bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypermethylation of Hepatic Glucokinase and L-Type Pyruvate Kinase Promoters in High-Fat Diet–Induced Obese Rats
Authors: Jiang Minghong , Zhang Yuhao , Liu Meng , Lan Michael Shihli , Fei Jing , Fan Weiwei , Gao Xin , Lu Daru 
Published: January 2011

Abstract
Obesity-dependent insulin resistance and type 2 diabetes mellitus are closely associated with decreased glucose utilization and down-regulation of hepatic glycolytic enzymes expression. Previously, we showed that DNA hypermethylation is involved in age-dependent susceptibility to hepatic insulin resistance and diabetes. However, what we cannot distinguish is whether the age-related obesity contributes to DNA hypermethylation in those natural aging rats. In the present study, we hypothesize that DNA methylation plays a crucial role in the regulation of glycolytic enzymes in the high-fat diet–induced obesity. Here, we report that DNA hypermethylation is correlated with a decline in hepatic glucokinase (Gck) and L-type pyruvate kinase (LPK) expression in high-fat diet–induced obese rats as compared with the control diet group. Down-regulation of Gck and LPK expression are reversed by the 5-aza-2′-deoxycytidine in the cell model of steatosis. These novel observations indicate that DNA methylation is involved in the development of metabolic diseases, such as obesity, insulin resistance, type 2 diabetes mellitus, and nonalcoholic steatohepatitis, suggesting that the hypermethylation level of Gck and LPK promoters may be a useful parameter for the evaluation of obesity-induced insulin resistance and fatty liver.
Surgical Results of Thyroid Nodules according to a Management Guideline Based on the BRAFV600E Mutation Status
Authors: Kim Suk Kyeong , Hwang Tae Sook , Yoo Young Bum , Han Hye Seung , Kim Dong-Lim , Song Kee-Ho , Lim So Duk , Kim Wan Seop , Paik Nam Sun 
Published: January 2011

Context:
In Korea, where PTC comprises about 90–95% of the reported thyroid cancers, the prevalence of BRAFV600E mutation in papillary thyroid carcinoma (PTC) is above 80%.

Objective:
We analyzed the surgical result according to a management guideline based on the BRAFV600E mutation status of thyroid nodules.

Design:
A total of 865 thyroid nodules were prospectively analyzed for their cytology and BRAFV600E mutation status by pyrosequencing. For the patients who had a diagnosis of atypical cells of undetermined significance (ACUS), we recommended surgery when there was positivity for BRAFV600E mutation or the nodules were clinically suspicious.

Results:
Among 865 cases, 504, 141, 54, 140, 10, and 16 were diagnosed as benign, ACUS, suspicious for malignancy, malignant, suspicious for follicular neoplasm, and nondiagnostic, respectively. None of the 504 benign, 45 (31.9%) of the 141 ACUS, 46 (85.2%) of the 54 suspicious for malignancy, 129 (92.1%) of the 140 malignant, and one (10%) of the 10 suspicious for follicular neoplasm cases showed BRAFV600E mutation. Surgery was recommended to all 45 patients with BRAFV600E mutation-positive ACUS nodules; among them, 30 patients underwent surgery, 29 had PTC, and one had nodular hyperplasia. All the patients diagnosed as suspicious for malignancy or malignant were advised to undergo an operation, and they turned out to have PTCs regardless of their BRAFV600E mutation status.

Conclusions:
We found that performing BRAFV600E mutation analysis on the fine-needle aspiration biopsy specimens was of great help to make a therapeutic decision for thyroid nodules when the fine-needle aspiration biopsy results were equivocal.
SHBG, Sex Hormones, and Inflammatory Markers in Older Women
Authors: Maggio Marcello , Ceda Gian Paolo , Lauretani Fulvio , Bandinelli Stefania , Corsi Anna Maria , Giallauria Francesco , Guralnik Jack M. , Zuliani Giovanni , Cattabiani Chiara , Parrino Stefano , Ablondi Fabrizio , Dall'Aglio Elisabetta , Ceresini Graziano , Basaria Shehzad , Ferrucci Luigi 
Published: January 2011

Abstract

Context:
In premenopausal and older women, high testosterone and estradiol (E2) and low SHBG levels are associated with insulin resistance and diabetes, conditions characterized by low-grade inflammation.

Objective:
The aim of the study was to examine the relationship between SHBG, total testosterone, total E2, and inflammatory markers in older women.

Design and Patients:
We conducted a retrospective cross-sectional study of 433 women at least 65 yr old from the InCHIANTI Study, Italy, who were not on hormone replacement therapy or recently hospitalized and who had complete data on SHBG, testosterone, E2, C-reactive protein (CRP), IL-6, soluble IL-6 receptor (sIL-6r), and TNF-α. Relationships between sex hormones and inflammatory markers were examined by multivariate linear regression analyses adjusted for age, body mass index, smoking, insulin, physical activity, and chronic disease.

Results:
In fully adjusted analyses, SHBG was negatively associated with CRP (P = 0.007), IL-6 (P = 0.008), and sIL-6r (P = 0.02). In addition, testosterone was positively associated with CRP (P = 0.006), IL-6 (P = 0.001), and TNF-α (P = 0.0002). The negative relationship between testosterone and sIL-6r in an age-adjusted model (P = 0.02) was no longer significant in a fully adjusted model (P = 0.12). E2 was positively associated with CRP (P = 0.002) but not with IL-6 in fully adjusted models. In a final model including E2, testosterone, and SHBG, and all the confounders previously considered, SHBG (0.23 ± 0.08; P = 0.006) and E2 (0.21 ± 0.08; P = 0.007), but not testosterone (P = 0.21), were still significantly associated with CRP.

Conclusion:
In late postmenopausal women not on hormone replacement therapy, SHBG and E2 are, respectively, negative and positive, independent and significant correlates of a proinflammatory state.
Interaction between Testosterone and Growth Hormone on Whole-Body Protein Anabolism Occurs in the Liver
Authors: Birzniece Vita , Meinhardt Udo J. , Umpleby Margot A. , Handelsman David J. , Ho Ken K. Y. 
Published: January 2011

Abstract

Context:
GH and testosterone both exert protein-anabolic effects and may act synergistically. Liver and muscle are major sites of protein metabolism.

Objective:
Our objective was to determine whether the site of GH and testosterone interaction on protein metabolism is primarily hepatic or extrahepatic.

Design:
In this open-label randomized crossover study, the impact on whole-body protein metabolism of oral (solely hepatic testosterone exposure) and transdermal (systemic testosterone exposure) testosterone replacement in the presence or absence of GH was compared.

Patients and Intervention:
Eleven hypopituitary men with GH and testosterone deficiency were randomized to 2-wk treatments with transdermal testosterone (10 mg) or oral testosterone (40 mg), with or without GH replacement (0.6 mg/d). The dose of testosterone administered orally achieves physiological portal testosterone concentrations without spillover into the systemic circulation.

Main Outcome Measures:
Whole-body leucine turnover was measured, from which leucine rate of appearance (LRa), an index of protein breakdown, and leucine oxidation (Lox), a measure of irreversible protein loss, were estimated at the end of each treatment.

Results:
In the absence of GH, neither transdermal nor oral testosterone affected LRa or Lox. GH therapy significantly increased LRa, an effect equally reduced by transdermal and oral testosterone administration. GH replacement alone did not significantly change Lox, whereas addition of testosterone treatment reduced Lox, with the effect not significantly different between transdermal and oral testosterone.

Conclusions:
In the doses used, testosterone stimulates protein anabolism by reducing protein breakdown and oxidation only in the presence of GH. Because the net effect on protein metabolism during GH therapy is not different between systemic and solely hepatic testosterone administration, we conclude that the liver is the primary site of this hormonal interaction.
Role of Reactive Oxygen Species in Injury-Induced Insulin Resistance
Authors: Zhai Lidong , Ballinger Scott W. , Messina Joseph L. 
Published: January 2011

AbstractAcute insulin resistance is common after injury, infection, and critical illness. To investigate the role of reactive oxygen species (ROS) in critical illness diabetes, we measured hepatic ROS, which rapidly increased in mouse liver. Overexpression of superoxide dismutase 2, which decreased mitochondrial ROS levels, protected mice from the development of acute hepatic insulin resistance. Insulin-induced intracellular signaling was dramatically decreased, and cellular stress signaling was rapidly increased after injury, resulting in the hyperglycemia of critical illness diabetes. Insulin-induced intracellular signaling, activation of stress (c-Jun N-terminal kinase) signaling, and glucose metabolism were all normalized by superoxide dismutase 2 overexpression or by pretreatment with antioxidants. Thus, ROS play an important role in the development of acute hepatic insulin resistance and activation of stress signaling after injury.
Nr4a1 siRNA Expression Attenuates α-MSH Regulated Gene Expression in 3T3-L1 Adipocytes
Authors: Wang S.-C. Mary , Myers Stephen A. , Eriksson Natalie A. , Fitzsimmons Rebecca L. , Muscat George E. O. 
Published: January 2011

Abstract
Several recent investigations have underscored the growing role of melanocortin signaling in the peripheral regulation of lipid, glucose, and energy homeostasis. In addition, the melanocortins play a critical role in the central control of satiety. These observations, and the latest reports highlighting the emerging role of the nuclear hormone receptor (NR) 4A subgroup in metabolism, have prompted us to investigate the cross talk between [Nle4, d-Phe7] (NDP)-α-MSH and Nr4a signaling in adipose. We have shown that NDP-MSH strikingly and preferentially induces the expression of the NR4A subgroup (but not any other members of the NR superfamily) in differentiated 3T3-L1 adipocytes. Utilization of quantitative PCR on custom-designed metabolic TaqMan low-density arrays identified the concomitant and marked induction of the mRNAs encoding Il-6, Cox2, Pdk4, and Pck-1 after NDP-MSH treatment. Similar experiments demonstrated that the mRNA expression profile induced by cAMP and NDP-MSH treatment displayed unique but also overlapping properties and suggested that melanocortin-mediated induction of gene expression involves cAMP-dependent and -independent signaling. Nr4a1/Nur77 small interfering RNA (siRNA) expression suppressed NDP-MSH-mediated induction of Nr4a1/Nur77 and Nr4a3/Nor-1 (but not Nr4a2/Nurr1). Moreover, expression of the siRNA-attenuated NDP-MSH mediated induction of the mRNAs encoding Il-6, Cox2/Ptgs2, and Pck-1 expression. In addition, Nur77 siRNA expression attenuated NDP-MSH-mediated glucose uptake. In vivo, ip administration of NDP-MSH to C57 BL/6J (male) mice significantly induced the expression of the mRNA encoding Nur77 and increased IL-6, Cox2, Pck1, and Pdk4 mRNA expression in (inguinal) adipose tissue. We conclude that Nur77 expression is necessary for MSH-mediated induction of gene expression in differentiated adipocytes. Furthermore, this study demonstrates cross talk between MSH and Nr4a signaling in adipocytes.
Glucocorticoid-Mediated Repression of the Oncogenic microRNA Cluster miR-17∼92 Contributes to the Induction of Bim and Initiation of Apoptosis
Authors: Molitoris Jason K. , McColl Karen S. , Distelhorst Clark W. 
Published: January 2011

AbstractSynthetic glucocorticoids were one of the first effective treatments for lymphoid malignancies because of their ability to induce apoptosis and are still used in combination with other chemotherapeutic agents. Up-regulation of Bim, a proapoptotic member of the B-cell lymphoma-2 family, is an important mediator of glucocorticoid-induced apoptosis. Although glucocorticoids are known to elevate Bim mRNA and protein, little is known about the mechanism. Here, we report that glucocorticoids repress the expression of the microRNA cluster miR-17∼92, which results in elevated Bim protein expression as a mechanism by which glucocorticoids induce Bim. Using a luciferase-Bim 3′ untranslated region construct, we demonstrate that glucocorticoids mediate Bim induction posttranscriptionally after miR-17∼92 repression, resulting in increased Bim protein expression. Overexpression of miR-17∼92 microRNAs decreases Bim induction and attenuates glucocorticoid-mediated apoptosis. Conversely, knockdown of miR-17∼92 increases Bim protein expression and glucocorticoid-mediated apoptosis. These findings indicate that endogenous levels of miR-17∼92 repress Bim expression in T-cell lymphoid malignancies and that glucocorticoids induce Bim expression via down-regulation of the miR-17∼92 microRNA cluster. Our findings present a novel mechanism that contributes to the up-regulation of Bim and induction of apoptosis in lymphocytes after glucocorticoid treatment. Furthermore, our work demonstrating that inhibition of miR-17∼92 increases glucocorticoid-induced apoptosis highlights the potential importance of miR-17∼92 as a therapeutic target in leukemias and lymphomas.
Aurora Kinase B Activity Is Modulated by Thyroid Hormone during Transcriptional Activation of Pituitary Genes
Authors: Tardáguila Manuel , González-Gugel Elena , Sánchez-Pacheco Aurora 
Published: January 2011

AbstractCovalent histone modifications clearly play an essential role in ligand-dependent transcriptional regulation by nuclear receptors. One of the predominant mechanisms used by nuclear receptors to activate or repress target-gene transcription is the recruitment of coregulatory factors capable of covalently modify the amino terminal ends of histones. Here we show that the thyroid hormone (T3) produces a rapid increase in histone H3Ser10 phosphorylation (H3Ser10ph) concomitant to the rapid displacement of the heterochromatin protein 1β (HP1β) to the nuclear periphery. Moreover, we found that T3-mediated pituitary gene transcription is associated with an increase in H3Ser10ph. Interestingly, the Aurora kinase B inhibitor ZM443979 abolishes the effect of T3 on H3Ser10ph, blocks HP1β delocalization, and significantly reduces ligand-dependent transactivation. Similar effects were shown when Aurora kinase B expression was abrogated in small interfering RNA assays. In an effort to understand the underlying mechanism by which T3 increases H3Ser10ph, we demonstrate that liganded thyroid hormone receptor directly interacts with Aurora kinase B, increasing its kinase activity. Moreover, using chromatin immunoprecipitation assays, we have shown that Aurora kinase B participates of a mechanism that displaces HP1β from promoter region, thus preparing the chromatin for the transcriptional activation of T3 regulated genes. Our findings reveal a novel role for Aurora kinase B during transcriptional initiation in GO/G1, apart from its well-known mitotic activity.
Surface Hardening of an AISI D6 Cold Work Steel Using a Fiber Laser
Authors: Goia Flavia Aline , de Lima Milton Sergio Fernandes 
Published: January 2011

Abstract
Laser surface treatments represent some of the most advanced and versatile processes for enhanced materials applications. Laser hardening is a technique to generate a hard wear-resistant surface microstructure in metals due to the rapid heating and cooling cycles imposed by a laser beam. This work intends to understand the influence of the laser variables on hardness after laser hardening of an AISI D6 steel. A fiber laser, which is a new source available for industrial applications, has been used. The overall absorptivity measured was ∼37 % and the laser treatment produced two different zones: Remelted and heat-affected. The surface layer was remelted and composed of martensite and retained austenite. The region next to the free surface is composed of primary austenite dendrites with martensite plates with hardness between 400 and 500 HV. The region called the heat-affect zone is composed of martensite, retained austenite, and carbides and has a hardness up to 800 HV. The case depth in laser treated samples was between 1 and 2 mm.
Controlling Condensation Through the Use of Active and Passive Glazing Systems
Authors: Dunlap Andrew A. , Johnson Paul G. , Songer Curt A. 
Published: January 2011

Abstract
Special building occupancies, those with a high interior relative humidity, have a specific set of performance requirements to control condensation for exterior window and curtain wall systems. High levels of humidity, if not properly accommodated by glazed exterior wall systems, can result in condensation on and within glazing systems and adjacent construction. The performance of glazing has typically been viewed and analyzed based on overall system performance that generally results in a set of values that do not apply to project specific applications. With this approach, important aspects of a system, as applied to specific buildings, are often overlooked. In this circumstance, the result too often is unacceptable levels of condensation. Unfortunately, many within the design, manufacture, and construction communities do not fully understand the importance of treating each building for the unique set of conditions that it is, and the resultant consequence of not analyzing and treating each humidified building as a unique set of materials, systems, and environmental conditions. Similarly, the analysis methods and tools necessary to predict and prevent condensation are even less familiar within the design and construction industry. As a result, deficient systems and materials may often be installed in these applications, resulting in failures ranging from minor inconvenience to complete loss of service. There are, however, methods that can be used to reduce or eliminate such problems. This paper describes methods and procedures that can be utilized to understand and identify the performance levels required for high humidity spaces and analysis methods (including computer modeling) to predict performance of systems and materials, and this paper also describes both active and passive technologies that have been successful in meeting these needs. Passive design, through the use of high performance glazing, and active technologies, such as heat tracing and heated glass, are considered. Benefits, risks, and appropriate uses of each are identified. Examples are included to illustrate these approaches.
On the Importance of the Tax System in Marginal Cost of Funds Calculations
Authors: Beaud Mickael 
Published: January 2011

Abstract
Several papers have attempted to derive computable analytical formulas for the Marginal Cost of Funds (MCF). However, this literature is often cast in the pure labor supply general equilibrium model, which is not completely consistent with real tax systems where Labor Income Taxation (LIT) is not the only instrument used by governments. Hence, we explicitly introduce Value-Added Taxation (VAT) on consumption goods in the conventional model, and we derive an analytical formula for the MCF which does incorporate general equilibrium interactions between the different tax bases. Then, we illustrate how much this matter for empirical estimates of MCF using French data. Our numerical example suggests that, when computing MCF for a LIT reform, taking account of the impact of LIT reform on tax revenue from VAT can make a great deal of difference, typically increasing MCF and accounting for around 0.2 to 0.8 of estimates. In addition, MCF is then really less likely to be less than one than in the conventional framework.
Job Search, Conditional Treatment and Recidivism: The Employment Services for Ex-Offenders Program Reconsidered
Authors: Bierens Herman J , Carvalho Jose R 
Published: January 2011

Abstract
The objective of this paper is to re-evaluate the effect of the 1985 “Employment Services for Ex-Offenders” (ESEO) program on recidivism in San Diego, Chicago and Boston. The initial group of program participants was split randomly in a control group and a treatment group. The actual treatment (mainly being job related counseling) only takes place conditional on finding a job and not having been arrested for those selected in the treatment group. We use interval-censored proportional hazard models for job search and recidivism time, where the latter model incorporates the conditional treatment effect, depending on covariates. We find that the effect of the program depends on location and age. The ESEO program reduces the risk of recidivism only for ex-inmates over the age of 27 in San Diego and Chicago and over the age of 36 in Boston, but increases the risk of recidivism for the other ex-inmates in the treatment group.
Do Rising Top Incomes Lift All Boats?
Authors: Andrews Dan , Jencks Christopher , Leigh Andrew 
Published: January 2011

Abstract
Pooling data for 1905 to 2000, we find no systematic relationship between top income shares and economic growth in a panel of 12 developed nations observed between 22 and 85 years. After 1960, however, a one percentage point rise in the top decile’s income share is associated with a statistically significant 0.12 point rise in GDP growth during the following year. This relationship is not driven by changes in either educational attainment or top tax rates. If the increase in inequality is permanent, the increase in growth appears to be permanent. However, our estimates imply that it would take 13 years for the cumulative positive effect of faster growth on the mean income of the bottom nine deciles to offset the negative effect of reducing their share of total income.
Strategic Responses to Parallel Trade
Authors: Kyle Margaret 
Published: January 2011

Abstract
High prices for patented pharmaceuticals have prompted many governments to consider allowing competition from parallel imports, or products first sold at lower prices in other countries. This paper examines how pharmaceutical firms have responded to changes in intellectual property rights and trade barriers that legalized parallel imports within the European Union (EU). The threat of arbitrage by parallel traders reduces the ability of firms to price discriminate across countries. Due to regulations on price and antitrust law on rationing supply, pharmaceutical firms may rely on non-price responses. Such responses include differentiation of products across countries and selective culling of product lines to reduce arbitrage opportunities, as well as raising arbitrageurs costs through choice of packaging. Using a dataset of drug prices and sales from 1993-2004 covering 30 countries, I find evidence that the behavior of pharmaceutical firms in the EU with respect to their product portfolios is consistent with attempts to reduce parallel trade. This may at least partially explain why parallel trade has not yet resulted in significant price convergence across EU countries. Accounting for non-price strategic responses may therefore be important in assessing the welfare effects of competition from parallel imports.
Pecuniary and Non-Pecuniary Incentives in Prescription Pharmaceuticals: The Case of Statins
Authors: Limbrock Frank 
Published: January 2011

Abstract
Health insurance companies seek to influence the type of care patients receive in order to increase value in relation to cost. Traditional health insurance relies primarily on price mechanisms to affect patients' and doctors' choices, whereas managed care plans such as HMOs, as the name implies, affect choices directly thorough various forms of managed care. I investigate the effect of pecuniary and non-pecuniary incentives used by health insurance companies to influence prescription decisions in an important class of pharmaceuticals, cholesterol-lowering drugs called Statins, using a discrete-choice demand model on patient-level data. My results suggest that HMOs are significantly more successful at influencing drug choice than traditional indemnity insurers. In conjunction with volume-contingent discounts given by drug producers, this could explain part of the cost-effectiveness differential between HMOs and traditional indemnity insurers.