bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk for Diabetes Mellitus in Middle-Aged Caucasian Male Participants of the PROCAM Study: Implications for the Definition of Impaired Fasting Glucose by the American Diabetes Association
Authors: von Eckardstein Arnold , Schulte Helmut , Assmann Gerd 
Published: January 2014

Abstract
The criteria of the American Diabetes Association and the WHO for the diagnosis of diabetes mellitus are controversially discussed. In a prospective population study, we evaluated the data of 3737 men, aged 36–60 yr, without diabetes mellitus and with fasting serum glucose levels less than 7 mmol/L at entry into the study who had at least 1 repeat examination during a follow-up of 4–10 yr. During a mean follow-up of 6.3 yr, 200 men developed diabetes mellitus. They differed significantly from 3537 men by body mass index, fasting serum levels of glucose, high density lipoprotein cholesterol, and family history positive for diabetes mellitus. Receiver operating curve analysis revealed that a glucose level of 5.72 mmol/L was the best discriminatory cut-off. Upon global risk estimation by multiple logistic function (MLF) analysis, 69.6% of all diabetes mellitus incidences occurred in the highest quintile as defined by the MLF algorithm. The relative risk of a men in this quintile was 8.7 compared to that in the residual population. The performance of risk assessment by MLF as estimated by the area under the receiver operator characteristic curve was similar to fasting glucose levels.
Global risk estimation by multiple risk factors does not improve the prediction of diabetes mellitus by fasting glucose in middle-aged men. The lower discriminatory cut-off of 5.72 mmol/L glucose may help to reduce the previously reported discordance between impaired fasting glucose (American Diabetes Association) and impaired glucose tolerance (WHO) in diagnosis of the prediabetic state.
Postpartum Thyroid Dysfunction in Pregnant Thyroid Peroxidase Antibody-Positive Women Living in an Area with Mild to Moderate Iodine Deficiency: Is Iodine Supplementation Safe?
Authors: Nøhr Susanne B. , Jørgensen Annemette , Pedersen Klaus M. , Laurberg Peter 
Published: January 2014

Abstract
In moderately iodine-deficient, pregnant, thyroid peroxidase antibody (TPO-Ab)-positive women the role of iodine supplementation in the development of postpartum thyroid dysfunction (PPTD) was studied in a placebo-controlled, randomized, double blind trial. Screening for TPO-Ab was performed in early pregnancy in a population of healthy pregnant Danish women with no previous diagnosed thyroid disease (prevalence, 117 of 1284; 9.1%). The participants were randomized, stratified according to TPO-Ab level, to three groups. All participants received a daily vitamin and mineral tablet with 150 μg iodine or no iodine. The +/+ group received iodine during pregnancy and the postpartum period, the +/− group received iodine during pregnancy only, and the −/− group received no iodine supplementation. A total of 66 TPO-Ab positive women were followed, and in the postpartum period sera were collected at 8-week interval for biochemical evaluation of thyroid function and antibody level. Compliance was evaluated by 24-h urinary iodine measurements.
PPTD developed in 55% of the participants. In 67% of the cases abnormal TSH was accompanied by abnormalities in thyroid hormones, whereas 33% had abnormal serum TSH only. There was no statistically significant difference in the frequency of PPTD in the three groups:+ /+ group, 59% (95% confidence interval, 36−79%); +/− group, 60% (36−81%); and −/− group, 46% (26–67%). There were also no differences in the severity of the PPTD, as evaluated by duration and grade of deviation of TSH and thyroid hormones from normality. The occurrence, severity, and type of PPTD predominantly depended on the TPO-Ab level: TPO-Ab below 200 U/L at screening, 35% developed PPTD; TPO-Ab of 200–900 U/L, 54%; and TPO-Ab above 900 U/L, 75% developed PPTD. Women with low levels of antibodies predominantly remained euthyroid or had hyperthyroidism only, whereas women with high antibody levels had hyperthyroidism followed by hypothyroidism or hypothyroidism only. We conclude that iodine supplementation (150 μg) during pregnancy and the postpartum period to TPO-Ab-positive women living in an area with mild to moderate iodine deficiency did not induce or worsen PPTD. The study confirmed that screening for TPO-Ab in early pregnancy can predict women at high risk for development of PPTD.
Insulin Sensitivity Regulates Autonomic Control of Heart Rate Variation Independent of Body Weight in Normal Subjects1
Authors: Bergholm R. , Westerbacka J. , Vehkavaara S. , Seppälä-Lindroos A. , Goto T. , Yki-Järvinen H. 
Published: January 2014

It is unclear whether insulin sensitivity independent of body weight regulates control of heart rate variation (HRV) by the autonomic nervous system.
Insulin action on whole-body glucose uptake (M-value) and heart rate variability were measured in 21 normal men. The subjects were divided into 2 groups [normally insulin sensitive (IS, 8.0 ± 0.4 mg/kg·min) and less insulin sensitive (IR, 5.1 ± 0.3 mg/kg·min)] based on their median M-value (6.2 mg/kg·min). Spectral power analysis of heart rate variability was performed in the basal state and every 30 min during the insulin infusion.
The IS and IR groups were comparable, with respect to age (27 ± 2 vs. 26 ± 2 yr), body mass index (22 ± 1 vs. 23 ± 1 kg/m2), body fat (13± 1 vs. 13 ± 1%), systolic (121 ± 16 vs. 117 ± 14 mm Hg) and diastolic (74 ± 11 vs. 73 ± 11 mm Hg) blood pressures, and fasting plasma glucose (5.4 ± 0.1 vs. 5.5 ± 0.1 mmol/L) concentrations. Fasting plasma insulin was significantly higher in the IR (30 ± 4 pmol/L) than in the IS (17 ± 3 pmol/L, P &lt; 0.05) group. In the IS group, insulin significantly increased the normalized low-frequency (LFn) component, a measure of predominantly sympathetic nervous system activity, from 36 ± 5 to 48 ± 4 normalized units (nu; 0 vs. 30–120 min, P &lt; 0.001); whereas the normalized high-frequency (HFn) component, a measure of vagal control of HRV, decreased from 66 ± 9 to 48 ± 5 nu (P&lt; 0.001). No changes were observed in either the normalized LF component [35 ± 5 vs. 36 ± 2 nu, not significant (NS)] or the normalized HF component (52 ± 6 vs. 51 ± 4 nu, NS) in the IR group. The ratio LF/HF, a measure of sympathovagal balance, increased significantly in the IS group (0.92 ± 0.04 vs. 1.01 ± 0.04, P &lt; 0.01) but remained unchanged in the IR group (0.91 ± 0.04 vs. 0.92 ± 0.03, NS). Heart rate and systolic and diastolic blood pressures remained unchanged during the insulin infusion in both groups.
We conclude that insulin acutely shifts sympathovagal control of HRV toward sympathetic dominance in insulin-sensitive, but not in resistant, subjects. These data suggest that sympathetic overactivity is not a consequence of hyperinsulinemia.
Parathyroid Hormone-Related Protein-(1–36) Stimulates Renal Tubular Calcium Reabsorption in Normal Human Volunteers: Implications for the Pathogenesis of Humoral Hypercalcemia of Malignancy1
Authors: Syed Mushtaq A. , Horwitz Mara J. , Tedesco Mary Beth , Garcia-Ocaña Adolfo , Wisniewski Stephen R. , Stewart Andrew F. 
Published: January 2014

All would agree that hypercalcemia occurs among patients with humoral hypercalcemia of malignancy (HHM) as a result of osteoclastic bone resorption. Some studies suggest that enhanced renal calcium reabsorption, which plays an important pathophysiological role in the hypercalcemia occurring in primary hyperparathyroidism, is also important pathophysiologically in HHM. Other studies have not agreed. In large part, these differences result from the inability to accurately assess creatinine and calcium clearance in critically ill subjects with HHM. To circumvent these issues, we have developed steady state 48-h PTH-related protein (PTHrP) infusion and 8-h hypercalcemic calcium clamp protocols. These techniques allow assessment of the effects of steady state PTHrP and calcium infusions in normal healthy volunteers in a setting in which renal function is stable and measurable and in which the filtered load of calcium can be matched in PTHrP- and calcium-infused subjects.
Normal subjects were infused with saline (placebo), PTHrP, or calcium. Subjects receiving PTHrP, as expected, displayed mild hypercalcemia (10.2 mg/dL), suppression of endogenous PTH-(1–84), and phosphaturia. Subjects receiving the hypercalcemic calcium clamp displayed indistinguishable degrees of hypercalcemia and PTH suppression. Despite their matched degrees of hypercalcemia and PTH suppression, the two groups differed importantly with regard to fractional calcium excretion (FECa). The hypercalcemic calcium clamp group was markedly hypercalciuric (FECa averaged 6.5%), whereas FECa in the PTHrP-infused subjects was approximately 50% lower (between 2.5–3.7%), and no different from that in the normal controls, which ranged from 1.5–3.0%.
These studies demonstrate that PTHrP is able to stimulate renal calcium reabsorption in healthy volunteers. These studies suggest that PTHrP-induced renal calcium reabsorption, in concert with the well established acceleration of osteoclastic bone resorption, contributes in a significant way to the hypercalcemia observed in patients with HHM.
Interactions of Estrogen- and Thyroid Hormone Receptors on a Progesterone Receptor Estrogen Response Element (ERE) Sequence: a Comparison with the Vitellogenin A2 Consensus ERE
Authors: Scott Roderick E. M. , Wu-Peng X. Sharon , Yen Paul M. , Chin William W. , Pfaff Donald W. 
Published: January 2014

AbstractThe identification of hormone response elements in the promoter regions of hormonally regulated genes has revealed a striking similarity between the half-site of the estrogen-response element (ERE) and a consensus sequence constituting the thyroid hormone-response element. Because of the potential for thyroid hormone (T3) to affect estrogen (E)- and progesterone-dependent female reproductive behavior via EREs, we have begun to investigate the activity of an ERE identified in the progesterone receptor (PR) proximal promoter and its interactions with the estrogen receptor (ER) and thyroid hormone receptors (TR). In addition, we have compared ER and TR interactions on the PR ERE construct with that of the vitellogenin A2 (vit A2) consensus ERE. Electrophoretic mobility shift assays demonstrated that TR binds to the PR ERE as well as to the consensus ERE sequence in vitro. Further, these two EREs were differentially regulated by T3 in the presence of TR. T3 in the presence of TRα increased transcription from a PR ERE construct ∼5-fold and had no inhibitory effect on E induction. Similarly, T3 also activated a β-galactosidase reporter construct containing PR promoter sequences spanning −1400 to +700. In addition, the TR isoforms β1 and β2 also stimulated transcription from the PR ERE construct by 5- to 6-fold. A TRα mutant lacking the ability to bind AGGTCA sequences in vitro failed to activate transcription from the PR ERE construct, demonstrating dependence on DNA binding. In contrast to its actions on the PR ERE construct, TRα did not activate transcription from the vit A2 consensus ERE but rather attenuated E-mediated transcriptional activation. Attenuation from the vit A2 consensus ERE is not necessarily dependent on DNA binding as the TRα DNA binding mutant was still able to inhibit E-dependent transactivation. In contrast to TRα, the isoforms TRβ1 and TRβ2 failed to inhibit E-induced activation from the vit A2 consensus ERE. These results demonstrate that the PR ERE construct differs from the vit A2 consensus ERE in its ability to respond to TRs and that divergent pathways exist for activation and inhibition by TR. Since ERs, PRs, and TRs are all present in hypothalamic neurons, these findings may be significant for endocrine integration, which is important for reproductive behavior.
Colony-Stimulating Factor-1 Plays a Major Role in the Development of Reproductive Function in Male Mice
Authors: Cohen Paula E. , Hardy Matthew P. , Pollard Jeffrey W. 
Published: January 2014

AbstractColony-stimulating factor-1 (CSF-1) is the principal regulator of cells of the mononuclear phagocytic lineage that includes monocytes, tissue macrophages, microglia, and osteoclasts. Macrophages are found throughout the reproductive tract of both males and females and have been proposed to act as regulators of fertility at several levels. Mice homozygous for the osteopetrosis mutation (csfmop) lack CSF-1 and, consequently, have depleted macrophage numbers. Further analysis has revealed that male csfmop/csfmop mice have reduced mating ability, low sperm numbers, and 90% lower serum testosterone levels. The present studies show that this low serum testosterone is due to reduced testicular Leydig cell steroidogenesis associated with severe ultrastructural abnormalities characterized by disrupted intracellular membrane structures. In addition, the Leydig cells from csfmop/csfmop males have diminished amounts of the steroidogenic enzyme proteins P450 side chain cleavage, 3β-hydroxysteroid dehydrogenase, and P450 17α-hydroxylase-lyase, with associated reductions in the activity of all these steroidogenic enzymes, as well as in 17β-hydroxysteroid dehydrogenase. The CSF-1-deficient males also have reduced serum LH and disruption of the normal testosterone negative feedback response of the hypothalamus, as demonstrated by the failure to increase LH secretion in castrated males and their lack of response to exogenous testosterone. However, these males are responsive to GnRH and LH treatment. These studies have identified a novel role for CSF-1 in the development and/or regulation of the male hypothalamic-pituitary-gonadal axis.
Silencing of the Gene for the α-Subunit of Human Chorionic Gonadotropin by the Embryonic Transcription Factor Oct-3/4
Authors: Liu Limin , Leaman Douglas , Villalta Michel , Roberts R. Michael 
Published: January 2014

AbstractCG is required for maintenance of the corpus luteum during pregnancy in higher primates. As CG is a heterodimeric molecule, some form of coordinated control must be maintained over the transcription of its two subunit genes. We recently found that expression of human CG β-subunit (hCGβ) in JAr human choriocarcinoma cells was almost completely silenced by the embryonic transcription factor Oct-3/4, which bound to a unique ACAATAATCA octameric sequence in the hCGβ gene promoter. Here we report that Oct-3/4 is also a potent inhibitor of hCG α-subunit (hCGα) expression in JAr cells. Oct-3/4 reduced human GH reporter expression from the −170 hCGα promoter in either the presence or absence of cAMP by about 70% in transient cotransfection assays, but had no effect on expression from either the −148 hCGα or the −99 hCGα promoter. Unexpectedly, no Oct-3/4-binding site was identified within the −170 to −148 region of the hCGα promoter, although one was found around position −115 by both methylation interference footprinting and electrophoretic mobility shift assays. Site-directed mutagenesis of this binding site destroyed the affinity of the promoter for Oct-3/4, but did not affect repression of the promoter. Therefore, inhibition of hCGα gene transcription by Oct-3/4 appears not to involve direct binding of this factor to the site responsible for silencing. When stably transfected into JAr cells, Oct-3/4 reduced the amounts of both endogenous hCGα mRNA and protein by 70–80%. Oct-3/4 is therefore capable of silencing both hCGα and hCGβ gene expression. We suggest that as the trophoblast begins to form, reduction of Oct-3/4 expression permits the coordinated onset of transcription from the hCGα and hCGβ genes.
The Tripartite Basal Enhancer of the Gonadotropin-Releasing Hormone (GnRH) Receptor Gene Promoter Regulates Cell-Specific Expression Through a Novel GnRH Receptor Activating Sequence
Authors: Duval Dawn L. , Nelson Scott E. , Clay Colin M. 
Published: January 2014

AbstractThe molecular mechanisms regulating restricted expression of GnRH receptor and gonadotropin subunit genes to gonadotrope cells have been the focus of intense interest. Using deletion and mutational analysis we have identified a tripartite enhancer that regulates cell-specific expression of the GnRH receptor gene in the gonadotrope-derived αT3–1 cell line. Individual elements of this enhancer include binding sites for steroidogenic factor-1; activator protein 1 (AP-1); and a novel element referred to as the GnRH receptor activating sequence (GRAS). Mutation of each element alone results in loss of approximately 60% of promoter activity. Combinatorial mutations of any two elements decreases promoter activity by approximately 80%. Finally, mutation of all three elements reduces promoter activity to a level not different from promoterless vector. Using 2-bp mutations, we have defined the functional requirements for transcriptional activation by GRAS. The core motif of GRAS is at −391 to −380 bp relative to the start site of translation and has the sequence 5′-CTAGTCACAACA-3′. Three copies of GRAS or GRAS with a 2-bp mutation (μGRAS) were cloned into a luciferase expression vector immediately upstream of the thymidine kinase minimal promoter (TK) and tested for expression in αT3–1 cells. When compared with TK promoter alone, activity of 3xGRAS-TKLUC was increased by more than 5-fold while activity of 3xμGRAS-TKLUC was unchanged. When 3xGRAS-TKLUC was transfected into a variety of nongo-nadotrope cell lines, it did not increase activity of the TK promoter. We propose that basal activity of the GnRH receptor gene is regulated by a tripartite enhancer, and the key component of this enhancer is an element, GRAS, that activates transcription in a cell-specific fashion.
Role of Bag-1 in the Survival and Proliferation of the Cytokine-Dependent Lymphocyte Lines, Ba/F3 and Nb2
Authors: Clevenger Charles V. , Thickman Karen , Ngo Winnie , Chang Wan-Pin , Takayama Shinichi , Reed John C. 
Published: January 2014

AbstractThe expression and function of the newly identified Bcl-2- and Raf-1- binding protein, Bag-1, during the cytokine-regulated growth of B and T cell lines was examined. Immunoblot analysis of lysates from the interleukin-3 (IL-3)-dependent B cell line Ba/F3, and the PRL-dependent T cell line Nb2, revealed that variations in Bag-1 levels paralleled alterations in cellular proliferation, viability, and apoptosis induced by the presence or absence of growth factor. To test whether up-regulation of Bag-1 levels altered cellular survival and proliferation, Ba/F3 cells were transfected with a Bag-1 expression construct. The overexpression of Bag-1 in transfected Ba/F3 cells induced an IL-3-independent state. Such transfectants demonstrated sustained viability and proliferation, with minimal apoptosis, in the complete absence of exogenous IL-3. Bag-1 expression was also compared in glucocorticoid-sensitive Nb2 cells and a PRL-independent, glucocorticoid-resistant subline, SFJCD1, during culture of these lines in dexamethasone (Dex). Bag-1 levels were profoundly decreased by the addition of Dex to Nb2 cells, precedent to the onset of apoptotic cell death. In contrast, Dex treatment or PRL withdrawal had no effect on levels of Bag-1 within the SFJCD1 line. These findings establish that the overexpression of Bag-1 in the appropriate cellular context promotes cellular survival and growth, events that may result from the juxtaposition of this protein with mitogenic and antiapoptotic signaling pathways.
Differential Up-Regulation of Gap Junction Connexin 26 Gene in Mammary and Uterine Tissues: The Role of Sp Transcription Factors
Authors: Tu Zheng Jin , Kollander Rahn , Kiang David T. 
Published: January 2014

AbstractThe mRNA and protein expressions of connexin 26 (Cx26) in rat mammary gland and uterus can be up-regulated during pregnancy as well as by the administration of human CG (hCG). In the present study, we found that the time course and magnitude of Cx26 induction by hCG was different in these two tissues. The molecular mechanism underscoring this difference was therefore investigated. We had previously demonstrated that both Sp1 and Sp3 transcription factors play a functional role in Cx26 expression. By the electrophoretic mobility shift assay, nuclear extracts from both virgin mammary gland and uterus were capable of binding to a labeled oligonucleotide probe that contained the proximal GC box and formed three protein-DNA complexes (C1, C2, and C3). In the mammary gland, pregnancy enhanced the intensity of all three complexes, whereas in the uterine tissue there was a decrease in the C2 and C3 complexes and an emergence of a new major component, C4 complex. In the supershift study, the C1 complex could be supershifted only by an antibody against Sp1, whereas C2, C3, and C4 could all be supershifted by an antibody against Sp3, suggesting a potential presence of Sp3 isoforms of various sizes. We therefore conclude that the basal Sp profiles in virgin mammary gland and uterine tissue are similar. However, in response to pregnancy, the changes in Sp profile are tissue specific and may account for the temporal and quantitative differences between these two tissues in Cx26 induction.
Estrogen Receptor, a Common Interaction Partner for a Subset of Nuclear Receptors
Authors: Lee Soo-Kyung , Choi Hueng-Sik , Song Mi-Ryoung , Lee Mi-Ock , Lee Jae Woon 
Published: January 2014

AbstractNuclear receptors regulate transcription by binding to specific DNA response elements as homodimers or heterodimers. Herein, the yeast and mammalian two-hybrid tests as well as glutathione-S-transferase pull-down assays were exploited to demonstrate that estrogen receptor (ER) directly binds to a subset of nuclear receptors through protein-protein interactions between ligand-binding domains. These receptors include hepatocyte nuclear factor 4, thyroid hormone receptor (TR), retinoic acid receptor (RAR), ERβ, and retinoid X receptor (RXR). In yeast cells, a LexA fusion protein to the human ER ligand-binding domain (LexA/ER-LBD) was an inert transactivator of a LacZ reporter gene controlled by upstream LexA-binding sites. However, LexA/ER-LBD differentially modulated the LacZ reporter gene expression when coexpressed with native TRs, RARs, or RXRs. Similarly, cotransfection of these receptors in CV1 cells up- or down-regulated transactivations by ER. From these results, we propose that ER is a common interaction partner for a subset of receptors, and these interactions should mediate novel signaling pathways in vivo.