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1.
Pediatr Pulmonol ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31651095

RESUMO

BACKGROUND: Adrenal suppression is a side effect of long-term use of inhaled corticosteroids (ICS). Hair cortisol concentration (HCC) measurement is a noninvasive tool for measuring adrenal function that may be useful for asthmatic patients who are on long-term ICS treatment. The aim of this study was to compare HCC between children with and without asthma and to explore the association between HCC and ICS dose in asthmatic children. METHODS: A cross-sectional observational study in subjects with or without asthma (n = 72 and 226, respectively, age 6-21 years). Hair samples were obtained from the posterior vertex for each subject and data on medication use were collected using questionnaires. HCC was analyzed by liquid chromatography-mass spectrometry in the most proximal 3 cm of hair. RESULTS: Median HCC was significantly lower in subjects with asthma than in subjects without asthma: 1.83 pg/mg and 2.39 pg/mg, respectively (P value after adjustment for age, sex, and body mass index: .036). Median HCC was 1.98 pg/mg in asthmatics using no ICS, 1.84 pg/mg in those using a low dose, 1.75 pg/mg in those on a medium dose, and 1.46 in those using a high ICS dose (P = .54). CONCLUSION: We observed a significantly lower HCC in asthmatics than in healthy controls and a nonsignificant trend of lower HCC with increasing ICS dose. Whether HCC measurement may be used to detect individuals at risk for hypocortisolism and may be useful to monitor adrenal function in asthmatic children using ICS needs to be further investigated.

2.
Lancet Diabetes Endocrinol ; 7(9): 695-706, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31377265

RESUMO

BACKGROUND: Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T3) concentrations (Allan-Herndon-Dudley syndrome). This chronic thyrotoxicosis leads to progressive deterioration in bodyweight, tachycardia, and muscle wasting, predisposing affected individuals to substantial morbidity and mortality. Treatment that safely alleviates peripheral thyrotoxicosis and reverses cerebral hypothyroidism is not yet available. We aimed to investigate the effects of treatment with the T3 analogue Triac (3,3',5-tri-iodothyroacetic acid, or tiratricol), in patients with MCT8 deficiency. METHODS: In this investigator-initiated, multicentre, open-label, single-arm, phase 2, pragmatic trial, we investigated the effectiveness and safety of oral Triac in male paediatric and adult patients with MCT8 deficiency in eight countries in Europe and one site in South Africa. Triac was administered in a predefined escalating dose schedule-after the initial dose of once-daily 350 µg Triac, the daily dose was increased progressively in 350 µg increments, with the goal of attaining serum total T3 concentrations within the target range of 1·4-2·5 nmol/L. We assessed changes in several clinical and biochemical signs of hyperthyroidism between baseline and 12 months of treatment. The prespecified primary endpoint was the change in serum T3 concentrations from baseline to month 12. The co-primary endpoints were changes in concentrations of serum thyroid-stimulating hormone (TSH), free and total thyroxine (T4), and total reverse T3 from baseline to month 12. These analyses were done in patients who received at least one dose of Triac and had at least one post-baseline evaluation of serum throid function. This trial is registered with ClinicalTrials.gov, number NCT02060474. FINDINGS: Between Oct 15, 2014, and June 1, 2017, we screened 50 patients, all of whom were eligible. Of these patients, four (8%) patients decided not to participate because of travel commitments. 46 (92%) patients were therefore enrolled in the trial to receive Triac (median age 7·1 years [range 0·8-66·8]). 45 (98%) participants received Triac and had at least one follow-up measurement of thyroid function and thus were included in the analyses of the primary endpoints. Of these 45 patients, five did not complete the trial (two patients withdrew [travel burden, severe pre-existing comorbidity], one was lost to follow-up, one developed of Graves disease, and one died of sepsis). Patients required a mean dose of 38.3 µg/kg of bodyweight (range 6·4-84·3) to attain T3 concentrations within the target range. Serum T3 concentration decreased from 4·97 nmol/L (SD 1·55) at baseline to 1·82 nmol/L (0·69) at month 12 (mean decrease 3·15 nmol/L, 95% CI 2·68-3·62; p<0·0001), while serum TSH concentrations decreased from 2·91 mU/L (SD 1·68) to 1·02 mU/L (1·14; mean decrease 1·89 mU/L, 1·39-2·39; p<0·0001) and serum free T4 concentrations decreased from 9·5 pmol/L (SD 2·5) to 3·4 (1·6; mean decrease 6·1 pmol/L (5·4-6·8; p<0·0001). Additionally, serum total T4 concentrations decreased by 31·6 nmol/L (28·0-35·2; p<0·0001) and reverse T3 by 0·08 nmol/L (0·05-0·10; p<0·0001). Seven treatment-related adverse events (transiently increased perspiration or irritability) occurred in six (13%) patients. 26 serious adverse events that were considered unrelated to treatment occurred in 18 (39%) patients (mostly hospital admissions because of infections). One patient died from pulmonary sepsis leading to multi-organ failure, which was unrelated to Triac treatment. INTERPRETATION: Key features of peripheral thyrotoxicosis were alleviated in paediatric and adult patients with MCT8 deficiency who were treated with Triac. Triac seems a reasonable treatment strategy to ameliorate the consequences of untreated peripheral thyrotoxicosis in patients with MCT8 deficiency. FUNDING: Dutch Scientific Organization, Sherman Foundation, NeMO Foundation, Wellcome Trust, UK National Institute for Health Research Cambridge Biomedical Centre, Toulouse University Hospital, and Una Vita Rara ONLUS.

3.
Crit Rev Clin Lab Sci ; 56(7): 458-471, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31393193

RESUMO

Healthcare budgets worldwide are under constant pressure to reduce costs while improving efficiency and quality. This phenomenon is also visible in clinical laboratories. Efficiency gains can be achieved by reducing the error rate and by improving the laboratory's layout and logistics. Performance indicators (PIs) play a crucial role in this process as they allow for performance assessment. This review aids in the process for selecting laboratory PIs-which is not trivial-by providing an overview of frequently used PIs in the literature that can also be used in clinical laboratories. We conducted a systematic review of the laboratory medicine literature on PIs. As the testing process in clinical laboratories can be viewed as a production process, we also reviewed the production processes literature on PIs. The reviewed literature relates to the design, optimization or performance assessment of such processes. The most frequently cited PIs relate to pre-analytical errors, timeliness, resource utilization, cost, and the amount of congestion. Their citation frequency in the literature is used as a proxy for their importance. PIs are discussed in terms of their definition, measurability and impact. The use of suitable PIs is crucial in production processes, including clinical laboratories. By also reviewing the production processes literature, additional relevant PIs for clinical laboratories were found. The PIs in the laboratory medicine literature mostly relate to laboratory errors, while the PIs in the production processes literature relate to the amount of congestion in the process.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31329930

RESUMO

CONTEXT: Turner syndrome (TS), a common genetic disorder in women, usually manifests in traits as short stature and premature ovarian failure. Many patients also have an increased risk of cardiometabolic disorders and psychological distress which are features that overlap with those of a prolonged hypercortisolistic state. Long-term cortisol levels in TS are however not explored yet. OBJECTIVE: To investigate whether TS is associated with increased long-term cortisol concentrations as measured in scalp hair and whether these are linked to cardiometabolic and psychological parameters. DESIGN: Prospective observational case-control study. SETTING: Academic outpatient TS expertise center. PARTICIPANTS: Fifty-five patients with TS (53% 45,X karyotype), and 110 age-matched female community controls from the general population-based Lifelines cohort study. MAIN OUTCOME MEASURES: Hair cortisol concentrations (HCC), anthropometrics, biochemical parameters, and psychological questionnaires for perceived stress (PSS-14), fatigue (CIS-20), and health-related quality of life (RAND-36). RESULTS: In comparison to matched controls, patients with TS had higher HCC (geometric mean, 3.51 pg/mg [95% CI, 2.64 to 4.65] vs. 2.39 pg/mg [2.13 to 2.68], P=.003) and a worse cardiometabolic profile in terms of fasting glucose, and triglycerides. HCC was only associated with total cholesterol levels (standardized ß=.294 , P=.047), and showed no relationship with any of the psychological outcomes. Interestingly, a higher HCC was inversely associated with height in TS only (standardized ß=-.307 , P=.023). CONCLUSIONS: Patients with TS are chronically exposed to higher cortisol levels, which is associated with short stature and increased total cholesterol levels, and potentially contributes to the known elevated cardiovascular disease risk.

6.
Am J Clin Nutr ; 110(2): 437-450, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31165884

RESUMO

BACKGROUND: Folate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans. OBJECTIVE: The aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes. METHODS: A large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes. RESULTS: The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74 folate-associated DMRs, of which 73 were negatively associated with folate intake. The most significant folate-associated DMR was a 400-base pair (bp) spanning region annotated to the LGALS3BP gene. In the categorical model, vitamin B-12 intake was associated with 29 DMRs annotated to 48 genes, of which the most significant was a 1100-bp spanning region annotated to the calcium-binding tyrosine phosphorylation-regulated gene (CABYR). Vitamin B-12 intake was not associated with DMPs. CONCLUSIONS: We identified novel epigenetic loci that are associated with folate and vitamin B-12 intake. Interestingly, we found a negative association between folate and DNA methylation. Replication of these methylation loci is necessary in future studies.

7.
J Clin Endocrinol Metab ; 104(8): 3437-3449, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31127821

RESUMO

CONTEXT: Metyrapone and ketoconazole, frequently used steroidogenesis inhibitors for treatment of Cushing syndrome, can be associated with side effects and limited efficacy. Osilodrostat is a CYP11B1 and CYP11B2 inhibitor, with unknown effects on other steroidogenic enzymes. OBJECTIVE: To compare the effects of osilodrostat, metyrapone, and ketoconazole on adrenal steroidogenesis, and pituitary adenoma cells in vitro. METHODS: HAC15 cells, 17 primary human adrenocortical cell cultures, and pituitary adenoma cells were incubated with osilodrostat, metyrapone, or ketoconazole (0.01 to 10 µM). Cortisol and ACTH were measured using chemiluminescence immunoassays, and steroid profiles by liquid chromatography-mass spectrometry. RESULTS: In HAC15 cells, osilodrostat inhibited cortisol production more potently (IC50: 0.035 µM) than metyrapone (0.068 µM; P < 0.0001), and ketoconazole (0.621 µM; P < 0.0001). IC50 values of osilodrostat and metyrapone for basal cortisol production varied with a 25- and 18-fold difference, respectively, with comparable potency. Aldosterone production was inhibited more potently by osilodrostat vs metyrapone and ketoconazole. Osilodrostat and metyrapone treatment resulted in strong inhibition of corticosterone and cortisol, 11-deoxycortisol accumulation, and modest effects on adrenal androgens. No pituitary-directed effects of osilodrostat were observed. CONCLUSIONS: Under our study conditions, osilodrostat is a potent cortisol production inhibitor in human adrenocortical cells, comparable with metyrapone. All steroidogenesis inhibitors showed large variability in sensitivity between primary adrenocortical cultures. Osilodrostat might inhibit CYP11B1 and CYP11B2, in some conditions to a lesser extent CYP17A1 activity, and a proximal step in the steroidogenesis. Osilodrostat is a promising treatment option for Cushing syndrome, and in vivo differences with metyrapone are potentially driven by pharmacokinetic differences.

8.
BMC Cancer ; 19(1): 325, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953466

RESUMO

BACKGROUND: For progressive metastatic medullary thyroid carcinoma (MTC), the available treatment options with tyrosine kinase inhibitors result in grade 3-4 adverse events in a large number of patients. Peptide Receptor Radionuclide Therapy (PRRT), which has also been suggested to be a useful treatment for MTC, is usually well tolerated, but evidence on its effectivity is very limited. METHODS: Retrospective evaluation of treatment effects of PRRT in a highly selected group of MTC patients, with progressive disease or refractory symptoms. In addition, a retrospective evaluation of uptake on historical 111In-DTPA-octreotide scans was performed in patients with detectable tumor size > 1 cm. RESULTS: Over the last 17 years, 10 MTC patients were treated with PRRT. Four out of 10 patients showed stable disease at first follow-up (8 months after start of therapy) whereas the other 6 were progressive. Patients with stable disease were characterized by a combination of both a high uptake on 111In-DTPA-octreotide scan (uptake grade ≥ 3) and a positive somatostatin receptor type 2a (SSTR2a) expression of the tumor by immunohistochemistry. Retrospective evaluation of historical 111In-DTPA-octreotide scans of 35 non-treated MTC patients revealed low uptake (uptake grade 1) in the vast majority of patients 31/35 (89%) with intermediate uptake (uptake grade 2) in the remaining 4/35 (11%). CONCLUSIONS: PRRT using 177Lu-octreotate could be considered as a treatment in those patients with high uptake on 111In-DTPA-octreotide scan (uptake grade 3) and positive SSTR2a expression in tumor histology. Since this high uptake was present in a very limited number of patients, this treatment is only suitable in a selected group of MTC patients.


Assuntos
Carcinoma Neuroendócrino/radioterapia , Octreotida/análogos & derivados , Radioimunoterapia/métodos , Receptores de Somatostatina/metabolismo , Neoplasias da Glândula Tireoide/radioterapia , Adulto , Idoso , Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Octreotida/administração & dosagem , Octreotida/uso terapêutico , Seleção de Pacientes , Ácido Pentético/administração & dosagem , Ácido Pentético/análogos & derivados , Intervalo Livre de Progressão , Cintilografia/métodos , Estudos Retrospectivos , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Adulto Jovem
9.
Psychoneuroendocrinology ; 106: 147-154, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30981088

RESUMO

Aggression and distrust are often challenging problems in mental health treatment. Converging evidence reveals that oxytocin increases trust in social interactions and decreases fear of social betrayal. However, oxytocin has also been associated with protective behavior and, as such, might increase defensive aggressive reactions. In this randomized double-blind, placebo-controlled study, the effects of intranasal oxytocin (32IU) on task-related aggressive responses were measured using the Point Subtraction Aggression Paradigm (PSAP). Fifty-seven healthy males were enrolled and randomized to oxytocin (N = 30) or placebo (n = 27). Salivary oxytocin, cortisol and testosterone were measured serially prior to the intervention, and then before and after the PSAP, to evaluate the effects of oxytocin administration on hormonal functioning in relation to aggression. In addition, oxytocin was measured in urine collected directly after the experimental task, reflecting the 2 h period after oxytocin or placebo administration. The proportion of aggressive responses to the PSAP was significantly lower in participants receiving oxytocin versus placebo (ß= -0.46, P = 0.01). No significant effect of oxytocin was found regarding defensive reactions. Urinary oxytocin was negatively associated with the proportion of aggressive responses to the PSAP in both the oxytocin and the placebo group (ß= -0.02, P < 0.01), suggesting that higher levels of urinary oxytocin corresponded with reduced aggressive responding. Our results indicate that oxytocin administration reduces aggressive behavior in healthy young men. Moreover, increased endogenous urinary oxytocin is associated with less aggressive responding. Taken together, these findings suggest that oxytocin signaling has a causal influence on aggressive behavior.

10.
J Clin Endocrinol Metab ; 104(12): 5957-5967, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30920622

RESUMO

CONTEXT: Although the consequences of severe iodine deficiency are beyond doubt, the effects of mild to moderate iodine deficiency in pregnancy on child neurodevelopment are less well established. OBJECTIVE: To study the association between maternal iodine status during pregnancy and child IQ and identify vulnerable time windows of exposure to suboptimal iodine availability. DESIGN: Meta-analysis of individual participant data from three prospective population-based birth cohorts: Generation R (Netherlands), INMA (Spain), and ALSPAC (United Kingdom); pregnant women were enrolled between 2002 and 2006, 2003 and 2008, and 1990 and 1992, respectively. SETTING: General community. PARTICIPANTS: 6180 mother-child pairs with measures of urinary iodine and creatinine concentrations in pregnancy and child IQ. Exclusion criteria were multiple pregnancies, fertility treatment, medication affecting the thyroid, and preexisting thyroid disease. MAIN OUTCOME MEASURE: Child nonverbal and verbal IQ assessed at 1.5 to 8 years of age. RESULTS: There was a positive curvilinear association of urinary iodine/creatinine ratio (UI/Creat) with mean verbal IQ only. UI/Creat <150 µg/g was not associated with lower nonverbal IQ (-0.6 point; 95% CI: -1.7 to 0.4 points; P = 0.246) or lower verbal IQ (-0.6 point; 95% CI: -1.3 to 0.1 points; P = 0.082). Stratified analyses showed that the association of UI/Creat with verbal IQ was only present up to 14 weeks of gestation. CONCLUSIONS: Fetal brain development is vulnerable to mild to moderate iodine deficiency, particularly in the first trimester. Our results show that potential randomized controlled trials investigating the effect of iodine supplementation in women with mild to moderate iodine deficiency on child neurodevelopment should begin supplementation not later than the first trimester.

11.
Neuroendocrinology ; 109(2): 171-178, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30759443

RESUMO

BACKGROUND/AIMS: The current diagnostic workup of Cushing's syndrome (CS) requires various tests which only capture short-term cortisol exposure, whereas patients with endogenous CS generally have elevated cortisol levels over longer periods of time. Scalp hair assessment has emerged as a convenient test in capturing glucocorticoid concentrations over long periods of time. The aim of this multicenter, multinational, prospective, case-control study was to evaluate the diagnostic efficacy of scalp hair glucocorticoids in screening of endogenous CS. METHODS: We assessed the diagnostic performances of hair cortisol (HairF), hair cortisone (HairE), and the sum of both (sumHairF+E), as measured by a state-of-the-art LC-MS/MS technique, in untreated patients with confirmed endogenous CS (n = 89) as well as in community controls (n = 295) from the population-based Lifelines cohort study. RESULTS: Both glucocorticoids were significantly elevated in CS patients when compared to controls. A high diagnostic efficacy was found for HairF (area under the curve 0.87 [95% CI: 0.83-0.92]), HairE (0.93 [0.89-0.96]), and sumHairF+E (0.92 [0.88-0.96]) (all p < 0.001). The participants were accurately classified at the optimal cutoff threshold in 86% of the cases (81% sensitivity, 88% specificity, and 94% negative predictive value [NPV]) by HairF, in 90% of the cases (87% sensitivity, 90% specificity, and 96% NPV) by HairE, and in 87% of the cases (86% sensitivity, 88% specificity, and 95% NPV) by the sumHairF+E. HairE was shown to be the most accurate in differentiating CS patients from controls. CONCLUSION: Scalp hair glucocorticoids, especially hair cortisone, can be seen as a promising biomarker in screening for CS. Its convenience in collection and workup additionally makes it feasible for first-line screening.

12.
Horm Res Paediatr ; 90(5): 299-307, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30541006

RESUMO

BACKGROUND: Hair glucocorticoids (GCs) offer a retrospective view on chronic GC exposure. We assessed whether maternal pre- and postnatal stress was associated with neonatal and maternal hair GCs postpartum (pp). METHODS: On the first day pp 172 mother-infant pairs donated hair, of whom 67 had consulted a centre of expertise for psychiatric disorders during pregnancy. Maternal stress was scored on the Hospital Anxiety and Depression Scale during the first/second (n = 46), third trimester (n = 57), and pp (n = 172). Hair cortisol and cortisone levels were determined by liquid chromatography-tandem mass spectrometry, and associations with maternal hospital anxiety subscale (HAS) and hospital depression subscale (HDS) scores, and antidepressant use were analyzed with linear regression. RESULTS: Neonatal hair GCs were negatively associated with elevated HAS-scores during the first/second trimester, log 10 (ß [95% CI]) cortisol -0.19 (-0.39 to 0.02) p = 0.07, cortisone -0.10 (-0.25 to 0.05) p = 0.17; third trimester, cortisol -0.17 (-0.33 to 0.00) p = 0.05, cortisone -0.17 (-0.28 to -0.05) p = 0.01; and pp, cortisol -0.14 (-0.25 to -0.02) p = 0.02, cortisone -0.07 (-0.16 to 0.02) p = 0.10. A similar pattern was observed for elevated HDS-scores. Maternal hair GCs were positively associated with elevated HAS-scores pp (cortisol 0.17 [0.01 to 0.32] p = 0.04, cortisone 0.18 [0.06 to 0.31] p = 0.01), but not prenatally or with elevated HDS-scores. Antidepressant use was associated with elevated maternal hair GCs (p ≤ 0.05), but not with neonatal hair GCs. CONCLUSION: Exposure to excessive pre- and perinatal maternal stress was associated with a decrease in neonatal hair GCs, while elevated stress-scores around birth were associated with increased maternal hair GCs and elevated stress-scores earlier in gestation were not associated with maternal hair GCs pp. Further studies are needed to test associations with infant neurodevelopment.


Assuntos
Cortisona/análise , Cabelo/química , Hidrocortisona/análise , Complicações na Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Estresse Psicológico/metabolismo , Adulto , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Complicações na Gravidez/metabolismo , Espectrometria de Massas em Tandem
13.
Horm Res Paediatr ; : 1-10, 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30408796

RESUMO

OBJECTIVE: Congenital hypothyroidism (CH) per se, when not treated or undertreated, may lead to severe behavioural problems (cretinism), whereas overtreatment of CH seems associated with attention problems. DESIGN AND METHODS: For 55 CH patients, prospectively followed from birth until 11 years, parents rated the Child Behaviour Checklist and teachers the Teacher's Report Form at children's ages 6 and 11 years. We related scores regarding Attention, Delinquency, and Aggression (ADA scores, indicative for attention deficit hyperactivity syndrome, ADHD), and scores regarding Withdrawn, Anxious, Social, and Thought problems (WAST scores, indicative for autism) to the occurrence of over- and undertreatment in five age periods. Over- and undertreatment were defined as free thyroxine (fT4) concentrations above/below the range of the patient's individual fT4 steady state concentration. RESULTS: ADA scores at 6 and 11 years for patients overtreated in the period 1-3 months postnatally were higher than those for patients who were not overtreated. Patients with severe CH undertreated in the period 3-6 months postnatally had higher WAST scores at 6 and 11 years than all other patients. CONCLUSIONS: This is the first study suggesting that permanent ADHD as well as autism in CH patients at ages 6 and 11 years are the result of early overtreatment and undertreatment, respectively.

14.
Psychoneuroendocrinology ; 101: 246-252, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30472466

RESUMO

BACKGROUND: Depressive and anxiety disorders have been linked to a dysregulated hypothalamus-pituitary-adrenal (HPA)-axis. Hair cortisol levels (HairF) reflect integrated long-term cortisol regulation and are therefore promising endocrine markers of chronic (psychological and physical) stress. Our aim was to assess hair cortisol levels in persons with a depressive and/or anxiety disorder and to compare their levels with that of persons in remission and healthy controls. METHODS: Data from 1166 participants of the Netherlands Study of Depression and Anxiety (NESDA) were used, including 266 participants with a recent (1-month) diagnosis of a depressive and/or anxiety disorder, 655 participants with a diagnosis in remission, and 245 healthy controls. HairF was measured in the proximal three cm of scalp hair, using LC-MS/MS. RESULTS: Compared to the healthy controls no differences on HairF or HairE levels were found for depressive and anxiety disorders alone. However the presence of a comorbid depressive and anxiety disorder was significantly associated with increased HairF levels (ß = 0.07; p = .031), as was the severity of depressive symptoms (ß = 0.06; p = .029), but no differences were found on HairE nor the HairF:HairE ratio. CONCLUSIONS: Persons with current diagnosis of comorbid depression and anxiety show moderately higher levels of cortisol than patients with only depression or anxiety, or patients in remission and healthy controls, which may be indicative of a chronic state of hyperactivation of the HPA axis.

15.
Clin Chem Lab Med ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30496132

RESUMO

Background Failure to report a creatinine concentration, especially in icteric patients who are eligible for a liver transplant, can result in a life-threatening situation. We assessed the influence of bilirubin interference on several creatinine assays and investigated ways to circumvent icteric interference without interfering with our normal automated sample logistics. Methods Using icteric patient sera (total bilirubin >255 µmol/L) we determined creatinine concentrations using an enzymatic and Jaffé assay (Roche Diagnostics) in both normal (i.e. undiluted) and decreased mode (i.e. diluted) as well as an enzyme-coupled amperometric assay on a Radiometer ABL837 FLEX analyzer. Creatinine concentrations from the five methods were compared with an in-house developed LC-MS/MS method. Passing and Bablok (proportional and constant bias) as well as difference plot parameters (bias and 95% limits of agreement [LoA]) were calculated. Interferograph-based regression analysis of the enzymatic and Jaffé results was used to investigate if such an approach could be used to report corrected creatinine concentrations in icteric patient sera. Results In icteric patient sera the enzyme-coupled amperometric assay was hardly influenced by icteric interference as shown by a difference plot bias of -1.5% (95% LoA -11.6 to +8.5%). The undiluted Jaffé method had a bias of -1.4% with a very broad 95% LoA (-35.1 to +32.2%) emphasizing the poor specificity of this method. The undiluted enzymatic method had the largest bias (-13.4%, 95% LoA -35.8 to +9.0%). Diluting sera in the enzymatic method did not improve the bias (-10.5%, 95% LoA -25.4 to 4.4%), while diluting the Jaffé method resulted in a bias increase (+11.4%, 95% LoA -14.7 to 37.5%). Using interferograph-based regression analysis we were able to reliably correct enzymatic creatinine concentrations in 97 out of 100 icteric patient sera. Conclusions Analytically, quantifying creatinine in icteric sera using the Radiometer ABL837 FLEX analyzer is the method of choice within our laboratory. However, not all laboratories are equipped with this method and even if available, the limited number of highly icteric patient sera makes this method costly. For those laboratories using the Roche enzymatic method, mathematically correcting an icteric creatinine concentration using an interferograph based on an LC-MS/MS reference method is a suitable alternative to report reliable creatinine results in icteric patients.

16.
Artigo em Inglês | MEDLINE | ID: mdl-30423129

RESUMO

Context: Thyroid hormone (TH) is important for normal brain development. The type 2 deiodinase (D2) controls TH action in the brain by activating T4 to T3. The enzymatic activity of D2 depends on the incorporation of selenocysteine (Sec) for which the SECIS element located in the 3`UTR is indispensable. We hypothesized that mutations in the SECIS element could impact on D2 function, resulting in a neurocognitive phenotype. Objective: To identify mutations in the SECIS element of DIO2 in patients with intellectual disability (ID) and to test their functional consequences. Design, setting and patients: The SECIS element of DIO2 was sequenced in 387 patients with unexplained ID, based on a predefined pattern of thyroid function tests. SECIS element read-through in wild-type (WT) or mutant D2 was quantified by a luciferase reporter system in transfected cells. Functional consequences were assessed by quantifying D2 activity in cell lysate or intact cell metabolism studies. Results: Sequence analysis revealed 2 heterozygous mutations: c.5703C>T and c.5730A>T, which were also present in unaffected family members. Functional evaluation showed that both mutations did not affect D2 enzyme activity in cell lysates or intact cells, although the 5730A>T mutation decreased SECIS element read-through by 75%. In the patient harboring the c.5730A>T variant, whole genome sequencing revealed a pathogenic deletion of the STXBP1 gene. Conclusion: We report 2 families with mutations in the SECIS element of D2. Although functional analysis shows that nucleotide 5730 is important for normal SECIS element read-through, both variants do not segregate with a distinct phenotype.

17.
Horm Res Paediatr ; 90(3): 181-189, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30286459

RESUMO

BACKGROUND: The analysis of insulin-like growth factor I (IGF-I) is an important tool for pediatricians in the diagnosis and treatment of growth hormone deficiency in children. However, significant differences exist in IGF-I assays and normative datasets, which can have important clinical consequences. METHODS: IGF-I analyses were performed using the IDS-iSYS platform on 1,897 samples from pediatric patients (0.5-18 years old). Z-scores were calculated based on normative IGF-I data from Bidlingmaier et al. (SD-BM) [J Clin Endocrinol Metab. 2014 May; 99(5): 1712-21] and normative IGF-I data from the IGF-I harmonization program in the Netherlands (SD-NL). The differences in Z-scores were analyzed at relevant clinical decision points (-2 SD, +2 SD). These normative datasets were also compared to normative data reported by Elmlinger et al. [Clin Chem Lab Med. 2004; 42(6): 654-64]. RESULTS: The difference in Z-score between SD-BM and SD-NL was highest in males between 0 and 3 years old, exceeding 2 SD. Clinically relevant discordance between both Z-scores at -2 and +2 SD was found in 12.7% of all samples. The IGF-I levels at -2 and +2 SD reported in the normative dataset of Elmlinger et al. were up to 100% higher than the IGF-I levels reported by Bidlingmaier et al. or the Dutch harmonization program. CONCLUSION: Pediatricians and laboratory specialists should be aware of relevant differences that can exist between IGF-I assays and normative data. Well-defined pediatric reference ranges for the IDS-iSYS platform are highly desirable.

18.
Eur Respir J ; 52(3)2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30166324

RESUMO

Forskolin-induced swelling (FIS) of intestinal organoids from individuals with cystic fibrosis (CF) measures function of the cystic fibrosis transmembrane conductance regulator (CFTR), the protein mutated in CF.We investigated whether FIS corresponds with clinical outcome parameters and biomarkers of CFTR function in 34 infants diagnosed with CF. Relationships with FIS were studied for indicators of pulmonary and gastrointestinal disease.Children with low FIS had higher levels of immunoreactive trypsinogen (p=0.030) and pancreatitis-associated protein (p=0.039), more often had pancreatic insufficiency (p<0.001), had more abnormalities on chest computed tomography (p=0.049), and had lower z-scores for maximal expiratory flow at functional residual capacity (p=0.033) when compared to children with high FIS values. FIS significantly correlated with sweat chloride concentration (SCC) and intestinal current measurement (ICM) (r= -0.82 and r=0.70, respectively; both p<0.001). Individual assessment of SCC, ICM and FIS suggested that FIS can help to classify individual disease severity.Thus, stratification by FIS identified subgroups that differed in pulmonary and gastrointestinal outcome parameters. FIS of intestinal organoids correlated well with established CFTR-dependent biomarkers such as SCC and ICM, and performed adequately at group and individual level in this proof-of-concept study.

19.
J Clin Endocrinol Metab ; 103(11): 4125-4134, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30020476

RESUMO

Context: Although the skeleton is a well-known thyroid hormone target organ, very little data are available on the association of thyroid function with bone outcomes during childhood. Objective: To study the association of thyroid function with bone mass during childhood. Design, Setting, and Participants: Population-based prospective cohort including 4204 children with TSH and free T4 (FT4) measured at the age of 6 years. Main Outcome Measures: Bone density was assessed by a total body dual-energy X-ray absorptiometry scan at the median age of 6 years (95% range, 5.6 to 7.9) and at the age of 10 years (95% range, 9.0 to 10.9) in 4204 and 3404 participants, respectively. Results: There was an inverse association of TSH with bone mineral density (BMD) at the age of 6 (ß -0.028 ± 0.011, P = 0.009) and with follow-up measurements at the age of 10 (ß -0.027 ± 0.011, P = 0.014), but not with bone mineral content (BMC) at the age of 6 (ß -0.028 ± 0.015, P = 0.06) or for follow-up measurements of BMC at the age of 10 (ß -0.011 ± 0.015, P = 0.47). There was an inverse association of FT4 with BMD (ß -0.016 ± 0.006, P = 0.014) and BMC (ß -0.023 ± 0.009, P = 0.009) cross-sectionally, and also at the age of 10 years (BMD: ß -0.018 ± 0.007, P = 0.007; BMC: ß -0.021 ± 0.009, P = 0.020). Conclusion: A higher FT4 concentration is associated with lower bone mass at the age of 6 and at the age of 10 years. These data provide insights into the effects of thyroid function on bone physiology during childhood.

20.
BJPsych Open ; 4(4): 180-185, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29988976

RESUMO

Background: The serotonin transporter gene-linked polymorphic region (5-HTTLPR) has previously been associated with hypothalamus-pituitary-adrenal axis function. Moreover, it has been suggested that this association is moderated by an interaction with stressful life experiences. Aims: To investigate the moderation of cortisol response to psychosocial stress by 5-HTTLPR genotype, either directly or through an interaction with early life stress. Method: A total of 151 women, 85 of which had personality psychopathology, performed the Trier Social Stress Test while cortisol responsivity was assessed. Results: The results demonstrate a main effect of genotype on cortisol responsivity. Women carrying two copies of the long version of 5-HTTLPR exhibited stronger cortisol responses to psychosocial stress than women with at least one copy of the short allele (P = 0.03). However, the proportion of the variance of stress-induced cortisol responsivity explained by 5-HTTLPR genotype was not further strengthened by including early life adversity as a moderating factor (P = 0.52). Conclusions: Our results highlight the need to clarify gender-specific biological factors influencing the serotonergic system. Furthermore, our results suggest that childhood maltreatment, specifically during the first 15 years of life, is unlikely to exert a moderating influence of large effect on the relationship between the 5-HTTLPR genotype and cortisol responsivity to psychosocial stress. Declaration of interest: None.

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