bluuebunny/crossref_metadata_2025 huggingface dataset:
Is allergic disease curable or transferable with allogeneic hematopoietic cell transplantation?
Authors: Khan Faisal , Hallstrand Teal S. , Geddes Michelle N. , Henderson William R. , Storek Jan
Published: May 2008

In the pathogenesis of allergic asthma/rhinitis, 2 main types of cells play a role: hematolymphatic cells (mast cells, eosinophils, T cells, B cells) and nonhematolymphatic cells (airway smooth muscle cells, epithelial cells). It is not known which one of the 2 cell types plays the primary role. Here we review the literature on allergic disease transfer and potential cure with allogeneic hematopoietic cell transplantation (HCT), as transferability and curability would support a primary role of hematolymphatic cells and have implications for donor selection for HCT and possible future treatment of severe allergic disease with HCT. A total of 18 nonallergic recipients were reported to develop allergic disease after transplantation; however, conclusive information for transfer was available for only 5 cases. Allergic disease was reported to abate in 3 allergic recipients; however, conclusive information for “cure” was available for only 2 cases. Problems in interpreting the reports include incomplete data on allergic disease in the donor or recipient before transplantation, not knowing the denominator, and the lack of controls. In summary, review of the literature generates the hypothesis that allergic disease is transferable and curable with HCT. A prospective study, including appropriate controls, is needed to evaluate this hypothesis.
An interactive workshop plus locally adapted guidelines can improve General Practitioners asthma management and knowledge: A cluster randomised trial in the Australian setting
Authors: Liaw Siaw-Teng , Sulaiman Nabil D , Barton Christopher A , Chondros Patty , Harris Claire A , Sawyer Susan , Dharmage Shyamali C
Published: May 2008

Background

A cluster randomised trial was conducted to determine the effectiveness of locally adapted practice guidelines and education about paediatric asthma management, delivered to general practitioners (GPs) in small group interactive workshops.

Methods

Twenty-nine practices were randomly allocated to one of three study arms. Australian asthma management guidelines were adapted to accommodate characteristics of the local area. GPs in the intervention arm (Group 1, n = 18 GPs) participated in a small group based education program and were provided with the adapted guidelines. One control arm (Group 2, n = 18 GPs) received only the adapted guidelines, while the other control arm (Group 3, n = 15 GPs) received an unrelated education intervention. GPs' knowledge, attitudes and management of paediatric asthma was assessed.

Results

Post intervention, intervention arm GPs were no more likely to provide a written asthma action plan, but were better able to assess the severity of asthma attack (Group 1vs Group 2 p = 0.05 and Group 1 vs Group 3 p = 0.01), better able to identify patients at high risk of severe attack (Group 1vs Group 3 p = 0.06), and tended to score higher on the asthma knowledge questionnaire (Group 1 vs Group 2 p = 0.06 and Group 1 vs Group 3 p = 0.2). Most intervention arm GPs felt more confident than control GPs to manage acute asthma attack and ongoing management of infrequent episodic asthma.

Conclusion

Using interactive small group workshops to disseminate locally adapted guidelines was associated with improvement in GP's knowledge and confidence to manage asthma, but did not change GP's self-reported provision of written action plans.
Simultaneous monitoring of independent gene expression patterns in two types of cocultured fibroblasts with different color-emitting luciferases
Authors: Noguchi Takako , Ikeda Masaaki , Ohmiya Yoshihiro , Nakajima Yoshihiro
Published: May 2008

Background

Luciferase assay systems enable the real-time monitoring of gene expression in living cells. We have developed a dual-color luciferase assay system in which the expression of multiple genes can be tracked simultaneously using green- and red-emitting beetle luciferases. We have applied the system to monitoring independent gene expressions in two types of cocultured fibroblasts in real time.

Results

Two Rat-1 cell lines were established that stably express either green- or red-emitting luciferases under the control of the mBmal1 promoter, a canonical clock gene. We cocultured these cell lines, and gene expression profiles in both were monitored simultaneously. The circadian rhythms of these cell lines are independent, oscillating following their intrinsic circadian phases, even when cocultured. Furthermore, the independent rhythms were synchronized by medium change as an external stimulus.

Conclusion

Using this system, we successfully monitored independent gene expression patterns in two lines of cocultured fibroblasts.
Atelier paludisme: an international malaria training course held in Madagascar
Authors: Domarle Olivier , Randrianarivelojosia Milijaona , Duchemin Jean-Bernard , Robert Vincent , Ariey Frédéric
Published: May 2008

The Atelier Paludisme (Malaria Workshop) is an international training course organized by the Institut Pasteur de Madagascar, which has been held annually for the past five years. The course was designed for both young and experienced researchers, as well as for healthcare professionals, mostly from malaria-endemic countries. Its objective is to provide participants with a broad knowledge of all features of malaria, to improve their skills in project management, to break geographical isolation by using the Internet as a source of documentary information. This six-week course makes use of concepts of andragogy and problem-based learning, i.e. a relationship between participants and tutors, which promotes a process of exchange rather than the simple transmission of knowledge, where participants have to search actively for information. This approach to training, combined with the wide background and experience of those involved, creates positive dynamics and enables participants to acquire new skills, develop their critical and analytical abilities. This paper describes the course and the lessons learned from its evaluation.
Successful resuscitation of an elderly man with deep accidental hypothermia using portable extracorporeal circulation in the emergency department: a case report
Authors: Cooper Simone S , Papadimos Thomas J , Campbell Jeffery A , Cerilli Gregory J , Omer Shuab , Braida Anthony L , Hassan Ali M
Published: May 2008

Introduction

Deep accidental hypothermia (body temperature below 28°C) is rare and has a high mortality rate. Successful resuscitation usually occurs in the young, but a prompt intervention using a portable extracorporeal cardiopulmonary circulation device can also provide a good outcome for older persons.

Case presentation

We report the successful resuscitation of an 82-year-old male from deep accidental hypothermia using portable extracorporeal circulation in the emergency department.

Conclusion

This successful resuscitation of an 82-year-old patient demonstrates that a prompt intervention by a medical team that trains together, using a mobile cardiopulmonary bypass device via a percutaneous approach, can potentially provide good outcomes for all victims of deep accidental hypothermia, both in the operating suites and the emergency department.
Intact and total insulin-like growth factor-binding protein-3 (IGFBP-3) levels in relation to breast cancer risk factors: a cross-sectional study
Authors: Diorio Caroline , Brisson Jacques , Bérubé Sylvie , Pollak Michael
Published: May 2008

Introduction

Levels of insulin-like growth factor (IGF)-I and its main binding protein (IGFBP-3) have been associated with breast cancer risk among premenopausal women. However, associations of IGFBP-3 levels with breast cancer risk have been inconsistent, possibly due to the different predominant forms of circulating IGFBP-3 (intact versus fragmented) that were measured in these studies. Here, we examine the association of breast cancer risk factors with intact and total IGFBP-3 levels.

Methods

This cross-sectional study includes 737 premenopausal women recruited at screening mammography. Plasma intact and total IGFBP-3 and IGF-I levels were measured by enzyme-linked immunosorbent assay methods. Percent and absolute breast density were estimated using a computer-assisted method. The associations were evaluated using generalized linear models and Pearson (r) or Spearman (rs) partial correlation coefficients.

Results

Means ± standard deviations of intact and total IGFBP-3 levels (ng/mL) were 1,044 ± 234 and 4,806 ± 910, respectively. Intact and total IGFBP-3 levels were correlated with age and smoking. Levels of intact IGFBP-3 were negatively correlated with waist-to-hip ratio (WHR) (r = -0.128; P = 0.0005), parity (rs = -0.078; P = 0.04), and alcohol intake (r = -0.137; P = 0.0002) and positively correlated with energy intake (r = 0.075; P = 0.04). In contrast, total IGFBP-3 levels were positively correlated with WHR (r = 0.115; P = 0.002), parity (rs = 0.089; P = 0.02), body mass index (BMI) (r = 0.115; P = 0.002), physical activity (r = 0.118; P = 0.002), and IGF-I levels (r = 0.588; P < 0.0001) and negatively correlated with percent or absolute breast density (r = -0.095; P = 0.01 and r = -0.075; P = 0.04, respectively).

Conclusion

Our data show that associations of some breast cancer risk factors with intact levels of IGFBP-3 are different from those with total (intact and fragmented) IGFBP-3 levels. These findings suggest that different molecular forms of IGFBP-3 may bear different relations to premenopausal breast cancer risk.
Interleukin 21: a cytokine/cytokine receptor system that has come of age
Authors: Leonard Warren J , Zeng Rong , Spolski Rosanne
Published: May 2008

Interleukin-21 (IL-21) and its receptor represent the sixth cytokine system whose actions were recognized to require the common cytokine receptor γ chain. IL-21 is produced by activated CD4+ T cells, natural killer T cells, and follicular T helper cells and has actions on a range of lymphohematopoietic lineages. Among its many effects, IL-21 serves a critical role for immunoglobulin production and terminal B cell differentiation, acts as a T cell comitogen and can drive the expansion of CD8+ T cells, can negatively regulate dendritic cell function and plays an essential role in the differentiation of Th17 cells. Importantly, IL-21 is implicated in the pathogenesis of autoimmunity and exhibits potent actions as an antitumor agent. The ability to regulate and manipulate the actions of IL-21, therefore, has important implications for immunoregulation and the therapy of human disease.
Anti-CD25 antibodies affect cytokine synthesis pattern of human dendritic cells and decrease their ability to prime allogeneic CD4+ T cells
Authors: Mnasria K , Lagaraine C , Velge-Roussel F , Oueslati R , Lebranchu Y , Baron C
Published: May 2008

Anti-CD25 monoclonal antibodies are widely used in clinical transplantation to prevent acute allograft rejection. Although their effects on T lymphocytes have been extensively studied, their impact on human dendritic cells (DC) has never been reported. Furthermore, the role of the IL-2 in DC functions has not yet been fully elucidated. In this study, we confirm that the stimulation of human monocyte-derived DC with LPS strongly induced the expression of CD25 and that LPS-matured DC also expressed the β and γ chain of the IL-2R. We also showed that adding anti-CD25 monoclonal antibodies to LPS induced a decrease in IL-12, IL-1, TNF-α, IL-6, and IFN-γ production and an increase in IL-10 synthesis by DC compared with stimulation with LPS alone. Furthermore, we showed that these modifications diminished the T helper priming ability of DC and polarized the alloimmune response toward TH2. In contrast, humanized anti-CD25 monoclonal antibodies did not affect the up-regulation of CD86, CD80, CD83, HLADR, or CD40 induced upon LPS stimulation. Taken together, this study discloses some previously unrecognized effects of anti-CD25 monoclonal antibodies on DC that may contribute to their clinical efficacy. In addition, this study also shed some light on the role of the IL-2 in human DC activation.
Macrophages define the invasive microenvironment in breast cancer
Authors: Pollard Jeffrey W
Published: May 2008

In many human cancers, the abundance of macrophages in the tumor microenvironment is correlated with poor prognosis. Experimental evidence for the causal relationship between macrophages and poor prognosis came from mouse models of breast cancer in which genetic ablation of macrophages resulted in attenuation of tumor progression and metastasis, and premature recruitment to hyperplastic lesions accelerated these processes. Malignancy is defined by the invasion of tumor cells into the stroma, a process that allows escape of these cells into the circulation and dissemination to distant sites. In this review, I argue that macrophages are recruited to the invasive front by expression of tumor-derived chemotactic factors and in response to the disruption of the basement membrane. At this invasive site, macrophages enhance tumor cell migration and invasion through their secretion of chemotactic and chemokinetic factors including epidermal growth factor (EGF). They promote angiogenesis by the synthesis of angiogenic factors including vascular endothelial growth factor (VEGF), and they remodel the extracellular matrix and in particular, regulate collagen fibrillogenesis. A combination of these factors provides a triple-whammy, as the more mobile and invasive tumor cells track along collagen fibers that are also anchored to blood vessels, which are fabricated at sites of invasion and through which macrophages potentiate tumor cell intravasation. All of these activities suggest that macrophage functions are significant targets for the generation of novel therapeutics that should improve the current cytotoxic armamentarium.
Chemokines in and out of the central nervous system: much more than chemotaxis and inflammation
Authors: Cardona Astrid E , Li Meizhang , Liu Liping , Savarin Carine , Ransohoff Richard M
Published: May 2008

Actions of chemokines and the interaction with specific receptors go beyond their original, defined role of recruiting leukocytes to inflamed tissues. Chemokine receptor expression in peripheral elements and resident cells of the central nervous system (CNS) represents a relevant communication system during neuroinflammatory conditions. The following examples are described in this review: Chemokine receptors play important homeostatic properties by regulating levels of specific ligands in blood and tissues during healthy and pathological conditions; chemokines and their receptors are clearly involved in leukocyte extravasation and recruitment to the CNS, and current studies are directed toward understanding the interaction between chemokine receptors and matrix metalloproteinases in the process of blood brain barrier breakdown. We also propose novel functions of chemokine receptors during demyelination/remyelination, and developmental processes.
Strategies for Risk Communication
Authors: Tucker W. Troy , Ferson Scott
Published: May 2008

This volume presents the proceedings of the symposium entitled Strategies for Risk Communication: Evolution, Evidence, Experience. The symposium was held in Montauk, Long Island, New York on May 15–17, 2006. It explored practical methods and robust theories of risk communication informed by recent research in risk perception, neuroscience, and the evolutionary social sciences. The symposium focused on what experimental, survey, and brain imaging research has uncovered about how humans process and perceive uncertainty and risks and what the evolutionary history of humans suggests about how we understand and respond to risks. The purpose of the symposium and of this collection of papers is to begin to synthesize the findings from these diverse fields and inform the development of practical strategies for risk communication.
Numeracy and the Perception and Communication of Risk
Authors: Peters Ellen
Published: May 2008

In the present paper, I focus on a small but important piece of the risk communication/perception puzzle, namely how individuals who differ in number ability comprehend and use numeric information about risks differently. Highly numerate individuals appear to pay more attention to numbers, better comprehend them, translate them into meaningful information, and ultimately use them in decisions. Decisions of the less numerate are informed less by numbers and more by other non‐numeric sources of information, such as their emotions, mood states, and trust or distrust in science, the government, and experts. Careful attention to information presentation, however, allows the less numerate to understand and use numbers more effectively in decisions. As a result, the challenge is not merely to communicate accurate information to the public but to understand how to present that information so that it is used in risky decisions.
Evolution, Risk, and Neural Representation
Authors: Watson Karli K.
Published: May 2008

Animals navigating through an uncertain world invariably face risks, such as the risk of starvation or predation. Ethological studies suggest that sensitivity to risk in animals has evolved to maximize their Darwinian fitness, which includes optimizing their probability of survival and reproduction, among other considerations. Concomitantly, natural selection has shaped the neural circuitry underlying risky decision making, and recent evidence suggests that risk may be explicitly represented in the brain. Neurons in monkey posterior cingulate cortex show sensitivity to risk during a decision‐making task, whereas dopaminergic neurons appear to reflect the degree of reward uncertainty. While such studies bear direct relevance to human neurobiology, it is highly likely that human behavior toward risk was also shaped by evolutionarily recent neural specializations, such as the von Economo neurons. For this reason, both animal and human studies are necessary to reveal the neural mechanisms that underlie risky decision making.
The Neuronal Substrate of Risky Choice
Authors: Vorhold Verena
Published: May 2008

This chapter provides an overview of studies in the field of neuroscience that investigate some of the processes and concepts of risk perception, risky choice, and decision making under risk. First, early studies in the field of neuroscience addressing the diminished decision‐making abilities in lesion patients are presented. A classical task in this research field is described along with its neural implications. After this, the underlying model, its hypotheses, and neuronal implications are discussed. Different aspects within risky decision making, such as the influence of memory, inhibition, motivation, and personality, on risky choice and the respective underlying neuronal substrate are described. After this, studies of risky decision making in healthy subjects are reviewed. A selection of studies shows that theories focusing on cognitive aspects only have to be enriched in order to allow for additional aspects within risky decision making (e.g., emotion). Next, the classical economic approaches and the development of theories incorporating further aspects within economical decision making and the underlying neuronal substrate will be presented. Finally, research in the field of neuroeconomics, focusing on the role of social decision making and evaluative judgment within risky decision making, is reviewed.
A Frequency/Consequence‐based Technique for Visualizing and Communicating Uncertainty and Perception of Risk
Authors: Slavin David , Troy Tucker W. , Ferson Scott
Published: May 2008

This chapter presents an approach under development for communicating uncertainty regarding risk. The approach relies on a risk imaging technology that decomposes risk into two basic elements: (i) the frequency of each kind of harm associated with a hazard and (ii) the adversity of each of those harms. Because different kinds of harm are often measured along incompatible dimensions, adversity is quantified on an ordinal scale. Frequency is quantified on a ratio scale. Sampling error, measurement error, and bias all contribute to uncertainty about frequency. Differences in opinion, measurement error, and choice of dimensions lead to uncertainty about adversity. In this chapter, risk is imaged as an area circumscribed by uncertainty bounds around all of the harms. This area is called therisk profileof a hazard. Different individuals and groups respond to uncertainty and risk differently, and the risk profile can be further focused to visualize particular risk perceptions. These alternate risk visualizations may be contrasted and compared across management choices or across different risk perceivers to facilitate communication and decision making. To illustrate the method, we image published clinical trial data.
Risk Communication and Risky Choice in Context
Authors: Wang Xiao‐Tian
Published: May 2008

This chapter takes a synthetic approach to six related lines of research on decision making at risk and views risky choice as a function of cue use with priorities in the context of risk communication. An evolutionary analysis of risk and risk communication is presented in which risk is defined not only as variance in monetary payoff but also as variance in biological relatedness, social relations, and ultimately in reproductive fitness. Empirical evidence of ecological and social significance embedded in risk messages is analyzed, and how these risk cues affect behavioral decision making is examined. A new explanatory framework, the ambiguity and ambivalence hypothesis, identifies two key preconditions contributing to inconsistency and biases in making risky choices as a result of cue use in the course of risk communication.
Models and Methods in Delay Discounting
Authors: Tesch Aaron D. , Sanfey Alan G.
Published: May 2008

Delay discounting (DD) is a term typically used to describe the devaluation of rewards over time, and much research across a wide variety of domains has illustrated that people in general prefer a smaller reward delivered soon as opposed to a larger reward delivered at a later stage. Despite numerous attempts, a single unified model of DD that accounts for the varied pattern of results typically observed has been elusive. One of the difficulties in deriving a unified model is the presence of many framing and context effects, situations in which changing, apparently irrelevant, aspects of the choice scenarios lead to different selections. Additionally, different paradigms of DD research use quite different methodology, which poses challenges for a unified model. This chapter describes some of the difficulties in creating a single DD model and suggests some experiments that would help integrate different paradigms to create a clearer picture of DD.
Science, Precaution, and the Politics of Technological Risk
Authors: Stirling Andy
Published: May 2008

This paper examines apparent tensions between “science‐based,”“precautionary,” and “participatory” approaches to decision making on risk. Partly by reference to insights currently emerging in evolutionary studies, the present paper looks for ways to reconcile some of the contradictions. First, I argue that technological evolution is a much more plural and open‐ended process than is conventionally supposed. Risk politics is thus implicitly as much about social choice of technological pathways as narrow issues of safety. Second, it is shown how conventional “science‐based” risk assessment techniques address only limited aspects of incomplete knowledge in complex, dynamic, evolutionary processes. Together, these understandings open the door to more sophisticated, comprehensive, rational, and robust decision‐making processes. Despite their own limitations, it is found that precautionary and participatory approaches help to address these needs. A concrete framework is outlined through which the synergies can be more effectively harnessed. By this means, we can hope simultaneously to improve scientific rigor and democratic legitimacy in risk governance.
Thyroid Hormone Promotes Cell Invasion through Activation of Furin Expression in Human Hepatoma Cell Lines
Authors: Chen Ruey-Nan , Huang Ya-Hui , Lin Ya-Chu , Yeh Chau-Ting , Liang Ying , Chen Shen-Liang , Lin Kwang-Huei
Published: May 2008

The objective of this study was to identify genes regulated by thyroid hormone (T3) and associated with tumor invasion. The gene encoding furin, as previously identified by cDNA microarray, is known to be up-regulated by T3 treatment, and stimulated furin production occurs in thyroidectomized rats after administration of T3. Presently, by using serial deletion of the promoter and EMSAs, the T3 response element on the furin promoter was localized to the −6317/−6302 region. T3-mediated furin up-regulation was cooperative with TGF-β because T3 induction increased after Smad3/4 addition. Furthermore, the invasiveness of HepG2-thyroid hormone receptor (TR) cells was significantly increased by T3 treatment, perhaps due to furin processing of matrix metalloproteinase-2 and -9. In addition, furin up-regulation either by stable overexpression or T3 and/or TGF-β induction was evident in severe-combined immune-deficient mice inoculated with HepG2-TRα1 cells. The HepG2-furin mice displayed a higher metastasis index and tumor size than HepG2-neo mice. Notably, the increased liver and lung tumor number or size in the hyperthyroid severe-combined immune-deficient mice as well as TGF-β mice was attributed specifically to furin overexpression in the HepG2-TRα1 cells. Furthermore, this study demonstrated that furin overexpression in some types of hepatocellular carcinomas is TR dependent and might play a crucial role in the development of hepatocellular carcinoma. Thus, T3 regulates furin gene expression via a novel mechanism or in cooperation with TGF-β to enhance tumor metastasis in vitro and in vivo.
Reduction of Hypothalamic Protein Tyrosine Phosphatase Improves Insulin and Leptin Resistance in Diet-Induced Obese Rats
Authors: Picardi Paty Karoll , Calegari Vivian Cristine , de Oliveira Prada Patrícia , Contin Moraes Juliana , Araújo Eliana , Gomes Marcondes Maria Cristina Cintra , Ueno Miriam , Carvalheira José Barreto Campello , Velloso Licio Augusto , Abdalla Saad Mario José
Published: May 2008

Protein tyrosine phosphatase (PTP1B) has been implicated in the negative regulation of insulin and leptin signaling. PTP1B knockout mice are hypersensitive to insulin and leptin and resistant to obesity when fed a high-fat diet. We investigated the role of hypothalamic PTP1B in the regulation of food intake, insulin and leptin actions and signaling in rats through selective decreases in PTP1B expression in discrete hypothalamic nuclei. We generated a selective, transient reduction in PTP1B by infusion of an antisense oligonucleotide designed to blunt the expression of PTP1B in rat hypothalamic areas surrounding the third ventricle in control and obese rats. The selective decrease in hypothalamic PTP1B resulted in decreased food intake, reduced body weight, reduced adiposity after high-fat feeding, improved leptin and insulin action and signaling in hypothalamus, and may also have a role in the improvement in glucose metabolism in diabetes-induced obese rats.
Nitroalkenes Suppress Lipopolysaccharide-Induced Signal Transducer and Activator of Transcription Signaling in Macrophages: A Critical Role of Mitogen-Activated Protein Kinase Phosphatase 1
Authors: Ichikawa Tomonaga , Zhang Jifeng , Chen Kai , Liu Yusen , Schopfer Francisco J. , Baker Paul R. S. , Freeman Bruce A. , Chen Yuqing E. , Cui Taixing
Published: May 2008

Nitration products of unsaturated fatty acids are formed via NO-dependent oxidative reactions and appear to be a new class of endogenous antiinflammatory mediators. Nitroalkene derivatives of nitrated linoleic acid (LNO2) and nitrated oleic acid (OA-NO2) alleviate inflammatory responses in macrophages, but the underlying mechanisms remain to be fully defined. Herein we report that LNO2 and OA-NO2 suppress proinflammatory signal transducer and activator of transcription (STAT) signaling in macrophages. In RAW264.7 cells, a murine macrophage cell line, LNO2 and OA-NO2 inhibited the lipopolysaccharide (LPS)-induced STAT1 phosphorylation and the STAT1-dependent transcriptional activity, thereby suppressing expression of its target gene such as iNOS and MCP-1. The nitroalkene-mediated inhibition of STAT1 activity was not affected by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (a NO scavenger), GW9662 (a peroxisome proliferator-activated receptor-γ-specific antagonist) or glutathione (an antioxidant), suggesting an underlying mechanism independent of NO, peroxisome proliferator-activated receptor-γ, or thio-nitralkylation. In contrast, LNO2 or OA-NO2 alone up-regulated both mRNA and protein levels of MAPK phosphatase 1 (MKP-1) and strongly augmented the LPS-induced MKP-1 protein expression. Knockdown of MKP-1 by MKP-1 small interfering RNA enhanced the LPS-induced STAT1 phosphorylation, suggesting that MKP-1 acts as a negative regulator for LPS-induced STAT signaling. In addition, the nitroalkene-mediated inhibitory effects on STAT1 phosphorylation, iNOS expression, and MCP-1 secretion were also largely attenuated by the MKP-1 small interfering RNA approach. Taken together, our data demonstrate that nitroalkenes inhibit proinflammatory STAT signaling through inducting MKP-1 in macrophages.
Epididymis Expresses the Highest 5′-Deiodinase Activity in the Male Reproductive System: Kinetic Characterization, Distribution, and Hormonal Regulation
Authors: Anguiano Brenda , Aranda Nuri , Delgado Guadalupe , Aceves Carmen
Published: May 2008

We characterized the enzymes that catalyze the deiodination of T4 to T3 in the male reproductive tract. Testis, epididymis (EPI), seminal vesicles, prostate, bulbourethral glands, spermatozoa, and semen were taken from sexually mature rats (300 g). Iodothyronine 5′-deiodinase (5′-D) activity was quantified by the radiolabeled-iodide-release method. 5′-D activity was 10-fold higher in EPI and semen than in the rest of the tissues. In EPI, semen, and prostate, the enzymatic activity was completely inhibited by 1 mm 6-n-propyl-2-thiouracil, whereas in the other tissues the inhibition was partial (50%). The high susceptibility to 6-n-propyl-2-thiouracil inhibition, a ping-pong kinetic pattern, and low cofactor (Michaelis Menten constant for dithiothreitol = 0.7 mm) and high substrate (Michaelis Menten constant for reverse T3 = 0.4 μm) requirements indicate that EPI 5′-D corresponds to type 1 deiodinase (D1). Real-time RT-PCR amplification of D1 mRNA in this tissue confirms this conclusion. The highest EPI D1 expression occurred at the onset of puberty and sexual maturity, and in the adult, this activity was more abundant in corpus and caput than in the caudal region. EPI D1 expression was elevated under conditions of hyperthyroidism and with addition of 17β-estradiol. Our data also showed a direct association between D1 and a functional epididymis marker, the neutral α-glucosidase enzyme, suggesting that local generation of T3 could be associated with the development and function of EPI and/or spermatozoa maturation. Further studies are necessary to analyze the possible physiological relevance of 5′-D in the male reproductive system.
7B2 Prevents Unfolding and Aggregation of Prohormone Convertase 2
Authors: Lee Sang-Nam , Lindberg Iris
Published: May 2008

Prohormone convertase 2 (PC2) requires interaction with the neuroendocrine protein 7B2 for the production of an activatable zymogen; the mechanism for this effect is unknown. 7B2 could act proactively to generate an activation-competent form of pro-PC2 during synthesis, or block spontaneous generation of activation-incompetent forms. We here demonstrate that addition of exogenous recombinant 7B2 to CHO cells expressing pro-PC2 prevented the unfolding and aggregation of secreted PC2 forms in a dose-dependent manner, as assessed by aggregation assays, activity assays, cross-linking experiments, and sucrose density gradients. Intracellular pro-PC2 was also found to exist in part as higher-order oligomers that were reduced in the presence of coexpressed 7B2. 7B2 addition did not result in the acquisition of enzymatic competence unless added before or very rapidly after pro-PC2 secretion, indicating that an activation-competent structure cannot be maintained in the absence of 7B2. Velocity sedimentation experiments showed that addition of extracellular 7B2 solubilized three different PC2 species from a precipitable aggregate: two activatable pro-PC2 species, the intact zymogen and a zymogen with a partially cleaved propeptide, and an inactive 66-kDa form. Our results suggest that 7B2 possesses chaperone activity that blocks partially unfolded pro-PC2 forms from losing catalytic competence and then aggregating. The loss of the catalytically competent conformer appears to represent the earliest indicator of pro-PC2 unfolding and is followed on a slower time scale by the appearance of aggregates. Because 7B2 expression is not confined to areas expressing pro-PC2, 7B2 may represent a general intracellular and extracellular secretory chaperone.
Epidermal Growth Factor Induces G Protein-Coupled Receptor 30 Expression in Estrogen Receptor-Negative Breast Cancer Cells
Authors: Albanito Lidia , Sisci Diego , Aquila Saveria , Brunelli Elvira , Vivacqua Adele , Madeo Antonio , Lappano Rosamaria , Pandey Deo Prakash , Picard Didier , Mauro Loredana , Andò Sebastiano , Maggiolini Marcello
Published: May 2008

Different cellular receptors mediate the biological effects induced by estrogens. In addition to the classical nuclear estrogen receptors (ERs)-α and -β, estrogen also signals through the seven-transmembrane G-protein-coupled receptor (GPR)-30. Using as a model system SkBr3 and BT20 breast cancer cells lacking the classical ER, the regulation of GPR30 expression by 17β-estradiol, the selective GPR30 ligand G-1, IGF-I, and epidermal growth factor (EGF) was evaluated. Transient transfections with an expression plasmid encoding a short 5′-flanking sequence of the GPR30 gene revealed that an activator protein-1 site located within this region is required for the activating potential exhibited only by EGF. Accordingly, EGF up-regulated GPR30 protein levels, which accumulated predominantly in the intracellular compartment. The stimulatory role elicited by EGF on GPR30 expression was triggered through rapid ERK phosphorylation and c-fos induction, which was strongly recruited to the activator protein-1 site found in the short 5′-flanking sequence of the GPR30 gene. Of note, EGF activating the EGF receptor-MAPK transduction pathway stimulated a regulatory loop that subsequently engaged estrogen through GPR30 to boost the proliferation of SkBr3 and BT20 breast tumor cells. The up-regulation of GPR30 by ligand-activated EGF receptor-MAPK signaling provides new insight into the well-known estrogen and EGF cross talk, which, as largely reported, contributes to breast cancer progression. On the basis of our results, the action of EGF may include the up-regulation of GPR30 in facilitating a stimulatory role of estrogen, even in ER-negative breast tumor cells.
X-Linked Inhibitor of Apoptosis Protein Levels and Protein Kinase C Activity Regulate the Sensitivity of Human Endometrial Carcinoma Cells to Tumor Necrosis Factorα-Induced Apoptosis
Authors: Van Themsche Céline , Lafontaine Lyne , Asselin Eric
Published: May 2008

Endometrial carcinomas are often chemoresistant. TNFα shows potent antitumor activity against various cancers, and if it demonstrates good antitumor activity against endometrial cancer, the cytokine could represent a valuable alternative therapeutic approach. We have tested the ability of TNFα to induce apoptosis in endometrial carcinoma cells, and examined a putative role for X-linked inhibitor of apoptosis protein (XIAP) in regulating cellular sensitivity to the cytokine. Exposure to TNFα triggered TNF-R1-dependent activation of caspases-8, -9, and -3, down-regulated Akt and XIAP proteins and induced dose-dependent and time-dependent apoptosis in Ishikawa cells. On the opposite, TNFα up-regulated XIAP in Hec-1A cells; in these cells, the cytokine induced delayed TNF-R1-dependent activation of caspase-8, and failed to activate caspases -9 and -3 and to induce apoptosis. However, XIAP small interfering RNA restored TNFα-induced caspase signaling and apoptosis in Hec-1A cells; XIAP small interfering RNA also increased TNFα-induced apoptosis in Ishikawa cells. In addition, inhibition of protein kinase C activity enhanced TNFα-induced down-regulation of XIAP and potentiated apoptosis induction, in both Ishikawa and Hec-1A cells. Finally, we found XIAP immunoreactivity in epithelial cells from a large number of human endometrial tumor tissue samples, indicating that XIAP is produced by endometrial tumor cells in vivo. This could allow XIAP to play a putative in vivo role in counteracting TNFα-induced apoptosis in endometrial tumor cells; in this case, direct or indirect targeting of XIAP should potentiate the antitumor effect of TNFα.
Thyroid Hormone Action in the Adult Brain: Gene Expression Profiling of the Effects of Single and Multiple Doses of Triiodo-l-Thyronine in the Rat Striatum
Authors: Diez Diego , Grijota-Martinez Carmen , Agretti Patrizia , De Marco Giuseppina , Tonacchera Massimo , Pinchera Aldo , Morreale de Escobar Gabriella , Bernal Juan , Morte Beatriz
Published: May 2008

Thyroid hormones have profound effects on mood and behavior, but the molecular basis of thyroid hormone action in the adult brain is relatively unknown. In particular, few thyroid hormone-dependent genes have been identified in the adult brain despite extensive work carried out on the developing brain. In this work we performed global analysis of gene expression in the adult rat striatum in search for genomic changes taking place after administration of T3 to hypothyroid rats. The hormone was administered in two different schedules: 1) a single, large dose of 25 μg per 100 g body weight (SD) or 2) 1.5 μg per 100 g body weight once daily for 5 d (RD). Twenty-four hours after the single or last of multiple doses, gene expression in the striatum was analyzed using Codelink microarrays. SD caused up-regulation of 149 genes and down-regulation of 88 genes. RD caused up-regulation of 18 genes and down-regulation of one gene. The results were confirmed by hybridization to Affymetrix microarrays and by TaqMan PCR. Among the genes identified are genes involved in circadian regulation and the regulation of signaling pathways in the striatum. These results suggest that thyroid hormone is involved in regulation of striatal physiology at multiple control points. In addition, they may explain the beneficial effects of large doses of thyroid hormone in bipolar disorders.
Role of Akt/GSK-3β/β-Catenin Transduction Pathway in the Muscle Anti-Atrophy Action of Insulin-Like Growth Factor-I in Glucocorticoid-Treated Rats
Authors: Schakman O. , Kalista S. , Bertrand L. , Lause P. , Verniers J. , Ketelslegers J. M. , Thissen J. P.
Published: May 2008

Decrease of muscle IGF-I plays a critical role in muscle atrophy caused by glucocorticoids (GCs) because IGF-I gene electrotransfer prevents muscle atrophy caused by GCs. The goal of the present study was to identify the intracellular mediators responsible for the IGF-I anti-atrophic action in GC-induced muscle atrophy. We first assessed the IGF-I transduction pathway alterations caused by GC administration and their reversibility by local IGF-I overexpression performed by electrotransfer. Muscle atrophy induced by dexamethasone (dexa) administration occurred with a decrease in Akt (−53%; P <0.01) phosphorylation together with a decrease in β-catenin protein levels (−40%; P <0.001). Prevention of atrophy by IGF-I was associated with restoration of Akt phosphorylation and β-catenin levels. We then investigated whether muscle overexpression of these intracellular mediators could mimic the IGF-I anti-atrophic effects. Overexpression of a constitutively active form of Akt induced a marked fiber hypertrophy in dexa-treated animals (+175% of cross-sectional area; P <0.001) and prevented dexa-induced atrophy. This hypertrophy was associated with an increase in phosphorylated GSK-3β (+17%; P <0.05) and in β-catenin content (+35%; P <0.05). Furthermore, overexpression of a dominant-negative GSK-3β or a stable form of β-catenin increased fiber cross-sectional area by, respectively, 23% (P <0.001) and 29% (P <0.001) in dexa-treated rats, preventing completely the atrophic effect of GC. In conclusion, this work indicates that Akt, GSK-3β, and β-catenin probably contribute together to the IGF-I anti-atrophic effect in GC-induced muscle atrophy.
CCAAT/Enhancer Binding Protein-β Is a Transcriptional Regulator of Peroxisome-Proliferator-Activated Receptor-γ Coactivator-1α in the Regenerating Liver
Authors: Wang Haitao , Peiris T. Harshani , Mowery A. , Le Lay John , Gao Yan , Greenbaum Linda E.
Published: May 2008

The transcriptional coactivator peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) is induced in the liver in response to fasting and coordinates the activation of targets necessary for increasing energy production for gluconeogenesis and ketogenesis. After partial hepatectomy, the liver must restore its mass while maintaining metabolic homeostasis to ensure survival. Here we report that PGC-1α is rapidly and dramatically induced after hepatectomy, with an amplitude of induction that exceeds the fasting response. Maximal activation of PGC-1α after hepatectomy is dependent on the basic leucine zipper transcription factor, CCAAT/enhancer binding protein-β (C/EBPβ), a critical factor in hepatocyte proliferation. We demonstrate in vivo C/EBPβ binding to C/EBP and cAMP response element sites in the PGC-1α promoter and show that the C/EBP site is essential for PGC-1α activation. Expression of the PGC-1α target, carnitine palmitoyl transferase 1a, the rate-limiting enzyme in fatty acid β-oxidation, and of long-chain acyl-coenzyme A dehydrogenase, an enzyme involved in β-oxidation of long chain fatty acids, was significantly reduced in C/EBPβ−/− livers after hepatectomy. These findings identify C/EBPβ as a direct activator of PGC-1α in the regenerating liver. The demonstration of a functional link between C/EBPβ and PGC-1α activation provides a likely mechanism for how upstream signaling pathways in the regenerating liver can enable the adaptation to the changed metabolic status.
Active Living and Biking: Tracing the Evolution of a Biking System in Arlington, Virginia
Authors: Hanson Royce , Young Garry
Published: May 2008

In Arlington, Virginia, a steady evolutionary change in biking policy during the last three decades has yielded some of the nation's best biking assets. It has a comprehensive, well-connected, highly integrated, well-mapped, and well-signed system of shared-use paved trails, bike lanes, bike routes, and other biking assets, such as workplace showers. Understanding the conditions that led to Arlington's current biking system can provide lessons in the strategy and tactics of active-living politics.

One potentially effective political strategy that was successful in Arlington is for activists to pressure elected officials to select professional managers who see bikeways as crucial to the overall transportation system. Then it is important to formalize the government-citizen relationship through an advisory panel. Also, in Arlington, the incremental creation of biking assets helped create demand for more and better facilities. In turn, this created political support for expanding and upgrading. Finally, Arlington used potentially negative circumstances (e.g., the building of highway corridors, the introduction of the Metro) as opportunities to change the built environment in ways that have encouraged more active living.
Active Living as an Institutional Challenge: Lessons from the Robert Wood Johnson Foundation's “Celebrate Fitness” Program
Authors: Brown Lawrence D. , Kraft M. Katherine
Published: May 2008

Native American youth suffer disproportionately from a range of adverse health conditions. Empowering youth leaders to work on community-based solutions has proved effective in reducing tobacco use and gun violence and is now emerging as a promising approach to improving fitness and health. This article, based on direct observation and interviews with key informants, examines the implementation of a Robert Wood Johnson Foundation–funded project that gave tribal youth councils minigrants to design and run diverse projects that encourage physical activity in their communities. The article highlights the institutional challenges that confront health-promotion strategies for disadvantaged populations. Unless they take proper account of organizational, political, environmental, and cultural forces, funders' interventions have limited chances for success and sustainability.
Advocating for Active Living on the Rural-Urban Fringe: A Case Study of Planning in the Portland, Oregon, Metropolitan Area
Authors: Adler Sy , Dobson Noelle , Fox Karen Perl , Weigand Lynn
Published: May 2008

This case study is about the politics of incorporating active-living elements into a concept plan for a new community of about 68,000 people on the edge of the Portland, Oregon, metropolitan area. Development on the rural-urban fringe is ongoing in metropolitan areas around the United States. In this article, we evaluate the product of the concept-planning process from the standpoint of the extent to which environmental elements conducive to active living were included. We also analyze four issues in which challenges to the incorporation of active-living features surfaced: choices related to transportation facilities, the design and location of retail stores, the location of schools and parks, and the location of a new town center. Overall, the Damascus/Boring Concept Plan positions the area well to promote active living. Analyses of the challenges that emerged yielded lessons for advocates regarding ways to deal with conflicts between facilitating active living and local economic development and related tax-base concerns and between active-living elements and school-district planning autonomy as well as the need for advocates to have the capacity to present alternatives to the usual financial and design approaches taken by private- and public-sector investors.
Turning Brownfields into Greenspaces: Examining Incentives and Barriers to Revitalization
Authors: Siikamäki Juha , Wernstedt Kris
Published: May 2008

This study employs interviews, document review, and a national survey of local government officials to investigate the factors that influence the success of efforts to convert underutilized contaminated properties into greenspace. We find that the presence of contamination continues to be a concern despite federal and state efforts to ease liability fears but also that site and project features can overcome this hurdle. In particular, jurisdictions appear more likely to convert distressed properties into greenspace if recreational parks, rather than open space, are planned, sites are already owned rather than available only through tax foreclosure, and the state is perceived as being supportive of the conversion. In addition, mixed public-private funding and site locations in residential areas are more likely to attract community support for conversion projects.