bluuebunny/crossref_metadata_2025_split huggingface dataset:
Suppression of the Basic Transcription Element-Binding Protein in Brain Neuronal Cultures Inhibits Thyroid Hormone-Induced Neurite Branching
Authors: Cayrou Christelle , Denver Robert J. , Puymirat Jack 
Published: January 2014

AbstractThe molecular mechanisms underlying the effect of thyroid hormone (T3) on neurite outgrowth are unknown. We recently identified the small GC-box binding protein BTEB (basic transcription element-binding protein) as a T3-regulated gene in the developing rat brain. BTEB mRNAs are rapidly (by 1 h) up-regulated by T3 in primary rat embryonic neuronal cultures. Antisense oligodeoxynucleotides (ODNs), added to the cultures, reduced by 60% the level of BTEB mRNA. Addition of BTEB antisense ODNs to the cultures, before the onset of neurite polarity, had no effect on neurite elaboration but significantly decreased, in a dose-dependent manner, the effect of T3 on neurite branching. We then examined the effects of antisense ODNs on a thyroid hormone target neuronal population, i.e. the acetylcholinesterase-positive neurons after the onset of neurite polarity. Exposure to BTEB antisense ODNs completely abolished the effects of T3 on neurite branching and on the elaboration of neuritic filopodia-like structures in acetylcholinesterase cells. By contrast, antisense ODNs did not alter the effect of T3 on neurite length. Our results show that titration of BTEB levels by T3 regulates the degree of neurite branching and that the T3-induced neurite elongation and the T3-induced neurite branching are regulated by distinct mechanisms.
Gastric Parietal Cells: Potent Endocrine Role in Secreting Estrogen as a Possible Regulator of Gastro-Hepatic Axis
Authors: Ueyama Takashi , Shirasawa Nobuyuki , Numazawa Mitsuteru , Yamada Keiko , Shelangouski Momoko , Ito Takao , Tsuruo Yoshihiro 
Published: January 2014

AbstractEstrogen, if it is produced in the gastrointestinal tract, may overflow into the systemic circulation in the case of increased portal-systemic shunting. This idea is in accord with a significant step-up in serum estradiol (E2) concentration in the portal vein of rats, compared with that in the artery. Gene expression of aromatase, estrogen synthetase, was demonstrated by RT-PCR in the gastric mucosa of male and female adult rats, equivalent to that in the ovary. Aromatase activity and production of E2 in the gastric mucosa were demonstrated by 3H2O assay and gas chromatography-mass spectrometry, and they were inhibited by aromatase inhibitor, 4-hydroxyandrostenedione. Conversion of 14C-androstenedione to 14C-E2 through 14C-testosterone in cultured gastric mucosa was also demonstrated. Parietal cells exhibited strong signals for aromatase mRNA and immunoreactive protein by in situ hybridization histochemistry and immunohistochemistry. Estrogen receptor α mRNA and immunoreactive protein were demonstrated in hepatocytes by RT-PCR, in situ hybridization histochemistry, and immunohistochemistry. Total gastrectomy reduced portal venous E2 concentration, without changing systemic E2 concentration, together with down-regulation of estrogen receptor α mRNA level in the liver. These findings indicate that gastric parietal cells play a potent endocrine role in secreting estrogen that may function as a regulator of the gastro-hepatic axis.
Phosphodiesterase 8B Gene Polymorphism Is Associated with Subclinical Hypothyroidism in Pregnancy
Authors: Shields Beverley M. , Freathy Rachel M. , Knight Bridget A. , Hill Anita , Weedon Michael N. , Frayling Timothy M. , Hattersley Andrew T. , Vaidya Bijay 
Published: January 2014

ABSTRACT

Background:
Maternal subclinical hypothyroidism is associated with a number of adverse outcomes in pregnancy. The Endocrine Society’s recent consensus guidelines have recommended treatment with T4 for this condition in pregnancy. The single nucleotide polymorphism rs4704397 in the phosphodiesterase 8B (PDE8B) gene has been found to be associated with altered serum TSH concentrations in the general population. We aimed to assess whether genetic variation in TSH due to the rs4704397 genotype affects the number of individuals classified as having subclinical hypothyroidism in pregnancy.

Methods:
Serum TSH, FT4, FT3, and thyroid peroxidase antibodies (TPOAbs) were measured in 970 pregnant women at 28 wk gestation. rs4704397 genotype was available on 877 subjects. Reference range calculations were based on the TPOAb-negative women.

Results:
TSH, but not FT4, FT3, or TPOAbs, varied with genotype and was highest in those with the AA genotype (median, 2.16, 1.84, and 1.73 mIU/liter for AA, AG, and GG genotypes, respectively; P = 0.0004). A greater proportion of women with the AA genotype had TSH concentrations above 4.21 mIU/liter, the upper limit of the reference range, compared with the AG and GG genotypes (9.6 vs. 3.5%, respectively; P = 0.004). Maternal PDE8B genotype was not associated with offspring birthweight or gestational age at delivery.

Conclusion:
Genetic variation in TSH levels in pregnancy associated with the PDE8B rs4704397 genotype has implications for the number of women treated for subclinical hypothyroidism under current guidelines. Consideration should be made to individualization of normal ranges, potential effects on pregnancy outcome, and intention to treat for subclinical hypothyroidism in pregnancy.
Worsening of Obesity and Metabolic Status Yields Similar Molecular Adaptations in Human Subcutaneous and Visceral Adipose Tissue: Decreased Metabolism and Increased Immune Response
Authors: Klimčáková Eva , Roussel Balbine , Márquez-Quiñones Adriana , Kováčová Zuzana , Kováčiková Michaela , Combes Marion , Šiklová-Vítková Michaela , Hejnová Jindra , Šrámková Petra , Bouloumié Anne , Viguerie Nathalie , Štich Vladimir , Langin Dominique 
Published: January 2014

Context: It is not known whether biological differences reported between sc adipose tissue (SAT) and visceral adipose tissue (VAT) depots underlie the pathogenicity of visceral fat.
Objective: We compared SAT and VAT gene expression according to obesity, visceral fat accumulation, insulin resistance, and presence of the metabolic syndrome.
Design: Subjects were assigned into four groups (lean, overweight, obese, and obese with metabolic syndrome).
Setting: Subjects were recruited at a university hospital.
Patients: Thirty-two women were included.
Main Outcome Measures: Anthropometric measurements, euglycemic-hyperinsulinemic clamps, blood analyses, and computed tomography scans were performed, and paired samples of SAT and VAT were obtained for DNA microarray-based gene expression profiling.
Results: Considering the two fat depots together, 1125 genes were more and 1025 genes were less expressed in lean compared with metabolic syndrome subjects. Functional annotation clustering showed, from lean to metabolic syndrome subjects, progressive down-regulation of metabolic pathways including branched-chain amino acid, fatty acid, carbohydrate, and mitochondrial energy metabolism and up-regulation of immune response genes involved in toll-like receptor, TNF, nuclear factor-κB, and apoptosis pathways. Metabolism and immune response genes showed an opposite correlation with fat mass, fat distribution, or insulin resistance indices. These associations were similar in SAT and VAT, although about 1000 genes showed differential expression between SAT and VAT.
Conclusions: The increase in adiposity and the worsening of metabolic status are associated with a coordinated down-regulation of metabolism-related and up-regulation of immune response-related gene expression. Molecular adaptations in SAT prove as discriminating as those in VAT.
GH Response to Oral Glucose Tolerance Test: A Comparison between Patients with Acromegaly and Other Pituitary Disorders
Authors: Verrua E. , Filopanti M. , Ronchi C. L. , Olgiati L. , Ferrante E. , Giavoli C. , Sala E. , Mantovani G. , Arosio M. , Beck-Peccoz P. , Lania A. G. , Spada A. 
Published: January 2014

Context: The cutoff value of nadir GH after an oral glucose tolerance test (OGTT) used to define disease remission in acromegaly is higher than that observed in healthy subjects. However, it is uncertain whether the impaired GH inhibition might be related to subtle abnormalities of GH secretion or to functional and/or anatomical hypothalamic-pituitary disconnection due to tumor per se or treatments.
Objective: The objective of the study was to evaluate the impact of pituitary disorders other than acromegaly on GH response to OGTT.
Design, Subjects, and Methods: Thirty-three patients (24 females and nine males, aged 50.1 ± 12.3 yr, 13 operated and two irradiated) with various hypothalamic-pituitary disorders (HPDs), 45 healthy subjects (controls), and 42 cured acromegalic patients matched for sex, age. and body mass index were investigated. All subjects were studied for IGF-I levels and GH levels before and during the OGTT.
Results: In HPD patients mean postglucose nadir GH levels were 0.11 ± 0.08 μg/liter without any difference between patients treated with neurosurgery and/or radiotherapy and untreated and between patients with and without pituitary stalk alterations and/or hyperprolactinemia. Mean nadir GH values were similar in HPD patients and controls (0.11 ± 0.08 vs. 0.08 ± 0.08 μg/liter, P = 0.23) and lower than those found in cured acromegalic patients (0.18 ± 0.13 μg/liter, P = 0.02), although there was an overlapping in about half of patients.
Conclusions: Hypothalamic control of glucose-mediated GH suppression is not perturbed in patients with HPD. These data indicate that defective GH suppression to glucose that is found in acromegaly is unlikely to reflect a lack of integrity of hypothalamic function.
Somatotroph Tumor Progression during Pegvisomant Therapy: A Clinical and Molecular Study
Authors: Marazuela M. , Paniagua A. E. , Gahete M. D. , Lucas T. , Alvarez-Escolá C. , Manzanares R. , Cameselle-Teijeiro J. , Luque-Ramirez M. , Luque R. M. , Fernandez-Rodriguez E. , Castaño J. P. , Bernabeu I. 
Published: January 2014

Context: There is concern that pegvisomant could be associated with a higher risk of tumor growth. The rate and possible determinants of this tumor growth are unknown.
Objective: The objective of the study was to investigate the clinical, immunohistological, and molecular factors conditioning tumor growth in patients taking pegvisomant.
Design and Setting: This was a cross-sectional study performed from 2004 to 2010 in four university hospitals in Spain.
Patients: Seventy-five acromegalic patients with active disease resistant to somatostatin analogs treated with pegvisomant were followed up for a mean of 29 ± 20 months.
Main Outcome Measures: Magnetic resonance images before initiation of pegvisomant, at 6 months, and then yearly were examined in all patients. Immunohistological and molecular studies were performed in tumors that grew.
Results: A significant increase in tumor size was observed in five patients (6.7%). Absence of previous irradiation (P = 0.014) and shorter duration of prepegvisomant somatostatin analog therapy (P &lt; 0.001) were associated with an increased risk of tumor growth. A stepwise multivariate linear regression analysis (R2 = 0.334, P &lt; 0.001) identified the duration of somatostatin analog therapy prior to pegvisomant (beta = −4.509, P = 0.014) as the only significant predictor of tumor growth. In those tumors that grew, GH expression and insulin receptor expression were higher (P = 0.033 in both cases) than in the control group.
Conclusions: No previous radiotherapy, shorter duration of prepegvisomant somatostatin analog therapy, and higher tumor expression of GH and insulin receptor could be risk factors for tumor growth during pegvisomant therapy.
Preconception Folic Acid Use Modulates Estradiol and Follicular Responses to Ovarian Stimulation
Authors: Twigt John M. , Hammiche Fatima , Sinclair Kevin D. , Beckers Nicole G. , Visser Jenny A. , Lindemans Jan , de Jong Frank H. , Laven Joop S. E. , Steegers-Theunissen Régine P. 
Published: January 2014

Background: Folate is a methyl donor. Availability of folate affects DNA methylation profiles and thereby gene expression profiles. We investigated the effects of low-dose folic acid use (0.4 mg/d) on the ovarian response to mild and conventional ovarian stimulation in women.
Methods: In a randomized trial among subfertile women, 24 and 26 subjects received conventional and mild ovarian stimulation, respectively. Blood samples were taken during the early follicular phase of the cycle prior to treatment and on the day of human chorionic gonadotropin administration for determination of serum total homocysteine, anti-Müllerian hormone (AMH), estradiol, and folate. Folic acid use was validated by questionnaire and serum folate levels. Preovulatory follicles were visualized, counted, and diameters recorded using transvaginal ultrasound. The relation between folic acid use and ovarian response was assessed using linear regression analysis.
Results: Folic acid use modified the ovarian response to ovarian stimulation treatment. The estradiol response was higher in nonfolic acid users receiving conventional treatment [βinteraction = 0.52 (0.07–0.97); P = 0.03], and this effect was independent of serum AMH levels and the preovulatory follicle count. In the conventional treatment, the mean follicle number was also greater in nonusers compared with the users group (14.1 vs. 8.9, P = 0.03).
Conclusion: Low-dose folic acid use attenuates follicular and endocrine responses to conventional stimulation, independent of AMH and follicle count. The nature of this observation suggests that the effect of folic acid is most prominent during early follicle development, affecting immature follicles. Deleterious effects of folate deficiency, like DNA hypomethylation and oxidative stress, can help to explain our observations.
Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism and Severe Hypoglycemia Complicating Type 2 Diabetes: The Fremantle Diabetes Study
Authors: Davis Wendy A. , Brown Simon G. A. , Jacobs Ian G. , Bulsara Max , Beilby John , Bruce David G. , Davis Timothy M. E. 
Published: January 2014

Abstract

Aims/Hypotheses:
The aims of this study were to determine whether the angiotensin-converting enzyme (ACE) gene I/D polymorphisms independently predict severe hypoglycemia in community-dwelling type 2 patients.

Methods:
Six hundred two patients who were ACE genotyped at baseline and assessed in 1998 were followed up to the end of June 2006. Severe hypoglycemia was defined as that requiring documented health service use as the primary diagnosis. Cox proportional hazards modeling was used to determine the predictors of first episode and zero-inflated negative binomial regression modeling identified predictors of frequency.

Results:
Forty-nine patients (8.1%) experienced 63 episodes of severe hypoglycemia. After adjusting for previously identified significant independent predictors of time to first episode, both ACE DD genotype and ACE inhibitor therapy, but not their interaction, added to the model [hazard ratio (95% confidence interval): 2.34 (1.29–4.26), P = 0.006, and 1.77 (0.99–3.13), P = 0.052, respectively]. Similarly, after adjusting for previously identified risk factors for multiple episodes of severe hypoglycemia, ACE DD genotype was independently associated with increased risk [incidence relative risk (95% confidence interval): 1.80 (1.00–3.24), P = 0.050].

Conclusions/Interpretation:
ACE DD genotype is associated with an increased the risk of the first episode of severe hypoglycemia and its subsequent frequency approximately 2-fold in well-characterized patients with type 2 diabetes. Consistent with previous case-control studies, ACE inhibitor therapy was a weak predictor of severe hypoglycemia. ACE I/D genotyping might provide useful adjunctive prognostic information when intensive glycemic control measures are contemplated.
Using Dilution Techniques and Multifrequency Bioelectrical Impedance to Assess Both Total Body Water and Extracellular Water at Baseline and During Recombinant Human Growth Hormone (GH) Treatment in GH-Deficient Adults*
Authors: Janssen Y. J. H. , Deurenberg P. , Roelfsema F. 
Published: January 2014

Abstract
Due to the use of various, and mostly indirect, methods to estimate total body water (TBW) and extracellular water (ECW), there is no agreement about whether body water distribution, i.e. the ECW to TBW ratio, is normal in GH-deficient (GHD) subjects at baseline and during recombinant human GH (rhGH) treatment. We studied body water distribution in 14 patients with adult-onset GHD and in 28 healthy controls. We also investigated the effect of GH replacement therapy for 4 and 52 weeks on body water distribution. All patients started with a dose of 0.6 IU rhGH/day for the first 4 weeks. After 52 weeks, the dose varied between 0.6–1.8 IU/day. TBW and ECW were measured by dilution of deuterium and bromide, respectively. Both parameters were also estimated using multifrequency bioelectrical impedance (BIA).
Patients with GHD had significantly lower ECW and TBW than healthy controls. In addition, the ECW to TBW ratio was significantly lower in GHD patients than in healthy controls. Four weeks of GH treatment significantly increased body weight, TBW, ECW, and ECW/TBW. A further increase in TBW, but not ECW, was found after 52 weeks of treatment. The mean increases in TBW and ECW from the baselines were 2.5 ± 0.3 and 2.0 ± 0.3 L, respectively.
The correlation coefficient and the estimated reliability between measured and estimated TBW and ECW at any time point were all high (&gt;0.91 and &gt;0.95, respectively). In general, both ECW and TBW were overestimated by multifrequency BIA in GHD adults. During treatment, the overestimation of both ECW and TBW diminished. The estimation error was correlated with the level of the body water compartment and the ratio of ECW to TBW. The estimated change in ECW with rhGH treatment was underestimated by multifrequency BIA.
We conclude that GHD adults have lower ECW and TBW and a lower ECW to TBW ratio, as measured by dilution techniques. The ECW to TBW ratio can be normalized within 4 weeks of rhGH treatment at a dose of 0.6 IU/day. Finally, we conclude that multifrequency impedance measurements do not give valid estimates of body water compartments in the follow-up of patients with GHD.
Evaluation of the Dexamethasone Suppression Test for the Diagnosis of Glucocorticoid-Remediable Aldosteronism1
Authors: Litchfield W. Reid , New Maria I. , Coolidge Caroline , Lifton Richard P. , Dluhy Robert G. 
Published: January 2014

Glucocorticoid-remediable aldosteronism (GRA) is a rare form of inherited hypertension caused by a characteristic gene duplication. With the advent of definitive genetic testing for GRA, the performance of the traditional screening test for GRA, the dexamethasone suppression test (DST), can be evaluated. We compared the DST to direct genetic testing in 24 patients referred for genetic screening for GRA (12 GRA positive and 12 GRA negative) based on clinical and biochemical findings, DST, and family history. Plasma aldosterone was measured before and after oral dexamethasone administration to determine the extent to which aldosterone was suppressed by glucocorticoids in each patient group. The results of the DST in these subjects were also compared to those in 19 historical patients with primary aldosteronism[ 4 bilateral hyperplasia and 15 aldosterone-producing adenoma (APA)] reported previously. The DST differentiated GRA-positive from GRA-negative patients with 92% sensitivity and 100% specificity. Cutoffs based on the post-DST plasma aldosterone level (&lt;4 ng/dL) or percent suppression compared to baseline (&gt;80%) were equally effective in correctly diagnosing GRA (only one GRA-positive patient would have been incorrectly diagnosed). However, DST in 15 APA patients revealed that 33% had greater than 80% suppression of aldosterone, and 1 had aldosterone levels below 4 ng/dL.
We conclued that a post-DST aldosterone level below 4 ng/dL will correctly diagnose GRA patients with high sensitivity and specificity. Suppression compared to baseline can be misleading, as evidenced by the results in APA patients and referred subjects who genetically screened negative.
Stimulation of Mitochondrial Fatty Acid Oxidation by Growth Hormone in Human Fibroblasts1
Authors: Leung Kin-Chuen , Ho Ken K. Y. 
Published: January 2014

In vivo administration of GH induces lipolysis and lipid oxidation. However, it is not clear whether the stimulation of lipid oxidation is a direct effect of GH or is driven by increased substrate supply secondary to lipolysis. An in vitro bioassay has been established for assessing β-oxidation of fatty acids in mitochondria, based on the measurement of conversion of tritiated palmitic acid to 3H2O by fibroblasts in culture. We have modified this assay to investigate whether GH stimulates fatty acid oxidation.GH stimulated oxidation of palmitic acid maximally by 26.7 ± 2.5% (mean ± sem; P &lt; 0.0001). The stimulation was biphasic, with the oxidation rate increasing with increasing GH concentration to a peak response at 1.5 nmol/L and declining to a level not significantly different from control thereafter. Insulin-like growth factor-I at concentrations of up to 250 nmol/L had no significant effect on fatty acid oxidation. GH-binding protein attenuated the effect of GH. An anti-GH receptor (GHR) antibody (MAb263), which dimerizes the receptor and induces GH-like biological actions, significantly stimulated fatty acid oxidation. Another anti-GHR antibody (MAb5), which prevents receptor dimerization, suppressed GH action. In summary, GH directly stimulated fatty acid oxidation, an action not mediated by insulin-like growth factor-I. Dimerization of GHRs was necessary for this effect. This bioassay is a practical tool for studying the regulatory effects of GH on lipid oxidation.
Leptin Synthesis Is Resistant to Acute Effects of Insulin in Insulin-Dependent Diabetes Mellitus Patients*
Authors: Tuominen Juha A. , Ebeling Pertti , Stenman Ulf-Håkan , Heiman Mark L. , Stephens Thomas W. , Koivisto Veikko A. 
Published: January 2014

Abstract
Insulin stimulates ob gene expression and increases serum leptin concentrations in mice and in noninsulin-dependent diabetes mellitus patients. Obese women have higher ob gene messenger ribonucleic acid levels than obese men, suggesting that sex hormones are involved in the regulation of leptin synthesis. We studied the relationship among leptin, insulin, and testosterone in 15 men with insulin-dependent diabetes mellitus (IDDM; age, 29 ± 2 yr; body mass index, 22.7 ± 0.5 kg/m2; body fat, 9.5 ± 1.0%; insulin dose, 44 ± 4 U/day; hemoglobin A1c, 8.1 ± 0.3%; diabetes duration, 12.7 ± 2.0 yr) and 15 healthy control subjects (age, 27 ± 1 yr; body mass index, 22.6 ± 0.4 kg/m2; body fat, 9.6 ± 0.5%) in the fasting state. In addition, the effect of a 4-h euglycemic hyperinsulinemia (∼600 pmol/L) on the plasma leptin concentration was determined. The fasting leptin concentration was negatively correlated to plasma testosterone (r = −0.55; P &lt; 0.05) in IDDM patients. The fasting plasma leptin level rose 25% in healthy subjects (from 1.0 ± 0.2 to 1.3 ± 0.3 ng/mL; P &lt; 0.05). The leptin levels were higher in IDDM subjects (P &lt; 0.01) and remained unchanged (2.7 ± 0.2 vs. 2.7 ± 0.2 ng/mL) during hyperinsulinemia.
We reached the following conclusions. 1) In nonobese IDDM patients, leptin synthesis is resistant to the acute effect of insulin. 2) Serum testosterone may contribute to the regulation of leptin synthesis in IDDM patients.