Salivary cortisol as a tool for physiological studies and diagnostic strategies

Salivary cortisol is an index of plasma free cortisol and is obtained by a noninvasive procedure. We have been using salivary cortisol as a tool for physiological and diagnostic studies, among them the emergence of circadian rhythm in preterm and term infants. The salivary cortisol circadian rhythm in term and premature infants was established between 8 and 12 postnatal weeks. In the preterm infants the emergence of circadian rhythm was parallel to the onset of sleep rhythm. We also studied the use of salivary cortisol for screening for Cushing's syndrome (CS) in control and obese outpatients based on circadian rhythm and the overnight 1 mg dexamethasone (DEX) suppression test. Salivary cortisol was suppressed to less than 100 ng/dl after 1 mg DEX in control and obese patients. A single salivary cortisol measurement at 23:00 h and again after 1 mg DEX above the 90th percentile of the obese group values had sensitivity and specificity of 93 and 93% (23:00 h), and 91 and 94% (after DEX), respectively. The sensitivity improved to 100% when we combined both parameters. We also studied 11 CS children and 21 age-matched primary obese children for whom salivary cortisol sensitivity and specificity were 100/95% (23:00 h), and 100/95% (1 mg DEX), respectively. Similar to adults, sensitivity and specificity of 100% were obtained by combining 23:00 h and 1 mg DEX. The measurement of salivary cortisol is a useful tool for physiological studies and for the diagnosis of CS in children and adults on an outpatient basis

Salivary cortisol as a tool for physiological studies and diagnostic strategies

Salivary cortisol is an index of plasma free cortisol and is obtained by a noninvasive procedure. We have been using salivary cortisol as a tool for physiological and diagnostic studies, among them the emergence of circadian rhythm in preterm and term infants. The salivary cortisol circadian rhythm in term and premature infants was established between 8 and 12 postnatal weeks. In the preterm infants the emergence of circadian rhythm was parallel to the onset of sleep rhythm. We also studied the use of salivary cortisol for screening for Cushing's syndrome (CS) in control and obese outpatients based on circadian rhythm and the overnight 1 mg dexamethasone (DEX) suppression test. Salivary cortisol was suppressed to less than 100 ng/dl after 1 mg DEX in control and obese patients. A single salivary cortisol measurement at 23:00 h and again after 1 mg DEX above the 90th percentile of the obese group values had sensitivity and specificity of 93 and 93% (23:00 h), and 91 and 94% (after DEX), respectively. The sensitivity improved to 100% when we combined both parameters. We also studied 11 CS children and 21 age-matched primary obese children for whom salivary cortisol sensitivity and specificity were 100/95% (23:00 h), and 100/95% (1 mg DEX), respectively. Similar to adults, sensitivity and specificity of 100% were obtained by combining 23:00 h and 1 mg DEX. The measurement of salivary cortisol is a useful tool for physiological studies and for the diagnosis of CS in children and adults on an outpatient basis

Genetic Predictors Of Long-term Response To Growth Hormone (gh) Therapy In Children With Gh Deficiency And Turner Syndrome: The Influence Of A Socs2 Polymorphism

Design and Patients: Genotypes were correlated with adult height data of 65 Turner syndrome (TS) and 47GHdeficiency (GHD) patients treated with rhGH, by multiple linear regressions. Generalized multifactor dimensionality reduction was used to evaluate gene-gene interactions.Background: There is great interindividual variability in the response to GH therapy. Ascertaining genetic factors can improve the accuracy of growth response predictions. Suppressor of cytokine signaling (SOCS)-2 is an intracellular negative regulator of GH receptor (GHR) signaling. CopyrightObjective: The objective of the study was to assess the influence of a SOCS2 polymorphism (rs3782415) and its interactive effect with GHR exon 3 and -202 A/C IGFBP3 (rs2854744) polymorphisms on adult height of patients treated with recombinant human GH (rhGH).Results: Baseline clinical data were indistinguishable among patients with different genotypes. Adult height SD scores of patients with at least one SOCS2 single-nucleotide polymorphism rs3782415-C were 0.7 higher than those homozygous for the T allele (P < .001). SOCS2 (P = .003), GHR-exon 3 (P=.016) and-202 A/C IGFBP3 (P=.013) polymorphisms, together with clinical factors accounted for 58% of the variability in adult height and 82% of the total height SD score gain. Patients harboring any two negative genotypes in these three different loci (homozygosity for SOCS2 T allele; the GHR exon 3 full-length allele and/or the -202C-IGFBP3 allele) were more likely to achieve an adult height at the lower quartile (odds ratio of 13.3; 95% confidence interval of 3.2-54.2, P = .0001).Conclusion: The SOCS2 polymorphism (rs3782415) has an influence on the adult height of children with TS andGHDafter long-term rhGH therapy. Polymorphisms located inGHR, IGFBP3, and SOCS2 loci have an influence on the growth outcomes of TS and GHD patients treated with rhGH. The use of these genetic markers could identify among rhGH-treated patients those who are genetically predisposed to have less favorable outcomes.999E1808E1813Geffner, M.E., Dunger, D.B., Future directions: Growth prediction models (2007) Horm Res., 68, pp. 51-56Flores-Morales, A., Greenhalgh, C.J., Norstedt, G., Rico-Bautista, E., Negative regulation of growth hormone receptor signaling (2006) Mol Endocrinol., 20, pp. 241-253Greenhalgh, C.J., Rico-Bautista, E., Lorentzon, M., SOCS2 negatively regulates growth hormone action in vitro and in vivo (2005) J Clin Invest., 115, pp. 397-406Wassenaar, M.J., Dekkers, O.M., Pereira, A.M., Impact of the exon 3-deleted GH receptor polymorphism on baseline height and the growth response to recombinant human growth hormone therapy in growth hormone deficient(GHD)andnon-GHDchildren with short stature: A systematic review and meta-analysis (2009) J Clin Endocrinol Metab., 94, pp. 3721-3730Renehan, A.G., Solomon, M., Zwahlen, M., Growth hormone receptor polymorphism and growth hormone therapy response in children: A Bayesian meta-analysis (2012) AmJ Epidemiol., 175, pp. 867-877Costalonga, E.F., Antonini, S.R., Guerra-Junior, G., Mendonca, B.B., Arnhold, I.J., Jorge, A.A., The-202 A allele of insulin-like growth factor binding protein-3 (IGFBP3) promoter polymorphism is associated with higher IGFBP-3 serum levels and better growth response to growth hormone treatment in patients with severe growth hormone deficiency (2009) J Clin Endocrinol Metab., 94, pp. 588-595Braz, A.F., Costalonga, E.F., Montenegro, L.R., The interactive effect of GHR-exon 3 and-202 A/C IGFBP3 polymorphisms on rhGH responsiveness and treatment outcomes in patients with Turner syndrome (2012) J Clin Endocrinol Metab., 97, pp. E671-E677Weedon, M.N., Lango, H., Lindgren, C.M., Genome-wide association analysis identifies 20 loci that influence adult height (2008) Nat Genet., 40, pp. 575-583Gudbjartsson, D.F., Walters, G.B., Thorleifsson, G., Manysequence variants affecting diversity of adult human height (2008) Nat Genet., 40, pp. 609-615Chan, Y., Holmen, O.L., Dauber, A., Common variants show predicted polygenic effects on height in the tails of the distribution, except in extremely short individuals (2011) PLoS Genet., 7, p. e1002439Lou, X.Y., Chen, G.B., Yan, L., A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence (2007) Am J Hum Genet., 80, pp. 1125-1137Lango Allen, H., Estrada, K., Lettre, G., Hundreds of variants clustered in genomic loci and biological pathways affect human height (2010) Nature., 467, pp. 832-838Lanktree, M.B., Guo, Y., Murtaza, M., Meta-analysis of dense genecentric association studies reveals common and uncommon variants associated with height (2011) Am J Hum Genet., 88, pp. 6-18Ranke, M.B., Lindberg, A., Albertsson-Wikland, K., Wilton, P., Price, D.A., Reiter, E.O., Increased response, but lower responsiveness, to growth hormone (GH) in very young children (aged 0-3 years) with idiopathicGHDeficiency: Analysis of data from KIGS (2005) J Clin Endocrinol Metab., 90, pp. 1966-1971Ranke, M.B., Lindberg, A., Chatelain, P., Prediction of long-term response to recombinant human growth hormone in Turner syndrome: Development and validation of mathematical models. KIGS International Board. Kabi International Growth Study (2000) J Clin Endocrinol Metab., 85, pp. 4212-4218Ranke, M.B., Lindberg, A., Cowell, C.T., Prediction of response to growth hormone treatment in short children born small for gestational age: Analysis of data from KIGS (Pharmacia International Growth Database) (2003) J Clin Endocrinol Metab., 88, pp. 125-131Clayton, P., Chatelain, P., Tato, L., Apharmacogenomic approach to the treatment of children withGHdeficiency or Turner syndrome (2013) Eur J Endocrinol., 169, pp. 277-289Stevens, A., Clayton, P., Tato, L., Pharmacogenomics of insulinlike growth factor-I generation during GH treatment in children with GH deficiency or Turner syndrome (2014) Pharmacogenomics J., 14, pp. 54-6

Expression Profile Of Apoptosis-related Genes In Childhood Adrenocortical Tumors: Low Level Of Expression Of Bcl2 And Tnf Genes Suggests A Poor Prognosis

Background: Impaired apoptosis has been implicated in the development of childhood adrenocortical tumors (ACT), although the expression of apoptosis-related gene expression in such tumors has not been reported. Methods: The mRNA expression levels of the genes CASP3, CASP8, CASP9, FAS, TNF, NFKB, and BCL2 were analyzed by quantitative real-time PCR in consecutive tumor samples obtained at diagnosis from 60 children with a diagnosis of ACT and in 11 non-neoplastic adrenal samples. BCL2 and TNF protein expression was analyzed by immunohistochemistry. Results: A significant association was observed between tumor size ≥100 g and lower expression levels of the BCL2 (P=0.03) and TNF (P=0.05) genes; between stage IV and lower expression levels of CASP3 (P=0.008), CASP9 (P=0.02), BCL2 (P=0.002), TNF (P=0.05), and NFKB (P=0.03);Weiss score ≥3 and lower expression of TNF (P=0.01); unfavorable event and higher expression values of CASP9 (P=0.01) and lower values of TNF (P=0.02); and death and lower expression of BCL2 (P=0.04). Underexpression of TNF was associated with lower event-free survival in uni- and multivariate analyses (P<0.01). Similar results were observed when patients with Weiss score <3 were excluded. 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