). At the level of steroidogenesis, the metabolite steviol (500-25,000 ng/ml) increased progesterone production significantly by 2.3 fold when exposed to 10,000 ng/ml (p=<0.05) and 5 fold when exposed to 25,000 ng/ml (p=<0.001). Additionally, steviol was found to induce an agonistic response on CatSper, a progesterone receptor of sperm, causing a rapid influx of Ca(2+). The response was fully inhibited using a specific CatSper inhibitor. These findings highlight the potential for steviol to act as a potential endocrine disruptor.

  13. Exposure to an Extremely-Low-Frequency Magnetic Field Stimulates Adrenal Steroidogenesis via Inhibition of Phosphodiesterase Activity in a Mouse Adrenal Cell Line.

    Science.gov (United States)

    Kitaoka, Kazuyoshi; Kawata, Shiyori; Yoshida, Tomohiro; Kadoriku, Fumiya; Kitamura, Mitsuo

    2016-01-01

    Extremely low-frequency magnetic fields (ELF-MFs) are generated by power lines and household electrical devices. In the last several decades, some evidence has shown an association between ELF-MF exposure and depression and/or anxiety in epidemiological and animal studies. The mechanism underlying ELF-MF-induced depression is considered to involve adrenal steroidogenesis, which is triggered by ELF-MF exposure. However, how ELF-MFs stimulate adrenal steroidogenesis is controversial. In the current study, we investigated the effect of ELF-MF exposure on the mouse adrenal cortex-derived Y-1 cell line and the human adrenal cortex-derived H295R cell line to clarify whether the ELF-MF stimulates adrenal steroidogenesis directly. ELF-MF exposure was found to significantly stimulate adrenal steroidogenesis (p steroidogenesis via an increase in intracellular cAMP caused by the inhibition of phosphodiesterase activity in Y-1 cells. The same mechanism may trigger the increase in adrenal steroid secretion in mice observed in our previous study.

  14. Comet assay as a procedure for detecting possible genotoxicity induced by non-ionizing radiation

    Directory of Open Access Journals (Sweden)

    Zsuzsanna Nemeth

    2015-05-01

    In our laboratory we use comet assay for testing genotoxicity of non-ionizing radiation for more than ten years. In the experiments we use whole blood samples (human or dog, cell lines (e.g. H295R cell line or 3 dimensional in vitro skin tissue (epidermis models. In our protocol a slightly modified alkaline Comet assay method of Singh et al. (1988 is used. On our poster there will be presented a brief summary of our experiments with exposure to different types of radiation (ELF, RF, and intermediate frequency. In our protocols the non-ionizing radiation was often combined with ionizing radiation to see whether the non-ionizing radiation can influence the repair of the DNA damage induced by ionizing radiation. For the evaluation of the slides mainly Komet 4.0 image analysis system software (Kinetic Imaging, Liverpool, UK was used, but as we got familiarized with other methods for slide evaluation like grading the comets by visual scoring into 5 categories or the CaspLab software, the comparison of these three methods will be also presented.

  15. Special Section: Human Rights

    Science.gov (United States)

    Frydenlund, Knut; And Others

    1978-01-01

    Eleven articles examine human rights in Europe. Topics include unemployment, human rights legislation, role of the Council of Europe in promoting human rights, labor unions, migrant workers, human dignity in industralized societies, and international violence. Journal available from Council of Europe, Directorate of Press and Information, 67006…

  16. Scalability of human models

    NARCIS (Netherlands)

    Rodarius, C.; Rooij, L. van; Lange, R. de

    2007-01-01

    The objective of this work was to create a scalable human occupant model that allows adaptation of human models with respect to size, weight and several mechanical parameters. Therefore, for the first time two scalable facet human models were developed in MADYMO. First, a scalable human male was

  17. Visualizing Humans by Computer.

    Science.gov (United States)

    Magnenat-Thalmann, Nadia

    1992-01-01

    Presents an overview of the problems and techniques involved in visualizing humans in a three-dimensional scene. Topics discussed include human shape modeling, including shape creation and deformation; human motion control, including facial animation and interaction with synthetic actors; and human rendering and clothing, including textures and…

  18. The Human/Machine Humanities: A Proposal

    Directory of Open Access Journals (Sweden)

    Ollivier Dyens

    2016-03-01

    Full Text Available What does it mean to be human in the 21st century? The pull of engineering on every aspect of our lives, the impact of machines on how we represent ourselves, the influence of computers on our understanding of free-will, individuality and species, and the effect of microorganisms on our behaviour are so great that one cannot discourse on humanity and humanities without considering their entanglement with technology and with the multiple new dimensions of reality that it opens up. The future of humanities should take into account AI, bacteria, software, viruses (both organic and inorganic, hardware, machine language, parasites, big data, monitors, pixels, swarms systems and the Internet. One cannot think of humanity and humanities as distinct from technology anymore.

  19. From Human Past to Human Future

    OpenAIRE

    Robert G. Bednarik

    2013-01-01

    This paper begins with a refutation of the orthodox model of final Pleistocene human evolution, presenting an alternative, better supported account of this crucial phase. According to this version, the transition from robust to gracile humans during that period is attributable to selective breeding rather than natural selection, rendered possible by the exponential rise of culturally guided volitional choices. The rapid human neotenization coincides with the development of numerous somatic an...

  20. ISS Payload Human Factors

    Science.gov (United States)

    Ellenberger, Richard; Duvall, Laura; Dory, Jonathan

    2016-01-01

    The ISS Payload Human Factors Implementation Team (HFIT) is the Payload Developer's resource for Human Factors. HFIT is the interface between Payload Developers and ISS Payload Human Factors requirements in SSP 57000. ? HFIT provides recommendations on how to meet the Human Factors requirements and guidelines early in the design process. HFIT coordinates with the Payload Developer and Astronaut Office to find low cost solutions to Human Factors challenges for hardware operability issues.

  1. Has Human Evolution Stopped?

    OpenAIRE

    TEMPLETON, Alan R

    2010-01-01

    It has been argued that human evolution has stopped because humans now adapt to their environment via cultural evolution and not biological evolution. However, all organisms adapt to their environment, and humans are no exception. Culture defines much of the human environment, so cultural evolution has actually led to adaptive evolution in humans. Examples are given to illustrate the rapid pace of adaptive evolution in response to cultural innovations. These adaptive responses have important ...

  2. Preference for human eyes in human infants.

    Science.gov (United States)

    Dupierrix, Eve; de Boisferon, Anne Hillairet; Méary, David; Lee, Kang; Quinn, Paul C; Di Giorgio, Elisa; Simion, Francesca; Tomonaga, Masaki; Pascalis, Olivier

    2014-07-01

    Despite evidence supporting an early attraction to human faces, the nature of the face representation in neonates and its development during the first year after birth remain poorly understood. One suggestion is that an early preference for human faces reflects an attraction toward human eyes because human eyes are distinctive compared with other animals. In accord with this proposal, prior empirical studies have demonstrated the importance of the eye region in face processing in adults and infants. However, an attraction for the human eye has never been shown directly in infants. The current study aimed to investigate whether an attraction for human eyes would be present in newborns and older infants. With the use of a preferential looking time paradigm, newborns and 3-, 6-, 9-, and 12-month-olds were simultaneously presented with a pair of nonhuman primate faces (chimpanzees and Barbary macaques) that differed only by the eyes, thereby pairing a face with original nonhuman primate eyes with the same face in which the eyes were replaced by human eyes. Our results revealed that no preference was observed in newborns, but a preference for nonhuman primate faces with human eyes emerged from 3months of age and remained stable thereafter. The findings are discussed in terms of how a preference for human eyes may emerge during the first few months after birth.

  3. Economics of human trafficking.

    Science.gov (United States)

    Wheaton, Elizabeth M; Schauer, Edward J; Galli, Thomas V

    2010-01-01

    Because freedom of choice and economic gain are at the heart of productivity, human trafficking impedes national and international economic growth. Within the next 10 years, crime experts expect human trafficking to surpass drug and arms trafficking in its incidence, cost to human well-being, and profitability to criminals (Schauer and Wheaton, 2006: 164-165). The loss of agency from human trafficking as well as from modern slavery is the result of human vulnerability (Bales, 2000: 15). As people become vulnerable to exploitation and businesses continually seek the lowest-cost labour sources, trafficking human beings generates profit and a market for human trafficking is created. This paper presents an economic model of human trafficking that encompasses all known economic factors that affect human trafficking both across and within national borders. We envision human trafficking as a monopolistically competitive industry in which traffickers act as intermediaries between vulnerable individuals and employers by supplying differentiated products to employers. In the human trafficking market, the consumers are employers of trafficked labour and the products are human beings. Using a rational-choice framework of human trafficking we explain the social situations that shape relocation and working decisions of vulnerable populations leading to human trafficking, the impetus for being a trafficker, and the decisions by employers of trafficked individuals. The goal of this paper is to provide a common ground upon which policymakers and researchers can collaborate to decrease the incidence of trafficking in humans.

  4. Human assisted robotic exploration

    Science.gov (United States)

    Files, B. T.; Canady, J.; Warnell, G.; Stump, E.; Nothwang, W. D.; Marathe, A. R.

    2016-05-01

    In support of achieving better performance on autonomous mapping and exploration tasks by incorporating human input, we seek here to first characterize humans' ability to recognize locations from limited visual information. Such a characterization is critical to the design of a human-in-the-loop system faced with deciding whether and when human input is useful. In this work, we develop a novel and practical place-recognition task that presents humans with video clips captured by a navigating ground robot. Using this task, we find experimentally that human performance does not seem to depend on factors such as clip length or familiarity with the scene and also that there is significant variability across subjects. Moreover, we find that humans significantly outperform a state-of-the-art computational solution to this problem, suggesting the utility of incorporating human input in autonomous mapping and exploration techniques.

  5. Human Use Index (Future)

    Data.gov (United States)

    U.S. Environmental Protection Agency — Human land uses may have major impacts on ecosystems, affecting biodiversity, habitat, air and water quality. The human use index (also known as U-index) is the...

  6. Human Papillomavirus (HPV) Vaccines

    Science.gov (United States)

    ... Directory Cancer Prevention Overview Research Human Papillomavirus (HPV) Vaccines On This Page What are human papillomaviruses? Which ... infections? Can HPV infections be prevented? What HPV vaccines are available? Who should get the HPV vaccines? ...

  7. Human Use Index

    Data.gov (United States)

    U.S. Environmental Protection Agency — Human land uses may have major impacts on ecosystems, affecting biodiversity, habitat, air and water quality. The human use index (also known as U-index) is the...

  8. Telling the Human Story.

    Science.gov (United States)

    Richardson, Miles

    1987-01-01

    Proposes that one of the fundamental human attributes is telling stories. Explores the debate on whether Neanderthals possessed language ability. Discusses the role of the "human story" in teaching anthropology. (DH)

  9. Human Services Offices

    Data.gov (United States)

    Fairfax County, Virginia — This data contains point features representing the human services offices within Fairfax County.“HS_Region” is the office for each human services region, “DFS_Area”...

  10. Human Resource Accounting System

    Science.gov (United States)

    Cerullo, Michael J.

    1974-01-01

    Main objectives of human resource accounting systems are to satisfy the informational demands made by investors and by operating managers. The paper's main concern is with the internal uses of a human asset system. (Author)

  11. The Growing Human Population.

    Science.gov (United States)

    Keyfitz, Nathan

    1989-01-01

    Discusses the issue of human population. Illustrates the projections of the growing human population in terms of developed and less developed countries. Describes the family planning programs in several countries. Lists three references for further reading. (YP)

  12. Human bites (image)

    Science.gov (United States)

    Human bites present a high risk of infection. Besides the bacteria which can cause infection, there is ... the wound extends below the skin. Anytime a human bite has broken the skin, seek medical attention.

  13. Monogenic human obesity syndromes

    National Research Council Canada - National Science Library

    Farooqi, I S; O'Rahilly, S

    2004-01-01

    .... This chapter will consider the human monogenic obesity syndromes that have been characterized to date and discuss how far such observations support the physiological role of these molecules in the regulation of human body weight and neuroendocrine function.

  14. Skin and the non-human human

    DEFF Research Database (Denmark)

    Rösing, Lilian Munk

    2013-01-01

    The article puts forward an aesthetic and psychoanalytic analysis of Titian's painting, The Flaying of Marsyas, arguing that the painting is a reflection on the human subject as a being constituted by skin and by a core of non-humanity. The analysis is partly an answer to Melanie Hart's (2007......) article 'Visualizing the mind: Looking at Titian's Flaying of Marsyas', addressing features of the painting not commented on by Hart, and supplementing Hart's (Kleinian) theoretical frame by involving Didier Anzieu's 'skin ego', Slavoj Zizek's concept of the 'non-human', Giorgio Agamben's term...

  15. Human productivity program definition

    Science.gov (United States)

    Cramer, D. B.

    1985-01-01

    The optimization of human productivity on the space station within the existing resources and operational constraints is the aim of the Human Productivity Program. The conceptual objectives of the program are as follows: (1) to identify long lead technology; (2) to identify responsibility for work elements; (3) to coordinate the development of crew facilities and activities; and (4) to lay the foundation for a cost effective approach to improving human productivity. Human productivity work elements are also described and examples are presented.

  16. Human Resource Management System

    OpenAIRE

    Navaz, A. S. Syed; Fiaz, A. S. Syed; Prabhadevi, C.; V.Sangeetha; Gopalakrishnan,S.

    2013-01-01

    The paper titled HUMAN RESOURCE MANAGEMENT SYSTEM is basically concerned with managing the Administrator of HUMAN RESOURCE Department in a company. A Human Resource Management System, refers to the systems and processes at the intersection between human resource management and information technology. It merges HRM as a discipline and in particular its basic HR activities and processes with the information technology field, whereas the programming of data processing systems evolved into standa...

  17. Human nature and enhancement.

    Science.gov (United States)

    Buchanan, Allen

    2009-03-01

    Appeals to the idea of human nature are frequent in the voluminous literature on the ethics of enhancing human beings through biotechnology. Two chief concerns about the impact of enhancements on human nature have been voiced. The first is that enhancement may alter or destroy human nature. The second is that if enhancement alters or destroys human nature, this will undercut our ability to ascertain the good because, for us, the good is determined by our nature. The first concern assumes that altering or destroying human nature is in itself a bad thing. The second concern assumes that human nature provides a standard without which we cannot make coherent, defensible judgments about what is good. I will argue (1) that there is nothing wrong, per se, with altering or destroying human nature, because, on a plausible understanding of what human nature is, it contains bad as well as good characteristics and there is no reason to believe that eliminating some of the bad would so imperil the good as to make the elimination of the bad impermissible, and (2) that altering or destroying human nature need not result in the loss of our ability to make judgments about the good, because we possess a conception of the good by which we can and do evaluate human nature. I will argue that appeals to human nature tend to obscure rather than illuminate the debate over the ethics of enhancement and can be eliminated in favor of more cogent considerations.

  18. Human Document Project

    NARCIS (Netherlands)

    Vries, de J.; Abelmann, L.; Manz, A.; Elwenspoek, M.C.

    2012-01-01

    “The Human Document Project” is a project which tries to answer all of the questions related to preserving information about the human race for tens of generations of humans to come or maybe even for a future intelligence which can emerge in the coming thousands of years. This document mainly focuss

  19. Has Human Evolution Stopped?

    Directory of Open Access Journals (Sweden)

    Alan R. Templeton

    2010-07-01

    Full Text Available It has been argued that human evolution has stopped because humans now adapt to their environment via cultural evolution and not biological evolution. However, all organisms adapt to their environment, and humans are no exception. Culture defines much of the human environment, so cultural evolution has actually led to adaptive evolution in humans. Examples are given to illustrate the rapid pace of adaptive evolution in response to cultural innovations. These adaptive responses have important implications for infectious diseases, Mendelian genetic diseases, and systemic diseases in current human populations. Moreover, evolution proceeds by mechanisms other than natural selection. The recent growth in human population size has greatly increased the reservoir of mutational variants in the human gene pool, thereby enhancing the potential for human evolution. The increase in human population size coupled with our increased capacity to move across the globe has induced a rapid and ongoing evolutionary shift in how genetic variation is distributed within and among local human populations. In particular, genetic differences between human populations are rapidly diminishing and individual heterozygosity is increasing, with beneficial health effects. Finally, even when cultural evolution eliminates selection on a trait, the trait can still evolve due to natural selection on other traits. Our traits are not isolated, independent units, but rather are integrated into a functional whole, so selection on one trait can cause evolution to occur on another trait, sometimes with mildly maladaptive consequences.

  20. Has human evolution stopped?

    Science.gov (United States)

    Templeton, Alan R

    2010-07-01

    It has been argued that human evolution has stopped because humans now adapt to their environment via cultural evolution and not biological evolution. However, all organisms adapt to their environment, and humans are no exception. Culture defines much of the human environment, so cultural evolution has actually led to adaptive evolution in humans. Examples are given to illustrate the rapid pace of adaptive evolution in response to cultural innovations. These adaptive responses have important implications for infectious diseases, Mendelian genetic diseases, and systemic diseases in current human populations. Moreover, evolution proceeds by mechanisms other than natural selection. The recent growth in human population size has greatly increased the reservoir of mutational variants in the human gene pool, thereby enhancing the potential for human evolution. The increase in human population size coupled with our increased capacity to move across the globe has induced a rapid and ongoing evolutionary shift in how genetic variation is distributed within and among local human populations. In particular, genetic differences between human populations are rapidly diminishing and individual heterozygosity is increasing, with beneficial health effects. Finally, even when cultural evolution eliminates selection on a trait, the trait can still evolve due to natural selection on other traits. Our traits are not isolated, independent units, but rather are integrated into a functional whole, so selection on one trait can cause evolution to occur on another trait, sometimes with mildly maladaptive consequences.

  1. (Human) Resourcing For CI

    DEFF Research Database (Denmark)

    Jørgensen, Frances; S., Jacob; Kofoed, Lise Busk

    2005-01-01

    More and more, the ability to compete in today’s market is viewed as being dependent on human capital. One of the most challenging aspects of human resource management involves supplying the organization with the human capital necessary to fulfill its objectives. This task becomes especially...

  2. Human Machine Learning Symbiosis

    Science.gov (United States)

    Walsh, Kenneth R.; Hoque, Md Tamjidul; Williams, Kim H.

    2017-01-01

    Human Machine Learning Symbiosis is a cooperative system where both the human learner and the machine learner learn from each other to create an effective and efficient learning environment adapted to the needs of the human learner. Such a system can be used in online learning modules so that the modules adapt to each learner's learning state both…

  3. Monogenic human obesity.

    Science.gov (United States)

    Farooqi, I Sadaf

    2008-01-01

    We and others have identified several single gene defects that disrupt the molecules in the leptinmelanocortin pathway causing severe obesity in humans. In this review, we consider these human monogenic obesity syndromes and discuss how far the characterisation of these patients has informed our understanding of the physiological role of leptin and the melanocortins in the regulation of human body weight and neuroendocrine function.

  4. From Human Past to Human Future

    Directory of Open Access Journals (Sweden)

    Robert G. Bednarik

    2013-01-01

    Full Text Available This paper begins with a refutation of the orthodox model of final Pleistocene human evolution, presenting an alternative, better supported account of this crucial phase. According to this version, the transition from robust to gracile humans during that period is attributable to selective breeding rather than natural selection, rendered possible by the exponential rise of culturally guided volitional choices. The rapid human neotenization coincides with the development of numerous somatic and neural detriments and pathologies. Uniformitarian reasoning based on ontogenic homology suggests that the cognitive abilities of hominins are consistently underrated in the unstable orthodoxies of Pleistocene archaeology. A scientifically guided review establishes developmental trajectories defining recent changes in the human genome and its expressions, which then form the basis of attempts to extrapolate from them into the future. It is suggested that continuing and perhaps accelerating unfavorable genetic changes to the human species, rather than existential threats such as massive disasters, pandemics, or astrophysical events, may become the ultimate peril of humanity.

  5. Humanity at the Edge

    DEFF Research Database (Denmark)

    Svendsen, Mette N.; Gjødsbøl, Iben M.; Dam, Mie S.

    2017-01-01

    At the heart of anthropology and the social sciences lies a notion of human existence according to which humans and animals share the basic need for food, but only humans have the capacity for morality. Based on fieldwork in a pig laboratory, a neonatal intensive care unit (NICU), and a dementia ...... human and animal value and agency with approaches that focus on human experience and virtue ethics, we argue that ‘the human’ at stake in the moral laboratory of feeding precarious lives puts ‘the human’ in anthropology at disposal for moral experimentation....

  6. Jordan Adjusted Human Development

    OpenAIRE

    Ababsa, Myriam

    2014-01-01

    Jordan Human Development Index (HDI) and Adjusted Human Development Index (IHDI) In 1990, the United Nations Development Programme designed a Human Development Index composed of life expectancy at birth, level of education and gross domestic product (GDP) per capita. In 2011, the UNDP ranked Jordan 95th out of 187 countries with a human development index of 0.698, up from 0.591 in 1990, making it the leading medium-range country for human development (fig. VIII.1). In 2010, the inequality adj...

  7. Human Beings And Water

    OpenAIRE

    2016-01-01

    The writer of this paper on this writing is talking about the human beings and water. Water is one of the very fundamentally things that human beings need to keep their lives. Human beings sometimes do not realise that the water is very important for them because they actually cannot live their lives without the present of water. Human beings can keep their lives without rice, but cannot without water. For instances the use of water for human beings are domestic use, cooking, washing, bathing...

  8. Human rights and bioethics.

    Science.gov (United States)

    Barilan, Y M; Brusa, M

    2008-05-01

    In the first part of this article we survey the concept of human rights from a philosophical perspective and especially in relation to the "right to healthcare". It is argued that regardless of meta-ethical debates on the nature of rights, the ethos and language of moral deliberation associated with human rights is indispensable to any ethics that places the victim and the sufferer in its centre. In the second part we discuss the rise of the "right to privacy", particularly in the USA, as an attempt to make the element of personal free will dominate over the element of basic human interest within the structure of rights and when different rights seem to conflict. We conclude by discussing the relationship of human rights with moral values beyond the realm of rights, mainly human dignity, free will, human rationality and response to basic human needs.

  9. Human Milk Banking.

    Science.gov (United States)

    Haiden, Nadja; Ziegler, Ekhard E

    2016-01-01

    Human milk banks play an essential role by providing human milk to infants who would otherwise not be able to receive human milk. The largest group of recipients are premature infants who derive very substantial benefits from it. Human milk protects premature infants from necrotizing enterocolitis and from sepsis, two devastating medical conditions. Milk banks collect, screen, store, process, and distribute human milk. Donating women usually nurse their own infants and have a milk supply that exceeds their own infants' needs. Donor women are carefully selected and are screened for HIV-1, HIV-2, human T-cell leukemia virus 1 and 2, hepatitis B, hepatitis C, and syphilis. In the milk bank, handling, storing, processing, pooling, and bacterial screening follow standardized algorithms. Heat treatment of human milk diminishes anti-infective properties, cellular components, growth factors, and nutrients. However, the beneficial effects of donor milk remain significant and donor milk is still highly preferable in comparison to formula.

  10. Human Capital and Sustainability

    Directory of Open Access Journals (Sweden)

    Garry Jacobs

    2011-01-01

    Full Text Available A study of sustainability needs to consider the role of all forms of capital—natural, biological, social, technological, financial, cultural—and the complex ways in which they interact. All forms of capital derive their value, utility and application from human mental awareness, creativity and social innovation. This makes human capital, including social capital, the central determinant of resource productivity and sustainability. Humanity has entered the Anthropocene Epoch in which human changes have become the predominant factor in evolution. Humanity is itself evolving from animal physicality to social vitality to mental individuality. This transition has profound bearing on human productive capabilities, adaptability, creativity and values, the organization of economy, public policy, social awareness and life styles that determine sustainability. This article examines the linkages between population, economic development, employment, education, health, social equity, cultural values, energy intensity and sustainability in the context of evolving human consciousness. It concludes that development of human capital is the critical determinant of long-term sustainability and that efforts to accelerate the evolution of human consciousness and emergence of mentally self-conscious individuals will be the most effective approach for ensuring a sustainable future. Education is the primary lever. Human choice matters.

  11. Integrated Environmental Modelling: human decisions, human challenges

    Science.gov (United States)

    Glynn, Pierre D.

    2015-01-01

    Integrated Environmental Modelling (IEM) is an invaluable tool for understanding the complex, dynamic ecosystems that house our natural resources and control our environments. Human behaviour affects the ways in which the science of IEM is assembled and used for meaningful societal applications. In particular, human biases and heuristics reflect adaptation and experiential learning to issues with frequent, sharply distinguished, feedbacks. Unfortunately, human behaviour is not adapted to the more diffusely experienced problems that IEM typically seeks to address. Twelve biases are identified that affect IEM (and science in general). These biases are supported by personal observations and by the findings of behavioural scientists. A process for critical analysis is proposed that addresses some human challenges of IEM and solicits explicit description of (1) represented processes and information, (2) unrepresented processes and information, and (3) accounting for, and cognizance of, potential human biases. Several other suggestions are also made that generally complement maintaining attitudes of watchful humility, open-mindedness, honesty and transparent accountability. These suggestions include (1) creating a new area of study in the behavioural biogeosciences, (2) using structured processes for engaging the modelling and stakeholder communities in IEM, and (3) using ‘red teams’ to increase resilience of IEM constructs and use.

  12. Human organ markets and inherent human dignity.

    Science.gov (United States)

    MacKellar, Calum

    2014-01-01

    It has been suggested that human organs should be bought and sold on a regulated market as any other material property belongingto an individual. This would have the advantage of both addressing the grave shortage of organs available for transplantation and respecting the freedom of individuals to choose to do whatever they want with their body parts. The old arguments against such a market in human organs are, therefore, being brought back into question. The article examines the different arguments both in favour and against the sale of human organs. It concludes that the body and any of its elements is a full expression of the whole person. As such, they cannot have a price if the individual is to retain his or her full inherent dignity and if society is to retain and protect this very important concept.

  13. Chimeras and human dignity.

    Science.gov (United States)

    de Melo-Martín, Inmaculada

    2008-12-01

    Discussions about whether new biomedical technologies threaten or violate human dignity are now common. Indeed, appeals to human dignity have played a central role in national and international debates about whether to allow particular kinds of biomedical investigations. The focus of this paper is on chimera research. I argue here that both those who claim that particular types of human-nonhuman chimera research threaten human dignity and those who argue that such threat does not exist fail to make their case. I first introduce some of the arguments that have been offered supporting the claim that the creation of certain sorts of chimeras threatens or violates human dignity. I next present opponents' assessments of such arguments. Finally I critically analyze both the critics' and the supporters' claims about whether chimera research threatens human dignity.

  14. Human Performance in Space

    Science.gov (United States)

    Jones, Patricia M.; Fiedler, Edna

    2010-01-01

    Human factors is a critical discipline for human spaceflight. Nearly every human factors research area is relevant to space exploration -- from the ergonomics of hand tools used by astronauts, to the displays and controls of a spacecraft cockpit or mission control workstation, to levels of automation designed into rovers on Mars, to organizational issues of communication between crew and ground. This chapter focuses more on the ways in which the space environment (especially altered gravity and the isolated and confined nature of long-duration spaceflight) affects crew performance, and thus has specific novel implications for human factors research and practice. We focus on four aspects of human performance: neurovestibular integration, motor control and musculo-skeletal effects, cognitive effects, and behavioral health. We also provide a sampler of recent human factors studies from NASA.

  15. Developing human technology curriculum

    Directory of Open Access Journals (Sweden)

    Teija Vainio

    2012-10-01

    Full Text Available During the past ten years expertise in human-computer interaction has shifted from humans interacting with desktop computers to individual human beings or groups of human beings interacting with embedded or mobile technology. Thus, humans are not only interacting with computers but with technology. Obviously, this shift should be reflected in how we educate human-technology interaction (HTI experts today and in the future. We tackle this educational challenge first by analysing current Master’s-level education in collaboration with two universities and second, discussing postgraduate education in the international context. As a result, we identified core studies that should be included in the HTI curriculum. Furthermore, we discuss some practical challenges and new directions for international HTI education.

  16. Humanities, Digital Humanities, Media studies, Internet studies

    DEFF Research Database (Denmark)

    Brügger, Niels

    the interplay between four areas which until now to a certain extent have been separated: Traditional Hu- manities, Digital Humanities, Media studies, and Internet studies. The vision is followed by an outline of how it can be unfolded in concrete activities, in the form of research projects, research......Todays expanding digital landscape constitutes an important research object as well as the research environment for the Humanities at the beginning of the 21st century. Taking this state of affairs as a starting point this inaugural lecture presents a vision for how the digital affects...

  17. Advancing Human Rights

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    The National Human Rights Action Plan of China (2012-2015) was initiated after the successful conclusion of the National Human Rights Action Plan of China (2009-2010).The Chinese government in late July published an assessment report on the implementation of the plan,elaborating on the full implementation of China's first-ever national program on human rights development,which was drafted in April 2009.

  18. Human hemoglobin genetics

    Energy Technology Data Exchange (ETDEWEB)

    Honig, G.R.; Adams, J.G.

    1986-01-01

    This book contains the following 10 chapters: Introduction; The Human Hemoglobins; The Human Globin Genes; Hemoglobin Synthesis and Globin Gene Expression; The Globin Gene Mutations - A. Mechanisms and Classification; The Globin Gene Mutations - B. Their Phenotypes and Clinical Expression; The Genetics of the Human Globin Gene Loci: Formal Genetics and Gene Linkage; The Geographic Distribution of Globin Gene Variation; Labortory Identification, Screening, Education, and Counseling for Abnormal Hemoglobins and Thalassemias; and Approaches to the Treatment of the Hemoglobin Disorders.

  19. Modern Human Capital Management

    OpenAIRE

    Feldberger, Madita

    2008-01-01

    Title: Modern Human Capital Management Seminar date: 30th of May 2008 Course: Master thesis in Business Administration, 15 ECTS Authors: Madita Feldberger Supervisor: Lars Svensson Keywords: Human capital, SWOT Analysis, Strategic Map, Balanced Scorecard Research Problem: Despite of the success of Human Capital Management (HCM) in research it did not arrive yet in the HR departments of many companies. Numerous firms even have problems to set their strategic goals with focus on HR. The HR Bala...

  20. Robotics for Human Exploration

    Science.gov (United States)

    Fong, Terrence; Deans, Mathew; Bualat, Maria

    2013-01-01

    Robots can do a variety of work to increase the productivity of human explorers. Robots can perform tasks that are tedious, highly repetitive or long-duration. Robots can perform precursor tasks, such as reconnaissance, which help prepare for future human activity. Robots can work in support of astronauts, assisting or performing tasks in parallel. Robots can also perform "follow-up" work, completing tasks designated or started by humans. In this paper, we summarize the development and testing of robots designed to improve future human exploration of space.

  1. [Human physiology: kidney].

    Science.gov (United States)

    Natochin, Iu V

    2010-01-01

    The content of human physiology as an independent part of current physiology is discussed. Substantiated is the point that subjects of human physiology are not only special sections of physiology where functions are inherent only in human (physiology of intellectual activity, speech, labor, sport), but also in peculiarities of functions, specificity of regulation of each of physiological systems. By the example of physiology of kidney and water-salt balance there are shown borders of norm, peculiarities of regulation in human, new chapters of renal physiology which have appeared in connection with achievements of molecular physiology.

  2. Human Performance Research Center

    Data.gov (United States)

    Federal Laboratory Consortium — Biochemistry:Improvements in energy metabolism, muscular strength and endurance capacity have a basis in biochemical and molecular adaptations within the human body....

  3. Extraterritorial Human Rights Obligations

    DEFF Research Database (Denmark)

    Amsinck Boie, Hans Nikolaj; Torp, Kristian

    adequately be addressed without including the approach to the problem taken in practice; Corporate Social Responsibility, CSR. The book therefore draws upon the concept of CSR and the approaches developed here and discusses whether states may utilize the CSR-based concept of human rights due diligence...... to fulfil their possible obligations to protect against human rights violations by corporations.......The book addresses the issue of corporate respect for human rights by examining if and how states are obligated to ensure that corporations originating from their jurisdiction respect human rights when they operate abroad. The existence of such a duty is much debated by academics at national...

  4. The psychology of humanness.

    Science.gov (United States)

    Haslam, Nick; Loughnan, Steve; Holland, Elise

    2013-01-01

    This chapter explores the ways in which the concept of "humanness" illuminates a wide and fascinating variety of psychological phenomena. After introducing the concept--everyday understandings of what it is to be human--we present a model of the diverse ways in which humanness can be denied to people. According to this model people may be perceived as lacking uniquely human characteristics, and thus likened to animals, or as lacking human nature, and thus likened to inanimate objects. Both of these forms of dehumanization occur with varying degrees of subtlety, from the explicit uses of derogatory animal metaphors, to stereotypes that ascribe lesser humanness or simpler minds to particular groups, to nonconscious associations between certain humans and nonhumans. After reviewing research on dehumanization through the lens of our model we examine additional topics that the psychology of humanness clarifies, notably the perception of nonhuman animals and the objectification of women. Humanness emerges as a concept that runs an integrating thread through a variety of research literatures.

  5. The Human Toolmaker

    OpenAIRE

    Kassuba, Tanja; Kastner, Sabine

    2014-01-01

    Do you enjoy building airplanes, cars, houses, or robots with Lego blocks? Humans are the only animal species that can create complicated constructions from simple Lego blocks – our Lego building ability is “human-specific,” since it is only found in human beings. What would our closest relatives, apes or monkeys, do with a box of Lego blocks? They would probably chew on them, and lose interest when they find out that they are not edible! Why are humans the only Lego builders in the animal ki...

  6. Photography after the Human

    OpenAIRE

    Zylinska, Joanna

    2016-01-01

    How can we visualise and subsequently reimagine the abstraction that is the extinction of human species while there is still time? The article addresses this question by considering the existence of images – and, in particular, light-induced mechanical images known as photographs – after the human. The “after the human” designation does not just refer to the material disappearance of the human in some kind of distant future, but also to the present imagining of the disappearance of the human ...

  7. Refractoriness in human atria

    DEFF Research Database (Denmark)

    Skibsbye, Lasse; Jespersen, Thomas; Christ, Torsten

    2016-01-01

    drugs. Cardiomyocyte excitability depends on availability of sodium channels, which involves both time- and voltage-dependent recovery from inactivation. This study therefore aims to characterise how sodium channel inactivation affects refractoriness in human atria. METHODS AND RESULTS: Steady......-state activation and inactivation parameters of sodium channels measured in vitro in isolated human atrial cardiomyocytes were used to parameterise a mathematical human atrial cell model. Action potential data were acquired from human atrial trabeculae of patients in either sinus rhythm or chronic atrial...... in pharmacological management of chronic atrial fibrillation....

  8. Humanities, Digital Humanities, Media studies, Internet studies

    DEFF Research Database (Denmark)

    Brügger, Niels

    the interplay between four areas which until now to a certain extent have been separated: Traditional Hu- manities, Digital Humanities, Media studies, and Internet studies. The vision is followed by an outline of how it can be unfolded in concrete activities, in the form of research projects, research...

  9. Developing Human Resources through Actualizing Human Potential

    Science.gov (United States)

    Clarken, Rodney H.

    2012-01-01

    The key to human resource development is in actualizing individual and collective thinking, feeling and choosing potentials related to our minds, hearts and wills respectively. These capacities and faculties must be balanced and regulated according to the standards of truth, love and justice for individual, community and institutional development,…

  10. Human Rights, History of

    NARCIS (Netherlands)

    de Baets, Antoon; Wright, James

    2015-01-01

    In this article, six basic debates about human rights are clarified from a historical perspective: the origin of human rights as moral rights connected to the natural law doctrine and opposed to positive rights; the wave of criticism of their abstract and absolute character by nineteenth-century

  11. Introduction to human factors

    Energy Technology Data Exchange (ETDEWEB)

    Winters, J.M.

    1988-03-01

    Some background is given on the field of human factors. The nature of problems with current human/computer interfaces is discussed, some costs are identified, ideal attributes of graceful system interfaces are outlined, and some reasons are indicated why it's not easy to fix the problems. (LEW)

  12. Human Capital and Retirement

    NARCIS (Netherlands)

    P. Alders

    1999-01-01

    textabstractThis paper investigates the relation between human capital and retirement when the age of retirement is endogenous. This relation is examined in a life-cycle earnings model. An employee works full time until retirement. The worker accumulates human capital by training- on-the-job and by

  13. Cohabitation: Humans & Agriculture

    NARCIS (Netherlands)

    Woodington, W.

    2012-01-01

    This "designers' manual" is made during the TIDO-course AR0531 Smart & Bioclimatic Design. Cohabitation of humans and agriculture can be used to improve building climate, human health and the state of the world. It affects building design and requires new building components. This manual explains w

  14. Manage "Human Capital" Strategically

    Science.gov (United States)

    Odden, Allan

    2011-01-01

    To strategically manage human capital in education means restructuring the entire human resource system so that schools not only recruit and retain smart and capable individuals, but also manage them in ways that support the strategic directions of the organization. These management practices must be aligned with a district's education improvement…

  15. Human Resource Accounting

    Science.gov (United States)

    Woodruff, Robert L., Jr.

    1973-01-01

    An interview is reported which discussed the implications for the hiring, recruiting, screening and development of employees in the light of human resource accounting, here defined as the identification, accumulation and dissemination of information about human resources in dollar terms. (SA)

  16. Hooking Kids with Humanities.

    Science.gov (United States)

    Anstead, Neil L.

    1993-01-01

    Humanitas is part of Collaboratives for Humanities and Arts Teaching (CHART), a nationwide network funded primarily by the Rockefeller Foundation. In 11 large school districts and numerous rural districts, high school teachers, academics, artists, and business and community leaders are cooperating to promote teaching of the arts and humanities.…

  17. The Human Technology

    DEFF Research Database (Denmark)

    Fausing, Bent

    with fundamental human values like intuition, vision and sensing; all the qualities the technology, the industrialisation and rationalisation, or in short modernity, has been criticized for having taken away from human existence. What technology has taken away now comes back through new technology as an aid...

  18. Manage "Human Capital" Strategically

    Science.gov (United States)

    Odden, Allan

    2011-01-01

    To strategically manage human capital in education means restructuring the entire human resource system so that schools not only recruit and retain smart and capable individuals, but also manage them in ways that support the strategic directions of the organization. These management practices must be aligned with a district's education improvement…

  19. Translating the human microbiome

    NARCIS (Netherlands)

    Brown, J.; Vos, de W.M.; Distefano, P.S.; Doré, J.; Huttenhower, C.; Knight, R.; Lawley, T.D.; Raes, J.; Turnbaugh, P.

    2013-01-01

    Over the past decade, an explosion of descriptive analyses from initiatives, such as the Human Microbiome Project (HMP) and the MetaHIT project, have begun to delineate the human microbiome. Inhabitants of the intestinal tract, nasal passages, oral cavities, skin, gastrointestinal tract and urogenit

  20. Human Rights Guaranteed

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    Report says China’s human rights plan successfully implemented According to a detailed assessment report published by China’s State Council Information Office (SCIO),all the measures outlined in the National Human Rights Action Plan of China (2009-10) had been successfully put into place by the end of 2010.

  1. Defects in Human Nature

    Institute of Scientific and Technical Information of China (English)

    黄靓

    2008-01-01

    By tracing the defects of society back to the defects of human nature, humanity's essence is proved to be inherent evil. Man's natural tendency to do evil remain harnessed through the controls and conventions imposed by civilization, however, when rules or civilization are weakened, man' s dark side is unleashed.

  2. Humanism within Globalization

    Science.gov (United States)

    Weber, Jennifer E.

    2014-01-01

    The complexity of adult learning connects it to almost all other facets of human endeavor. Consequently, the future of adult education depends, to a large extent on who participates and the quality of such participation. Quality participation, when teamed with environments committed to a concern for humanity, launches opportunities for varied…

  3. Report Details Human Resources

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    China issues its first white paper on human resources The Chinese Government issued a white paper on its human resources on September 10, highlighting the country’s policies to cope with employment pressures and a lack of "high-level innovative talents.

  4. Modeling human color categorization

    NARCIS (Netherlands)

    van den Broek, Egon; Schouten, Th.E.; Kisters, P.M.F.

    2008-01-01

    A unique color space segmentation method is introduced. It is founded on features of human cognition, where 11 color categories are used in processing color. In two experiments, human subjects were asked to categorize color stimuli into these 11 color categories, which resulted in markers for a Colo

  5. Humanism within Globalization

    Science.gov (United States)

    Weber, Jennifer E.

    2014-01-01

    The complexity of adult learning connects it to almost all other facets of human endeavor. Consequently, the future of adult education depends, to a large extent on who participates and the quality of such participation. Quality participation, when teamed with environments committed to a concern for humanity, launches opportunities for varied…

  6. Damping Effect of Humans

    DEFF Research Database (Denmark)

    Pedersen, Lars

    Passive humans (sitting or standing) might well be present on flooring-systems, footbridges or other structures that carry humans. An active croud of people might generate structural vibrations, and these might be problematic. The passive crowd of people, however, will interact with the structural...

  7. Human Mind Maps

    Science.gov (United States)

    Glass, Tom

    2016-01-01

    When students generate mind maps, or concept maps, the maps are usually on paper, computer screens, or a blackboard. Human Mind Maps require few resources and little preparation. The main requirements are space where students can move around and a little creativity and imagination. Mind maps can be used for a variety of purposes, and Human Mind…

  8. Translating the human microbiome

    NARCIS (Netherlands)

    Brown, J.; Vos, de W.M.; Distefano, P.S.; Doré, J.; Huttenhower, C.; Knight, R.; Lawley, T.D.; Raes, J.; Turnbaugh, P.

    2013-01-01

    Over the past decade, an explosion of descriptive analyses from initiatives, such as the Human Microbiome Project (HMP) and the MetaHIT project, have begun to delineate the human microbiome. Inhabitants of the intestinal tract, nasal passages, oral cavities, skin, gastrointestinal tract and urogenit

  9. Human Resource Construction

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Centering on strategic objective of reform and development,CIAE formulated its objectives in human resource construction for the 13th Five-year Plan period,and achieved new apparent progress in human resource construction in 2015.1 Implementation of"LONGMA Project"

  10. Modeling human color categorization

    NARCIS (Netherlands)

    van den Broek, Egon; Schouten, Th.E.; Kisters, P.M.F.

    A unique color space segmentation method is introduced. It is founded on features of human cognition, where 11 color categories are used in processing color. In two experiments, human subjects were asked to categorize color stimuli into these 11 color categories, which resulted in markers for a

  11. Human Rights Improving

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    China issues a white paper on its human rights,highlighting freedom of speech on the Interne The Chinese Government released a white paper on its human rights in 2009 on September 26,highlighting the role of Internet freedom and the country’s efforts in safeguarding citizens’legitimate civil and political rights.

  12. Human Rights, History of

    NARCIS (Netherlands)

    de Baets, Antoon; Wright, James

    2015-01-01

    In this article, six basic debates about human rights are clarified from a historical perspective: the origin of human rights as moral rights connected to the natural law doctrine and opposed to positive rights; the wave of criticism of their abstract and absolute character by nineteenth-century lib

  13. Designing Human Technologies

    DEFF Research Database (Denmark)

    Simonsen, Jesper

    and the design process, in ethical and society-related concerns, and in evaluating how designs fulfill needs and solve problems. Designing Human Technologies subscribes to a broad technology concept including information and communication, mobile, environmental/sustainable and energy technologies......, the Humanities, and Social Science. The initiative broadens the perspective of IS and recognize reflections on aesthetics, ethics, values, connections to politics, and strategies for enabling a better future as legitimate parts of the research agenda. Designing Human Technologies is a design-oriented Strategic...... a shared interdisciplinary research and educational collaboration. As a creative research initiative it focuses on change and innovative thinking. The innovativeness is a result of the strongly interdisciplinary perspective which is at the heart of Designing Human Technologies. Designing Human Technologies...

  14. Human Relations-skolen

    DEFF Research Database (Denmark)

    Scheuer, Steen

    2014-01-01

    Human Relations-skolen er en samlebetegnelse for to forskningsretninger, som tilsammen bidrog som nogle af de første til at indkredse og belyse de mellemmenneskelige relationers betydning for motivation og trivsel i arbejdslivet, og som skulle få stor ind"ydelse ikke bare på organisationsteorien......, som formulerede en række teorier og modeller om menneskets motivation, trivsel og behov i arbejdslivet. Selvom de ikke nødvendigvis relaterede sig til hinandens arbejde, er de forskellige bidragsydere i dag kendt som repræsentanter for den paradigmatiske betegnelse Human Relations. Undertiden skelnes...... der mellem Human Relations (Hawthorne-eksperimenter ne) og Neo-Human Relations (behovsteorierne), men i denne fremstilling bruges Human Relations som en samlebetegnelse for begge disse – noget forskellige – forskningstraditioner. De har i dag opnået stor udbredelse og er praktisk talt obligatorisk...

  15. Human to Human Transmission of Brucella Melitensis

    Directory of Open Access Journals (Sweden)

    Patrice Vigeant

    1995-01-01

    Full Text Available Human brucellosis is acquired mainly through contact with infected animal tissues, ingestion of unpasteurized dairy products or infected aerosols. Person to person transmission is still considered uncertain. The case of a woman diagnosed with proven brucellosis after her husband suffered a relapse of bacteremia with Brucella melitensis biotype 3, which was originally acquired abroad by eating goat cheese, is described. It was postulated that person to person spread of brucellosis is a likely mode of transmission in this case.

  16. Human to Human Transmission of Brucella Melitensis

    OpenAIRE

    Patrice Vigeant; Jack Mendelson; Miller, Mark A.

    1995-01-01

    Human brucellosis is acquired mainly through contact with infected animal tissues, ingestion of unpasteurized dairy products or infected aerosols. Person to person transmission is still considered uncertain. The case of a woman diagnosed with proven brucellosis after her husband suffered a relapse of bacteremia with Brucella melitensis biotype 3, which was originally acquired abroad by eating goat cheese, is described. It was postulated that person to person spread of brucellosis is a likely ...

  17. Archaea on human skin.

    Directory of Open Access Journals (Sweden)

    Alexander J Probst

    Full Text Available The recent era of exploring the human microbiome has provided valuable information on microbial inhabitants, beneficials and pathogens. Screening efforts based on DNA sequencing identified thousands of bacterial lineages associated with human skin but provided only incomplete and crude information on Archaea. Here, we report for the first time the quantification and visualization of Archaea from human skin. Based on 16 S rRNA gene copies Archaea comprised up to 4.2% of the prokaryotic skin microbiome. Most of the gene signatures analyzed belonged to the Thaumarchaeota, a group of Archaea we also found in hospitals and clean room facilities. The metabolic potential for ammonia oxidation of the skin-associated Archaea was supported by the successful detection of thaumarchaeal amoA genes in human skin samples. However, the activity and possible interaction with human epithelial cells of these associated Archaea remains an open question. Nevertheless, in this study we provide evidence that Archaea are part of the human skin microbiome and discuss their potential for ammonia turnover on human skin.

  18. Human Power Empirically Explored

    Energy Technology Data Exchange (ETDEWEB)

    Jansen, A.J.

    2011-01-18

    Harvesting energy from the users' muscular power to convert this into electricity is a relatively unknown way to power consumer products. It nevertheless offers surprising opportunities for product designers; human-powered products function independently from regular power infrastructure, are convenient and can be environmentally and economically beneficial. This work provides insight into the knowledge required to design human-powered energy systems in consumer products from a scientific perspective. It shows the developments of human-powered products from the first introduction of the BayGen Freeplay radio in 1995 till current products and provides an overview and analysis of 211 human-powered products currently on the market. Although human power is generally perceived as beneficial for the environment, this thesis shows that achieving environmental benefit is only feasible when the environmental impact of additional materials in the energy conversion system is well balanced with the energy demands of the products functionality. User testing with existing products showed a preference for speeds in the range of 70 to 190 rpm for crank lengths from 32 to 95 mm. The muscular input power varied from 5 to 21 W. The analysis of twenty graduation projects from the Faculty of Industrial Design Engineering in the field of human-powered products, offers an interesting set of additional practice based design recommendations. The knowledge based approach of human power is very powerful to support the design of human-powered products. There is substantial potential for improvements in the domains energy conversion, ergonomics and environment. This makes that human power, when applied properly, is environmentally and economically competitive over a wider range of applications than thought previously.

  19. Human pancreas development.

    Science.gov (United States)

    Jennings, Rachel E; Berry, Andrew A; Strutt, James P; Gerrard, David T; Hanley, Neil A

    2015-09-15

    A wealth of data and comprehensive reviews exist on pancreas development in mammals, primarily mice, and other vertebrates. By contrast, human pancreatic development has been less comprehensively reviewed. Here, we draw together those studies conducted directly in human embryonic and fetal tissue to provide an overview of what is known about human pancreatic development. We discuss the relevance of this work to manufacturing insulin-secreting β-cells from pluripotent stem cells and to different aspects of diabetes, especially permanent neonatal diabetes, and its underlying causes.

  20. Enhancing human capacities

    CERN Document Server

    Savulescu, Julian; Kahane, Guy

    2011-01-01

    Enhancing Human Capacities is the first to review the very latest scientific developments in human enhancement. It is unique in its examination of the ethical and policy implications of these technologies from a broad range of perspectives. Presents a rich range of perspectives on enhancement from world leading ethicists and scientists from Europe and North America The most comprehensive volume yet on the science and ethics of human enhancement Unique in providing a detailed overview of current and expected scientific advances in this area Discusses both general conceptual and ethical issues