The partial characterization of 1-oxygenated steroids from urine of a hypertensive newborn child.
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ABSTRACT:
SUBMITTER: Edwards RW
PROVIDER: S-EPMC1198792 | biostudies-other | 1968 Jun
REPOSITORIES: biostudies-other
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Project description:To comprehensively characterize androgens and androgen precursors in classic 21-hydroxylase deficiency (21OHD) and to gain insights into the mechanisms of their formation.Serum samples were obtained from 38 patients (19 men) with classic 21OHD, aged 3-59, and 38 sex- and age-matched controls; 3 patients with 11?-hydroxylase deficiency; 4 patients with adrenal insufficiency; and 16 patients (8 men) undergoing adrenal vein sampling. Paraffin-embedded normal (n = 5) and 21OHD adrenal tissues (n = 3) were used for immunohistochemical studies.We measured 11 steroids in all sera by liquid chromatography-tandem mass spectrometry. Immunofluroescence localized 3?-hydroxysteroid dehydrogenase type 2 (HSD3B2) and cytochrome b5 (CYB5A) within the normal and 21OHD adrenals.Four 11-oxygenated 19-carbon (11oxC19) steroids were significantly higher in male and female 21OHD patients than in controls: 11?-hydroxyandrostenedione, 11-ketoandrostenedione 11?-hydroxytestosterone, and 11-ketotestosterone (3-4-fold, P < 0.0001). For 21OHD patients, testosterone and 11-ketotestosterone were positively correlated in females, but inversely correlated in males. All 11oxC19 steroids were higher in the adrenal vein than in the inferior vena cava samples from men and women and rose with cosyntropin stimulation. Only trace amounts of 11oxC19 steroids were found in the sera of patients with 11?-hydroxylase deficiency and adrenal insufficiency, confirming their adrenal origin. HSD3B2 and CYB5A immunoreactivities were sharply segregated in the normal adrenal glands, whereas areas of overlapping expression were identified in the 21OHD adrenals.All four 11oxC19 steroids are elevated in both men and women with classic 21OHD. Our data suggest that 11oxC19 steroids are specific biomarkers of adrenal-derived androgen excess.
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Project description:Sex hormone steroidal drugs were reported to have modulating actions on the ion channel TRPM3. Pregnenolone sulphate (PS) presents the most potent known endogenous chemical agonist of TRPM3 and affects several gating modes of the channel. These includes a synergistic action of PS and high temperatures on channel opening and the PS-induced opening of a noncanonical pore in the presence of other TRPM3 modulators. Moreover, human TRPM3 variants associated with neurodevelopmental disease exhibit an increased sensitivity for PS. However, other steroidal sex hormones were reported to influence TRPM3 functions with activating or inhibiting capacity. Here, we aimed to answer how DHEAS, estradiol, progesterone and testosterone act on the various modes of TRPM3 function in the wild-type channel and two-channel variants associated with human disease. By means of calcium imaging and whole-cell patch clamp experiments, we revealed that all four drugs are weak TRPM3 agonists that share a common steroidal interaction site. Furthermore, they exhibit increased activity on TRPM3 at physiological temperatures and in channels that carry disease-associated mutations. Finally, all steroids are able to open the noncanonical pore in wild-type and DHEAS also in mutant TRPM3. Collectively, our data provide new valuable insights in TRPM3 gating, structure-function relationships and ligand sensitivity.
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Project description:Trisomy 16q is a rare disorder with severe abnormalities, which always leads to early postnatal mortality. It usually results from a parental translocation, exhibiting 16q duplication associated with another chromosomal deletion. The present study reports on the clinical presentation and molecular cytogenetic results of a small-for-gestational-age infant, consisting of partial trisomy 16q21?qter and monosomy 2p25.3?pter. The proband presented with moderately low birthweight, small anterior fontanelles, prominent forehead, low hairline, telecanthus, flat nasal bridge, choanal atresia, clinodactyly of the fifth fingers, urogenital anomalies, congenital muscular torticollis and congenital laryngomalacia. The last two traits have not previously been reported in any trisomy 16q and monosomy 2p cases. The proband was trisomic for the 16q21?qter chromosomal region with the karyotype 46,XY,der(2)t(2;16)(p25;q21)pat. The chromosomal anomaly was the result of unbalanced segregation of a paternal balanced translocation, 46,XY,t(2;16)(p25;q21). In this case, molecular cytogenetic analysis had a critical role in delineating the proband's clinical phenotype. Although this patient had a 16q21?qter duplication and a 2p25.3?pter deletion, the latter may have had mild phenotypic effects when associated with trisomy 16q. The literature was also reviewed, focusing on cases with the same breakpoints, localizations and clinical features reported in recent years.
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Project description:A new scalable enantioselective approach to functionalized oxygenated steroids is described. This strategy is based on chiral bis(oxazoline) copper(II) complex-catalyzed enantioselective and diastereoselective Michael reactions of cyclic ketoesters and enones to install vicinal quaternary and tertiary stereocenters. In addition, the utility of copper(II) salts as highly active catalysts for the Michael reactions of traditionally unreactive ?,?'-enones and substituted ?,?'-ketoesters that results in unprecedented Michael adducts containing vicinal all-carbon quaternary centers is also demonstrated. The Michael adducts subsequently undergo base-promoted diastereoselective aldol cascade reactions resulting in the natural or unnatural steroid skeletons. The experimental and computational studies suggest that the torsional strain effects arising from the presence of the ?(5)-unsaturation are key controlling elements for the formation of the natural cardenolide scaffold. The described method enables expedient generation of polycyclic molecules including modified steroidal scaffolds as well as challenging-to-synthesize Hajos-Parrish and Wieland-Miescher ketones.
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Project description:ImportanceAlthough the immediate impact of neonatal illness is well recognized, its wider and longer term outcomes on childhood mortality and the role of specific illnesses across childhood are unclear.ObjectiveTo investigate how many deaths in childhood are associated with neonatal illness and the underlying conditions of the children who died.Design, setting, and participantsThis population-based cohort study of children who died before age 10 years in England between April 1, 2019, and March 31, 2021, used data from the National Child Mortality Database. Data analysis was performed from September 2022 to May 2023.ExposureChildren who received care in a neonatal unit after birth plus those who died in the first day of life, before admission to a neonatal unit, were considered to have likely neonatal illness.Main outcomes and measuresThe primary outcome was the relative risk (RR) of dying, stratified by likely neonatal illness and specific neonatal conditions. Comparisons were made using the χ2 or likelihood ratio test, as appropriate.ResultsA total of 4829 children were included (median [IQR] age at death, 28 [2-274] days; 2606 boys [54.8%]; 2690 White children [64.0%]). Overall, 3456 children who died (71.6%) had evidence of likely neonatal illness. Children with neonatal illness were more likely to die before their tenth birthday than those without evidence of neonatal illness (RR, 13.82; 95% CI, 13.00-14.71). The estimated population-attributable risk fraction for neonatal illness among all deaths before age 10 years was 66.4% (95% CI, 64.9%-67.9%). Children with preceding neonatal illness who died were more likely to have underlying behavioral or developmental disorders (odds ratio [OR], 3.31; 95% CI, 2.47-4.42), chronic neurological disease (OR, 3.00; 95% CI, 2.51-3.58), and chronic respiratory disease (OR, 3.01; 95% CI, 2.43-3.73) than children without neonatal illness.Conclusions and relevanceIn this cohort study, most children who died before age 10 years had some evidence of neonatal illness, and they died of a range of causes, including infections and sudden, unexpected, unexplained death. These findings suggest that improvements to perinatal morbidity, an area with an existing evidence base for improvement, may have important impacts on child health across the next decade.
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Project description:CD8+ T-cells provide robust anti-viral immunity, yet how epitope-specific T-cells evolve across the human lifespan is unknown. We defined CD8+ T-cell immunity directed at the prominent influenza epitope, HLA-A*02:01-M158-66 (A2/M158) across four age groups (newborns, children, adults and elderly) ex vivo at phenotypic, single cell sequence (transcriptomic), clonal and functional levels. We identified a linear differentiation trajectory from newborns to children then adults, followed by divergence and a clonal reset in older adults. Gene profiles in older adults closely resembled those observed in newborns and children, despite being clonally-different. However, only child- and adult-derived A2/M158+CD8+ T-cells had the potential to differentiate into highly cytotoxic epitope-specific CD8+ T-cells, which was linked to highly functional public TCRab-signatures. Suboptimal TCRab-signatures detected in older adults led to poorer proliferation, polyfunctionality, avidity and recognition of peptide mutants, although displayed no signs of exhaustion. Our study suggests that priming T-cells at different stages of life might greatly affect CD8+ T-cell responses towards viral infections.
2023-08-16 | GSE237817 | GEO