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G Brabant

Publications and source records attributed to G Brabant.

At least 19 recordsLinked to original sources
PubMed2006

Predicting impaired glucose metabolism in women with polycystic ovary syndrome by decision tree modelling.

AIMS/HYPOTHESIS: Polycystic ovary syndrome (PCOS) is a risk factor of type 2 diabetes. Screening for impaired glucose metabolism (IGM) with an OGTT has been recommended, but this is relatively time-consuming and inconvenient. Thus, a strategy that could minimise the need for an OGTT would be beneficial. MATERIALS AND METHODS: Consecutive PCOS patients (n=118) with fasting glucose <6.1 mmol/l were included in the study. Parameters derived from medical history, clinical examination and fasting blood samples were assessed by decision tree modelling for their ability to discriminate women with IGM (2-h OGTT value >/=7.8 mmol/l) from those with NGT. RESULTS: According to the OGTT results, 93 PCOS women had NGT and 25 had IGM. The best decision tree consisted of HOMA-IR, the proinsulin:insulin ratio, proinsulin, 17-OH progesterone and the ratio of luteinising hormone:follicle-stimulating hormone. This tree identified 69 women with NGT. The remaining 49 women included all women with IGM (100% sensitivity, 74% specificity to detect IGM). Pruning this tree to three levels still identified 53 women with NGT (100% sensitivity, 57% specificity to detect IGM). Restricting the data matrix used for tree modelling to medical history and clinical parameters produced a tree using BMI, waist circumference and WHR. Pruning this tree to two levels separated 27 women with NGT (100% sensitivity, 29% specificity to detect IGM). The validity of both trees was tested by a leave-10%-out cross-validation. CONCLUSIONS/INTERPRETATION: Decision trees are useful tools for separating PCOS women with NGT from those with IGM. They can be used for stratifying the metabolic screening of PCOS women, whereby the number of OGTTs can be markedly reduced.

Adult↗
PubMed2006

Is there a need to redefine the upper normal limit of TSH?

Mild forms of hypothyroidism--subclinical hypothyroidism--have recently been discussed as being a risk factor for the development of overt thyroid dysfunction and for a number of clinical disorders. The diagnosis critically depends on the definition of the upper normal limit of serum TSH as, by definition, free thyroxine serum concentrations are normal. Cut-off levels of 4-5 mU TSH/l have been conventionally used to diagnose an elevated TSH serum concentration. Recent data from large population studies have suggested a much lower TSH cut-off with an upper limit of 2-2.5 mU/l but application of strict criteria for inclusion of subjects from the general population studies aiming at assessing TSH reference intervals (no personal or family history of thyroid disease, no thyroid antibodies and a normal thyroid on ultrasonography) did not result in an unequivocal upper limit of normal TSH at 2.0-2.5 mU/l. When summarizing the available evidence for lowered upper TSH cut-off values and their potential therapeutic implications there is presently insufficient justification to lower the upper normal limit of TSH and, for practical purposes, it is still recommended to maintain the TSH reference interval of 0.4-4.0 mU/l. Classifying subjects with a TSH value between 2 and 4 mU/l as abnormal, as well as intervening with thyroxine treatment in such subjects, is probably doing more harm than good.

Chemistry, Clinical↗
PubMed2005

Surgical treatment of primary hyperparathyroidism.

BACKGROUND: With the use of routine calcium evaluation, the incidence of primary hyperparathyroidism (pHPT) has considerably increased. The aim of our study was the assessment of the morbidity and the outcome of surgically treated patients with pHPT. METHODS: The charts of 279 patients (204 female, 75 male, median age: 58 years) who underwent surgery for pHPT between 1989 and 1999 were retrospectively reviewed. A follow-up was carried out on 235 patients after a mean period of 3.6 years (0.2-10 years). RESULTS: In 148 patients a unilateral, and in 130 patients a bilateral approach was taken. Transplanted parathyroid tissue was removed from the left forearm of one patient. At follow-up persistent hypocalcemia was seen in 30 patients (20 after bilateral, 10 after unilateral exploration). 6 patients (1 after bilateral, 5 after unilateral exploration) revealed a newly developed persistent paresis of the recurrent laryngeal nerve. In 5 patients persistent (1 after unilateral, 4 after bilateral exploration) and in 5 patients recurrent (2 after unilateral, 3 after bilateral exploration) pHPT could be observed. CONCLUSION: Both unilateral and bilateral cervical exploration for pHPT have a high rate of success with a low morbidity. Therefore, patients with assumed asymptomatic pHPT with unspecific neuropsychological abnormalities should also be evaluated for surgical intervention.

Female↗
PubMed2005

Wnt-5a has tumor suppressor activity in thyroid carcinoma.

Stabilization of beta-catenin by inhibition of its phosphorylation is characteristic of an activation of the canonical Wnt/beta-catenin signaling pathway and is associated with various human carcinomas. It contrasts to an as yet incompletely characterized action of an alternative noncanonical Wnt signaling pathway on neoplastic transformation. The aim of the present study was to test the effects of a member of the noncanonical Wnt signaling pathway, Wnt-5a, in primary thyroid carcinomas and in thyroid carcinoma cell lines. Compared to normal tissue Wnt-5a mRNA expression was clearly increased in thyroid carcinomas. Immunohistochemically, a bell-shaped response was observed with low to undetectable levels in normal tissue and in anaplastic tumors whereas differentiated thyroid carcinomas showed strong positive immunostaining for Wnt-5a. Transfection of Wnt-5a in a thyroid tumor cell line FTC-133 was able to reduce proliferation, migration, invasiveness and clonogenicity in these cells. These effects of Wnt-5a are associated with membranous beta-catenin translocation and c-myc oncogene suppression and are mediated through an increase in intracellular Ca(2+) release, which via CaMKII pathways promotes beta-catenin phosphorylation. Specific inhibition of beta-catenin phosphorylation by W-7, a calmodulin inhibitor, or by KN-93, a CaMKII inhibitor, supports these findings whereas PKC inhibitors were without effect. This interaction occurs downstream of GSK-3 beta as no Wnt-5a effect was seen on the Ser(9) phosphorylation of GSK-3 beta. Our data are compatible with the hypothesis that Wnt-5a serves as an antagonist to the canonical Wnt-signaling pathway with tumor suppressor activity in differentiated thyroid carcinomas.

Cell Division↗
PubMed2005

Precision of intracellular calcium spike timing in primary rat hepatocytes.

Extracellular stimuli are often encoded in the frequency, amplitude and duration of spikes in the intracellular concentration of calcium ([Ca2+]i). However, the timing of individual [Ca2+]i-spikes in relation to the dynamics of an extracellular stimulus is still an open question. To address this question, we use a systems biology approach combining experimental and theoretical methods. Using computer simulations, we predict that more naturalistic pulsed stimuli generate precisely-timed [Ca2+]i-spikes in contrast to the application of constant stimuli of the same dose. These computational results are confirmed experimentally in single primary rat hepatocytes upon alpha1-adrenergic stimulation. Hormonal signalling in analogy to neuronal signalling thus has the potential to make use of temporal coding on the level of single cells. The [Ca2+]i-signalling cascade provides a first example for increasing the information capacity of an intracellular regulatory signal beyond the known coding mechanisms of amplitude (AM) and frequency modulation (FM).

Algorithms↗
PubMed2005

Low serum levels of testosterone in men with minimal traumatic hip fractures.

Sex steroids are essential for accretion and maintenance of bone mass. Their importance for osteoporotic fractures in men, however, are undefined. We determined circulating levels of testosterone (T), non-SHBG-bound T (bT), free testosterone (FT), oestradiol (E2), intact parathormone (iPTH), 25-OH-vitamin D (25(OH)D), and trabecular bone mineral density at spinal level (tBMD) by single quantitative computed tomography (QCT), respectively, in elderly men 1-3.5 months after minimal traumatic hip fractures (MTHF, age=75+/-10 ys, n=27). A group of patients with non-immobilising stroke (S; age=73+/-8 ys, n=12) served as controls. Men with known secondary osteoporosis were excluded from the study. Furthermore, serum levels of T and E2 were compared to healthy controls aged 20-30 years (n=138) and 60-80 years (n=110). In addition a literature-based analysis of studies on testosterone in men hip fractures were conducted. Mean tBMD of men with MTFH (52.7+/-17.6 mg/cm3, T-score=- 4.5+/-0.6) was significantly lower than in men with S (78+/-16.3 mg/cm3, T-score=- 3.5+/-0.8). Significant differences of the means between both groups were observed for T, bT, and FT but not for E2, 25(OH)D, and iPTH, respectively. About 90 % of men with MTHF had T serum levels 2 SD below the mean of young controls. This proportion reduced to 30 % if compared with serum levels of 60-80-year-old healthy men whereas men after S remained well within the normal range adjusted for age. Mean serum levels of iPTH were within the normal range (1-6.8 pmol/l); 25(OH)D serum levels were at the lower end of the normal control levels (30-190 nmol/l). There was an inverse relationship between iPTH and 25(OH)D (r=- 0,4; p<0,03). In conclusion, low serum T is common in men with MTHF and only partly due to age. It appears to be a primary factor in fragility fractures in men and not simply secondary to morbidity following the fracture. In view of the scarce and inconsistent data published on this issue (1 longitudinal and 6 cross-sectional studies) the present study supports the patho-physiological relevance of low serum testosterone for the occurrence of MTHF in men.

Aged↗
PubMed2005

Hypothalamic-pituitary-thyroid axis in moderate and intense exercise.

Exercise exerts heterogeneous effects on TSH secretion. Whereas TSH is rapidly stimulated by physical exercise within minutes, and these effects are well supported by careful experiments, the results of studies concerning intermediate and long-term response of TSH release to exercise remain unclear, and the underlying mechanism for both is still open to speculation.

Animals↗
PubMed2005

Lithium stimulates proliferation in cultured thyrocytes by activating Wnt/beta-catenin signalling.

BACKGROUND: Lithium, clinically used in the treatment of bipolar disorders, is well known to induce thyroid growth. However, the mechanism involved is only incompletely characterized. Although it is conventionally believed that thyroid proliferation depends on the thyroid-stimulating hormone (TSH)/cAMP/cAMP response element binding protein (CREB) pathway, recent data indicate that Wnt/beta-catenin signalling may be of critical importance. In other cell types lithium activates canonical Wnt signalling by GSK-3beta inhibition, which in turn stabilizes cytosolic free beta-catenin. Here we investigated the potential modulation of Wnt/beta-catenin signalling under lithium treatment in primary and neoplastic human thyrocytes. METHODS: Primary (S18) and neoplastic (NPA, FTC133) thyrocytes treated with and without LiCl were analysed using Western blotting, immunoprecipitation, reporter-gene assay, MTT proliferation assay and transfection studies. RESULTS: LiCl dose-dependently inhibited GSK-3beta, stabilized free beta-catenin and inhibited beta-catenin degradation. Furthermore, LiCl altered the assembly of adherens junction by upregulating the E-cad-herin repressor, Snail, and downregulated E-cadherin expression. At a dose of 5 mM, LiCl significantly increased the proliferative potency of thyrocytes, which appeared to be mediated by beta-catenin, since nuclear beta-catenin stimulated T-cell factor/lymphoid enhancer factor (TCF/LEF)-mediated transcription and upregulated downstream targets like cyclin D1. To characterize the specificity of Wnt/beta-catenin-driven thyrocyte proliferation, we transfected primary thyrocytes and FTC133 cells with dominant negative TCF4 to block Wnt-dependent pathways or with dominant negative CREB to inhibit the TSH/cAMP cascade. In cells transfected with dominant negative CREB lithium-stimulated proliferation was unchanged whereas blocking Wnt/beta-catenin by dominant negative TCF4 reduced proliferation by approx. 50%. CONCLUSION: Our data indicate that Wnt/beta-catenin signalling is of major importance in the control of lithium-dependent thyrocyte proliferation.

Blotting, Western↗
PubMed2004

[Thyroid gland malfunction].

Uncharacteristic clinical symptoms such as cardiac arrhythmias, restlessness, changes in weight or hair loss may signify hyperthyroidism, whereas impairment of physical or mental vigilance may be a manifestation of hypothyroidism. In many cases the diagnosis can be established only on the basis of laboratory investigations, and, on account of the difficulty in establishing a differential diagnosis, these should not be stinted. However, when it comes to interpreting findings, consideration must be given to drug interference, such diseases as the nephrotic syndrome, serious general diseases or pregnancy. In the event of pathological laboratory findings, ultrasonography and scintigraphy are helpful further diagnostic measures. Antihyperthyroid drugs, surgery or radioiodine therapy are the leading therapeutic options for hyperthyroidism. As in the case of hypothyroidism treated with L-thyroxine, the primary target parameter is titration of TSH into the normal range.

Algorithms↗
PubMed2004

Calcitonin measurement to detect medullary thyroid carcinoma in nodular goiter: German evidence-based consensus recommendation.

Serum calcitonin (CT) has become a very specific and sensitive marker for human medullary thyroid carcinoma (MTC), a neuroendocrine tumor affecting about 1 % of patients with nodular thyroid disease. MTC is characterized by early micrometastasis and a lack of curative non-surgical treatment, so that early diagnosis is desirable. Based on a systematic review of scientific evidence, we propose multidisciplinary consensus recommendations for the clinical use of CT in patients with nodular goiter. To exclude MTC, serum CT should be determined in patients with nodular thyroid disease, using a two-site CT immunoassay. If basal serum CT exceeds 10 pg/ml, CT should be analysed by pentagastrin stimulation testing, after renal insufficiency and proton pump inhibitor medication have been ruled out. As the risk for MTC is higher than 50 % in patients with stimulated CT values > 100 pg/ml, thyroidectomy is advised in these individuals. If stimulated CT exceeds 200 pg/ml, thyroidectomy and lymphadenectomy is strongly recommended. Pentagastrin-stimulated CT values < 100 pg/ml are associated with a low risk of MTC, or very rarely, non-metastasizing micro-MTC (size < 10 mm). Therefore, regular clinical and biochemical follow-up is the preferred treatment in such patients, unless thyroid malignancy is suspected otherwise.

Calcitonin↗
PubMed2004

Ghrelin/Leptin-imbalance in patients with primary biliary cirrhosis.

BACKGROUND: The recently discovered peptide hormone ghrelin mainly produced in gastric oxyntic cells may act as a counterpart to leptin in the regulation of food intake and fat utilization. Leptin, involved in the stimulation of proinflammatory cytokines and catabolic energy balance, is elevated in patients with liver cirrhosis. In the present study, we evaluated serum ghrelin and bound leptin levels in patients with primary biliary cirrhosis (PBC) in relation to C-peptide and glucose concentration. METHODS: In 22 female patients with PBC (Child-Pugh stage A) and in 36 female controls we measured serum ghrelin, bound leptin, and C-peptide levels using specific immunoassays. RESULTS: In comparison to controls serum bound leptin levels were significantly higher in patients with PBC ( p < 0.01) whereas serum ghrelin levels were decreased compared to the control group ( p < 0.01). In parallel, C-peptide concentrations were increased ( p < 0.01) with no significant change in circulating glucose levels. CONCLUSION: Our data confirm in PBC patients that serum bound leptin levels are increased and clearly show a parallel decrease in serum ghrelin concentrations acting as a physiological counterpart to leptin. Furthermore, we suggest that these changes are linked to the insulin resistance observed in our patients.

Female↗
PubMed2004

In vivo and in vitro evidence for a hepatic modulation of the leptin signal in rats.

BACKGROUND: Leptin is primarily secreted by the adipose tissue. It binds not only to hypothalamic structures involved in energy regulation but also to many peripheral tissues including the liver. Leptin circulates in free and receptor-bound forms. Both components are differentially regulated under various pathophysiological conditions and serve different physiological functions. They are released from adipose tissue but previous data suggest an additional formation outside the fat compartment. Here we tested the contribution of the liver in binding and modulating leptin in the circulation. MATERIALS AND METHODS: In vivo experiments were performed with radioactive labelled leptin with and without pretreatment with unlabelled leptin in freely moving, chronic intravenously cannulated male rats. Livers were investigated by immunohistochemistry and in situ hybridization and immunoblotting was performed, followed by ex vivo liver perfusion studies with human recombinant leptin. RESULTS: In in vivo experiments radioactively labelled leptin (at low concentrations) is avidly bound to rat liver (greater than 80% of basal serum values 90 min following i.v. infusion). Pre-treatment with excess of unlabelled leptin in vivo revealed a rapid hepatic down-regulation of leptin receptor isoforms when tested by in situ hybridization, immunoblotting or immunohistochemistry. Ex vivo perfusion of rat liver with human recombinant leptin induced a dose- and time-dependent formation of receptor-bound leptin in the perfusate. CONCLUSIONS: The present data support an active role of the liver in the modulation of the leptin signal through different regulation of the soluble leptin receptor, the bound and free forms of the hormone, which may have important implications for leptin's central efficacy and the development of 'leptin resistance'.

Adipose Tissue↗
PubMed2003

[Intraarterial calcium stimulation (ASVS) for pancreatic insulinoma: comparison of preoperative localization procedures].

PURPOSE: Evaluation of clinical relevance of the arterial stimulation procedure with venous sampling (ASVS) in the preoperative localization of insulinoma. METHODS: Thirteen patients with endogenous hyperinsulinism underwent preoperative transabdominal ultrasound (US), helical CT (CT), MRI, endoscopic ultrasound (EUS), and angiography (DSA) in conjunction with the ASVS-test for the detection of insulinoma. The results were compared with intraoperative findings, intraoperative ultrasound (IOUS) and histology. RESULTS: Sensitivity was as follows: US 8%, MRI 27%, CT 46%, EUS 50%,DSA 69%,and ASVS 92%. Intraoperative palpation and IOUS yielded a sensitivity of 77%. In 3 patients the tumors were neither palpable nor detectable by IOUS, the mode of resection was based on preoperative diagnostics. The ASVS procedure as a functional test was superior to all other modalities for the preoperative tumor detection. CONCLUSION: The ASVS was the most sensitive diagnostic modality. It should especially be considered in terms of health economical aspects when CT or MRI do not yield conclusive results.

Adolescent↗
PubMed2003

The effect of pegvisomant-induced serum IGF-I normalization on serum leptin levels in patients with acromegaly.

BACKGROUND: In humans, serum leptin correlates positively with fat mass. GH is lipolytic and patients with active acromegaly have lowered serum leptin compared to age, sex and body mass index (BMI)-matched controls, but a direct influence of GH on serum leptin remains unclear. In patients with acromegaly, total leptin increases following successful pituitary surgery and during somatostatin (SMS) analogue therapy (despite no change in BMI) but whether this represents changes in soluble leptin receptor, bound or free leptin is unclear. Pegvisomant, a GH receptor antagonist capable of normalizing serum IGF-I in over 97% of patients, represents a novel treatment strategy in acromegaly and its effect on leptin has not previously been reported. PATIENTS: Sixteen patients (nine male (M), seven female (F), median age 52 years, range 27-78 years) with active acromegaly (serum IGF-I at least 30% above the upper limit of an age-related reference range) were studied. Serum IGF-I was normalized in all subjects with pegvisomant [mean duration 7 months (range 3-11 months), median dose 20 mg/day (range 10-40 mg/day)]. A single batch measurement of leptin, bound leptin (BL), soluble leptin receptor (SLR), insulin and glucose were performed on samples from baseline and first occurrence of serum IGF-I normalization. RESULTS: As in normal subjects, females with acromegaly had higher baseline serum leptin [median M = 6.1 (range 1.6-58.7), F = 25.9 (range 3.19-54.1) ng/ml; P = 0.04], which correlated positively with BMI (R = 0.78, P = 0.0004). Forward step-wise regression analysis demonstrated that BMI and gender accounted for 90% of the variance in mean serum log10 leptin. Pegvisomant-induced serum IGF-I normalization was associated with a rise in serum leptin [8.9 (range 1.6-58.3) to 12.7 (range 2.3-90.8) ng/ml, P < 0.0001]. Although the absolute increase was not significantly different, mean percentage increase was greater in men (M = 66.6 +/- 51%, F = 11.8 +/- 16%, P = 0.017) despite similar serum IGF-I and BMI in male and female subjects at baseline. No change in BL or SLR accompanied serum IGF-I normalization [0.27 (range 0.15-1.26) to 0.27 (range 0.14-1.2) nmol/l, P = 0.27 and 3.2 (range 1.2-6.8) to 2.7 (range 1-7.4) nmol/l, P = 0.5, respectively]. After normalization of serum IGF-I, a correlation between BMI and leptin remained (R = 0.86, P < 0.0001) and together BMI and gender accounted for 87% of the variance in mean log10 serum leptin (P = 0.0002). CONCLUSION: Pegvisomant-induced serum IGF-I normalization in patients with active acromegaly is associated with a significant increase in total, and by implication, free leptin.

Acromegaly↗
PubMed2003

Sex steroids and body composition in men with cystic fibrosis.

OBJECTIVE: Delayed sexual maturation and low body weight is common in cystic fibrosis (CF). Concomitant data on sex hormones and concomitant body composition are lacking in men with CF. DESIGN: Cross-sectional study. SUBJECTS AND METHODS: Serum levels of testosterone, 17beta-oestradiol (E(2)), 25-hydroxyvitamin D (25(OH)D), sex hormone-binding globulin (SHBG) and LH were measured by RIA and total and regional lean body mass (LBM), fat body mass (FBM), bone mineral content and bone mineral density (BMD) were assessed by dual-energy X-ray absorptiometry, in men with CF (n=40; age 24.7+/-5.4 years) and age-matched healthy controls (n=28; age 25.7+/-3.7). Only men without acute disease exacerbation or systemic glucocorticoid treatment were included. RESULTS: Mean levels of hormonal serum parameters differed significantly between healthy controls (testosterone=20.2+/-5.5 nmol/l; E(2)=95.0+/-20.2 pmol/l; 25(OH)D=62.8+/-28.3 nmol/l) and patients (testosterone=15.9+/-4.1 nmol/l; E(2)=60.7+/-19.4 pmol/l; 25(OH)D=39.5+/-17.8 nmol/l; P<0.001) while no difference was found for SHBG or LH. Eleven (for E(2), 19 of 40, for 25(OH)D, 20 of 40) out of 40 patients had serum testosterone levels 2 s.d. below the mean of normal. Men with CF showed a relative shift from FBM to LBM and a different body fat distribution compared with healthy controls (P<0.01). Testosterone was not correlated with weight, total or regional LBM or FBM, but significantly with BMD (r=0.32; P<0.05) independently from body height and 25(OH)D levels. E(2) was correlated with regional and total FBM (r=0.48; P<0.05). In a multiple regression analysis of the joint effect of testosterone and body components on E(2), a testosterone-independent effect was found for FBM. CONCLUSIONS: CF patients with stable disease have moderately reduced serum testosterone levels. This might already imply detrimental effects on bone. The change in LBM of patients appears to have no direct association with sex hormone levels while low FBM might cause reduced net conversion of serum testosterone to E(2) with possible effects on FBM distribution.

Absorptiometry, Photon↗
PubMed2002

A patient with autoimmune hepatitis type I, Addison's disease, atrophic thyroiditis, atrophic gastritis, exocrine pancreatic insufficiency, and heterozygous alpha1-antitrypsin deficiency.

This report describes a 60-yr-old white male presenting with decompensated liver cirrhosis. He had a history of Addison's disease for 36 yr, primary hypothyroidism for 5 yr, and moderate alcohol consumption. His laboratory studies and a liver biopsy supported the diagnosis of autoimmune hepatitis. Furthermore, he was found to be heterozygous for the piZ allele of the alpha1-antitrypsin gene with normal serum alpha1-antitrypsin levels and absence of pulmonary affection. Mucosal biopsies revealed moderately severe atrophic gastritis; however, signs of pernicious anemia were missing. An association of autoimmune hepatitis with endocrine disorders and atrophic gastritis has been described. Long term hydrocortisone therapy for his adrenal insufficiency may have prevented a faster course of the liver disease, whereas the heterozygous alpha1-antitrypsin deficiency and moderate alcohol consumption constituted additional risk factors ultimately leading to the development of cirrhosis.

Addison Disease↗