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Article ; Online: Sex Hormones and Adrenal Steroids: Biological Variation Estimated Using Direct and Indirect Methods.

Røys, Eirik Åsen / Guldhaug, Nora Alicia / Viste, Kristin / Jones, Graham Dallas / Alaour, Bashir / Sylte, Marit Sverresdotter / Torsvik, Janniche / Kellmann, Ralf / Strand, Heidi / Theodorsson, Elvar / Marber, Michael / Omland, Torbjørn / Aakre, Kristin Moberg

Clinical chemistry

2022 Volume 69, Issue 1, Page(s) 100–109

Abstract: Background: Biological variation (BV) data may be used to develop analytical performance specifications (APS), reference change values (RCV), and support the applicability of population reference intervals. This study estimates within-subject BV (CVI) ... ...

Abstract	Background: Biological variation (BV) data may be used to develop analytical performance specifications (APS), reference change values (RCV), and support the applicability of population reference intervals. This study estimates within-subject BV (CVI) for several endocrine biomarkers using 3 different methodological approaches. Methods: For the direct method, 30 healthy volunteers were sampled weekly for 10 consecutive weeks. Samples were analyzed in duplicate for 17-hydroxyprogesterone (17-OHP), androstenedione, cortisol, cortisone, estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), and testosterone. A CV-ANOVA with outlier removal and a Bayesian model were applied to derive the CVI. For estradiol, FSH and LH, only the male subgroup was included. In the indirect method, using the same analytes and groups, pairs of sequential results were extracted from the laboratory information system. The total result variation for individual pairs was determined by identifying a central gaussian distribution in the ratios of the result pairs. The CVI was then estimated by removing the effect of analytical variation. Results: The estimated CVI from the Bayesian model (μCVP(i)) in the total cohort was: 17-OHP, 23%; androstenedione, 20%; cortisol, 18%; cortisone, 11%; SHBG, 7.4%; testosterone, 16%; and for the sex hormones in men: estradiol, 14%; FSH, 8%; and LH, 26%. CVI-heterogeneity was present for most endocrine markers. Similar CVI data were estimated using the CV-ANOVA and the indirect method. Conclusions: Similar CVI data were obtained using 2 different direct and one indirect method. The indirect approach is a low-cost alternative ensuring implementation of CVI data applicable for local conditions.
MeSH term(s)	Male ; Humans ; Androstenedione ; Hydrocortisone ; Cortisone ; Bayes Theorem ; Gonadal Steroid Hormones ; Luteinizing Hormone ; Follicle Stimulating Hormone ; Estradiol ; Steroids ; Testosterone ; Sex Hormone-Binding Globulin
Chemical Substances	Androstenedione (409J2J96VR) ; Hydrocortisone (WI4X0X7BPJ) ; Cortisone (V27W9254FZ) ; Gonadal Steroid Hormones ; Luteinizing Hormone (9002-67-9) ; Follicle Stimulating Hormone (9002-68-0) ; Estradiol (4TI98Z838E) ; Steroids ; Testosterone (3XMK78S47O) ; Sex Hormone-Binding Globulin
Language	English
Publishing date	2022-11-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80102-1
ISSN	1530-8561 ; 0009-9147
ISSN (online)	1530-8561
ISSN	0009-9147
DOI	10.1093/clinchem/hvac175
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Article ; Online: Heterologous Expression of an Unusual Ketosynthase, SxtA, Leads to Production of Saxitoxin Intermediates in Escherichia coli.

Soeriyadi, Angela H / Mazmouz, Rabia / Pickford, Russell / Al-Sinawi, Bakir / Kellmann, Ralf / Pearson, Leanne A / Neilan, Brett A

Chembiochem : a European journal of chemical biology

2020 Volume 22, Issue 5, Page(s) 845–849

Abstract: Paralytic shellfish toxins (PSTs) are neurotoxic alkaloids produced by freshwater cyanobacteria and marine dinoflagellates. Due to their antagonism of voltage-gated sodium channels in excitable cells, certain analogues are of significant pharmacological ... ...

Abstract	Paralytic shellfish toxins (PSTs) are neurotoxic alkaloids produced by freshwater cyanobacteria and marine dinoflagellates. Due to their antagonism of voltage-gated sodium channels in excitable cells, certain analogues are of significant pharmacological interest. The biosynthesis of the parent compound, saxitoxin, is initiated with the formation of 4-amino-3-oxo-guanidinoheptane (ethyl ketone) by an unusual polyketide synthase-like enzyme, SxtA. We have heterologously expressed SxtA from Raphidiopsis raciborskii T3 in Escherichia coli and analysed its activity in vivo. Ethyl ketone and a truncated analogue, methyl ketone, were detected by HPLC-ESI-HRMS analysis, thus suggesting that SxtA has relaxed substrate specificity in vivo. The chemical structures of these products were further verified by tandem mass spectrometry and labelled-precursor feeding with [guanidino-
MeSH term(s)	Cylindrospermopsis/genetics ; Cylindrospermopsis/metabolism ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Poisons/metabolism ; Saxitoxin/genetics ; Saxitoxin/metabolism ; Substrate Specificity ; Voltage-Gated Sodium Channels/chemistry
Chemical Substances	Poisons ; Voltage-Gated Sodium Channels ; Saxitoxin (35523-89-8)
Language	English
Publishing date	2020-11-16
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2020469-3
ISSN	1439-7633 ; 1439-4227
ISSN (online)	1439-7633
ISSN	1439-4227
DOI	10.1002/cbic.202000675
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Article ; Online: An Ultrasensitive Routine LC-MS/MS Method for Estradiol and Estrone in the Clinically Relevant Sub-Picomolar Range.

Bertelsen, Bjørn-Erik / Kellmann, Ralf / Viste, Kristin / Bjørnevik, Anne Turid / Eikesdal, Hans Petter / Lønning, Per Eystein / Sagen, Jørn V / Almås, Bjørg

Journal of the Endocrine Society

2020 Volume 4, Issue 6, Page(s) bvaa047

Abstract: Background: Current analytical routine methods lack the sensitivity to monitor plasma estrogen levels in breast cancer patients treated with aromatase inhibitors. Such monitoring is warranted for premenopausal patients treated with an aromatase ... ...

Abstract	Background: Current analytical routine methods lack the sensitivity to monitor plasma estrogen levels in breast cancer patients treated with aromatase inhibitors. Such monitoring is warranted for premenopausal patients treated with an aromatase inhibitor and an LH-releasing hormone analogue in particular. Therefore, we aimed to develop a routine tandem mass spectroscopy combined with liquid chromatography (LC-MS/MS) method for estradiol (E2) and estrone (E1) for use in the sub-picomolar range. Method: Calibrators, quality controls (QC), or serum samples were spiked with isotope-labeled internal standard and purified by liquid-liquid extraction. The reconstituted extracts were analyzed by LC-MS/MS in negative electrospray ionization mode. QCs at 6 levels made from pooled patient sera were used to validate the accuracy, sensitivity, and precision of the method. Results: We achieved limits of quantification of 0.6 pmol/L (0.16 pg/mL) for E2 and 0.3 pmol/L (0.07 pg/mL) for E1. The coefficient of variation was below 9.0% at all QC levels for E2 (range, 1.7-153 pmol/L), and below 7.8% for E1 (range, 1.7-143 pmol/L). The method is traceable to the E2 reference standard BCR576. Reference ranges for E2 and E1 in healthy, postmenopausal women were obtained, for E2: 3.8 to 36 pmol/L, for E1: 22 to 122 pmol/L. We measured and confirmed ultra-low E2 and E1 concentrations in sera from patients on the aromatase inhibitors letrozole or exemestane. Conclusion: This ultrasensitive LC-MS/MS method is suitable for routine assessment of serum E1 and E2 levels in breast cancer patients during estrogen suppression therapy. The method satisfies all requirements for measurement of E2 in the clinical setting as stated by the Endocrine Society in 2013. Precis: We report an ultrasensitive LCMS/MS routine assay that measures pretreatment and suppressed levels of estradiol/estrone during aromatase inhibitor treatment of postmenopausal breast cancer patients.
Language	English
Publishing date	2020-04-21
Publishing country	United States
Document type	Journal Article
ISSN	2472-1972
ISSN (online)	2472-1972
DOI	10.1210/jendso/bvaa047
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Article ; Online: Bedtime Salivary Cortisol as a Screening Test for Cushing Syndrome in Children.

Ueland, Grethe Å / Kellmann, Ralf / Jørstad Davidsen, Melissa / Viste, Kristin / Husebye, Eystein S / Almås, Bjørg / Storr, Helen L / Sagen, Jørn V / Mellgren, Gunnar / Júlíusson, Petur B / Methlie, Paal

Journal of the Endocrine Society

2021 Volume 5, Issue 5, Page(s) bvab033

Abstract: Background: Diagnosing Cushing syndrome (CS) can be challenging. The 24-hour urine free cortisol (UFC) measurement is considered gold standard. This is a laborious test, dependent on correct urine collection. Late-night salivary cortisol is easier and ... ...

Abstract	Background: Diagnosing Cushing syndrome (CS) can be challenging. The 24-hour urine free cortisol (UFC) measurement is considered gold standard. This is a laborious test, dependent on correct urine collection. Late-night salivary cortisol is easier and is used as a screening test for CS in adults, but has not been validated for use in children. Objective: To define liquid chromatography tandem mass spectrometry (LC-MS/MS)-based cutoff values for bedtime and morning salivary cortisol and cortisone in children, and validate the results in children with and without CS. Methods: Bedtime and morning salivary samples were collected from 320 healthy children aged 4 to 16 years. Fifty-four patients from the children's outpatient obesity clinic and 3 children with pituitary CS were used for validation. Steroid hormones were assayed by LC-MS/MS. Cutoff levels for bedtime salivary cortisol and cortisone were defined by the 97.5% percentile in healthy subjects. Results: Bedtime cutoff levels for cortisol and cortisone were 2.4 and 12.0 nmol/L, respectively. Applying these cutoff levels on the verification cohort, 1 child from the obesity clinic had bedtime salivary cortisol exceeding the defined cutoff level, but normal salivary cortisone. All 3 children with pituitary CS had salivary cortisol and cortisone far above the defined bedtime cutoff levels. Healthy subjects showed a significant decrease in salivary cortisol from early morning to bedtime. Conclusions: We propose that bedtime salivary cortisol measured by LC-MS/MS with a diagnostic threshold above 2.4 nmol/L can be applied as a screening test for CS in children. Age- and gender-specific cutoff levels are not needed.
Language	English
Publishing date	2021-03-04
Publishing country	United States
Document type	Journal Article
ISSN	2472-1972
ISSN (online)	2472-1972
DOI	10.1210/jendso/bvab033
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Article: Biochemical characterization of paralytic shellfish toxin biosynthesis in vitro

Kellmann, Ralf / Neilan, Brett A

Journal of phycology. 2007 June, v. 43, no. 3

2007

Abstract: Saxitoxin (STX) and its analogs are voltage-gated sodium-channel blockers that cause paralytic shellfish poisoning (PSP) and negatively affect human health and seafood industries worldwide. Little is known about the molecular biology of PSP-toxin ... ...

Abstract	Saxitoxin (STX) and its analogs are voltage-gated sodium-channel blockers that cause paralytic shellfish poisoning (PSP) and negatively affect human health and seafood industries worldwide. Little is known about the molecular biology of PSP-toxin synthesis. Saxitoxin precursors were identified 25 years ago, and a hypothetical biosynthesis pathway was proposed; however, the correct sequence of reactions and enzymes involved in their catalysis remains to be identified. This study describes the optimization of in vitro biosynthesis of PSP toxins by cellular lysates of the toxic cyanobacterium Cylindrospermopsis raciborskii (Wołosz.) Seenaya et Subbaraju T3 and the characterization of its biochemical requirements. Enzymes involved in PSP-toxin synthesis are located in the cytosol. The molecular components of in vitro biosynthesis reactions could not be completely defined because of the requirement of an unknown cofactor. Evidence is presented that supports the previous suggestion that STX biosynthesis involves a Claisen condensation between arginine and acetate. In addition, carbamoyl phosphate was identified as a likely precursor for carbamated PSP toxins. Predictions have been made regarding the enzymes that may be involved in the biosynthesis of PSP toxins. These included class II aminotransferase; nonheme iron oxygenase, containing flavin, and possibly ferredoxin, as the prosthetic groups; and an O-carbamoyltransferase. On the other hand, the involvement of cytochrome P450 monooxygenase was excluded.
Keywords	Cylindrospermopsis raciborskii
Language	English
Dates of publication	2007-06
Size	p. 497-508.
Publisher	Blackwell Publishing Ltd
Publishing place	Oxford, UK
Document type	Article
ZDB-ID	281226-5
ISSN	0022-3646
ISSN	0022-3646
DOI	10.1111/j.1529-8817.2007.00351.x
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Article ; Online: Characterisation of the paralytic shellfish toxin biosynthesis gene clusters in Anabaena circinalis AWQC131C and Aphanizomenon sp. NH-5.

Mihali, Troco K / Kellmann, Ralf / Neilan, Brett A

BMC biochemistry

2009 Volume 10, Page(s) 8

Abstract: Background: Saxitoxin and its analogues collectively known as the paralytic shellfish toxins (PSTs) are neurotoxic alkaloids and are the cause of the syndrome named paralytic shellfish poisoning. PSTs are produced by a unique biosynthetic pathway, which ...

Abstract	Background: Saxitoxin and its analogues collectively known as the paralytic shellfish toxins (PSTs) are neurotoxic alkaloids and are the cause of the syndrome named paralytic shellfish poisoning. PSTs are produced by a unique biosynthetic pathway, which involves reactions that are rare in microbial metabolic pathways. Nevertheless, distantly related organisms such as dinoflagellates and cyanobacteria appear to produce these toxins using the same pathway. Hypothesised explanations for such an unusual phylogenetic distribution of this shared uncommon metabolic pathway, include a polyphyletic origin, an involvement of symbiotic bacteria, and horizontal gene transfer. Results: We describe the identification, annotation and bioinformatic characterisation of the putative paralytic shellfish toxin biosynthesis clusters in an Australian isolate of Anabaena circinalis and an American isolate of Aphanizomenon sp., both members of the Nostocales. These putative PST gene clusters span approximately 28 kb and contain genes coding for the biosynthesis and export of the toxin. A putative insertion/excision site in the Australian Anabaena circinalis AWQC131C was identified, and the organization and evolution of the gene clusters are discussed. A biosynthetic pathway leading to the formation of saxitoxin and its analogues in these organisms is proposed. Conclusion: The PST biosynthesis gene cluster presents a mosaic structure, whereby genes have apparently transposed in segments of varying size, resulting in different gene arrangements in all three sxt clusters sequenced so far. The gene cluster organizational structure and sequence similarity seems to reflect the phylogeny of the producer organisms, indicating that the gene clusters have an ancient origin, or that their lateral transfer was also an ancient event. The knowledge we gain from the characterisation of the PST biosynthesis gene clusters, including the identity and sequence of the genes involved in the biosynthesis, may also afford the identification of these gene clusters in dinoflagellates, the cause of human mortalities and significant financial loss to the tourism and shellfish industries.
MeSH term(s)	Anabaena/classification ; Anabaena/genetics ; Anabaena/metabolism ; Aphanizomenon/classification ; Aphanizomenon/genetics ; Aphanizomenon/metabolism ; Australia ; Base Sequence ; Biosynthetic Pathways ; Cloning, Molecular ; DNA, Bacterial/chemistry ; DNA, Bacterial/genetics ; Genes, Bacterial/genetics ; Inverted Repeat Sequences ; Molecular Sequence Data ; Molecular Structure ; Multigene Family ; Neurotoxins/biosynthesis ; Neurotoxins/chemistry ; Phylogeny ; RNA, Ribosomal, 16S/genetics ; Saxitoxin/analogs & derivatives ; Saxitoxin/biosynthesis ; Saxitoxin/chemistry ; Sequence Analysis, DNA
Chemical Substances	DNA, Bacterial ; Neurotoxins ; RNA, Ribosomal, 16S ; Saxitoxin (35523-89-8)
Language	English
Publishing date	2009-03-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2041216-2
ISSN	1471-2091 ; 1471-2091
ISSN (online)	1471-2091
ISSN	1471-2091
DOI	10.1186/1471-2091-10-8
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Article: Effects of defined mixtures of POPs and endocrine disruptors on the steroid metabolome of the human H295R adrenocortical cell line

Ahmed, Kareem Eldin Mohammed / Anders Goksøyr / Erik Ropstad / Hanne Friis Berntsen / Håvard G. Frøysa / Karin Elisabeth Zimmer / Nello Blaser / Odd André Karlsen / Ralf Kellmann / Steven Verhaegen

Chemosphere. 2019 Mar., v. 218

2019

Abstract: The presence of environmental pollutants in our ecosystem may impose harmful health effects to wildlife and humans. Several of these toxic chemicals have a potential to interfere with the endocrine system. The adrenal cortex has been identified as the ... ...

Abstract	The presence of environmental pollutants in our ecosystem may impose harmful health effects to wildlife and humans. Several of these toxic chemicals have a potential to interfere with the endocrine system. The adrenal cortex has been identified as the main target organ affected by endocrine disrupting chemicals. The aim of this work was to assess exposure effects of defined and environmentally relevant mixtures of chlorinated, brominated and perfluorinated chemicals on steroidogenesis, using the H295R adrenocortical cell line model in combination with a newly developed liquid chromatography tandem mass spectrometry (LC-MS/MS) method. By using this approach, we could simultaneously analyze 19 of the steroids in the steroid biosynthesis pathway, revealing a deeper insight into possible disruption of steroidogenesis. Our results showed a noticeable down-regulation in steroid production when cells were exposed to the highest concentration of a mixture of brominated and fluorinated compounds (10,000-times human blood values). In contrast, up-regulation was observed with estrone under the same experimental condition, as well as with some other steroids when cells were exposed to a perfluorinated mixture (1000-times human blood values), and the mixture of chlorinated and fluorinated compounds. Interestingly, the low concentration of the perfluorinated mixture alone produced a significant, albeit small, down-regulation of pregnenolone, and the total mixture a similar effect on 17-hydroxypregnenolone. Other mixtures resulted in only slight deviations from the control. Indication of synergistic effects were noted when we used a statistical model to improve data interpretation. A potential for adverse outcomes of human exposures is indicated, pointing to the need for further investigation into these mixtures.
Keywords	adrenal cortex ; biosynthesis ; blood ; bromination ; cell lines ; ecosystems ; endocrine-disrupting chemicals ; estrone ; humans ; liquid chromatography ; metabolome ; perfluorocarbons ; pollutants ; pregnenolone ; statistical models ; steroidogenesis ; synergism ; tandem mass spectrometry ; toxic substances ; wildlife
Language	English
Dates of publication	2019-03
Size	p. 328-339.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	120089-6
ISSN	1879-1298 ; 0045-6535 ; 0366-7111
ISSN (online)	1879-1298
ISSN	0045-6535 ; 0366-7111
DOI	10.1016/j.chemosphere.2018.11.057
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Article ; Online: LC-MS/MS based profiling and dynamic modelling of the steroidogenesis pathway in adrenocarcinoma H295R cells.

Ahmed, Kareem Eldin Mohammed / Frøysa, Håvard G / Karlsen, Odd André / Sagen, Jørn V / Mellgren, Gunnar / Verhaegen, Steven / Ropstad, Erik / Goksøyr, Anders / Kellmann, Ralf

Toxicology in vitro : an international journal published in association with BIBRA

2018 Volume 52, Page(s) 332–341

Abstract: Endocrine disrupting chemicals have been reported to exert effects directly on enzymes involved in steroid biosynthesis. Here, we present a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for profiling the steroid metabolome of H295R ...

Abstract	Endocrine disrupting chemicals have been reported to exert effects directly on enzymes involved in steroid biosynthesis. Here, we present a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for profiling the steroid metabolome of H295R human adrenocarcinoma cells. Our method can simultaneously analyse 19 precursors, intermediates and end-products, representing the adrenal steroid biosynthesis pathway. In order to obtain better insights into the processes of steroidogenesis, we investigated the dose-response relationship of forskolin, an activator of adenylate cyclase, on steroid production in H295R cells. We observed that 1.5 μM forskolin stimulated steroid production at approximately 50% of the maximum rate for most steroids. Hence, we studied the time course for steroid synthesis over 72 h in H295R cells that were stimulated with forskolin. At 24 h, we observed a peak in steroid levels for the intermediate metabolites, such as progesterone and pregnenolone, while end-products such as testosterone and cortisol continued to increase until 72 h. Finally, we show how global data provide a unique basis to develop a comprehensive, dynamic model for steroidogenesis using first order kinetics. The timeline data made it possible to estimate all reaction rate constants of the network. We propose this method as a unique and sensitive screening tool to identify effects on adrenal steroidogenesis by endocrine disrupting compounds.
MeSH term(s)	Adenylyl Cyclases ; Adrenocortical Carcinoma/metabolism ; Cell Line, Tumor ; Chromatography, Liquid ; Colforsin/pharmacology ; Endocrine Disruptors/pharmacology ; High-Throughput Screening Assays ; Humans ; Metabolome ; Steroids/metabolism ; Tandem Mass Spectrometry
Chemical Substances	Endocrine Disruptors ; Steroids ; Colforsin (1F7A44V6OU) ; Adenylyl Cyclases (EC 4.6.1.1)
Language	English
Publishing date	2018-07-11
Publishing country	England
Document type	Journal Article
ZDB-ID	639064-x
ISSN	1879-3177 ; 0887-2333
ISSN (online)	1879-3177
ISSN	0887-2333
DOI	10.1016/j.tiv.2018.07.002
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Article ; Online: The Short Cosyntropin Test Revisited: New Normal Reference Range Using LC-MS/MS.

Ueland, Grethe Å / Methlie, Paal / Øksnes, Marianne / Thordarson, Hrafnkell B / Sagen, Jørn / Kellmann, Ralf / Mellgren, Gunnar / Ræder, Maria / Dahlqvist, Per / Dahl, Sandra R / Thorsby, Per M / Løvås, Kristian / Husebye, Eystein S

The Journal of clinical endocrinology and metabolism

2018 Volume 103, Issue 4, Page(s) 1696–1703

Abstract: Background: The cosyntropin test is used to diagnose adrenal insufficiency (AI) and nonclassical congenital adrenal hyperplasia (NCCAH). Current cutoffs for cortisol and 17-hydroxyprogesterone (17-OHP) are derived from nonstandardized immunoassays. ... ...

Abstract	Background: The cosyntropin test is used to diagnose adrenal insufficiency (AI) and nonclassical congenital adrenal hyperplasia (NCCAH). Current cutoffs for cortisol and 17-hydroxyprogesterone (17-OHP) are derived from nonstandardized immunoassays. Liquid chromatography tandem mass spectrometry (LC-MS/MS) offers direct measurement of steroids, prompting the need to re-establish normal ranges. Objective: The goal of this study was to define cutoff values for cortisol and 17-OHP in serum by LC-MS/MS 30 and 60 minutes after intravenous administration of 250 µg tetracosactide acetate to healthy volunteers and to compare the results with LC-MS/MS with routine immunoassays. Methods: Cosyntropin testing was performed in healthy subjects (n = 138) and in patients referred for evaluation of adrenocortical function (n = 94). Steroids were assayed by LC-MS/MS and compared with two immunoassays used in routine diagnostics (Immulite and Roche platforms). The cutoff level for cortisol was defined as the 2.5% percentile in healthy subjects not using oral estrogens (n = 121) and for 17-OHP as the 97.5% percentile. Results: Cortisol cutoff levels for LC-MS/MS were 412 and 485 nmol/L at 30 and 60 minutes, respectively. Applying the new cutoffs, 13 of 60 (22%) subjects who had AI according to conventional criteria now had a normal test result. For 17-OHP, the cutoff levels were 8.9 and 9.0 nmol/L at 30 and 60 minutes, respectively. Conclusions: LC-MS/MS provides cutoff levels for cortisol and 17-OHP after cosyntropin stimulation that are lower than those based on immunoassays, possibly because cross-reactivity between steroid intermediates and cortisol is eliminated. This reduces the number of false-positive tests for AI and false-negative tests for NCCAH.
MeSH term(s)	17-alpha-Hydroxyprogesterone/blood ; Adolescent ; Adrenal Hyperplasia, Congenital/blood ; Adrenal Hyperplasia, Congenital/diagnosis ; Adrenal Insufficiency/blood ; Adrenal Insufficiency/diagnosis ; Adult ; Aged ; Aged, 80 and over ; Chromatography, Liquid ; Cosyntropin ; Female ; Humans ; Hydrocortisone/blood ; Male ; Middle Aged ; Reference Values ; Tandem Mass Spectrometry ; Young Adult
Chemical Substances	Cosyntropin (16960-16-0) ; 17-alpha-Hydroxyprogesterone (68-96-2) ; Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2018-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/jc.2017-02602
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Article ; Online: Effects of defined mixtures of POPs and endocrine disruptors on the steroid metabolome of the human H295R adrenocortical cell line.

Ahmed, Kareem Eldin Mohammed / Frøysa, Håvard G / Karlsen, Odd André / Blaser, Nello / Zimmer, Karin Elisabeth / Berntsen, Hanne Friis / Verhaegen, Steven / Ropstad, Erik / Kellmann, Ralf / Goksøyr, Anders

Chemosphere

2018 Volume 218, Page(s) 328–339

Abstract	The presence of environmental pollutants in our ecosystem may impose harmful health effects to wildlife and humans. Several of these toxic chemicals have a potential to interfere with the endocrine system. The adrenal cortex has been identified as the main target organ affected by endocrine disrupting chemicals. The aim of this work was to assess exposure effects of defined and environmentally relevant mixtures of chlorinated, brominated and perfluorinated chemicals on steroidogenesis, using the H295R adrenocortical cell line model in combination with a newly developed liquid chromatography tandem mass spectrometry (LC-MS/MS) method. By using this approach, we could simultaneously analyze 19 of the steroids in the steroid biosynthesis pathway, revealing a deeper insight into possible disruption of steroidogenesis. Our results showed a noticeable down-regulation in steroid production when cells were exposed to the highest concentration of a mixture of brominated and fluorinated compounds (10,000-times human blood values). In contrast, up-regulation was observed with estrone under the same experimental condition, as well as with some other steroids when cells were exposed to a perfluorinated mixture (1000-times human blood values), and the mixture of chlorinated and fluorinated compounds. Interestingly, the low concentration of the perfluorinated mixture alone produced a significant, albeit small, down-regulation of pregnenolone, and the total mixture a similar effect on 17-hydroxypregnenolone. Other mixtures resulted in only slight deviations from the control. Indication of synergistic effects were noted when we used a statistical model to improve data interpretation. A potential for adverse outcomes of human exposures is indicated, pointing to the need for further investigation into these mixtures.
MeSH term(s)	17-alpha-Hydroxypregnenolone/metabolism ; Adrenal Cortex/drug effects ; Adrenal Cortex/metabolism ; Cell Line ; Cell Line, Tumor ; Chromatography, Liquid ; Dose-Response Relationship, Drug ; Drug Synergism ; Endocrine Disruptors/administration & dosage ; Endocrine Disruptors/toxicity ; Environmental Exposure/adverse effects ; Environmental Pollutants/administration & dosage ; Environmental Pollutants/toxicity ; Halogenated Diphenyl Ethers/toxicity ; Humans ; Metabolome/drug effects ; Models, Statistical ; Polychlorinated Biphenyls/toxicity ; Steroids/metabolism ; Tandem Mass Spectrometry
Chemical Substances	Endocrine Disruptors ; Environmental Pollutants ; Halogenated Diphenyl Ethers ; Steroids ; 17-alpha-Hydroxypregnenolone (387-79-1) ; pentabromodiphenyl ether (7REL09ZX35) ; Polychlorinated Biphenyls (DFC2HB4I0K)
Language	English
Publishing date	2018-11-12
Publishing country	England
Document type	Journal Article
ZDB-ID	120089-6
ISSN	1879-1298 ; 0045-6535 ; 0366-7111
ISSN (online)	1879-1298
ISSN	0045-6535 ; 0366-7111
DOI	10.1016/j.chemosphere.2018.11.057
Database	MEDical Literature Analysis and Retrieval System OnLINE

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