bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermoinelasticity of Damaged Elastomers by Self-consistent Method
Authors: Mićunović M. , Kudrjavceva L. , Sumarac D.
Published: August 2008

This study deals with an elastomer body having a random 3D distribution of two types of inclusions: spheroidal mutually parallel voids and differently oriented reinforcing parallel elastomeric stiff spheroidal short fibers. By the effective field approach, the effective stiffness four-tensor as well as the effective thermal expansion two-tensor are formulated and found numerically. Simultaneous and sequential embeddings of inclusions are compared. Damage evolution is described by a modified Vakulenko's approach, the endochronic thermodynamics. A brief account of the problem of effective elastic and thermal symmetry is taken. The results of the theory are applied to creep of an elastomeric PU-based composite caused by triangular history of compressive stress.
Analytical Study of Finite Element Models for FRP Retrofitted Concrete Structure under Blast Loads
Authors: Nam Jin-Won , Kim Ho-Jin , Kim Sung-Bae , Jay Kim Jang-Ho , Keun Joo Byun
Published: August 2008

Fiber reinforced polymer (FRP) is one of the best retrofitting materials for blast resistance strengthening due to a number of advantages, such as excellent strength to self-weight ratio, large fatigue resistance capacity, etc. Presently, many different types of FRP models are used in blast analysis, but they are used randomly without fundamental scientific reasoning, thereby creating erroneous analytical results. Therefore, this study is carried out to assess and to compare a comprehensive finite element analytical model of FRP that can properly consider the properties of FRP as a retrofit material. After reviewing available FRP models currently used by researchers in the field, four analytical FRP models are selected to assess the behavior of FRP sheet and FRP retrofitted concrete structure; isotropic linear elastic shell element model (IES model), orthotropic linear elastic shell element without shear deformation model (OES model), orthotropic linear elastic shell element with shear deformation model (OESS model), and linear elastic beam element model (EB model). Using the selected FRP models, noise analysis of FRP sheet and FRP retrofitted concrete is carried out to confirm mesh sensitivity for convergence. In addition, finite element analysis of FRP retrofitted RC slab under blast load is performed to select the most appropriate FRP model and to validate the blast analysis technique. All of the analysis results for four selected FRP models are compared to verify and select the optimum model. Finally, a discussion about the study results with respect to code response criteria is presented.
Factors of the Psychopathic Personality Inventory
Authors: Ross Scott R. , Benning Stephen D. , Patrick Christopher J. , Thompson Angela , Thurston Amanda
Published: August 2008

Psychopathy is a personality disorder that includes interpersonal-affective and antisocial deviance features. The Psychopathic Personality Inventory (PPI) contains two underlying factors (fearless dominance and impulsive antisociality) that may differentially tap these two sets of features. In a mixed-gender sample of undergraduates and prisoners, we found that PPI fearless dominance was related to low Behavioral Inhibition System activity, high Behavioral Activation System (BAS) activity, expert prototype psychopathy scores, and primary psychopathy. Impulsive antisociality was related to high BAS activity and all psychopathy measures. High Extraversion and Openness and low Neuroticism and Agreeableness predicted fearless dominance, whereas high Neuroticism and low Agreeableness and Conscientiousness predicted impulsive antisociality. Although low levels of Agreeableness predicted both PPI factors, their differential relations with other five-factor model traits highlight differences in the way psychopathy manifests itself. Consistent with movements toward assessing personality disorder using the five-factor model, the authors report regression-based equations for the clinical assessment of these psychopathy dimensions using the NEO Personality Inventory—Revised (NEO-PI-R).
Making Patents and Intellectual Property Work
Authors: Carolan Michael S.
Published: August 2008

Patents are a performance , in both their creation and subsequent enactions. They require skill, tacit/embodied knowledge, and practice if they are to be successfully enacted. Western intellectual property law, however, is blind to the performative aspect of patents. This sociolegal reality has helped to create significant asymmetries between nations, particularly after the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) exported Western patent law to all corners of the globe. The article begins by reviewing the philosophical underpinnings of Western patent law, focusing specifically on those aspects that locate intellectual property within the disembodied subject. Next, attention turns to detailing the formation and implementation of TRIPS. Two asymmetries created by TRIPS are then discussed, which take place at the front and back ends of the patenting process. When taken together, these asymmetries work to further lock in global inequalities. The article concludes with suggestions about how these global inequalities might be reduced in light of this argument.
Environmental Inequality in Metropolitan America
Authors: Downey Liam , Dubois Summer , Hawkins Brian , Walker Michelle
Published: August 2008

This study compares the environmental hazard burden experienced by Blacks, Hispanics, Pacific Islanders, Native Americans, Asian Americans, and Whites in each of the 329 metropolitan areas in the continental United States, using toxicity-weighted air pollutant concentration data drawn from the Environmental Protection Agency's Risk-Screening Environmental Indicators project to determine whether and to what degree environmental inequality exists in each of these metropolitan areas. After demonstrating that environmental inequality outcomes vary widely across metropolitan areas and that each group in the analysis experiences a high pollution disadvantage in multiple metropolitan areas and a medium pollution disadvantage in many metropolitan areas, the authors test three hypotheses that make predictions about the role that residential segregation and racial income inequality play in producing environmental inequality. Using logistic regression models to test these hypotheses, the authors find that residential segregation and racial income inequality are relatively poor predictors of environmental inequality outcomes, that residential segregation can increase and decrease racial/ethnic group proximity to environmental hazards, and that the roles income inequality and residential segregation play in producing environmental inequality vary from one racial/ethnic group to another.
Eco-Effective Greening Decisions and Rationalizations
Authors: Backer Lise , Clark Timothy S.
Published: August 2008

Drawing on a social constructionist perspective, the authors present insights into the business case for eco-effective greening of business, based on analysis of Royal Dutch Shell's 1997 establishment of Shell Renewables as its fifth core business. They apply organizational decision-making theory to suggest that Shell's new eco-effective renewable energy business came about in a process fitting the garbage-can decision-making model—a model more aptly named after a recycling bin, they also argue. In rationalizing the decision after it had been made, Shell leveraged its energy-industry networks to enact a market for its new eco-effective products and services. The article concludes with the authors' observations that eco-effective greening can be a business case-in-the-making, with the economic outcome of developing eco-effective products and services dependent on how new green markets are created and pursued.
Corporate Social Responsibility and Corporate Sustainability
Authors: Montiel Ivan
Published: August 2008

This article reviews the different definitions of corporate social responsibility (CSR) and corporate sustainability (CS) used over time to reveal points of difference and congruence between the two terms. Management literature uses both CSR and CS to refer to social and environmental management issues, but there is no clear distinction between the two terms. First, the author quantifies the articles published about CSR and CS in both general management and specialized journals. Second, the author summarizes the different CSR- and CS-related definitions to identify the definitional differences between CSR and CS. Finally, the author identifies opportunities to reshape a rapidly changing field by enhancing collaboration among scholars devoted to studying CSR and CS issues.
The Sociology of Ecology
Authors: Bellamy Foster John , Clark Brett
Published: August 2008

Environmental sociology has been divided in recent years by a debate between realists and constructionists centering on the knowledge claims of ecological science. Following a consideration of this debate and its relation to both environmental sociology and the “sociology of ecology,” a “realist constructionism” is advanced, taking as its concrete case the conflict in the 1920s and 1930s between Jan Christian Smuts's organicist ecology and Arthur Tansley's ecosystem ecology. A central analytical issue (derived from Marx and Engels) is the “double transfer” of ideas from society to nature and back again and how this was manifested in the early 20th-century ecology in the form of a justification for ecological racism/apartheid.
The Validity and Reliability of the Self-Assessment and Program Review
Authors: Walker Bridget , Cheney Doug , Stage Scott
Published: August 2008

The Self-Assessment and Program Review (SAPR) was developed to provide an assessment tool that schools could use to track their progress in implementing key practices related to all three levels of schoolwide positive behavior supports (SWPBS). The SAPR is a team-based assessment tool, using both individual and team ratings of 10 evidence-based subscales and related indicators, to monitor the implementation of SWPBS practices and assist teams in developing and monitoring plans for school improvement. This article describes the background, development, features, and details of the initial psychometric properties of the measure. The role and function of the SWPBS leadership team were also analyzed for their influence on the assessment and implementation process. Overall, results suggest that the SAPR is both reliable and valid, and it provides a useful and efficient tool to leadership teams interested in assessing their implementation of key SWPBS practices.
Compelling Identity: Selves and Insecurity in Global, Corporate Management Development
Authors: Gagnon Suzanne
Published: August 2008

Adopting a post-structuralist analytical framework, this article fuses two seminal notions, Alvesson and Willmott's identity regulation in organizations and Collinson's emphasis on insecurity within processes of identity construction, to unravel subjectivities and the production of identity in two global, corporate management development programs. Drawing on interviews and observation in the settings, the article contrasts discursive practices in the two programs. It then examines the micro-processes of program participants' identity work in each context, using as a heuristic tool Collinson's theory of conforming, dramaturgical and resisting selves. Contributing to critical studies in management education, this framing draws attention to the dynamics of power in shaping identities within management development. The study suggests new notions of how identity regulation and insecurity interact, relating to two `ideal types' or models of management development emerging in the fieldwork.
Cognitive and Practice-based Theories of Organizational Knowledge and Learning: Incompatible or Complementary?
Authors: Marshall Nick
Published: August 2008

Cognitive and practice-based approaches to organizational knowledge and learning are typically portrayed as incommensurable, with the result that there has been little positive dialogue between the two traditions. This article argues that the incompatibility of the two sets of approaches has been overstated and that there is actually much that each can learn from the other. Cognitive approaches, which have often been accused of offering an effectively individualized, static and representationalist understanding of organizational knowledge, can benefit from taking on board the practice-based view of knowledge as historically, culturally and socially situated. However, the article also suggests that practice-based theories would do well to draw insights from cognitive approaches, particularly regarding the role of cognitive frameworks or schemas in guiding knowledge processes. To provide an example of how cognitive and practice-based approaches can be integrated, the latter part of the article offers an empirical illustration of how a team of consulting engineers represent and perform alternative schemas of project work through their day-to-day practices.
Shared Knowledge and Understandings in Organizations: Its Development and Impact in Organizational Learning Processes
Authors: Schulz Klaus-Peter
Published: August 2008

This article considers the meaning of background assumptions in the process of learning and development in organizations, and builds on actor and activity theoretical views. Learning is assumed as collective development in social systems as stated in Engeström's theory of expansive learning. The question is answered as to how background assumptions change and develop in the expansive learning cycle. Therefore, Engeström's model is fused with the concepts `theory in use' by Argyris and Schön, and `local theory' by Baitsch. The inter-relation between the change in background assumptions and expansive learning is discussed in a case study from the pharmaceutical industry. The case study describes a process simulation designed for staff training in the production area. Results are based on a qualitative empirical survey of process simulation and its effect on daily work.
Genome-wide profiling of follicular lymphoma by array comparative genomic hybridization reveals prognostically significant DNA copy number imbalances
Authors: Cheung K.-John J. , Shah Sohrab P. , Steidl Christian , Johnson Nathalie , Relander Thomas , Telenius Adele , Lai Betty , Murphy Kevin P. , Lam Wan , Al-Tourah Abdulwahab J. , Connors Joseph M. , Ng Raymond T. , Gascoyne Randy D. , Horsman Douglas E.
Published: August 2008

The secondary genetic events associated with follicular lymphoma (FL) progression are not well defined. We applied genome-wide BAC array comparative genomic hybridization to 106 diagnostic biopsies of FL to characterize regional genomic imbalances. Using an analytical approach that defined regions of copy number change as intersections between visual annotations and a Hidden Markov model–based algorithm, we identified 71 regional alterations that were recurrent in at least 10% of cases. These ranged in size from approximately 200 kb to 44 Mb, affecting chromosomes 1, 5, 6, 7, 8, 10, 12, 17, 18, 19, and 22. We also demonstrated by cluster analysis that 46.2% of the 106 cases could be sub-grouped based on the presence of +1q, +6p/6q−, +7, or +18. Survival analysis showed that 21 of the 71 regions correlated significantly with inferior overall survival (OS). Of these 21 regions, 16 were independent predictors of OS using a multivariate Cox model that included the international prognostic index (IPI) score. Two of these 16 regions (1p36.22-p36.33 and 6q21-q24.3) were also predictors of transformation risk and independent of IPI. These prognostic features may be useful to identify high-risk patients as candidates for risk-adapted therapies.
Prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia
Authors: Thomas Deborah A. , O'Brien Susan , Jorgensen Jeffrey L. , Cortes Jorge , Faderl Stefan , Garcia-Manero Guillermo , Verstovsek Srdan , Koller Charles , Pierce Sherry , Huh Yang , Wierda William , Keating Michael J. , Kantarjian Hagop M.
Published: August 2008

Immunophenotypic classification of acute lymphoblastic leukemia (ALL) has well-recognized prognostic implications. The significance of CD20 expression has been evaluated in childhood precursor B-lineage ALL with conflicting results. We retrospectively analyzed the influence of CD20 expression on outcome in 253 adults with de novo precursor B-lineage ALL treated with either conventional (VAD/CVAD) or intensive (hyper-CVAD) frontline chemotherapy regimens in the pre-rituximab era. Overall, CD20 positivity of at least 20% was associated with lower 3-year rates of complete remission duration (CRD; 20% vs 55%, P < .001) and overall survival (OS; 27% vs 40%, p = .03). In the CD20 negative subset, the 3-year rates for CRD (58% vs 42%, p = .04) and OS (60% vs 28%, P < .001) were superior for hyper-CVAD compared with VAD/CVAD; rates were particularly favorable for the CD20 negative younger age group (68% and 85%, respectively). In contrast, 3-year CRD and OS rates were uniformly poor for the CD20-positive group regardless of therapy (27% or less). Multivariate analysis for event-free survival identified older age, leukocyte count higher than 30 × 109/L, presence of Philadelphia chromosome, high systemic risk classification, and CD20 positivity as independent predictors of worse outcome. In conclusion, CD20 expression in de novo adult precursor B-lineage ALL appears to be associated with a poor prognosis. Incorporation of monoclonal antibodies directed against CD20 into frontline chemotherapy regimens warrants investigation.
Association of narcolepsy-cataplexy with HLA-DRB1 and DQB1in Mexican patients: A relationship between HLA and gender is suggested
Authors: Alaez Carmen , Lin Ling , Flores-A Hilario , Vazquez Miriam , Munguia Andrea , Mignot Emmanuel , Haro Reyes , Baker Harry , Gorodezky Clara
Published: August 2008

Background

Narcolepsy-cataplexy is characterized by excessive daytime sleepiness with recurrent episodes of irresistible sleep, cataplexy, hallucinations and sleep paralysis. Its aetiology is unknown, but it is positively associated with the human leukocyte antigens (HLA) in all studied populations. The purpose of the present study was to investigate the association of HLA class II DRB1/DQB1 alleles with narcolepsy-cataplexy in Mexican Mestizo patients.

Methods

This is a case-control study of consecutive patients and ethnically matched controls. We included 32 patients diagnosed with typical narcolepsy-cataplexy, of the National Institute of Neurology, of the Institute of Psychiatry and at the Center of Narcolepsy at Stanford University. As healthy controls, 203 Mexican Mestizos were included. DRB1 alleles were identified using sequence based typing. A PCR-SSOP reverse dot blot was used for DQB1 typing. Allele frequency was calculated by direct counting and the significance of the differences was assessed using the Yates Chi square. Odds ratio and confidence intervals were evaluated.

Results

HLA-DRB1*1501 (OR = 8.2; pc < 0.0001) and DQB1*0602 (OR = 8.4; pc < 0.0001) were found positively associated with narcolepsy. When deleting DQB1*0602+ patients from the analysis, DQB1*0301 was also found increased (OR = 2.7; p = 0.035; pc = NS). DQB1*0602/DQB1*0301 genotype was present in 15.6% of the cases (OR = 11.5; p = 0.00035), conferring a high risk. DRB1*0407 (OR = 0.2; p = 0.016 pc = NS) and DQB1*0302(OR = 0.4; p = 0.017, pc = NS) were found decreased in the patients. The gender stratification analysis showed a higher risk in females carrying DRB1*1501 (OR = 15.8, pc < 0.0001) and DQB1*0602 (OR = 19.8, pc < 0.0001) than in males (OR = 5.0 for both alleles; p = 0.012, pc = NS for DRB1 & p = 0.0012, pc = 0.017 for DQB1). The susceptibility alleles found in Mexicans with narcolepsy are also present in Japanese and Caucasians; DRB1*04 linked protection has also been shown in Koreans. A stronger HLA association is suggested in females, in accordance with the sexual dimorphism claimed previously.

Conclusion

This knowledge may contribute to a better understanding of the disease pathogenesis in different populations. The evaluation of the risk to develop narcolepsy-cataplexy in carriers of the described alleles/genotypes may also be possible. A larger sample should be analysed in Mexican and in other Hispanic patients to confirm these results.
Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital
Authors: Bruce David , Nokes Tim JC
Published: August 2008

Introduction

Major blood loss can often be life-threatening and is most commonly encountered in the settings of surgery and trauma. Patients receiving anticoagulant therapy are also at increased risk of bleeding. We investigated the use of a prothrombin complex concentrate (PCC; Beriplex P/N, CSL Behring, Marburg, Germany) to treat severe bleeding in a variety of settings: cardiac surgery, warfarin therapy and other surgery.

Methods

Thirty consecutive patients who had received PCC were identified from blood transfusion records. For cardiac surgery and warfarin reversal, PCC was administered in accordance with hospital protocols. PCC was administered to cardiac and other surgical patients responding poorly to recognized blood products, whereas it was administered first-line to patients with life-threatening bleeds and requiring warfarin reversal, in accordance with British Committee for Standards in Haematology guidelines. We conducted a retrospective analysis of patient records in order to ascertain PCC dose, use of other blood products and response to PCC (clotting screen results before and after PCC administration, haemostasis achievement, and survival).

Results

Six patients (20%) were excluded because of inadequate documentation (n = 5) or acquired haemophilia (n = 1). Therefore, 24 patients were included in the analysis: coronary artery bypass graft (n = 5), mitral/aortic valve replacement (n = 2), other surgery (n = 9) and warfarin reversal (n = 8). Most patients (83.3%) received no more than 1500 IU of Beriplex P/N 500. Considerable reduction in administration of other blood products was seen during the 24 hours after PCC administration. Partial or complete haemostasis was achieved in 14 out of 18 cases (77.8%). In total, 12 out of 24 patients (50%) died during the study; two-thirds of the deaths were considered unrelated to bleeding. No thrombotic complications or adverse drug reactions were observed.

Conclusion

This study emphasizes the value of PCC in reversing the effects of oral anticoagulant therapy in bleeding patients. It also demonstrates the potential value of PCC in controlling bleeding in patients undergoing cardiac and other surgical procedures. The use of PCC in bleeding patients without hereditary or anticoagulation-related coagulopathy is novel, and further investigation is warranted. In the future, it may be possible to use PCC as a substitute for fresh frozen plasma in this setting; adequate documentation is crucial for all blood products.
Distinct chemokine and cytokine gene expression pattern of murine dendritic cells and macrophages in response toMycobacterium tuberculosisinfection
Authors: Jang Sihyug , Uzelac Aleksandra , Salgame Padmini
Published: August 2008

In this study, the early innate cytokine and chemokine response of murine dendritic cells (DCs) and macrophages to Mycobacterium tuberculosis infection was compared. The findings indicate a dissimilar gene expression pattern between the two cell types. The expression of IL-12 and IL-23, important for promoting Th1 and Th17 cells, respectively, was up-regulated only in DCs. In addition, expression of CCL1 and CCL17, which are important in recruitment of T regulatory cells, was DC-specific, as was the expression of the immunosuppressive cytokine IL-10. Macrophages, in contrast, exhibited enhanced expression for CCL2 and CXCL10, chemokines that recruit cells to sites of inflammation, and for mycobactericidal molecules NO synthase 2 and TNF. Together, the findings suggest that a component of the innate DC response is not only programmed toward Th1 priming but is also for controlling the magnitude of the Th1 response, and part of the macrophage response is intended for recruiting cells to the lung and for mycobactericidal functions.
Knockdown of Macrophage Migration Inhibitory Factor Disrupts Adipogenesis in 3T3-L1 Cells
Authors: Ikeda Daisuke , Sakaue Shinji , Kamigaki Mitsunori , Ohira Hiroshi , Itoh Naofumi , Ohtsuka Yoshinori , Tsujino Ichizo , Nishimura Masaharu
Published: August 2008

Obesity is a condition in which adipose tissue mass is expanded. Increases in both adipocyte size and number contribute to enlargement of adipose tissue. The increase in cell number is thought to be caused by proliferation and differentiation of preadipocytes. Macrophage migration inhibitory factor (MIF) is expressed in adipocytes, and intracellular MIF content is increased during adipogenesis. Therefore, we hypothesized that MIF is associated with adipocyte biology during adipogenesis and focused on the influence of MIF on adipogenesis. To examine the effects of MIF on adipocytes, MIF expression in 3T3-L1 preadipocytes was inhibited by RNA interference, and cell differentiation was induced by standard procedures. The triglyceride content of MIF small interfering RNA (siRNA)-transfected 3T3-L1 cells was smaller than that of nonspecific siRNA-transfected cells. In addition, MIF knockdown apparently abrogated increases in adiponectin mRNA levels during differentiation. Gene expression of peroxisome proliferator-activated receptor (PPAR)γ, CCAAT/enhancer binding protein (C/EBP)α, and C/EBPδ decreased with MIF siRNA transfection, but C/EBPβ expression increased. Cell number and incorporation of 5-bromo-2-deoxyuridine into cells decreased from 1–3 d and from 14–20 h, respectively, after induction of differentiation in MIF siRNA-transfected cells, thus suggesting that MIF siRNA inhibits mitotic clonal expansion. Taken together, these results indicated that MIF regulates differentiation of 3T3-L1 preadipocytes, at least partially, through inhibition of mitotic clonal expansion and/or C/EBPδ expression.
The Effects of Apelin on the Electrical Activity of Hypothalamic Magnocellular Vasopressin and Oxytocin Neurons and Somatodendritic Peptide Release
Authors: Tobin Vicky A. , Bull Philip M. , Arunachalam Sathya , O'Carroll Anne-Marie , Ueta Yoichi , Ludwig Mike
Published: August 2008

Apelin, a novel peptide originally isolated from bovine stomach tissue extracts, is widely but selectively distributed throughout the nervous system. Vasopressin and oxytocin are synthesized in the magnocellular neurons of the hypothalamic supraoptic nucleus (SON) and paraventricular nucleus, which are apelin-rich regions in the central nervous system. We made extracellular electrophysiological recordings from the transpharyngeally exposed SON of urethane-anaesthetized rats to assess the role of apelin in the control of the firing activity of identified magnocellular vasopressin and oxytocin neurons in vivo. Apelin-13 administration onto SON neurons via microdialysis revealed cell-specific responses; apelin-13 increased the firing rates of vasopressin cells but had no effect on the firing rate of oxytocin neurons. A direct excitatory effect of apelin-13 on vasopressin cell activity is also supported by our in vitro studies showing depolarization of membrane potential and increase in action potential firing. To assess the effects of apelin-13 on somatodendritic peptide release, we used in vitro release studies from SON explants in combination with highly sensitive and specific RIA. Apelin-13 decreases basal (by 78%; P < 0.05; n = 6) and potassium-stimulated (by 57%; P < 0.05; n = 6) vasopressin release but had no effect on somatodendritic oxytocin release. Taken together, our data suggest a local autocrine feedback action of apelin on magnocellular vasopressin neurons. Furthermore, these data show a marked dissociation between axonal and dendritic vasopressin release with a decrease in somatodendritic release but an increase in electrical activity at the cell bodies, indicating that release from these two compartments can be regulated wholly independently.
Synergistic Up-Regulation of Prostaglandin E Synthase Expression in Breast Cancer Cells by 17β-Estradiol and Proinflammatory Cytokines
Authors: Frasor Jonna , Weaver Aisha E. , Pradhan Madhumita , Mehta Kinnari
Published: August 2008

Inflammatory mediators, such as cytokines and prostaglandins, play a fundamental role in estrogen-dependent breast cancer through their ability to up-regulate aromatase expression and subsequent local production of estrogens in the breast. To study the link between estrogens and inflammation further, we examined the regulation of prostaglandin E synthase (PTGES), a key enzyme in the production of prostaglandin E2. We found that 17β-estradiol (E2) rapidly and robustly up-regulates PTGES mRNA and protein levels in estrogen receptor (ER)-positive breast cancer cells through ER recruitment to an essential estrogen response element located in the 5′ flanking region of the PTGES gene. PTGES is also up-regulated by the proinflammatory cytokines TNFα or IL-1β. Surprisingly, the combination of E2 and cytokines leads to a synergistic up-regulation of PTGES in an ER and nuclear factor-κB (NFκB)-dependent manner. This is in contrast to the mutual transrepression between ER and NFκB that has been well characterized in other cell types. Furthermore, we found enhanced recruitment of ERα as well as the NFκB family member, p65, to the PTGES estrogen response element by the combination of E2 and TNFα compared with either E2 or TNFα alone. The synergistic up-regulation of PTGES may result in enhanced prostaglandin E2 production, which in turn may further enhance aromatase expression and production of local estrogens. Our findings suggest that a finely tuned positive feedback mechanism between estrogens and inflammatory factors may exist in the breast and contribute to hormone-dependent breast cancer growth and progression.
Analysis of Lysophosphatidic Acid (LPA) Receptor and LPA-Induced Endometrial Prostaglandin-Endoperoxide Synthase 2 Expression in the Porcine Uterus
Authors: Seo Heewon , Kim Mingoo , Choi Yohan , Lee Chang-Kyu , Ka Hakhyun
Published: August 2008

Lysophosphatidic acid (LPA), a simple phospholipid-derived mediator with diverse biological actions, acts through the specific G protein-coupled receptors endothelial differentiation gene (EDG) 2, EDG4, EDG7, and GPR23. Recent studies indicate a critical role for LPA receptor signaling in embryo implantation. To understand how LPA acts in the uterus during pregnancy in pigs, we evaluated: 1) spatial and temporal expression of LPA receptors in the uterine endometrium during the estrous cycle and pregnancy and in early-stage concepti, 2) LPA levels in uterine luminal fluids from d 12 of the estrous cycle and pregnancy, 3) effects of steroid hormones on EDG7 mRNA levels, and 4) effects of LPA on prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA levels in the uterine endometrium using explant cultures. Of the four receptors, EDG7 was dominant, and its expression was regulated by pregnancy stage and status. EDG7 expression was highest on d 12 pregnancy, and localized to the luminal and glandular epithelium, and EDG7 mRNA levels were elevated by estrogen in the endometrium. EDG7 expression was also detected in concepti of d 12 and 15. LPA with various fatty acyl groups was present in the uterine lumen on d 12 of both the estrous cycle and pregnancy. LPA increased PTGS2 mRNA abundance in the uterine endometrium. These results indicate that LPA produced in the uterine endometrium may play a critical role in uterine endometrial function and conceptus development through EDG7-mediated PTGS2 expression during implantation and establishment of pregnancy in pigs.
Nonclassical Estrogen Modulation of Presynaptic GABA Terminals Modulates Calcium Dynamics in Gonadotropin-Releasing Hormone Neurons
Authors: Romanò Nicola , Lee Kiho , Ábrahám István M. , Jasoni Christine L. , Herbison Allan E.
Published: August 2008

There is increasing recognition that estrogen exerts multifaceted regulatory effects on GnRH neurons. The acute effects of estrogen on calcium dynamics in these cells were examined using a transgenic mouse line that allows real-time measurement of intracellular calcium concentration ([Ca2+]i) in GnRH neurons in the acute brain slice preparation. 17-β-Estradiol (E2) at 100 pm–100 nm was found to activate [Ca2+]i transients in approximately 40% of GnRH neurons with an approximate 15-min latency. This effect was not replicated by E2-BSA, which limits E2 action to the membrane, 17-α-estradiol, the inactive isomer at classical estrogen receptors (ERs), or G-1 the GPR30 agonist. E2 continued to activate [Ca2+]i transients when transcription was blocked. An ER α-selective agonist was equally potent in activating [Ca2+]i transients, and E2 remained effective in ERβ knockout × GnRH-Pericam mice. E2’s activation of [Ca2+]i transients continued in the presence of tetrodotoxin, which blocks action potential-dependent transmission, but was abolished completely by the further addition of a γ-aminobutyric acid (GABA)A receptor antagonist. Exogenous GABA was found to initiate [Ca2+]i transients in GnRH neurons. Whole cell, voltage-clamp recordings of GnRH-green fluorescence protein neurons revealed that E2 generated discrete bursts of miniature inhibitory postsynaptic currents with a latency of approximately 15 min. These observations provide evidence for a new mechanism of nonclassical estrogen action within the brain. Estrogen interacts with the classical ERα at the level of the GABAergic nerve terminal to regulate action potential-independent GABA release that, in turn, controls postsynaptic calcium dynamics.
Kinesin Superfamily-Associated Protein 3 Is Preferentially Expressed in Glutamatergic Neurons and Contributes to the Excitatory Control of Female Puberty
Authors: Choi Jungil , Ha Chang Man , Choi Eun Jung , Jeong Choon Soo , Park Jeong Woo , Baik Ja-Hyun , Park Jae-Yong , Costa Maria E. , Ojeda Sergio R. , Lee Byung Ju
Published: August 2008

It was earlier shown that expression of kinesin superfamily-associated protein 3 (KAP3), involved in the neuronal anterograde, microtubule-dependent transport of membrane organelles, increases in the hypothalamus of female rats during the juvenile phase of sexual development. KAP3 mRNA is abundant in the hypothalamus, suggesting that it might be expressed in broadly disseminated neuronal systems controlling neuroendocrine function. The present study identifies one of these systems and provides evidence for an involvement of KAP3 in the excitatory control of female puberty. In situ hybridization and immunohistofluorescence studies revealed that the KAP3 gene is expressed in glutamatergic neurons but not in GABAergic or GnRH neurons. Hypothalamic KAP3 mRNA levels increase during the juvenile period of female prepubertal development, remaining elevated throughout puberty. These changes appear to be, at least in part, estradiol dependent because ovariectomy decreases and estradiol increases KAP3 mRNA abundance. Lowering hypothalamic KAP3 protein levels via intraventricular administration of an antisense oligodeoxynucleotide resulted in reduced release of both glutamate and GnRH from the median eminence and delayed the onset of puberty. The median eminence content of vesicular glutamate transporter 2, a glutamate neuron-selective synaptic protein, and synaptophysin, a synaptic vesicle marker, were also reduced, suggesting that the loss of KAP3 diminishes the anterograde transport of these proteins. Altogether, these results support the view that decreased KAP3 synthesis diminishes GnRH output and delays female sexual development by compromising hypothalamic release of glutamate.
Cold Tolerance in Hypothyroid Rabbits: Role of Skeletal Muscle Mitochondria and Sarcoplasmic Reticulum Ca2+ ATPase Isoform 1 Heat Production
Authors: Arruda Ana Paula , Ketzer Luisa A. , Nigro Mariana , Galina Antonio , Carvalho Denise P. , de Meis Leopoldo
Published: August 2008

Brown adipose tissue (BAT) is involved in rat and mice thermoregulation, and heat produced by BAT depends on the concerted action of thyroid hormones and catecholamines. Little is known about cold-induced thermogenesis in mammals that have little or no BAT, such as rabbits. In these animals, thermogenesis primarily occurs in skeletal muscle. In this work, we have studied the effect of cold acclimation (4 C for 10 d) in normal and hypothyroid rabbits. It is known that hypothyroid rats die after a few hours of cold exposure. We now show that, different from rats, hypothyroid rabbits sustain their body temperature and survive after 10 d cold exposure. When compared with rabbits kept at room temperature, the muscles of cold-exposed rabbits showed a dark red color characteristic of oxidative muscle fibers. According to this pattern, we observed that in both normal and hypothyroid rabbits, cold exposure promotes an increase in oxygen consumption by skeletal muscle mitochondria. Moreover, in red muscle, cold acclimation induces an increase in the expression and activity of sarcoplasmic reticulum Ca2+ ATPase isoform 1 (SERCA1), one of the muscle enzymes involved in heat production. We conclude that rabbit cold tolerance is probably related to increased muscle oxidative metabolism and heat production by SERCA1 and that these changes are not completely dependent on normal thyroid function.
Modulation of Bone Morphogenetic Protein-9 Expression and Processing by Insulin, Glucose, and Glucocorticoids: Possible Candidate for Hepatic Insulin-Sensitizing Substance
Authors: Caperuto Luciana Chagas , Anhê Gabriel Forato , Cambiaghi Tavane David , Akamine Eliana Hiromi , do Carmo Buonfiglio Daniella , Cipolla-Neto José , Curi Rui , Bordin Silvana
Published: August 2008

Bone morphogenetic protein 9 (BMP-9), a member of the TGF-β superfamily predominantly expressed in nonparenchymal liver cells, has been demonstrated to improve glucose homeostasis in diabetic mice. Along with this therapeutic effect, BMP-9 was proposed as a candidate for the hepatic insulin-sensitizing substance (HISS). Whether BMP-9 plays a physiological role in glucose homeostasis is still unknown. In the present study, we show that BMP-9 expression and processing is severely reduced in the liver of insulin-resistant rats. BMP-9 expression and processing was directly stimulated by in situ exposition of the liver to the combination of glucose and insulin and oral glucose in overnight fasted rats. Additionally, prolonged fasting (72 h) abrogated refeeding-induced BMP-9 expression and processing. Previous exposition to dexamethasone, a known inductor of insulin resistance, reduced BMP-9 processing stimulated by the combination of insulin and glucose. Finally, we show that neutralization of BMP-9 with an anti-BMP-9 antibody induces glucose intolerance and insulin resistance in 12-h fasted rats. Collectively, the present results demonstrate that BMP-9 plays an important role in the control of glucose homeostasis of the normal rat. Additionally, BMP-9 is expressed and processed in an HISS-like fashion, which is impaired in the presence of insulin resistance. BMP-9 regulation according to the feeding status and the presence of diabetogenic factors reinforces the hypothesis that BMP-9 might exert the role of HISS in glucose homeostasis physiology.
The Pairing of a Selective Estrogen Receptor Modulator, Bazedoxifene, with Conjugated Estrogens as a New Paradigm for the Treatment of Menopausal Symptoms and Osteoporosis Prevention
Authors: Kharode Yogendra , Bodine Peter V. N. , Miller Christopher P. , Lyttle C. Richard , Komm Barry S.
Published: August 2008

The menopausal transition is associated with decreased ovarian function and concomitant decline in estrogen production, which may result in physiological effects such as hot flashes, reduced bone mass, and altered lipid profile. It is well established that these unfavorable changes are effectively offset with estrogen therapy (ET) or, in women with a uterus, estrogens in combination with a progestin (hormone therapy). Selective estrogen receptor (ER) modulators (SERMs), which exhibit both ER agonist and antagonist activities depending on the target tissue, have been regarded as offering the potential to provide the benefits of ET and hormone therapy with an improved safety and tolerability profile. To date, no SERM alone has demonstrated an ideal benefit-risk profile for menopausal therapy. The tissue-selective estrogen complex, or the pairing of a SERM with estrogens, may provide an optimal blend of ER agonist and antagonist activities. We evaluated the physiological profile of this novel therapeutic paradigm by using various in vivo models to assess uterine, vasomotor, lipid, and skeletal responses to a tissue-selective estrogen complex partnering bazedoxifene with conjugated estrogens (CE). Bazedoxifene at 3.0 mg/kg effectively antagonized CE-induced uterine stimulation without reversing the positive effects of CE on vasomotor instability. When paired with CE, bazedoxifene at 3.0 mg/kg reduced total cholesterol levels by up to 20% compared with CE alone and significantly increased total bone density relative to control. These preclinical findings showed that the appropriate dose combination of bazedoxifene/CE exhibits positive vasomotor, lipid, and skeletal responses with minimal uterine stimulation.
Potential prospects of chitosan derivative trimethyl chitosan chloride (TMC) as a polymeric absorption enhancer: synthesis, characterization and applications
Authors: Sahni Jasjeet K , Chopra Shruti , Ahmad Farhan J , Khar Roop K
Published: August 2008

In recent years, researchers have been working extensively on various novel properties of polymers to develop increased efficiency of drug delivery and improve bioavailability of various drug molecules, especially macromolecules. Chitosan, a naturally occurring polysaccharide, because of its protonated/polymeric nature, provides effective and safe absorption of peptide and protein drugs. Its transmucosal absorption is, however, limited to acidic media because of its strong intermolecular hydrogen bonds. A new partially quaternized chitosan derivative, N-trimethyl chitosan chloride (TMC), has been synthesized with improved solubility, safety and effectiveness as an absorption enhancer at neutral pH and in aqueous environment. It enhances the absorption, especially of peptide drugs, by reversible opening of tight junctions in between epithelial cells, thereby facilitating the paracellular diffusion of peptide drugs. This derivative thus opens new perspectives as a biomaterial for various pharmaceutical applications/drug delivery systems. This review deals with the potential use of the quaternized chitosan derivative as a permeation enhancer for the mucosal delivery of macromolecular drugs along with its other biomedical applications.
An investigation into solvent-membrane interactions when assessing drug release from organic vehicles using regenerated cellulose membranes
Authors: Reid Monica L , Brown Marc B , Moss Gary P , Jones Stuart A
Published: August 2008

The influence of organic solvents on artificial membranes when assessing drug release from topical formulations is, generally, poorly characterised yet current guidelines require no characterisation of the membrane before, during or after an experiment. Therefore, the aim of this study was to determine the effect of solvent-membrane interactions when using in-vitro Franz cell methods for the assessment of corticosteroid release and to assess compliance or otherwise with Higuchi's equation. The rate of beclometasone dipropionate monohydrate (BDP) and betamethasone 17-valerate (BMV) release across a regenerated cellulose membrane (RCM), from both saturated solutions and commercial formulations, was determined. Increasing the ratio of organic solvent, compared with aqueous phase, in the donor fluid (DF) resulted in up to a 416-fold increase in steady-state flux. Further, alterations in the receiver fluid (RF) composition caused, in some cases, 337-fold increases in flux. Analysis indicated that the RCM remained chemically unchanged, that its pore size remained constant and that no drug partitioned into the membrane, regardless of the DF or RF employed. However, it was observed that the organic solvents had a thinning effect on the RCM, resulting in enhanced flux, which was potentially due to the variation in the diffusional path length. Such findings raise issues of the veracity of data produced from any membrane release study involving a comparison of formulations with differing solvent content.
Distribution of an intravenous injectable nimodipine nanosuspension in mice
Authors: Xiong Ruolan , Lu Weigen , Yue Peng , Xu Rong , Li Jun , Chen Tingting , Wang Peiquan
Published: August 2008

The distribution of an intravenous injectable nimodipine nanosuspension with mean particle size of both 300 and 650 nm in mice was systemically investigated compared with that of a nimodipine ethanol formulation (Nimotop) and a nanosuspension coated with Tween-80. The results showed that the 650-nm nanoparticles provided significantly higher drug concentrations in the liver, spleen and lungs because of their capture by Kupffer cells in the mononuclear phagocyte system, but lower drug concentrations in the brain compared with Nimotop and smaller nanoparticles. These nanoparticles failed to give increased brain concentrations even when coated with Tween-80. The 300-nm nanoparticles could effectively increase drug concentrations in the brain and remarkably reduce drug concentrations in the liver, spleen and lungs, indicating that the nimodipine nanosuspension may be a promising formulation with no ethanol, but the particle size must be small.
Metabolic effects of various antidiabetic and hypolipidaemic agents on a high-fat diet and multiple low-dose streptozocin (MLDS) mouse model of diabetes
Authors: Arulmozhi Dakshinamoorty Kandasamy , Kurian Rubin , Bodhankar Subodh L , Veeranjaneyulu Addepalli
Published: August 2008

Insulin resistance and subsequent insulin secretory defect are two main features of type 2 diabetes and associated metabolic disorders. The animal models of type 2 diabetes are very complex and are as heterogeneous as the disease. We have evaluated the effect of various antidiabetic and lipid lowering agents (fenofibrate, rosiglitazone, glimepiride, metformin and simvastatin) on the metabolic abnormalities induced by combining a high-fat diet and multiple low-dose streptozocin (MLDS) in mice. Male Swiss albino mice were orally treated with the above agents and fed with a diet containing high fat for 28 days. On day 15 the animals were injected intraperitoneally with low-dose streptozocin (40 mg kg−1), which was administered for five consecutive days. At the end of the 28-day treatment plasma metabolic parameters (glucose, triglyceride and immunoreactive insulin) were estimated. The antidiabetic and hypolipidaemic agents exhibited differential effects on these metabolic parameters. With the exception of fenofibrate all these agents reduced the plasma glucose levels, and the effects of metformin and rosiglitazone on glucose were found to be statistically significant. Although the effect of the test drugs on cholesterol was modest, a significant decrease in triglyceride levels was observed with sub-chronic treatment with these agents. Interestingly, glimepiride mildly elevated the insulin levels while the other antidiabetics and hypolipidaemics reduced the insulin levels, with metformin and rosiglitazone exhibiting statistically significant effects on insulin. To our knowledge this is the first report on the effect of various peroxisome proliferator-activated receptor modulators and newer antidiabetics on the metabolic effects induced by the combined high-fat diet and MLDS model of type 2 diabetes in Swiss albino mice. The results suggested the complexity of the hyperglycaemia, hyperinsulinaemia and hypertriglyceridaemia induced by the high-fat diet and MLDS mouse model, and their correction by various antidiabetics and antihyperlipidaemics may have involved diverse mechanisms.