bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of a Short-Term Vitamin D3 and Calcium Supplementation on Blood Pressure and Parathyroid Hormone Levels in Elderly Women1
Authors: Pfeifer Michael , Begerow Bettina , Minne Helmut W. , Nachtigall Detlef , Hansen Corinna 
Published: January 2014

Calcium supplementation is effective in reducing blood pressure in various states of hypertension, including pregnancy-induced hypertension and preeclampsia. In addition, calcitropic hormones are associated with blood pressure. The hypothesis is that short-term therapy with calcium and vitamin D3 may improve blood pressure as well as secondary hyperparathyroidism more effectively than calcium monotherapy.
The effects of 8 weeks of supplementation with vitamin D3 (cholecalciferol) and calcium on blood pressure and biochemical measures of bone metabolism were studied. The sample consisted of 148 women (mean ± sd age, 74 ± 1 yr) with a 25-hydroxycholecalciferol (25OHD3) level below 50 nmol/L. They received either 1200 mg calcium plus 800 IU vitamin D3 or 1200 mg calcium/day. We measured intact PTH, 25OHD3, 1,25-dihydroxyvitamin D3, blood pressure, and heart rate before and after treatment.
Compared with calcium, supplementation with vitamin D3 and calcium resulted in an increase in serum 25OHD3 of 72% (P &lt; 0.01), a decrease in serum PTH of 17% (P = 0.04), a decrease in systolic blood pressure (SBP) of 9.3% (P = 0.02), and a decrease in heart rate of 5.4% (P = 0.02). Sixty subjects (81%) in the vitamin D3 and calcium group compared with 35 (47%) subjects in the calcium group showed a decrease in SBP of 5 mm Hg or more (P = 0.04). No statistically significant difference was observed in the diastolic blood pressures of the calcium-treated and calcium- plus vitamin D3-treated groups (P = 0.10). Pearson coefficients of correlation between the change in PTH and the change in SBP were 0.49 (P &lt; 0.01) for the vitamin D3 plus calcium group and 0.23 (P &lt; 0.01) for the calcium group.
A short-term supplementation with vitamin D3 and calcium is more effective in reducing SBP than calcium alone. Inadequate vitamin D3 and calcium intake could play a contributory role in the pathogenesis and progression of hypertension and cardiovascular disease in elderly women.
Macrophage Migration Inhibitory Factor and Hypothalamo-Pituitary-Adrenal Function during Critical Illness
Authors: Beishuizen Albertus , Thijs Lambertus G. , Haanen Clemens , Vermes István 
Published: January 2014

In patients with septic shock (n = 32), multitrauma (n = 8), and hospitalized matched controls (n = 41), we serially measured serum macrophage inhibitory factor (MIF), cortisol, plasma ACTH, tumor necrosis factor-α, and interleukin-6 (IL-6) immunoreactivity during 14 days or until discharge/death. MIF levels were significantly elevated on day 1 in septic shock (14.3 ± 4.5 μg/L), as opposed to trauma (3.1 ± 1.7 μg/L) and control patients (2.5 ± 2.1 μg/L). The time course of MIF, parallel to cortisol, but in contrast to ACTH, showed persistently elevated levels in septic patients. On admission, nonsurvivors of septic shock (n = 11) showed significantly higher MIF levels than survivors (18.4 ± 4.8 and 10.2 ± 4.2 μg/L, respectively). Patients with septic adult respiratory distress syndrome (ARDS; n = 8) showed higher MIF levels than those who did not develop ARDS (19.4 ± 4.7 vs. 9.2 ± 4.3 μg/L, respectively). Multiple logistic regression analysis demonstrated that both MIF and ARDS were independent predictors of adverse outcome. On admission, tumor necrosis factor-α, IL-6, procalcitonin, and lipopolysaccharide-binding protein levels were higher in patients with septic shock than in patients with multitrauma. In septic patients, regression analysis showed significant correlations between MIF and cortisol as well as between MIF and IL-6 levels and disease severity scores. No relation was found between MIF and markers of the acute phase response (procalcitonin, C- reactive protein, and lipopolysaccharide-binding protein). In multitrauma patients, MIF levels were not elevated at any time point and were not related to other variables.Our data suggest that during immune-mediated inflammation (such as septic shock) MIF is an important neuroendocrine mediator: a contraregulator of the immunosuppressive effects of glucocorticoids.
RAPID COMMUNICATION: Predominant Intracellular Overexpression of the Na+/I− Symporter (NIS) in a Large Sampling of Thyroid Cancer Cases
Authors: Dohán Orsolya , Baloch Zubair , Bánrévi Zsuzsa , Livolsi Virginia , Carrasco Nancy 
Published: January 2014

ABSTRACT
Here we report the analysis of the Na+/I− symporter (NIS) protein expression in 57 thyroid cancer samples by immunohistochemistry with high-affinity anti-NIS Abs. As many as 70% of these samples exhibited increased NIS expression with respect to the normal surrounding thyroid tissue. Most significantly, NIS was located in these samples either in both the plasma membrane and intracellular compartments simultaneously, or exclusively in intracellular compartments. This suggests that NIS is clearly expressed or even overexpressed in most thyroid cancer cells, but malignant transformation in some of these cells interferes either with the proper targeting of NIS to the plasma membrane, or with the mechanisms that retain NIS in the plasma membrane after it has been targeted. The results further indicate that, in addition to indicating NIS expression in cases where it is absent (∼30%), improvements in 131I radioablation therapy might result from promoting targeting of NIS to the plasma membrane in the majority (∼70%) of thyroid cancers.
Flutamide Decreases Cortisol Clearance in Patients with Congenital Adrenal Hyperplasia
Authors: Charmandari Evangelia , Calis Karim A. , Keil Margaret F. , Mohassel Maryam R. , Remaley Alan , Merke Deborah P. 
Published: January 2014

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency is characterized by a defect in cortisol and aldosterone secretion and adrenal hyperandrogenism. Current treatment is to provide adequate glucocorticoid and mineralocorticoid substitution to prevent adrenal crises and to suppress excess adrenal androgen secretion. Satisfactory adrenocortical suppression often requires supraphysiological doses of hydrocortisone, which may produce an unacceptable degree of hypercortisolism. A new four-drug treatment regimen of flutamide, testolactone, reduced hydrocortisone dose, and 9α-fludrocortisone has been shown to achieve normal growth and development after 2 yr of therapy and may, therefore, represent a potential alternative approach to the treatment of children with classic congenital adrenal hyperplasia.
We investigated the effect of flutamide and testolactone, and flutamide alone, on cortisol clearance by performing clearance studies twice in 13 children (6 males and 7 females; age range, 7.0–14.5 yr) with classic 21-hydroxylase deficiency. All studies were conducted at least 3 months after institution of the four-drug treatment regimen. In eight patients (group 1), the first cortisol clearance study was performed on the four-drug regimen, and the second study was performed after a 48-h washout period off flutamide and testolactone. In five patients (group 2), the first study was conducted 1 wk after discontinuation of testolactone and while patients were receiving flutamide, hydrocortisone and 9α-fludrocortisone, and the second study was performed after a 48-h washout period off flutamide. Oral hydrocortisone was held on the day of the clearance studies, and all patients received a continuous infusion of hydrocortisone (0.6 mg/m2·h) from 1800 h to 0200 h, with cortisol concentrations measured once hourly. In addition, an in vitro study was conducted to exclude the possibility of an analytical interference of flutamide, 2-hydroxyflutamide, and testolactone with the serum cortisol immunoassay.
Total body cortisol clearance was significantly lower during treatment with the four-drug regimen than during treatment with hydrocortisone and 9α-fludrocortisone (153.5 ± 26.8 vs.355.4 ± 65.8 ml/min; P = 0.001). Similar results were obtained comparing flutamide, hydrocortisone, and 9α-fludrocortisone therapy to hydrocortisone and 9α-fludrocortisone therapy (155.8 ± 26.5 vs. 281.8 ± 96.2 ml/min; P = 0.037). The in vitro study indicated that an interference with the serum cortisol immunoassay was unlikely.
These findings indicate that the addition of flutamide and testolactone to the treatment regimen of hydrocortisone and 9α-fludrocortisone decreases cortisol clearance in patients with classic 21-hydroxylase deficiency, and this effect seems to be due to flutamide. Glucocorticoid replacement doses should be reduced when flutamide is added to the treatment regimen of patients receiving hydrocortisone.
Melatonin Secretion and Increased Daytime Sleepiness in Childhood Craniopharyngioma Patients
Authors: Müller Hermann L. , Handwerker Georg , Wollny Brigitte , Faldum Andreas , Sörensen Niels 
Published: January 2014

Craniopharyngioma is a rare dysontogenetic benign tumor. Patients frequently suffer from endocrine deficiencies, sleep disturbances, and obesity due to pituitary and hypothalamic lesions. A self-assessment daytime sleepiness questionnaire (German version of the Epworth Sleepiness Scale) was used to evaluate 79 patients with childhood craniopharyngioma. Because hypothalamic lesions may explain daytime sleepiness in craniopharyngioma patients, salivary melatonin and cortisol concentrations were examined in obese and nonobese craniopharyngioma patients (n = 79), patients with hypothalamic pilocytic astrocytoma (n = 19), and control subjects (n = 30).
Using a general linear model procedure analyzing the influence of body mass index (BMI) and tumor diagnosis on diurnal salivary melatonin, we found that morning salivary melatonin levels were related to BMI (by F test, P = 0.004) and tumor diagnosis (by F test, P = 0.032). Also for nighttime salivary melatonin levels significant relations with BMI (by F test, P &lt; 0.001) and tumor diagnosis (by F test, P = 0.025) were detectable. Melatonin concentrations in saliva of craniopharyngioma patients collected at night or in the morning showed a negative correlation (night: Spearman’s ρ = −0.42; P = 0.001; morning: Spearman’s ρ = −0.31; P = 0.020) with the patient’s Epworth Sleepiness Scale score. Severely obese craniopharyngioma patients and severely obese hypothalamic tumor patients had similar patterns of melatonin secretion. Differences in terms of diurnal salivary cortisol concentrations were not detectable when patient groups and controls were compared.
We speculate that hypothalamic lesions might be responsible for both obesity and daytime sleepiness. As decreased nocturnal melatonin levels were associated with increased daytime sleepiness, BMI, and hypothalamic tumor diagnosis, further studies on the beneficial effects of melatonin substitution on daytime sleepiness and weight control in these patients are warranted.
Multiple Characteristics of a Pentameric Regulatory Array Endow the Human α-Subunit Glycoprotein Hormone Promoter with Trophoblast Specificity and Maximal Activity
Authors: Budworth Paul R. , Quinn Patrick G. , Nilson John H. 
Published: January 2014

AbstractTrophoblast-specific expression of the humanα -subunit glycoprotein hormone gene requires a tightly linked array of five different regulatory elements [trophoblast-specific element (TSE), α-activating element (αACT), a tandem cAMP response element (CRE), junctional regulatory element (JRE), and a CCAAT box]. We examined their contextual contributions to trophoblast-specific expression by using transfection assays to evaluate activity of systematic block replacement mutations made within the 1500-bp 5′-flanking region of the human α-subunit gene. While all five elements were required for full activity, only the TSE and JRE displayed trophoblast specificity. Interestingly, the TSE-binding protein has limited tissue distribution whereas a JRE-binding protein appears trophoblast specific. Likewise, replacement studies with an AP-1 element that binds heterodimers of jun and fos indicated that this element was incapable of compensating for either the tandem CRE or JRE. This preference for both CRE- and JRE-binding proteins provides another avenue for configuring an α-subunit promoter with trophoblast specificity. Additional analysis with a cAMP response element binding protein (CREB)-Gal4 fusion protein further underscored the importance of CREB as well as suggested that transcriptional contributions come from both the DNA-binding domain and transactivation domain of this protein. We also examined the interactive nature of the pentameric array by placing a 15-bp random sequence between each element. Remarkably, only the insertion 3′ of the CCAAT box diminished promoter activity. This suggested the absence of direct interactions between the transcriptional factors that bind each element in the array. It also suggested that the CCAAT box is position-dependent relative to the TATA box. This position dependence appeared cell-specific, as it was not manifest in a gonadotrope cell line (αT3–1 cells). Thus, the CCAAT box also has tissue-specific characteristics that assist in targeting expression of the α-subunit gene to trophoblasts. Together, these data suggest that multiple characteristics of a complex pentameric array of regulatory elements endow the α-subunit promoter with trophoblast specificity and maximal activity.
Identification of a Novel Transferable cis Element in the Promoter of an Estrogen-Responsive Gene that Modulates Sensitivity to Hormone and Antihormone
Authors: Montano Monica M. , Kraus W. Lee , Katzenellenbogen Benita S. 
Published: January 2014

AbstractThe estrogen receptor (ER) is a ligand-regulated transcription factor that acts at the promoters of estrogen-regulated genes to modulate their expression. In the present study, we examined three estrogen-regulated promoters, namely the rat progesterone receptor gene distal (PRD) and proximal (PRP) promoters and the human pS2 gene promoter, and observed marked differences in their sensitivity to stimulation by estrogen and repression of estrogen-stimulated transcription by antiestrogen (AE)-occupied ER. ER-containing MCF-7 human breast cancer cells were transfected with reporter gene constructs containing estrogen response elements upstream of the three gene promoters. In this system, PRP and PRD showed similar dose-response curves for stimulation by estradiol whereas pS2 was activated by even lower concentrations of estradiol. By contrast, PRD was much less sensitive to repression of estrogen-stimulated activity by all AEs studied, relative to the PRP and the pS2 promoters. Using deletion and mutational analysis, we have identified a transferable cis element at −131 to −94 bp in PRD that is involved in modulating the sensitivity of this promoter to both estrogens and AEs. The element reduced the magnitude of estrogen-stimulated activity, enhanced the ability of AEs to repress estrogen-stimulated activity, and elicited similiar effects when transferred to the promoter of another estrogen-responsive gene. Thus, removal of this region from PRD further accentuated the insensitivity of this promoter to AE while enhancing its sensitivity (both EC50 and fold induction) to estrogen. Gel mobility shift assays showed that proteins from nuclear extracts of MCF-7 cells interact with this element and that the binding of these proteins is inversely correlated with the transcriptional effectiveness of the ER. The findings demonstrate that a specific cis element from the promoter of an estrogen-responsive gene can alter the transcriptional activity of hormone and antihormone-occupied receptor bound at its response element near the promoter. Such ligand response modulatory elements, and changes in the levels and activity of factors that bind to such elements, may underlie the different sensitivities of steroid hormone-regulated genes to both hormones and antihormones.
Phosphatidylinositol 3-Kinase Is a Requirement for Insulin-Like Growth Factor I-Induced Differentiation, but not for Mitogenesis, in Fetal Brown Adipocytes
Authors: Valverde Angela M. , Lorenzo Margarita , Navarro Paloma , Benito Manuel 
Published: January 2014

AbstractIn the present study we have examined the role of phosphatidylinositol 3-kinase (PI 3-kinase) in the insulin-like growth factor I (IGF-I)-signaling pathways involved in differentiation and in mitogenesis in fetal rat brown adipocytes. Activation of PI 3-kinase in response to IGF-I was markedly inhibited by two PI 3-kinase inhibitors (wortmannin and LY294002) in a dose-dependent manner. IGF-I-stimulated glucose uptake was also inhibited by both compounds. The expression of adipogenic-related genes such as fatty acid synthase, malic enzyme, glycerol 3-phosphate dehydrogenase, and acetylcoenzyme A carboxylase induced by IGF-I was totally prevented in the presence of IGF-I and any of those inhibitors, resulting in a marked decrease of the cytoplasmic lipid content. Moreover, the expression of the thermogenic marker uncoupling protein induced by IGF-I was also down-regulated in the presence of wortmannin/LY294002. IGF-I-induced adipogenic- and thermogenic-related gene expression was only partly inhibited by the p70S6k inhibitor rapamycin. In addition, pretreatment of brown adipocytes with either wortmannin or LY294002, but not with rapamycin, blocked protein kinase C ζ activation by IGF-I. In contrast, IGF-I-induced fetal brown adipocyte proliferation was PI 3-kinase-independent. Our results show for the first time an essential requirement of PI 3-kinase in the IGF-I-signaling pathways leading to fetal brown adipocyte differentiation, but not leading to mitogenesis. In addition, protein kinase C ζ seems to be a signaling molecule also involved in the IGF-I differentiation pathways downstream from PI 3-kinase.
Human Estrogen Receptor (ER) Gene Promoter-P1: Estradiol-Independent Activity and Estradiol Inducibility in ER+ and ER− Cells
Authors: Treilleux Isabelle , Peloux Nadine , Brown Myles , Sergeant Alain 
Published: January 2014

AbstractEstrogen receptor (ER) is expressed at a low level in normal tissues such as breast and uterus but at a high level in breast and endometrial carcinomas. A proximal element (ERF-1) located between positions +133 and +204 relative to the promoter P1 major initiation site has been recently identified in ER+ cells and contributes to the differential promoter activity between ER+ and ER− cells. In this study, MCF7 and HeLa cells were transfected with chloramphenicol acetyltransferase constructs containing ER gene promoter P1 sequences. We show here that the sequences lying between nucleotides +13 to +212 are also essential for transcription at the ER gene promoter P1 in ER− cells, which do not express ERF-1. Interestingly, on gel shift experiments, a complex specific to ER− cells forms in the region spanning nucleotides +123 to +210. We also show that promoter P1 is responsive to estradiol in cells expressing endogenous (MCF7) or exogenous ER. We further demonstrate, using mutational analysis and gel retardation assays, that the three half-estrogen response elements located between nucleotides −420 and −892 are responsible for the estradiol inducibility of promoter P1. Because estradiol has a mitogenic effect on both breast and endometrial epithelial cells, our data would give an insight into the role of estrogens in the occurence of breast and endometrial carcinomas.
A Novel Thyroid Transcription Factor Is Essential for Thyrotropin-Induced Up-Regulation of Na+/I− Symporter Gene Expression
Authors: Ohmori Masayuki , Endo Toyoshi , Harii Norikazu , Onaya Toshimasa 
Published: January 2014

AbstractThe stimulation of iodide (I−) transport by TSH in FRTL-5 thyroid cells is partly due to an increase in Na+/I− symporter (NIS) gene expression. The identification of a TSH-responsive element (TRE) in the NIS promoter and its relationship to the action of thyroid transcription factor-1 (TTF-1) on the promoter are the subjects of this report. By transfecting NIS promoter-luciferase chimeric plasmids into FRTL-5 cells in the presence or absence of TSH, we identify a TRE between −420 and −370 bp of the NIS 5′-flanking region. Nuclear extracts from FRTL-5 cells cultured in the absence of TSH form two groups of protein-DNA complexes, A and B, in gel mobility shift assays using an oligonucleotide having the sequence from −420 to −385 bp. Only the A complex is increased by exposure of FRTL-5 cells to TSH or forskolin. The addition of TSH to FRTL-5 cells can increase the A complex at 3–6 h, reaching a maximum at 12 h. FRTL-5, but not nonfunctioning FRT thyroid or Buffalo rat liver (BRL) cell nuclear extracts, form the A complex. The TSH-increased nuclear factor in FRTL-5 cells interacting with the NIS TRE is distinct from TTF-1, thyroid transcription factor-2, or Pax-8, as evidenced by the absence of competition using oligonucleotides specific for these factors in gel shift assays. Neither is it the nuclear protein interacting with cAMP response element. The TRE is in the upstream of a TTF-1-binding site,− 245 to −230 bp. Mutation of the TRE causing a loss of TSH responsiveness also decreases TTF-1-induced promoter activity in a transfection experiment. The formation of the A complex between FRTL-5 nuclear extracts and the NIS TRE is redox-regulated. In sum, TSH/cAMP-induced up-regulation of the NIS requires a novel thyroid transcription factor, which also appears to be involved in TTF-1-mediated thyroid-specific NIS gene expression.
Agonist-Induced Phosphorylation of the Endogenous AT1 Angiotensin Receptor in Bovine Adrenal Glomerulosa Cells
Authors: Smith Roger D. , Baukal Albert J. , Zolyomi Annamaria , Gaborik Zsuzsanna , Hunyady Laszlo , Sun Lu , Zhang Meng , Chen Hao-Chia , Catt Kevin J. 
Published: January 2014

AbstractA polyclonal antibody was raised in rabbits against a fusion protein immunogen consisting of bacterial maltose-binding protein coupled to a 92-amino acid C-terminal fragment of the rat AT1b angiotensin II (Ang II) receptor. The antibody immunoprecipitated the photoaffinity-labeled bovine AT1 receptor (AT1-R), but not the rat AT2 receptor, and specifically stained bovine adrenal glomerulosa cells and AT1a receptor-expressing Cos-7 cells, as well as the rat adrenal zona glomerulosa and renal glomeruli. The antibody was employed to analyze Ang II-induced phosphorylation of the endogenous AT1-R immunoprecipitated from cultured bovine adrenal glomerulosa cells. Receptor phosphorylation was rapid, sustained for up to 60 min, and enhanced by pretreatment of the cells with okadaic acid. Its magnitude was correlated with the degree of ligand occupancy of the receptor. Activation of protein kinase A and protein kinase C (PKC) also caused phosphorylation of the receptor, but to a lesser extent than Ang II. Inhibition of PKC by staurosporine augmented Ang II-stimulated AT1-R phosphorylation, suggesting a negative regulatory role of PKC on the putative G protein-coupled receptor kinase(s) that mediates the majority of AT1-R phosphorylation. The antibody should permit further analysis of endogenous AT1-R phosphorylation in Ang II target cells.