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Background: Tobacco smoke is a major risk factor in the development of COPD. Secondhand smoke (SHS) exposure is a known risk factor in asthma, bronchitis, and coronary artery disease. Elastin is a recognized target for injury in COPD, and the amino acids desmosine and isodesmosine (D/I), which are specific for elastin degradation, are elevated in COPD. This study determined whether exposure to SHS affects elastin degradation in asymptomatic individuals.Methods: Two cohorts of asymptomatic individuals without evidence of respiratory or circulatory disease, exposed to SHS, were studied. Both cohorts comprised normal nonsmokers, active smokers, and those exposed to SHS. D/I were measured in plasma and quantified by high-performance liquid chromatography and tandem mass spectrometry by published methods. Plasma cotinine, a metabolite of nicotine, was also measured.Results: In each cohort, the levels of D/I in plasma were statistically significantly higher in secondhand-smoke-exposed subjects than in the normal nonexposed subjects. Smokers had the highest levels of D/I but their levels were not statistically significantly higher than those of the secondhand-smoke-exposed. Cotinine levels were elevated in secondhand-smoke-exposed subjects and active smokers but not in most nonsmoking control subjects.Conclusions: Results indicate a tissue matrix effect of degradation of body elastin from SHS exposure and possible lung structure injury, which may result in COPD. Long-term studies of individuals exposed to SHS for the development of COPD are warranted. [ABSTRACT FROM AUTHOR]

Aim: It has been suggested that there is an inverse association between breastfeeding and the risk of childhood cancer. We investigated the association between full breastfeeding and paediatric cancer (PC) in a case control study in Spain.Methods: Maternal reports of full breastfeeding, collected through personal interviews using the Paediatric Environmental History, were compared among 187 children 6 months of age or older who had PC and 187 age-matched control siblings.Results: The mean duration of full breastfeeding for cases were 8.43 and 11.25 weeks for controls. Cases had been significantly more often bottle-fed than controls (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.1-2.8). Cases were significantly less breastfed for at least 2 months (OR 0.5; 95% CI 0.3-0.8), for at least 4 months (OR 0.5; 95% CI 0.3-0.8), and for 24 weeks or more (OR 0.5; 95% CI 0.2-0.9).Conclusions: Breastfeeding was inversely associated with PC, the protection increasing with the duration of full breastfeeding. Additional research on possible mechanisms of this association may be warranted. Meanwhile, breastfeeding should be encouraged among mothers. [ABSTRACT FROM AUTHOR]

Objective To compare steroid profiles in the follicular fluid (FF) from women homozygous for the methylenetetrahydrofolate reductase (MTHFR) 677C>T mutation and wildtype controls and to correlate it with the folic acid administration scheme applied at the time of oocyte retrieval. Design Retrospective single center study. Subjects and Methods Infertile patients treated by using assisted reproductive techniques were genotyped routinely for the MTHFR 677C>T mutation. In 2006 they had received folic acid supplementation doses of 400 µg daily per os. This group was designated Group-400 (n = 10). From 2008 onwards, all of our infertility patients received a daily dose of 800 µg folic acid per os. Women from this group were designated Group-800 (n = 28). FF were collected and a panel of steroid hormones (estradiol, estrone, estriol, cortisol, progesterone, 17-OH progesterone, testosterone, androstenedione, aldosterone, DHEA, and DHEA-S) was measured by isotope dilution liquid chromatography-tandem mass spectrometry employing atmospheric pressure photo ionization (APPI). Results In Group-400, the FF hormone profile confirmed a significant reduction of estradiol in homozygous 677TT carriers (0.52 ± 0.08-fold, exact p = 0.032) and for the first time also revealed significantly reduced estriol concentrations in these individuals (0.54 ± 0.05-fold, p = 0.016), as compared to wildtype controls. In Group-800, no significant differences were found for concentrations of any of the steroid hormones between homozygous 677TT carriers and wildtype controls. Conclusions The current findings support and extend previous reports on reduced concentrations of specific steroid hormones in follicular fluids of homozygous MTHFR 677C>T mutation carriers. The restoration of the FF hormone profile by elevated-dose folic acid supplementation might impact performing ART in infertile women with the MTHFR 677TT-genotype. Further adequately powered studies are necessary to verify our finding and to demonstrate the clinical effect of enhanced folic supplementation on ovarian function., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: This study sought to determine whether levothyroxine pharmacokinetics (PKs) are affected by age, weight, and sex., Methods: A PK study was performed after administration of a tracer dose of carbon-13-labeled LT4 ( 13 C-LT4). The study was conducted at an academic medical center. Adults of any age being treated with levothyroxine for hypothyroidism were enrolled in the study. A single dose of 13 C-LT4 was administered. Eighteen serial plasma samples were collected. One sample was obtained before the 13 C-LT4 dose, and the majority of the remaining samples were collected over the 120-hour period post dosing. 13 C-LT4 concentration was quantified using liquid chromatography tandem mass spectrometry. PK analysis was conducted using a linear log trapezoidal non-compartmental analysis using Phoenix 6.4., Results: Eight males and 33 females with a median age of 50 years (range 22-78 years) and median weight of 65.9 kg (range 50-150 kg) were enrolled in the study. The median 13 C-LT4 dose administered was 100 μg (range 70-300 μg). The median oral clearance rate (CL/F), apparent volume of distribution (V/F), time to peak concentration (T max ), and dose-normalized peak concentration (C max ) of 13 C-LT4 were estimated to be 0.712 L/h, 164.9 L, 4 h, and 7.5 ng/L/μg, respectively. The dose-normalized area under the concentration-time curve from time 0 to 120 hours and half-life of the terminal distribution phase were 0.931 ng.h/mL/μg and 172.2 h, respectively. There was no significant difference in any 13 C-LT4 PK parameter between patients aged >60 years (n = 10) and patients aged ≤60 years (n = 31), nor was there a relationship between age as a continuous variable and 13 C-LT4 PK parameters. Sex only affected CL/F, V/F, and dose-normalized C max in univariate analyses. However, after adjusting for weight, sex was no longer a significant covariate. Weight was a significant predictor for CL/F, V/F and dose-normalized C max of 13 C-LT4 in multivariate analyses., Conclusion: Prior studies suggest that patient age affects levothyroxine dose requirement. This study did not identify an effect of age and suggests that age-related changes in levothyroxine pharmacokinetics may be mediated by age-related weight differences. Physicians should consider a patient's weight, rather than age, for estimating levothyroxine dosage requirement.

Introduction: Phenols and parabens are ubiquitous environmental contaminants. Evidence from animal studies and limited human data suggest they may be endocrine disruptors. In the current study, we examined associations of phenols and parabens with reproductive and thyroid hormones in 106 pregnant women recruited for the prospective cohort, "Puerto Rico Testsite for Exploring Contamination Threats (PROTECT)"., Methods: Urinary exposure biomarkers (bisphenol A, triclosan, benzophenone-3, 2,4-dichlorophenol, 2,5-dichlorophenol, butyl, methyl and propyl paraben) and serum hormone levels (estradiol, progesterone, sex hormone-binding globulin (SHBG), free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone) were measured at up to two time points during pregnancy (16-20 weeks and 24-28 weeks). We used linear mixed models to assess relationships between exposure biomarkers and hormone levels across pregnancy, controlling for urinary specific gravity, maternal age, BMI and education. In sensitivity analyses, we evaluated cross-sectional relationships between exposure and hormone levels stratified by study visit using linear regression., Results: An IQR increase in methyl paraben was associated with a 7.70% increase (95% CI 1.50, 13.90) in SHBG. Furthermore, an IQR increase in butyl paraben as associated with an 8.46% decrease (95% CI 16.92, 0.00) in estradiol, as well as a 9.34% decrease (95% CI -18.31,-0.38) in estradiol/progesterone. Conversely, an IQR increase in butyl paraben was associated with a 5.64% increase (95% CI 1.26, 10.02) in FT4. Progesterone was consistently negatively associated with phenols, but none reached statistical significance. After stratification, methyl and propyl paraben were suggestively negatively associated with estradiol at the first time point (16-20 weeks), and suggestively positively associated with estradiol at the second time point (24-28 weeks)., Conclusions: Within this ongoing birth cohort, certain phenols and parabens were associated with altered reproductive and thyroid hormone levels during pregnancy. These changes may contribute to adverse health effects in mothers or their offspring, but additional research is required., Competing Interests: Competing Financial Interests: The authors declare that they have no competing financial interests., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Thyroid functional disease, and in particular hypothyroidism, is highly prevalent among chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. In the general population, hypothyroidism is associated with impaired cardiac contractility, endothelial dysfunction, atherosclerosis and possibly higher cardiovascular mortality. It has been hypothesized that hypothyroidism is an under-recognized, modifiable risk factor for the enormous burden of cardiovascular disease and death in CKD and ESRD, but this has been difficult to test due to the challenge of accurate thyroid functional assessment in uremia. Low thyroid hormone levels (i.e. triiodothyronine) have been associated with adverse cardiovascular sequelae in CKD and ESRD patients, but these metrics are confounded by malnutrition, inflammation and comorbid states, and hence may signify nonthyroidal illness (i.e. thyroid functional test derangements associated with underlying ill health in the absence of thyroid pathology). Thyrotropin is considered a sensitive and specific thyroid function measure that may more accurately classify hypothyroidism, but few studies have examined the clinical significance of thyrotropin-defined hypothyroidism in CKD and ESRD. Of even greater uncertainty are the risks and benefits of thyroid hormone replacement, which bear a narrow therapeutic-to-toxic window and are frequently prescribed to CKD and ESRD patients. In this review, we discuss mechanisms by which hypothyroidism adversely affects cardiovascular health; examine the prognostic implications of hypothyroidism, thyroid hormone alterations and exogenous thyroid hormone replacement in CKD and ESRD; and identify areas of uncertainty related to the interplay between hypothyroidism, cardiovascular disease and kidney disease requiring further investigation., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Increasing scientific evidence suggests that exposure to phthalates during pregnancy may be associated with an elevated risk of adverse reproductive outcomes such as preterm birth. Maternal endocrine disruption across pregnancy may be one pathway mediating some of these relationships. We investigated whether urinary phthalate metabolites were associated with maternal serum thyroid (free thyroxine [FT4], free triiodothyronine [FT3], and thyroid-stimulating hormone [TSH]), and sex (estradiol, progesterone, and sex hormone-binding globulin [SHBG]) hormone levels at multiple time points during pregnancy., Methods: Preliminary data (n = 106) were obtained from an ongoing prospective birth cohort in Northern Puerto Rico. We collected urine and serum sample at the first and third study visits that occurred at 18 +/- 2 and 26 +/- 2 weeks of gestation, respectively. To explore the longitudinal relationships between urinary phthalate metabolites and serum thyroid and sex hormone concentrations, we used linear mixed models (LMMs) adjusted for prepregnancy body mass index (BMI) and maternal age. An interaction term was added to each LMM to test whether the effect of urinary phthalate metabolites on serum thyroid and sex hormone levels varied by study visit. In cross-sectional analyses, we stratified BMI- and age-adjusted linear regression models by study visit., Results: In adjusted LMMs, we observed significant inverse associations between mono-3-carboxypropyl phthalate (MCPP) and FT3 and between mono-ethyl phthalate (MEP) and progesterone. In cross-sectional analyses by study visit, we detected stronger and statistically significant inverse associations at the third study visit between FT3 and MCPP as well as mono-carboxyisooctyl phthalate (MCOP); also at the third study visit, significant inverse associations were observed between FT4 and metabolites of di-(2-ethylhexyl) phthalate (DEHP). The inverse association between MEP and progesterone was consistent across study visits., Conclusions: In this group of pregnant women, urinary phthalate metabolites may be associated with altered maternal serum thyroid and sex hormone levels, and the magnitude of these effects may depend on the timing of exposure during gestation.

Objective: To determine if various medical conditions affect the serum concentrations of 3,3'-diiodothyronine (3,3'-T2)., Methods: A total of 100 patients who were recruited from a group of inpatients and outpatients with a diverse range of medical conditions, donated a single blood sample that was assayed for thyroid hormone derivatives using liquid-chromatography tandem mass spectrometry (LC-MS/MS). The associations between 3,3'-T2 concentrations and physiologic data and medical conditions were assessed., Results: Higher quartiles of 3,3'-T2 concentrations (quartile 1: 2.01-7.48, quartile 2: 7.74-12.4, quartile 3: 12.5-17, quartile 4: 17.9-45.8 pg/mL) were associated with decreasing occurrence of critical illness (58%, 11%, 0%, 8%), stroke (29%, 7.7%, 4%, 0%), critical care unit hospitalization (75%, 39%, 8.3 %, 12%), and inpatient status (83%, 42%, 8%, 12%) (all P<.001). The same quartiles were associated with increasing frequency of thyroidectomy (4%, 12%, 17%, 60%). In multivariate analyses, after adjustment for age and sex, inpatient status was associated with decreasing concentrations of 3,3'-T2 (46% decrease for inpatients with 95% confidence interval [CI] 32-57%, P<.0001). Thyroidectomy was associated with increasing concentrations of 3,3'-T2 (29% increase (CI 0.5-66%, P = .049)., Conclusion: We observed associations between inpatient status and reduced 3,3'-T2 concentrations. This appears to be a global change associated with illness, rather than an association with specific medical conditions. We also observed higher 3,3'-T2 concentrations in athyreotic outpatients receiving thyroid-stimulating hormone (TSH) suppression therapy. This demonstrates that there is production of 3,3'-T2 from levothyroxine (LT4) in extrathyroidal tissues. Conversion of thyroxine (T4) to 3,3'-T2 via both triiodothyronine (T3) and reverse triiodothyronine (rT3) pathways may prevent excessive T3 concentrations in such patients.

Background: Both age and CYP3A5 genotype are important determinants of tacrolimus disposition in pediatric kidney transplant recipients. In a recent study in adults, POR*28 was associated with increased dosing requirements early after transplant of CYP3A5-expressing kidney transplant recipients. The authors aimed to evaluate the additional contribution of POR*28 to early tacrolimus disposition in pediatric kidney transplant recipients., Methods: Retrospective data of 43 pediatric kidney transplant recipients up to 14 days posttransplant were evaluated on tacrolimus dose and tacrolimus predose blood concentrations. Recipient POR*28 and CYP3A5 genotype were determined., Results: CYP3A5 expressers carrying at least 1 POR*28 allele had on average 18.3% lower tacrolimus predose concentrations and 20.2% lower concentration/dose ratios compared with CYP3A5 expressers with POR*1/*1 genotype (P = 0.002 and P = 0.001, respectively). In CYP3A5 nonexpressers, tacrolimus disposition did not significantly differ between POR genotypes., Conclusions: In this small cohort of pediatric kidney transplant recipients, POR*28 genotype seems to explain part of the variability found in tacrolimus disposition, in addition to age and CYP3A5 genotype. This finding should be validated in a larger population, and it would be worthwhile to evaluate the clinical impact of this genotype.

Serum thyrotropin (TSH) is considered the single most sensitive and specific measure of thyroid function in the general population owing to its negative logarithmic association with free triiodothyronine and free thyroxine concentrations. It is therefore often the test of choice for screening, diagnosis, and monitoring of primary hypothyroidism. Serum TSH concentrations can be analyzed quantitatively using third-generation immunoassays, whereas its bioactivity can be measured by TSH activity assays in cell culture. Theoretically, if serum TSH concentrations are directly related to TSH activity, the two tests should yield comparable results. However, on occasion, the results are discordant, with serum concentrations being higher than TSH biological activity. This review focuses on the dissociation between the clinical state and serum TSH concentrations and addresses clinically important aspects of TSH analysis.

Background: Gastroschisis, a birth defect characterized by herniated fetal abdominal wall, occurs more commonly in infants born to teenage and young mothers. Ischemia of the vascular vitelline vessels is the likely mechanism of pathogenesis. Given that chronic stress and violence against women are risk factors for cardiovascular disease we explored whether these may represent risk factors for gastroschisis, when they occur during pregnancy. A case-control study was conducted, with 15 incident cases of children born with gastroschisis in the Region of Murcia, Spain, from December 2007 to June 2013. Forty concurrent controls were recruited at gestation weeks 20-24 or post-partum. All mothers of cases and controls completed a comprehensive, in-person, 'green sheet' questionnaire on environmental exposures., Results: Mothers of children with gastroschisis were younger, smoked more cigarettes per week relative to controls, were exposed to higher amounts of illegal drugs, and suffered from domestic violence more frequently than the controls. Multivariable logistic regression analysis highlights periconceptional 'gender-related violence' (OR: 16.6, 95% CI 2.7 to 101.7) and younger maternal age (OR 1.1, 95% CI 1.0-1.3)., Conclusions: Violence against pregnant women is associated with birth defects, and should be studied in more depth as a cause-effect teratogenic. Psychosocial risk factors, including gender-based violence, are important for insuring the health and safety of the pregnant mother and the fetus.

Background: Tacrolimus metabolism depends on CYP3A4 and CYP3A5. We aimed to determine the relationship between the CYP3A4*22 polymorphism and combined CYP3A genotypes with tacrolimus disposition in pediatric heart transplant recipients., Methods: Sixty pediatric heart transplant recipients were included. Tacrolimus doses and trough concentrations were collected in the first 14 days post-transplantation. CYP3A phenotypes were defined as extensive (CYP3A5*1 + CYP3A4*1/*1 carriers), intermediate (CYP3A5*3/*3 + CYP3A4*1/*1 carriers) or poor (CYP3A5*3/*3 + CYP3A4*22 carriers) metabolizers., Results: CYP3A4*22 carriers needed 30% less tacrolimus (p = 0.016) to reach similar target concentrations compared with CYP3A4*1/*1 (n = 56) carriers. Poor CYP3A metabolizers required 17% (p = 0.023) less tacrolimus than intermediate and 48% less (p < 0.0001) than extensive metabolizers. Poor metabolizers showed 18% higher dose-adjusted concentrations than intermediate (p = 0.35) and 193% higher than extensive metabolizers (p < 0.0001)., Conclusion: Analysis of CYP3A4*22, either alone or in combination with CYP3A5*3, may help towards individualization of tacrolimus therapy in pediatric heart transplant patients.

The presence of thyroid autoantibodies is relatively high in women of childbearing age. There is evidence that positive thyroperoxidase antibody even in euthyroid women may increase the risk of spontaneous and recurrent pregnancy loss and preterm delivery. However, the evidence is not enough to justify recommendation on the screening of pregnant women for thyroid autoantibodies or LT4 supplementation for reducing maternal or fetal complications. In this paper we reviewed the related evidence and compared the new guidelines of the American Thyroid Association and Endocrine Society with respect to the screening and management of positive thyroperoxidase antibody in euthyroid pregnant women. As there was no major contradiction or disagreement between the two guidelines, either one of two guidelines may be used by clinicians for the appropriate management of thyroid autoimmunity during pregnancy.

During the last four decades, there have been considerable advances in the efficacy and precision of serum thyroid function testing. The development of the third generation assays for the measurement of serum thyroid stimulating hormone (TSH, thyrotropin) and the log-linear relationship with free thyroxine (T4) established TSH as the hallmark of thyroid function testing. While it is widely accepted that TSH outside of the normal range is consistent with thyroid dysfunction, a vast multitude of additional factors must be considered before an accurate clinical diagnosis can be made. This is especially important during pregnancy, when the thyroid is under considerable additional pregnancy-related demands requiring significant maternal physiological changes. This paper examines serum TSH measurement in pregnancy and some associated potential confounding factors.

Objectives: The aim of this study was to study the association of adherence to the Mediterranean diet in early pregnancy maternal and the offspring's risk of gastroschisis., Methods: Case-control study. We describe 11 cases of gastroschisis in the region of Murcia from 2007 to 2012 and 34 concurrent controls. At the time of diagnosis each of the cases completed a validated Food Frequency Questionnaire (FFQ) consisting of 98 items on the periconceptional diet. Confounding factors: smoking, exposure to cannabis / marihuana, age of the parents, BMI, income and educational level. We conducted a descriptive and multivariate logistic regression statistical analysis., Results: Mothers of children with gastroschisis were younger (20.8 years, 95% CI 17.3 to 24.2) and their diet consisted of less caloric intake, saturated fat and monounsaturated fats and proteins than controls. The Odds Ratio (OR) in the multivariate model controlling for confounding factors: maternal age (year) 0.70 (95% CI 0.51 to 0.96), monounsaturated fatty acids (oleic acid, g) 0.79 (95% CI 0.65 to 0, 97) and vegetable intake (rations/week) 0.70 (95% CI 0.48 to 1.00)., Conclusion: A maternal diet rich in oleic acid and vegetable products may prevent vascular risk of onphalomesenteric arteries reducing the risk of gastroschisis.

The last four decades have seen enormous growth in the efficacy of serum thyroid stimulating hormone (thyrotropin, TSH) assay methodology, establishing TSH as the hallmark of thyroid testing. At the center of the considerations is the strong inverse correlation between serum thyrotropin and free thyroxine concentrations. While it is widely accepted that elevated serum TSH concentrations are consistent with thyroid dysfunction, a vast multitude of additional factors must be considered before an accurate clinical diagnosis can be made followed by an appropriate treatment. Epidemiological studies have demonstrated slightly elevated serum TSH concentrations among the elderly population. There is, however, a debate whether these elevated TSH levels reflect an increased prevalence of hypothyroidism among the elderly or a normal aspect of healthy aging. A comprehensive analysis of the many variables associated with this debate and TSH measurement as a diagnostic tool in aging should provide insight into the clinical efforts to diagnose and treat thyroid disease, particularly in the elderly population.

Congenital fibrosarcoma (CFS) is a rare fibrous tissue malignancy that usually presents in the first few years of life. It is unique among human sarcomas in that it has an excellent prognosis. We describe a temporal clustering of a number of cases of CFS and investigate the possible associated prenatal risk factors. The Pediatric Environmental History, a questionnaire developed in our clinic that is instrumental in determining environmental risk factors for tumor-related disease, was essential in documenting the presence or absence of risk factors considered as human carcinogens. We found a history of exposure to petroleum products in four cases of CFS that occurred at a greater than expected rate in a short time frame-an apparent cancer cluster. We call attention to the possibility that exposure to petroleum products raises the risk of developing CFS. While future studies should focus on systematic investigation of CFS and its underlying mechanisms, this report suggests the need for proactive measures to avoid exposure to solvents and petroleum products during pregnancy.

Iodine deficiency is an important nutritional deficiency, with more than 2 billion people worldwide estimated to be at risk. The developing fetus and young children are particularly at risk. During pregnancy and lactation, iodine requirements increase, whether in iodine-poor or iodine-sufficient countries, making the mother and the developing fetus vulnerable. The American Thyroid Association (ATA) recommends 250 micrograms per day of iodine intake for pregnant and lactating women. The thyroid gland is able to adapt to the changes associated with pregnancy as long as sufficient iodine is present. Dietary intake is the sole source of iodine, which is essential to the synthesis of thyroid hormones. Iodine is found in multiple dietary sources including iodized salt, dairy products, seaweed, and fish. Prenatal vitamins containing iodine are a good source of iodine, but iodine content in multivitamin supplements is highly variable. Congenital hypothyroidism is associated with cretinism. Clinical hypothyroidism has been associated with increased risk of poor perinatal outcome including prematurity, low birth weight, miscarriage, preeclampsia, fetal death, and impaired fetal neurocognitive development. Subclinical hypothyroidism is also associated with poor pregnancy outcomes and potential fetal neurocognitive deficits, but the data are more variable than those for clinical hypothyroidism. We concur with the ATA recommendation that all pregnant and lactating women should ingest (through diet and supplements) 250 micrograms of iodine daily. To achieve this goal, we recommend that all pregnant and lactating women take daily iodine supplementation of 150 micrograms., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: In children, data on the combined impact of age, genotype, and disease severity on tacrolimus (TAC) disposition are scarce. The aim of this study was to evaluate the effect of these covariates on tacrolimus dose requirements in the immediate post-transplant period in pediatric kidney and liver recipients., Methods: Data were retrospectively collected describing tacrolimus disposition, age, CYP3A5 and ABCB1 genotype, and pediatric risk of mortality (PRISM) scores for up to 14 days post-transplant in children receiving liver and renal transplants. Initial TAC dosing was equal in all patients and adjusted using therapeutic drug monitoring. We determined the relationship between covariates and tacrolimus disposition., Results: Forty-eight kidney and 42 liver transplant recipients (median ages 11.5 and 1.5 years, ranges 1.5-17.7 and 0.05-14.8 years, respectively) received TAC post-transplant. In both transplant groups, younger children (<5 years) needed higher TAC doses than older children [kidney: 0.15 (0.07-0.35) vs. 0.09 (0.02-0.20) mg/kg/12h, p = 0.046, liver: 0.12 (0.04-0.32) vs. 0.09 (0.01-0.18) mg/kg/12h, p = 0.038]. In kidney but not liver transplants, CYP3A5 expressors needed significantly higher TAC doses than nonexpressors [0.15 (0.07-0.20) vs. 0.09 (0.02-0.35) mg/kg/12h, P = 0.001]. In these patients, age and CYP3A5 genotype were independently associated with TAC dosing requirement. In liver, but not kidney transplant patients, homozygous ABCB1 T-T-T haplotype carriers needed higher TAC doses than noncarriers [0.26 (0.15-0.32) vs. 0.11 (0.01-0.25) mg/kg/12h, p = 0.013]., Conclusion: CYP3A5 genotype may explain variation in tacrolimus disposition early after transplant in pediatric kidney recipients, independent of age-related variation. In contrast, in pediatric liver recipients, variation in tacrolimus disposition appears related to age and ABCB1 genotype. These findings illustrate the importance of the interplay among age, genotype, and transplant organ on tacrolimus disposition.

Background: Tacrolimus is one of the commonly used immunosuppressive drugs for pediatric heart transplants. Large variation exists in pharmacokinetics during the direct post-transplant period, resulting in an increased risk of adverse events. Limited data are available on the interaction of age, CYP3A5 and ABCB1 genotype, and disease severity on the variation in disposition and outcome in pediatric heart transplant recipients., Method: We studied the relationship between age and CYP3A5 and ABCB1 genotype and the Pediatric Risk of Mortality (PRISM) score on tacrolimus dose (mg/kg), steady-state trough concentrations, and concentration/dose ratio, as well as rejection and renal function for 14 days after heart transplant in children., Results: Tacrolimus was administered to 39 children (median age, 6.0 years) after transplant. A correlation was found between the age at the time of transplant and the tacrolimus dosing requirements (r(s) = -0.447, p = 0.004) and the concentration/dose ratio (r(s) = 0.351, p = 0.029). CYP3A5 expressors required median (interquartile range) higher doses of tacrolimus (0.14 [0.09] vs 0.06 [0.04] mg/kg/12 hours, p = 0.001), and had lower concentration/dose ratios (45.34 [44.54] vs 177.78 [145.38] ng/ml per mg/kg/12 hours, p < 0.0001). This relationship was not seen with the ABCB1 genotype. Age and CYP3A5 genotype predicted the tacrolimus dosing requirements as well as the concentration/dose ratio (R(2) = 0.351, p = 0.001 and R(2) = 0.521, p < 0.001). No relationship was found between any of the CYP3A5 or ABCB1 genotypes and the estimated glomerular filtration rate., Conclusion: Younger age and CYP3A5 expressor genotype were independently associated with higher dosing requirements and lower tacrolimus concentration/dose ratios., (Copyright © 2011 International Society for Heart and Lung Transplantation. All rights reserved.)

Context: Cigarette tobacco smoke is a potent environmental contaminant known to adversely affect health including fertility and pregnancy., Objective: To examine the associations between second-hand cigarette tobacco-smoke exposure, or active smoking and serum concentrations of steroid hormones using tandem mass spectrometry., Design: Healthy women (18-45 y) from the general community in the Metropolitan Washington, DC were recruited at the follicular stage of their menstrual cycle. Participants were assigned to one of three study groups: active smokers (N=107), passive smokers (N=86), or non-smokers (N=100). Classifications were based on a combination of self-reporting and serum cotinine concentrations., Methods: Serum androgens, estrogens, progestins, androstenedione, aldosterone, cortisol, corticosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), 11-deoxycortisol and 25-hydroxy-vitamin D3 (25-OHVitD3) and cotinine were measured by isotope dilution tandem mass spectrometry (LC/MS/MS) (API-5000). Kruskal-Wallis tests were used to assess median differences among the three groups, with Dunn's multiple comparison test for post hoc analysis., Results: Serum estrone, estradiol, and estriol concentrations were lower in active and passive smokers than in non-smokers. The three study groups differed significantly in serum concentrations of 16-OHE1, aldosterone and 25-OHVitD3, as well as in the ratios of many of the steroids. Pair-wise comparison of the groups demonstrated significant differences in hormone concentrations between (i) smokers and non-smokers for aldosterone: (ii) passive smokers and non-smokers for aldosterone, progesterone and estriol. Moreover, for smokers and passive smokers, there were no significant differences in these hormone concentrations., Conclusions: Smoke exposure was associated with lower than normal median steroid hormone concentrations. These processes may be instrumental in explaining some adverse effects of tobacco smoke on female health and fertility., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To evaluate the peer-reviewed literature on iodine deficiency and hypothyroxinemia in pregnancy., Methods: We review published studies on isolated hypothyroxinemia in pregnancy, methodology of free thyroxine (T4) assays, impact of iodine deficiency on free T4 levels, and status of ongoing prospective randomized trials of isolated hypothyroxinemia during pregnancy., Results: Hypothyroxinemia during pregnancy is common. Studies have demonstrated the pivotal role exerted by maternal T4 on fetal brain development and the negative impact of hypothyroxinemia on neurobehavioral performance in offspring. Two intervention studies have demonstrated a positive effect on neurodevelopment in children of mothers promptly supplemented with iodine compared with the neurodevelopment in children of nonsupplemented mothers. Free T4 assays presently in clinical use have limitations. Preliminary results of the Controlled Antenatal Thyroid Study (CATS) are somewhat mixed, and the National Institutes of Health Maternal Fetal Medicine Thyrotropin Study (TSH Study) will be completed in 2015. Knowledge regarding the impact of isolated hypothyroxinemia has progressed, but major questions remain. An optimal diagnostic test for free T4 during pregnancy (accurate, inexpensive, and widely available) remains elusive. Trimester-specific normative data and normal ranges from different geographic regions do not exist., Conclusions: Data published to date are insufficient to recommend levothyroxine therapy in pregnant women with isolated hypothyroxinemia. Adequate iodine intake should be recommended before conception and early in pregnancy.

Introduction: Autism is a complex neurodevelopmental disorder in which the interactions of genetic, epigenetic and environmental influences are thought to play a causal role. In humans, throughout embryonic and fetal life, brain development is exquisitely susceptible to injury caused by exposure to toxic chemicals present in the environment. Although the use of herbal supplements during pregnancy is relatively common, little information is available on their association with fetal neurodevelopment. This is, to the best of our knowledge, the first report in the literature to associate a new plausible mechanism of neurodevelopmental toxicity with a case of autism spectrum disorder through a vitamin deficiency potentiated by concomitant use of herbal supplements and ethanol exposure., Case Presentation: We describe the pediatric environmental history of a three-year-old Caucasian girl with an autism spectrum disorder. We utilized her pediatric environmental history to evaluate constitutional, genetic, and environmental factors pertinent to manifestation of neurodevelopment disorders. Both parents reported prenatal exposure to several risk factors of interest. A year prior to conception the mother began a weight loss diet and ingested 1200 mg/day of 'horsetail' (Equisetum arvense) herbal remedies containing thiaminase, an enzyme that with long-term use can lead to vitamin deficiency. The mother reported a significant weight loss during the pregnancy and a deficiency of B-complex vitamins. Thiamine (vitamin B1) deficiency could have been potentiated by the horsetail's thiaminase activity and ethanol exposure during pregnancy. No other risk factors were identified., Conclusions: A detailed and careful pediatric environmental history, which includes daily intake, herbal remedies and ethanol exposure, should be obtained from all patients with autism spectrum disorder. Maternal consumption of ethanol and of herbal supplements with suspected or potential toxicity should be avoided during pregnancy. The prospective parents should perform preconception planning before pregnancy.

In the euthyroid person, absolute free thyroxine concentrations remain constant and correlate with the tissue hormone level, its biologic effect and the metabolic status of the patient. However, most circulating thyroid hormone is bound to plasma proteins and only a minute amount is in the unbound free form. Studies have shown that current free thyroxine immunoassays are binding protein dependent. Novel high-performance liquid chromatography tandem mass spectrometry (LC/MS/MS) methods have successfully dealt with problems inherent in many immunoassays for thyroid hormones and afforded improved specificity and accuracy in thyroid hormone measurements. We emphasize problems with thyroid hormone testing employing immunoassays including direct and indirect thyroid hormone immunoassays, sample processing, methods of free hormone separation and review the emerging role of liquid chromatography-tandem mass spectrometry in thyroid hormone testing. The latest generation of tandem mass spectrometers has superior limits of quantification, permitting omission of previously employed derivatization steps. Liquid chromatography-tandem mass spectrometry affords the specificity, precision, and limits of quantification necessary for the reliable measurement of thyroid hormones, enhancing diagnostic capabilities, and affording the profiles of the iodothyronines and thyronamines. These methods are especially important in states of disease and during pregnancy when protein binding is a factor that interferes with other methods for thyroid hormone analysis., (Copyright © 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Physiological, hormonal, and genetic differences between males and females affect the prevalence, incidence, and severity of diseases and responses to therapy. Understanding these differences is important for designing safe and effective treatments. This paper summarizes sex differences that impact drug disposition and includes a general comparison of clinical pharmacology as it applies to men and women.

Pharmacokinetic studies are conducted in order to determine drug absorption, distribution, metabolism and excretion. This knowledge serves to help determine the appropriate and timely use of medications and is also an important step in providing individualized therapeutics according to patient characteristics, such as disease state and genotypes of drug metabolizing enzymes. An innovative way of conducting pharmacokinetic research in pregnancy is presented, with the drug levothyroxine (LT4). The stable, non-radioactive Carbon-13 isotope was used to prepare a derivative of LT4, which was then used to determine the pharmacokinetics of the drug in 9 pregnant women serving as their own controls. Of 9 study subjects, 6 returned to participate in the post partum (non-pregnant) portion of the study. The median time to peak blood level was determined to be at 8 hours post dose. The AUC(0-∞) results were significantly higher during pregnancy than in the same woman approximately 6 months post partum. The increase in LT4 AUC during pregnancy could be attributed to a decrease in LT4 clearance. Additionally, a large variability in the pharmacokinetics of LT4 was found in pregnant women, and a relatively narrower range of variability in non-pregnant women. In order to solidify these findings, a larger group of patients is required. In addition, the mechanisms responsible for the gestational differences in pharmacokinetics need to be investigated.

Purpose: Since 1992, the Centers for Disease Control and Prevention recommends that women of childbearing age consume 400 µg of folic acid per day to reduce the risk of neural tube defects (NTD). It has been speculated that both NTD and nervous system tumors (NST) may share common mechanisms of altered development. It examines the association between folic acid supplementation and the risk for childhood NST., Methods: Incident cases of children with cancer in Spain registered between 2004 and 2006 were identified through the MACAPE Network Group. Tumors were classified as tumors derived from the neuroectoderm (cases) and those with a mesoderm origin (controls). In a second analysis, NST were further divided into central nervous system tumors (CNST) and sympathetic nervous system tumors (SNST). We compared folic acid supplementation between the groups., Results: Overall, folic acid supplementation any time during pregnancy was similar between cases and controls (odds ratio (OR)=1.05; 95% confidence interval (CI) 0.92-1.20). However, supplementation before the 21st and 36th days of gestation resulted in significantly lower NST than in children with mesoderm tumors (OR=0.34; 95% CI 0.17-0.69 and OR=0.58; 95% CI 0.37-0.91, respectively). Preconceptional intakes of folic acid were also lower in NST although marginally nonsignificant (OR=0.44; 95% CI 0.10-1.02). When NST were divided into CNST and SNST, significant differences between tumors of mesoderm origin were only found for CNST., Conclusions: Our results support the hypothesis that folate supplementation reduces the risk of childhood NST, especially CNST. The specific mechanism and cellular role that folate may play in the development of CNST have yet to be elucidated.

The treatment of maternal hypothyroidism presents clinicians with a unique challenge, because dosing regimens previously developed and validated for nonpregnant women cannot be easily extrapolated to dosing in pregnancy. Thyroid hormone requirement increases by 20% to 40% early during pregnancy, persisting throughout gestation. Accordingly, women with treated hypothyroidism need to increase their levothyroxine dose to prevent maternal hypothyroidism and the associated impaired cognitive development and increased fetal mortality. We investigated the pharmacokinetic properties of levothyroxine during pregnancy through the use of a novel, traceable form of levothyroxine. The objective was to conduct a longitudinal study to determine whether levothyroxine pharmacokinetics differ in the pregnant versus nonpregnant state. We used a unique C-levothyroxine-tracer method to distinguish between endogenous and exogenous levothyroxine and studied the pharmacokinetics of a single oral dose of levothyroxine using tandem mass spectrometry. Moreover, we were able to detect single dose amounts of the drug, in picogram/mL concentrations. The area under the curve was 23.0 ng*h/mL in pregnancy and 14.8 ng*h/mL in nonpregnant women (P < 0.03) with median serum half-lives of 32.1 hours and 24.1 hours, respectively (P < 0.04). Further research involves the measurement of free thyroxine on these samples using tandem mass spectrometry. Future work should focus on the mechanisms responsible for the gestational differences in pharmacokinetics and whether these should necessitate dose schedule changes in pregnancy.

The diagnosis and monitoring of thyroid disease necessitates the knowledge of thyroid pathophysiology and of the technical limitations of current thyroid-related biochemical tests. Thyroid disease diagnosis and monitoring are further complicated during pregnancy and lactation, due to pregnancy-related changes in thyroid hormone metabolism. Dramatic changes that occur in thyroxine and triiodothyronine ranges during pregnancy pose challenges for hypothyroid gravidas. Very early in pregnancy, levothyroxine replacement needs to be increased. Moreover, increases in thyroid hormone replacement need to be conducted individually and on a timely basis. For reasons that are still not entirely clear, although dependent in part on changes in thyroxine binding, free thyroxine (FT4) levels decrease as pregnancy progresses necessitating the use of trimester-specific reference intervals for appropriate replacement. Thyroxine binding protein levels vary by hormonal status, inheritance, and disease states and are higher in pregnancy; hence, FT4 assays became popular because they measure the unbound hormone. However, current FT4 immunoassays are estimate tests that do not reliably measure FT4 and are known to be sensitive to alterations in binding proteins and therefore are method-specific. The need to reliably identify hypothyroxinemic pregnant patients, especially in the first trimester, is of prime importance for early fetal brain development before the fetal thyroid functions. This article addresses 1) the current limitations of laboratory-free thyroxine immunoassay methodologies and especially during pregnancy; 2) trimester-specific reference intervals for thyroid function tests; and 3) the study of levothyroxine pharmacokinetics in pregnant and nonpregnant women.

Introduction: Gastroschisis is a malformation with an unknown aetiology, likely involving genetic and environmental risk factors (RF). The aim of this paper is to develop the paediatric environmental clinical history (PECH) of two patients with gastroschisis., Patients and Methods: Review of the medical literature using Pubmed and the Developmental and Reproductive Toxicology Database. Search teratogenic substances using the Hazardous Substances Data Bank. Keywords used were: "Gastroschisis" and "Gastroschisis and Risk Factor"., Results: Among the RFs known and present in both cases were: short cohabitation, unintended pregnancies of relatively young mothers, recent change of paternity, excessive alcohol intake, important nutritional deficiencies, and active and passive smoking. Additionally, one of the cases was exposed to cocaine, cannabis smoke and ionizing radiation from an orthopantography during pregnancy., Conclusions: 1. The PECH should be obtained in all patients with gastroschisis. 2. A thorough PECH requires a proper review of the related RFs and basic training to characterise and quantify environmental exposures. 3. Following these steps, useful recommendations to improve patient care and family advice in future pregnancies are provided., (2009 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.)

Background: We evaluated the clinical validity of serum FT4 measurements by assessing its correlation with log TSH. To provide pediatric reference intervals (representative ranges) for FT4, and TSH on the Architect ci8200 integrated system., Methods: This population-based study encompassed 6023 children (3369 females and 2654 males). The percentile and Hoffmann approaches for obtaining reference intervals on these analytes were also compared., Results: FT4 correlation with log TSH was poor ( r=0.010 for males and 0.050 for females). Reference intervals were established. TSH and FT4 did not show a significant sex difference; moreover, the intervals decreased with age for FT4 and TSH., Conclusions: Whereas in a previous study ultrafiltration tandem mass spectrometry yielded a correlation of r=0.90 for FT4 vs. log TSH this present study reveals a poor FT4 vs. log TSH correlation in the pediatric population studied and indicates the FT4 immunoassay conducted on the Abbott Architect ci8200 is less useful clinically than might have been expected. Reference intervals using the Hoffmann approach for pediatric in- and out-patients compare well with previously published results utilizing the percentile approach., (Copyright 2009 Elsevier B.V. All rights reserved.)

Organophosphates are pesticides ubiquitous in the environment and have been hypothesized as one of the risk factors for acute lymphoblastic leukemia (ALL). In this study, we evaluated the associations of pesticide exposure in a residential environment with the risk for pediatric ALL. This is a case-control study of children newly diagnosed with ALL, and their mothers (n = 41 child-mother pairs) recruited from Georgetown University Medical Center and Children's National Medical Center in Washington, DC, between January 2005 and January 2008. Cases and controls were matched for age, sex, and county of residence. Environmental exposures were determined by questionnaire and by urinalysis of pesticide metabolites using isotope dilution gas chromatography-high-resolution mass spectrometry. We found that more case mothers (33%) than controls (14%) reported using insecticides in the home (P < 0.02). Other environmental exposures to toxic substances were not significantly associated with the risk of ALL. Pesticide levels were higher in cases than in controls (P < 0.05). Statistically significant differences were found between children with ALL and controls for the organophosphate metabolites diethylthiophosphate (P < 0.03) and diethyldithiophosphate (P < 0.05). The association of ALL risk with pesticide exposure merits further studies to confirm the association.

Background: Active and passive cigarette smoking are a risk factor among women of reproductive age-leading to reproductive health morbidity, including fetal and infant death and developmental problems with the newborn. However, the underlying physiological mechanisms for these ill-effects are not fully understood. Smoke exposure may affect various metabolic and biological processes, including hormone biosynthesis and secretion, interfere with thyroid hormone release, binding, transport, storage, and clearance, associated with adverse effects on the thyroid resulting in changes in circulating hormone concentrations. We measured and compared serum thyroid hormone and thyroid stimulating hormone (TSH) concentrations in active, passive, and nonsmokers and determined their association with cigarette tobacco smoke exposure. We use a comprehensive approach to assess the interrelationships between active and passive tobacco smoke exposure and thyroid hormone levels by employing innovative hormone analysis techniques., Methods: Serum was obtained from women (18-44 years of age). Thyroxine (T4), triiodothyronine (T3), and cotinine concentrations were quantified using isotope dilution high performance liquid chromatography tandem mass spectrometry, and TSH concentrations by chemiluminescence., Results: Serum concentrations of the various hormones of active smokers, passive smokers, and nonsmokers (nonexposed), respectively, were as follows. Median TSH concentrations were 1.02, 1.06, and 1.12 mIU/L (p < 0.001 for the comparison of each group with the other two groups), and mean TSH levels were 1.40 mIU/L, confidence interval (CI) 0.07-6.83 mIU/L; 1.30 mIU/L, CI 0.25-3.01 mIU/L; and 1.50 mIU/mL, CI 0.71-4.00 mIU/L. Median serum T4 concentrations were 7.6, 7.9, and 8.7 microg/dL, and median serum T3 concentrations were 92.0, 84.0, and 102.0 ng/dL (p < 0.0001). Mean T3 levels were 99.1 ng/dL, CI 52.1-204.3 ng/dL; 87.6 ng/dL, CI 40.1-160.2 ng/dL; and 106.6 ng/dL, CI 46.4-175.0 ng/dL. Pair-wise comparisons of the three study groups indicate statistically significant differences in serum T4 (p < 0.01) and T3 (p < 0.001) means for the comparison of each group with the other two groups., Conclusions: This study is unique in examining the association of serum cotinine and thyroid hormone concentrations using liquid chromatography tandem mass spectrometry in women smokers, passive smokers, and nonsmokers. Active and passive exposure to cigarette tobacco smoke is associated with a mild inhibitory effect on the thyroid reflected in higher serum T4 and T3 in nonsmokers compared to smokers in this cohort of women.

Background: Accurate measurement of free thyroid hormones is important for managing thyroid disorders. Ultrafiltration liquid chromatography tandem mass spectrometry (LC-MS/MS) can reliably measure the concentrations of small molecules, including thyroid hormones. Our study was designed to compare free thyroid hormone measurements performed with immunoassay and LC-MS/MS., Methods: We studied the performance of LC-MS/MS in 4 different populations comprising pediatric patients, euthyroid adults, and healthy nonpregnant and pregnant women. The samples obtained from each population numbered 38, 200, 28, and 128, respectively. Free thyroxine, free triiodothyronine, and thyroid-stimulating hormone (TSH) concentrations were documented., Results: LC-MS/MS measurement of free thyroid hormones provided better correlation with log-transformed serum TSH in each population and also the populations combined. The correlations between free thyroxine measured by LC-MS/MS and log TSH in the pediatric outpatients and healthy adults were -0.90 and -0.77, respectively. The correlations for immunoassay were -0.82 and -0.48. The correlations between free triiodothyronine measured by LC-MS/MS and TSH for both pediatric and healthy adult populations were -0.72 and -0.68, respectively., Conclusions: Free thyroid hormone concentrations measured by LC-MS/MS correlate to a greater degree with log TSH values compared to concentrations measured by immunoassay. This correlation was maintained across the patient populations we studied and may reflect the accuracy and specificity of LC-MS/MS. The superior ability of LC-MS/MS to enable documentation of the well-known thyroid hormone-TSH relationship supports the use of this measurement technique in a variety of clinical situations.

Background: The clinical value of free thyroxine (FT(4)) and free triiodothyronine (FT(3)) analysis depends on the reference intervals with which they are compared. We determined age- and sex-specific reference intervals for neonates, infants, and children 0-18 years of age for FT(4) and FT(3) using tandem mass spectrometry., Methods: Reference intervals were calculated for serum FT(4) (n = 1426) and FT(3) (n = 1107) obtained from healthy children between January 1, 2008, and June 30, 2008, from Children's National Medical Center and Georgetown University Medical Center Bioanalytical Core Laboratory, Washington, DC. Serum samples were analyzed using isotope dilution liquid chromatography tandem mass spectrometry (LC/MS/MS) with deuterium-labeled internal standards., Results: FT(4) reference intervals were very similar for males and females of all ages and ranged between 1.3 and 2.4 ng/dL for children 1 to 18 years old. FT(4) reference intervals for 1- to 12-month-old infants were 1.3-2.8 ng/dL. These 2.5 to 97.5 percentile intervals were much tighter than reference intervals obtained using immunoassay platforms 0.48-2.78 ng/dL for males and 0.85-2.09 ng/dL for females. Similarly, FT(3) intervals were consistent and similar for males and females and for all ages, ranging between 1.5 pg/mL and approximately 6.0 pg/mL for children 1 month of age to 18 years old., Conclusions: This is the first study to provide pediatric reference intervals of FT(4) and FT(3) for children from birth to 18 years of age using LC/MS/MS. Analysis using LC/MS/MS provides more specific quantification of thyroid hormones. A comparison of the ultrafiltration tandem mass spectrometric method with equilibrium dialysis showed very good correlation.

Objectives: To determine age and sex-specific pediatric reference intervals for aldosterone, 17alpha-hydroxyprogesterone, dehydroepiandrosterone, testosterone, and 25-hydroxy vitamin D(3)., Background and Design: Reference intervals were determined for neonates and children 0-18 years of age. The study was conducted at both Children's National Medical Center and Georgetown University using outpatient blood samples obtained between January 1, 2004 and June 30, 2008., Methods: Serum samples were analyzed using isotope dilution liquid chromatography tandem mass spectrometry (LC/MS/MS) with deuterium-labeled internal standards at Children's National Medical Center and Georgetown University Medical Center Bioanalytical Core Laboratory., Results and Conclusions: This is the first study to provide pediatric reference intervals of steroid hormones for children from birth to 18 years of age using LC/MS/MS. Reference intervals were established for aldosterone, 17alpha-hydroxyprogesterone, dehydroepiandrosterone, testosterone, and 25-hydroxy vitamin D(3). All the analytes exhibited at least some age dependence. Sex differences between early and late childhood and adolescence were found for 17alpha-hydroxyprogesterone and testosterone. Seasonal differences were apparent for 25-hydroxy vitamin D(3).

Background: New high-performance liquid chromatography/tandem mass spectrometry (LC-MS/MS) methods are among the most successful approaches to improve specificity problems inherent in many immunoassays., Content: We emphasize problems with immunoassays for the measurement of steroids and review the emerging role of LC-MS/MS in the measurement of clinically relevant steroids. The latest generation of tandem mass spectrometers has superior limits of quantification, permitting omission of previously employed derivatization steps. The measurement of steroid profiles in the diagnosis and treatment of congenital adrenal hyperplasia, adrenal insufficiency, chronic pelvic pain and prostatitis, oncology (breast cancer), and athletes has important new applications., Conclusions: LC-MS/MS now affords the specificity, imprecision, and limits of quantification necessary for the reliable measurement of steroids in human fluids, enhancing diagnostic capabilities, particularly when steroid profiles are available.

Significant differences that exist between the sexes affect the prevalence, incidence and severity of a broad range of diseases and conditions. Men and women also differ in their response to drug treatment. It is therefore essential to understand these reactions in order to appropriately conduct risk assessment and to design safe and effective treatments. Even from that modest perspective, how and when we use drugs can result in unwanted and unexpected outcomes. This review summarizes the sex-based differences that impact on pharmacokinetics, and includes a general comparison of clinical pharmacology as it applies to men, women and pregnant women. Sex-related or pregnancy-induced changes in drug absorption, distribution, metabolism and elimination, when significant, may guide changes in dosage regimen or therapeutic monitoring to increase its effectiveness or reduce potential toxicity. Given those parameters, and our knowledge of sex differences, we can derive essentially all factors necessary for therapeutic optimization. Since this is a rapidly evolving area, it is essential for the practitioner to review drug prescribing information and recent literature in order to fully understand the impact of these differences on clinical therapeutics.

Thyroid hormones are essential for cellular metabolism, growth, and development. In particular, an adequate supply of thyroid hormones is critical for fetal neurodevelopment. Thyroid hormone tissue activation and inactivation in brain, liver, and other tissues is controlled by the deiodinases through the removal of iodine atoms. Selenium, an essential element critical for deiodinase activity, is sensitive to mercury and, therefore, when its availability is reduced, brain development might be altered. This review addresses the possibility that high exposures to the organometal, methylmercury (MeHg), may perturb neurodevelopmental processes by selectively affecting thyroid hormone homeostasis and function.