bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding Intercivilizational Encounters
Authors: Arnason Johann P.
Published: August 2006

The notion of a ‘clash of civilizations’, which now seems to have become a fashionable cliché, should be discussed in the context of a broader set of questions: the problematic of intercivilizational encounters. This is an important but very underdeveloped part of the research programme now known as civilizational analysis. The article begins with a brief survey of the Indian experience. Indian history includes a long succession of intercivilizational encounters, both those initiated from the West (by Greeks, Muslims and Europeans) and those that brought Indian influence to bear on other regions (as did the spread of Buddhism to East Asia and the ‘Indianization’ of Southeast Asia). These examples serve to sketch a phenomenology of encounters. For a more theoretical approach, the article turns to the work of Benjamin Nelson, who first introduced the concept of intercivilizational encounters. His analyses focus on the encounters that involve contacts or conflicts between the basic ‘structures of consciousness’ that define different civilizations. Such interactions can lead to fusion or to prolonged internal conflicts, but they may also be instructive because of the very absence of significant effects: in the latter case, fundamental blockages to intercivilizational borrowing or engagement are built into the structures of consciousness. For Nelson, the early modern encounter between China and the West was a prime example of that kind. The last part of the article takes the question beyond Nelson’s historical cases and relates it to the advanced phase of modernity, where the dominant type of encounters is three-cornered: it involves Western and non-Western civilizations as well as the new (modern) civilizational patterns adumbrated in the West but open to redefinitions in other contexts.
Technical Gadgetry: Technological Development in the Aesthetic Economy
Authors: Böhme Gernot
Published: August 2006

The conception of the nature of modern technology and the understanding of its history is largely determined by Marx: technology is instrumental appropriation of nature and its development was driven by the bourgeoisie and capitalism. To this familiar conception the article opposes the concept of two technology types, which we find in the early modern engineer Salomon de Caus: useful and enjoyable technology. Enjoyable technology, which serves pleasure and not production, originates in the orientation to curiosities and representation at royal courts, limited neither by guild conservatism nor by considerations of profit. Precisely for this reason courtly technology was particularly creative. Against this historical background the article examines contemporary technological developments in the period of the transformation of capitalism into the aesthetic economy, in which technology development (apart from war) increasingly serves pleasure. Technology becomes plaything and life-style gadget. An explicit consumption of technology has emerged, in which Marx’s ideal obsolescence plays a leading role.
Staging the Absolute: The Total Work of Art from Wagner to Mallarmé
Authors: Roberts David
Published: August 2006

Heidegger places Wagner’s will to the total work of art at the centre of the long 19th century. Nietzsche’s and Mallarmé’s responses to Wagner reflect all the ambiguities of modernism’s myth of absolute creation: the dreams of a new mythology and a new community are shadowed by the knowledge that the gods are nothing more than our fictions. Nietzsche and Mallarmé continue and critically interrogate the two distinct lineages of the total work of art deriving from German romanticism and the French Revolution respectively, at the same time as they anticipate the contrary constructions of the sacred in society in Le Bon and Durkheim.
Zygmunt Bauman - To Build Anew
Authors: Beilharz Peter
Published: August 2006

This essay is a gift for Zygmunt Bauman on his 80th birthday. Its purpose is to celebrate his achievement by scanning it, in three sections. First, I indicate something of my own encounter with Bauman, my road to Leeds. Second, I seek, once again, to characterize his project and its key themes. Third, I indicate some of the features of what I take to be his legacy. Bauman’s sociology appeals because it combines East European Critical Theory with (if you like) a postmodern, or contemporary sociology of everyday life. His work mediates the themes of classical and modern sociology with present-day life and its uncertainties. Bauman’s is a critique of modernity as excess, but it always retains the sense that we could, after all, do other.
Determination of the Effects of Axial Load on the Natural Frequency of a Composite Beam with the Finite Element Method
Authors: Sarikanat Mehmet , Yildiz Hasan , Baltaci Aysun
Published: August 2006

The effects of axial load on the natural frequency in simply supported thick composite beams are determined using the finite element method. The material properties of the elements are calculated with two different average value methods (arithmetic and weighted average) and the effects of axial load on the natural frequency of the beam are examined. A computer program is developed to analyze the effect of axial load on the natural frequency. The finite element method is used to determine the axial load effects on the natural frequency of a fiber reinforced composite beam. The results are obtained and compared with the analytical solutions by taking different element numbers in the thickness direction. With the help of these two methods, eight-node brick elements are used in multilayer finite element analyses. It has been observed that the results obtained by the arithmetic average method are quite close to the analytic results.
Studies on Physicomechanical and Electrical Properties of SBR - Carbon Black Composites
Authors: Renukappa N. M. , Samuel R. D. Sudhaker , Siddaramaiah
Published: August 2006

A series of styrene-butadiene-rubber (SBR) composites have been vulcanized with different weight ratios of general purpose furnace carbon black, viz., 10, 30, 50, 70, and 90%. The compounded SBR composites have been characterized for physicomechanical properties, such as surface hardness, tensile strength, percentage elongation at break, and tensile modulus. The dimensional stability of SBR composites has been enhanced by an increase in carbon black loading because of the polymer-filler interaction or reinforcing effect of filler. The electrical properties such as dielectric constant (ε) and dissipation factor (tan δ) of the composites have been measured using a HP LCR meter. These properties have been measured at different frequencies and with a different amount of carbon black loading. A drastic improvement in the dielectric constant of the composites has been noticed because of an increase in carbon black loading in the SBR phase.
Hypervelocity Planar Plate Impact Experiments of Aramid Fiber-reinforced Plastics
Authors: Homae Tomotaka , Shimizu Toshihiko , Fukasawa Koushirou , Masamura Osami
Published: August 2006

Planar plate impact experiments of aramid fiber-reinforced plastics (AFRPs) have been carried out to determine its average shock Hugoniot and to examine response to shock compression using polyvinylidene difluoride (PVDF) stress gauges. The determined shock Hugoniot is Us1/4 2.42up + 1.18, where Us is the shock velocity and up is the particle velocity. The output waveforms of the stress gauges reveal that the shock impedance of an aramid-fabric ply is lower than that of resin matrix and once the shock wave passes through, the aramid-fabric ply and the resin matrix have almost equal shock impedance.
Crimes Mala in Se: An Equity-Based Definition
Authors: Davis Mark S.
Published: August 2006

Legal scholars have used the terms mala prohibita and mala in se to draw the distinction between legally proscribed and morally proscribed offenses. The former are those offenses that are wrong simply because there exist formal, codified rules prohibiting them. Efforts to define mala in se, on the other hand, have resulted in vague, often conflicting meanings that leave the analyst with little but examples to serve as definitions. As a result, some have argued that the distinctions mala in se and mala prohibita be abandoned altogether. If one examines mala in se from an equity theoretical viewpoint, incorporating the concepts of intent and harm, it may be possible to arrive at a more understandable and useful concept.
Re-Entry to Recovery
Authors: Brucker Debra
Published: August 2006

A demonstration project being designed by the Social Security Administration (SSA) and Rutgers University may provide an effective option for assisting eligible offenders with mental illness in obtaining employment during re-entry to their communities. The project, Early Intervention (EI), will provide temporary cash stipends, immediate Medicare, and innovative employment services and supports to eligible applicants for Social Security disability insurance (DI). The EI project is a broad departure from previous SSA employment initiatives in both philosophy and structure, addressing a host of commonly cited barriers to employment for persons with disabilities in new and different ways. Should the demonstration project prove successful and be adopted into a national program, EI has the potential to provide an important source of support to eligible offenders with mental illness who are transitioning back to their communities.
Moral Justifications on the Rehnquist Court
Authors: Chilton Bradley Stewart , Woods James A.
Published: August 2006

What moral justifications do we find in Fourth Amendment judicial opinions of the Rehnquist Court, and what does this suggest about future Court decision making? First, the authors develop the moral justification model of judicial decision making in a literature review, with linguistic patterns and categories by Hercules and Herbert for content analysis. Second, they discuss the methodological strategies used in this content analysis of official opinions of the Court on the Fourth Amendment from 1986 to 1994. Third, from this content analysis, the authors describe the patterns of moral justification in Rehnquist Court Fourth Amendment opinions, including the Court’s assessments of the moral virtue of “druggie” defendants. Finally, they draw conclusions from this analysis for a moral science of the politics of law.
Can Tuna Promote Sustainable Development in the Pacific?
Authors: Parris Hannah , Grafton R. Quentin
Published: August 2006

This article reviews the importance of tuna fisheries in the western and central Pacific Ocean to Pacific Island Countries (PICs) and examines whether current and proposed institutional mechanisms for tuna management are sufficient to promote long-term tuna-led development. Potential gains exist from cooperation on tuna management; however, it seems unlikely such benefits will be realized in the short or medium term despite the Convention on the Conservation and Management of Highly Migratory Fish Stocks in the Western and Central Pacific Ocean. Without improvements in the institutional capability of many PICs the tuna fisheries will likely fail to sustain the region's long-term development. Greater effort should be directed to support multinational institutions that reduce harvests, allow for transferability of harvesting rights across countries and vessels, manage financial risk, and for initiatives that improve the capacity and government effectiveness of PICs.
Corruption, Democracy, and Environmental Policy
Authors: Pellegrini Lorenzo , Gerlagh Reyer
Published: August 2006

Theoretical and empirical studies have shown that democracy and corruption influence environmental policies. In this article, the authors empirically analyze the relative importance of these determinants of environmental policy. When these variables are jointly included as explanatory variables in a multiple regression analysis, the authors found that corruption stands out as a substantial and significant determinant of environmental policies, while proxies for democracy have an insignificant impact. Nevertheless, democracy could affect environmental policy stringency given that countries with a history of democratic rule tend to be less corrupted. The authors argue that improving environmental quality following increasing income is less probable in developing countries with institutional disarray. Finally, and more optimistically, when considering the results in the context of institutions and growth, the authors conclude that there is scope for reaping a double dividend, when institutional improvements and reductions in corruption induce higher economic growth rates and stricter environmental policies.
Environmental Actions of Citizens
Authors: Mitchell Ross E.
Published: August 2006

The Citizen Submissions on Enforcement Matters is administered by the North American Commission for Environmental Cooperation (CEC), a trilateral institution established by the governments of Canada, Mexico, and the United States as part of the North American Agreement on Environmental Cooperation (NAAEC). The CEC received 55 submissions from June 1995 to May 2006, although these remain to be substantially discussed in the literature. This study fills in some of the gaps through an analysis of the submission process from an actor and results-based perspective. Two guiding questions form the basis for this article: What are some key demographic or geographical differences among “whistle-blowers” and has the submission process achieved its goals? The conclusion is that key differences among submitters are due to such interlinked factors as gender, place, and issue, which should be more carefully considered by the CEC and other related institutions to enhance effectiveness.
Investing in Natural Capital
Authors: Nino-Murcia Anamaria
Published: August 2006

This study quantifies the tangible, economic benefits of a nongovernmental organization's social forestry project to local people and analyzes the potential return from this investment in natural capital. The analysis was conducted in the Kumaun hill region of Uttaranchal, India, using participatory rapid appraisal, household survey, avoided cost method, and present value investment analysis. The annual value (based on the ecosystem service of goods provision) of the forest resource to local people was estimated at 903,337 rupees, and the total return on 8 years of investment through 2021 was projected to be 883%. Quantitative and qualitative results show that social forestry is a solid investment in natural and human capital. Overall, this study serves as one example of how ecosystem service valuation can be employed to achieve conservation and development goals.
The Environmental Conditions of the Working Class
Authors: Clark Brett , Foster John Bellamy
Published: August 2006

Both urban sociology in general and urban environmental justice studies began with Frederick Engels's seminal work The Condition of the Working Class in England in 1844 . Engels provided a walking tour of the environmental conditions in the manufacturing establishments and slums of the factory towns of England, together with a similar view of London. He addressed conditions of widespread pollution and helped lay the grounds for the development of social epidemiology. He connected this to his “Outlines of a Critique of Political Economy” that influenced his even more famous collaborator Karl Marx. For Engels, The Condition of the Working Class in England in 1844 was to be the first of a series of connected analyses of ecology that stretched through more than half a century and includedThe Housing Question andDialectics of Nature, making him one of the most important but underappreciated contributors to the development of environmental thought.
Louis Bromfield, Malabar Farm, and Faith in the Earth
Authors: Fleming Deborah
Published: August 2006

Louis Bromfield (1896-1956) produced at least two books whichshould be included n the canon of environmental writing and placehim among the ranks of notable literaryenvironmentalists— Pleasant Valley (1945) andMalabar Farm (1948). These books, as well as five other nonfiction works on sustainable agriculture and ecology, deserve to be placed in the literary tradition of Aldo Leopold's A Sand County Almanac. Bromfield himself should be considered to be a forerunner of the philosophies of Wendell Berry, Gary Snyder, and Wes Jackson. Bromfield's great success at popular fiction has caused him to be slighted not only by literary critics but also by environmentalist scholars; however, several recent critics have asserted that his fiction—much of which is concerned with environ-mental themes such as encroaching industrialism, despoilation of nature, and alienation of people from the land—as well as his nonfiction, should be reassessed. Placing him in the tradition of Sherwood Anderson, they believe that he has made a substantial contribution to the American literary canon.
Visible Braille/Invisible Blindness
Authors: Kleege Georgina
Published: August 2006

With the passage of the Americans with Disabilities Act (ADA) in 1990, braille signage began to appear in many public sites across the country. In many instances, however, the braille seems merely to refer to blindness rather than to aid blind people. Often, designers, though well-meaning, seem unaware of how braille is read or of the decline in braille literacy in recent decades. The use of braille serves as a visible gesture toward tolerance of difference but blind people who might derive meaning from it do not seem to be the intended audience. In some extreme cases, braille functions as a visual metaphor equating blindness with ignorance, prejudice, loss or despair, thus reinforcing negative stereotypes. This article examines the use of braille in several public sites and analyzes its effectiveness at promoting a more inclusive society. How will the use of braille in public places change as the blind continue to progress from the margins of cultural consciousness and become more visible in the public sphere?
Shame, Empathy and Looking Practices: Lessons from a Disability Studies Classroom
Authors: Benin David , Cartwright Lisa
Published: August 2006

This article proposes a use of Silvan Tomkins’s concept of shame to understand classroom practices of looking at photographs that represent bodies with visible disabilities. We consider an instance of classroom looking to suggest a concept of intersubjective, authorized public looking and to propose that the experiences of surprise and shame are constitutive of empathetic identification and the kind of social connectedness needed for a shared disability politics.
Communicating the terrorist risk: Harnessing a culture of fear?
Authors: Mythen Gabe , Walklate Sandra
Published: August 2006

Following the terrorist attacks in New York, Washington, Madrid and London, state agencies have been bound up with the problem of how to effectively communicate the risk of terrorism to the general public. This article charts the UK government's attempts to engage in this process and illustrates how the communication of the terrorist risk meshes into broader cultural formations of crime and (in)security. Our analytical framework utilizes the risk society as the scene in which governmental strategies are parcelled up and unpacked. It is posited that the framing of the terrorist problem through the political discourse of ‘new terrorism’ has built upon and escalated a cultural climate of fear and uncertainty. At the level of political communication, it will be elucidated that media representations of the terrorist threat have served to further embed discourses of responsibilization. In our view such processes not only articulate a reduced notion of safety, they also pave the way for the simplistic construction of a non-white ‘terroristic other’ that has negative consequences for ethnic minority groups in the UK.
How to explain a suicide
Authors: Drakeford Mark
Published: August 2006

This polemic explores a newspaper article about youth justice. It suggests that a dominant discourse holds a powerful hegemony over large parts of the British media through which young people generally, and those in trouble with the law, in particular, are demonized. When events take place which threaten to disrupt that discourse, strenuous journalistic efforts have to be made to counteract that disruption and to reaffirm established understandings, however flawed those understandings might be. This article anatomizes that process in operation and in relation to a particular event – the suicide, in 2004, of Adam Rickwood, the youngest child ever to take his own life while in the care and custody of the modern British penal system.
Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells
Authors: Gray Daniel H. D. , Seach Natalie , Ueno Tomoo , Milton Morag K. , Liston Adrian , Lew Andrew M. , Goodnow Christopher C. , Boyd Richard L.
Published: August 2006

Despite the importance of thymic stromal cells to T-cell development, relatively little is known about their biology. Here, we use single-cell analysis of stromal cells to analyze extensive changes in the number and composition of thymic stroma throughout life, revealing a surprisingly dynamic population. Phenotypic progression of thymic epithelial subsets was assessed at high resolution in young mice to provide a developmental framework. The cellular and molecular requirements of adult epithelium were studied, using various mutant mice to demonstrate new cross talk checkpoints dependent on RelB in the cortex and CD40 in the medulla. With the use of Ki67 and BrdU labeling, the turnover of thymic epithelium was found to be rapid, but then diminished on thymic involution. The various defects in stromal turnover and composition that accompanied involution were rapidly reversed following sex steroid ablation. Unexpectedly, mature cortical and medullary epithelium showed a potent capacity to stimulate naive T cells, comparable to that of thymic dendritic cells. Overall, these studies show that the thymic stroma is a surprisingly dynamic population and may have a more direct role in negative selection than previously thought.
Receptor-type protein tyrosine phosphatase gamma (PTPγ), a new identifier for myeloid dendritic cells and specialized macrophages
Authors: Lissandrini Daniele , Vermi William , Vezzalini Marzia , Sozzani Silvano , Facchetti Fabio , Bellone Graziella , Mafficini Andrea , Gentili Francesca , Ennas Maria Grazia , Tecchio Cristina , Sorio Claudio
Published: August 2006

Protein tyrosine phosphatase (PTPγ) is a receptor-like molecule with a known role in murine hematopoiesis. We analyzed the regulation of PTPγ expression in the human hematopoietic system, where it was detected in human peripheral blood monocytes and dendritic cells (DCs) of myeloid and plasmacytoid phenotypes. Its expression was maintained during in vitro monocyte differentiation to dendritic cells (moDC) and was further increased after maturation with bacterial lipopolysaccharide (LPS), CD40L, and TNFα. But PTPγ was absent when monocytes from the same donor were induced to differentiate in macrophages. B and T lymphocytes did not express PTPγ. Rather, PTPγ mRNA was expressed in primary and secondary lymphoid tissues, and the highest expression was in the spleen. PTPγ was detected by immunohistochemistry in subsets of myeloid-derived DCs and specialized macrophages (tingible bodies, sinus and alveolar macrophages). Classic macrophages in infective or reactive granulomatous reactions did not express PTPγ. Increased PTPγ expression was associated with a decreased ability to induce proliferation and interferon-γ secretion in T cells by moDCs from patients with advanced pancreatic cancer. Taken together, these results indicate that PTPγ is a finely regulated protein in DC and macrophage subsets in vitro and in vivo.
Can volunteer companions prevent falls among inpatients? A feasibility study using a pre-post comparative design
Authors: Giles Lynne C , Bolch Denise , Rouvray Robyn , McErlean Beth , Whitehead Craig H , Phillips Paddy A , Crotty Maria
Published: August 2006

Background

Falls in hospital are frequent and their consequences place an increased burden on health services. We evaluated a falls prevention strategy consisting of the introduction of volunteers to 'sit' with patients identified as being at high risk of falling.

Methods

Two four bed 'safety bays' located on medical wards in two hospitals within southern Adelaide were used. Ward fall rates (expressed as falls per 1000 occupied bed days) were compared in the baseline period (February-May 2002) with the implementation period (February – May 2003) using incident rate ratios and 95% confidence intervals. The number of hours of volunteered time was also collected.

Results

No patient falls occurred on either site when volunteers were present. However, there was no significant impact on overall ward fall rates. In the baseline period, there were 70 falls in 4828 OBDs (14.5 falls per 1000 OBDs). During the implementation period, there were 82 falls in 5300 OBDs (15.5 falls per 1000 OBD). The IRR for falls in the implementation versus baseline period was 1.07 (95%CI 0.77 – 1.49; P = 0.346). Volunteers carried out care activities (e.g. cutting up food), provided company, and on occasions advocated on behalf of the patients. Volunteers donated 2345 hours, at an estimated value to the hospitals of almost $57,000.

Conclusion

Volunteers may play an important and cost-effective role in enhancing health care and can prevent falls in older hospital patients when they are present. Full implementation of this program would require the recruitment of adequate numbers of volunteers willing to sit with all patients considered at risk of falling in hospital. The challenge for future work in this area remains the sustainability of falls prevention strategies.
Down-regulation of c-Myc following MEK/ERK inhibition halts the expression of malignant phenotype in rhabdomyosarcoma and in non muscle-derived human tumors
Authors: Marampon Francesco , Ciccarelli Carmela , Zani Bianca M
Published: August 2006

Background

Expression of c-myc proto-oncogene is inappropriate in a wide range of human tumors, and is a downstream target of Ras/Raf/ERK pathway, which promotes c-Myc stability by enhancing c-Myc expression and activity.

The aim of this study was to investigate whether the oncogenic phenotype in the human muscle-derived Rhabdomyosarcoma (RD) cell line and in non muscle-derived human tumor cell lines (SW403, IGR39 and PC3) can be blocked by disrupting the c-Myc pathway either by means of pharmacological MEK/ERK inhibition or by direct inactivation of the c-Myc protein.

Results

We demonstrate that, in all the tumor cell lines used, the MEK/ERK inhibitor U0126 rapidly induces c-Myc de-phosphorylation, which is followed by a marked reduction in its expression level, by inhibition of proliferation and by reversion of anchorage-independent growth. These data suggest that the targeting of pathways controlling c-Myc expression or stability reverses deregulated growth of different tumor-derived cell lines. Indeed, in RD cells, we found a marked down-regulation of cyclins E2, A and B and CDK2, all of which are known to be targets of c-Myc. Moreover, ectopic MadMyc chimera, a c-Myc function antagonist, causes dramatic growth arrest, CDK and cyclin modulation as well as inhibition of anchorage-independent growth in RD cells, as occurs in U0126-treated cells. In particular, we found that the mere inhibition of c-Myc by MadMyc chimera rescues the myogenic program, MHC expression and the acquisition of the myogenic-like phenotype in RD cells.

Conclusion

Our data provide evidence of the key role played by the MEK/ERK pathway in the growth arrest and transformation phenotype of Rhabdomyosarcoma and of non muscle-derived tumor cell lines. In fact, MEK/ERK inhibitor, U0126, induces growth arrest, anchorage-dependent growth of these cell lines. In addition, the results of this study demonstrate that the direct inactivation of c-Myc by Mad/Myc chimera rescues myogenic program and leads to the reversal of the Rhabdomyosarcoma phenotype. In conclusion these data strongly suggest that the targeting of c-Myc by means of the MEK inhibitor can be tested as a promising strategy in anti-cancer therapy.
Barriers and facilitators to implementing shared decision-making in clinical practice: a systematic review of health professionals' perceptions
Authors: Gravel Karine , Légaré France , Graham Ian D
Published: August 2006

Background

Shared decision-making is advocated because of its potential to improve the quality of the decision-making process for patients and ultimately, patient outcomes. However, current evidence suggests that shared decision-making has not yet been widely adopted by health professionals. Therefore, a systematic review was performed on the barriers and facilitators to implementing shared decision-making in clinical practice as perceived by health professionals.

Methods

Covering the period from 1990 to March 2006, PubMed, Embase, CINHAL, PsycINFO, and Dissertation Abstracts were searched for studies in English or French. The references from included studies also were consulted. Studies were included if they reported on health professionals' perceived barriers and facilitators to implementing shared decision-making in their practices. Shared decision-making was defined as a joint process of decision making between health professionals and patients, or as decision support interventions including decision aids, or as the active participation of patients in decision making. No study design was excluded. Quality of the studies included was assessed independently by two of the authors. Using a pre-established taxonomy of barriers and facilitators to implementing clinical practice guidelines in practice, content analysis was performed.

Results

Thirty-one publications covering 28 unique studies were included. Eleven studies were from the UK, eight from the USA, four from Canada, two from the Netherlands, and one from each of the following countries: France, Mexico, and Australia. Most of the studies used qualitative methods exclusively (18/28). Overall, the vast majority of participants (n = 2784) were physicians (89%). The three most often reported barriers were: time constraints (18/28), lack of applicability due to patient characteristics (12/28), and lack of applicability due to the clinical situation (12/28). The three most often reported facilitators were: provider motivation (15/28), positive impact on the clinical process (11/28), and positive impact on patient outcomes (10/28).

Conclusion

This systematic review reveals that interventions to foster implementation of shared decision-making in clinical practice will need to address a broad range of factors. It also reveals that on this subject there is very little known about any health professionals others than physicians. Future studies about implementation of shared decision-making should target a more diverse group of health professionals.
Effects of 17β-estradiol and flutamide on inflammatory response and distant organ damage following trauma-hemorrhage in metestrus females
Authors: Hildebrand Frank , Hubbard William J , Choudhry Mashkoor A , Thobe Bjoern M , Pape Hans-Christoph , Chaudry Irshad H
Published: August 2006

We hypothesized that administration of androgen receptors antagonist flutamide following trauma-hemorrhage (T-H) in metestrus females will maintain immune function and reduce remote organ damage under those conditions. Female B57BL/J6 mice (metestrus state, 8–12 weeks old) underwent laparotomy and hemorrhagic shock (35.0±5.0 mmHg for 90 min) and then received 17β-estradiol (E2; 50 μg/25 g), flutamide (625 μg/25 g), or E2 + flutamide. Four hours after resuscitation, plasma cytokine and chemokine (TNF-α, IL-6, IL-10, IFN-γ, and MCP-1) concentrations and their release in vitro by hepatic and pulmonary tissue macrophages (MΦ) were determined by flow cytometry. Organ damage was assessed by edema formation (wet-to-dry weight ratio) and neutrophil infiltration [myeloperoxidase (MPO) activity]. Administration of E2, flutamide, or E2 + flutamide following T-H resulted in a significant decrease in systemic TNF-α, IL-6, and MCP-1 concentrations under those conditions. This was accompanied by significantly decreased in vitro TNF-α release by Kupffer cells after administration of E2, flutamide, or E2 + flutamide. The in vitro release of proinflammatory cytokines by alveolar MΦ, however, was reduced significantly only by the addition of E2 or E2 + flutamide but not by the addition of flutamide. A significant decrease in pulmonary and hepatic edema formation as well as neutrophil infiltration in the lung was observed after E2, flutamide and E2 + flutamide administration. In contrast, hepatic neutrophil infiltration was only significantly reduced following E2 and E2 + flutamide administration. Thus, although flutamide does not produce synergistic, salutary effects with E2, its administration in females following T-H also produces salutary effects on the immune and organ function, similar to E2 administration under those conditions.
Immature monocytes from G-CSF-mobilized peripheral blood stem cell collections carry surface-bound IL-10 and have the potential to modulate alloreactivity
Authors: Fraser A R , Cook G , Franklin I M , Templeton J G , Campbell M , Holyoake T L , Campbell J D M
Published: August 2006

Production of the anti-inflammatory cytokine IL-10 by monocytes has been implicated as a probable negative regulator of graft-versus-host disease (GvHD) in patients undergoing allogeneic stem cell transplants (SCT). Monocytes from G-CSF-mobilized peripheral blood stem cell (gmPBSC) collections have been reported to produce more IL-10 than unmobilized monocytes in response to proinflammatory factors such as LPS. Why this should occur is unclear. In this study, monocyte phenotype and IL-10 localization and release were investigated in PB mononuclear cells (MNC) from 27 healthy donors mobilized for allogeneic SCT and from 13 patients with hematological malignancies mobilized for autologous SCT. All isolates contained elevated total percentages of monocytes in comparison with unmobilized PB, a high proportion of which displayed an immature phenotype. Stimulation of gmPB MNC with an inflammatory stimulus [fixed Staphylococcus aureus cells (SAC)] induced rapid up-regulation of CD14, indicating conversion to mature status. Localization studies indicated that IL-10 was predominantly present, bound on the surface of CD64+/CD14low/neg immature monocytes. Inflammatory stimuli (LPS, polyinosinic:polycytidylic acid, or SAC) induced release of variable quantities of IL-10 from the cell surface. MNC, separated into surface IL-10-positive or -negative fractions, differed in their ability to stimulate alloreactivity in MLR, and IL-10+ MNC induced significantly lower levels of proliferation than IL-10− MNC. Thus, the subset of immature monocytes carrying surface-bound IL-10 in gmPB has the potential to modulate alloreactivity and GvHD after allogeneic SCT through cell-to-cell contact and released IL-10.
Clinical Activity of Pertuzumab (rhuMAb 2C4), a HER Dimerization Inhibitor, in Advanced Ovarian Cancer: Potential Predictive Relationship With Tumor HER2 Activation Status
Authors: Gordon Michael S. , Matei Daniela , Aghajanian Carol , Matulonis Ursula A. , Brewer Molly , Fleming Gini F. , Hainsworth John D. , Garcia Agustin A. , Pegram Mark D. , Schilder Russell J. , Cohn David E. , Roman Lynda , Derynck Mika K. , Ng Kimmie , Lyons Benjamin , Allison David E. , Eberhard David A. , Pham Thinh Q. , Dere Randall C. , Karlan Beth Y.
Published: August 2006

Purpose

Ovarian cancers (OCs) frequently have HER2 activation in the absence of HER2 overexpression. Pertuzumab, a humanized antibody that prevents HER2 dimerization and inhibits multiple HER-mediated pathways, was studied in a phase II, multicenter trial in advanced, refractory OC.

Patients and Methods

Sixty-one patients (cohort 1) with relapsed OC received a loading dose of 840 mg pertuzumab intravenously followed by 420 mg every 3 weeks; 62 patients (cohort 2) received 1,050 mg every 3 weeks. Response rate was the primary end point. Fresh tumor biopsies were obtained in cohort 1 to assay for phosphorylated HER2 (pHER2).

Results

Median age was 57 years and median number of prior chemotherapy regimens was five. Fifty-five patients in cohort 1 and 62 patients in cohort 2 were assessable for efficacy. There were five partial responses (response rate [RR] = 4.3%; 95% CI, 1.7% to 9.4%), eight patients (6.8%) with stable disease (SD) lasting at least 6 months, and 10 patients with CA-125 reduction of at least 50% (includes two partial responses and four patients with SD ≥ 6 months; total clinical activity, 14.5%). Median progression-free survival (PFS) was 6.6 weeks. Eight of 28 tumor biopsies (28.6%) were pHER2+ by enzyme-linked immunosorbent assay (ELISA; without gene amplification). Median PFS for pHER2+ patients was 20.9 weeks (n = 8) versus 5.8 weeks for pHER2− (n = 20; P = .14) and 9.1 weeks for unknown pHER2 status (n = 27). Pertuzumab was well tolerated with diarrhea in 69.1% (11.4% grade 3, no grade 4). Five patients had asymptomatic left ventricular ejection fraction decreases to less than 50% (one confirmed by central facility).

Conclusion

Pertuzumab is well tolerated with a RR of 4.3% in heavily-pretreated OC patients. Further studies on pHER2 as a diagnostic are warranted.
Efficacy of Adjuvant Radiotherapy of the Tumor Bed on Local Recurrence of Adrenocortical Carcinoma
Authors: Fassnacht Martin , Hahner Stefanie , Polat Buelent , Koschker Ann-Cathrin , Kenn Werner , Flentje Michael , Allolio Bruno
Published: August 2006

Context: Local tumor recurrence is common in adrenocortical carcinoma (ACC) and is the most frequent cause for reoperation. Although radiotherapy is often considered ineffective in the treatment of ACC, the limited number of available studies does not support this statement.

Objective: The objective of the study was investigation of adjuvant tumor bed irradiation in the treatment of ACC.

Design: We performed a retrospective analysis.

Patients: The German ACC Registry (n = 285) was screened for patients who had received tumor bed radiotherapy in an adjuvant setting (no macroscopic evidence for residual disease after surgery). Fourteen patients without distant metastases (World Health Organization stage I, one patient; stage II, seven; stage III, three; and stage IV, three) were matched with 14 patients for resection status, adjuvant mitotane treatment, stage, and tumor size. Median follow-up of patients still alive (n = 15) was 37 months.

Main Outcome Measure: Survival without local recurrence and disease-free survival was the main outcome measure.

Results: Local recurrence was observed in two of 14 patients in the radiotherapy group and in 11 of 14 control patients. The probability to be free of local recurrence 5 yr after surgery differed significantly [79% (95% confidence interval, 53–100) vs. 12% (0–30); P < 0.01]. However, disease-free and overall survival were not significantly different between the two groups. Acute adverse events related to radiotherapy were mostly mild. One patient developed a partial Budd-Chiari syndrome.

Conclusion: These data from the largest series of ACC patients treated with adjuvant tumor bed irradiation suggest that radiotherapy is effective in reducing the high rate of local recurrence in ACC. A randomized trial in high-risk patients is needed to further evaluate the efficacy of radiotherapy as an adjuvant treatment option in ACC.
Increased Subcutaneous and Epicardial Adipose Tissue Production of Proinflammatory Cytokines in Cardiac Surgery Patients: Possible Role in Postoperative Insulin Resistance
Authors: Kremen Jaromir , Dolinkova Marketa , Krajickova Jana , Blaha Jan , Anderlova Katerina , Lacinova Zdena , Haluzikova Denisa , Bosanska Lenka , Vokurka Martin , Svacina Stepan , Haluzik Martin
Published: August 2006

Context: Hyperglycemia and insulin resistance frequently occur in critically ill patients even without a history of diabetes.

Objective: Our objective was to study the role of adipose tissue hormonal production in the development of insulin resistance in cardiac surgery patients.

Participants, Interventions, and Settings: Fifteen patients with elective cardiac surgery underwent blood sampling before, at the end, and 6, 12, 24, 48, and 120 h after the end of their operation. Epicardial and sc adipose tissue sampling was done at the beginning and at the end of surgery in the Department of Cardiac Surgery.

Main Outcome Measures: We measured serum concentrations and sc and epicardial adipose tissue mRNA expression of IL-6, monocyte chemoattractant protein-1 (MCP-1), TNF-α, leptin, resistin, and adiponectin and sc and epicardial adipose tissue mRNA expression of CD14, CD45, and CD68.

Results: The rate of insulin infusion required to maintain euglycemia increased up to 7-fold 12 h after the operation, suggesting the development of insulin resistance. Serum IL-6 levels increased 43-fold 12 h after surgery. MCP-1 peaked 6-fold at the end of surgery. Smaller peaks of TNF-α and leptin appeared 6 and 12 h after surgery, respectively. Resistin levels peaked 4-fold 24 h after surgery, but adiponectin levels were not significantly affected. TNF-α and CD45 mRNA expression increased markedly during the operation in sc adipose tissue. IL-6, resistin, and MCP-1 mRNA expression increased in both sc and epicardial adipose tissue. Leptin, adiponectin, CD14, and CD68 mRNA expression did not change significantly.

Conclusions: Both sc and epicardial adipose tissue is a source of proinflammatory cytokines in cardiac surgery patients and may contribute to the development of postoperative insulin resistance.
Brain-specific BNIP-2-homology protein Caytaxin relocalises glutaminase to neurite terminals and reduces glutamate levels
Authors: Buschdorf Jan Paul , Li Chew Li , Zhang Bin , Cao Qiong , Liang Feng-Yi , Liou Yih-Cherng , Zhou Yi Ting , Low Boon Chuan
Published: August 2006

Human Cayman ataxia and mouse or rat dystonia are linked to mutations in the genes ATCAY (Atcay) that encode BNIP-H or Caytaxin, a brain-specific member of the BNIP-2 family. To explore its possible role(s) in neuronal function, we used protein precipitation and matrix-assisted laser desorption/ionisation mass spectrometry and identified kidney-type glutaminase (KGA) as a novel partner of BNIP-H. KGA converts glutamine to glutamate, which could serve as an important source of neurotransmitter. Co-immunoprecipitation with specific BNIP-H antibody confirmed that endogenous BNIP-H and KGA form a physiological complex in the brain, whereas binding studies showed that they interact with each other directly. Immunohistochemistry and in situ hybridisation revealed high BNIP-H expression in hippocampus and cerebellum, broadly overlapping with the expression pattern previously reported for KGA. Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. It also reduced the steady-state levels of glutamate by inhibiting KGA enzyme activity. These results strongly suggest that through binding to KGA, BNIP-H could regulate glutamate synthesis at synapses during neurotransmission. Thus, loss of BNIP-H function could render glutamate excitotoxicity or/and deregulated glutamatergic activation, leading to ataxia, dystonia or other neurological disorders.
Activation of Tie2 by angiopoietin-1 and angiopoietin-2 results in their release and receptor internalization
Authors: Bogdanovic Elena , Nguyen Vicky P. K. H. , Dumont Daniel J.
Published: August 2006

The receptor tyrosine kinase Tie2 is highly expressed in endothelial cells and is crucial for angiogenesis and vascular maintenance. The ligands for Tie2 are the angiopoietins, of which angiopoietin-1 and angiopoietin-2 have been the most studied. Angiopoietin-1 has been characterized as the primary activating ligand for Tie2 whereas the role of angiopoietin-2 remains controversial; activating Tie2 in some studies and inhibiting Tie2 in others. Our studies were aimed at understanding the regulation of Tie2 in endothelial cells by angiopoietin-1 and angiopoietin-2 and revealed that both ligands activated Tie2 in a concentration-dependent manner. Angiopoietin-2 was considerably weaker at activating Tie2 compared with angiopoietin-1 suggesting that angiopoietin-2 may be a partial agonist. Activation of Tie2 by these ligands resulted in differential turnover of the receptor where binding of angiopoietin-1, and to a lesser extent angiopoietin-2, induced rapid internalization and degradation of Tie2. Furthermore, our binding studies demonstrate that both ligands are differentially released from the endothelial cell surface after receptor activation and accumulate in the surrounding medium. Altogether, these data begin our understanding of the regulation of Tie2 and the activity of the angiopoietins after engaging the endothelial cell surface.
RhoA-kinase coordinates F-actin organization and myosin II activity during semaphorin-3A-induced axon retraction
Authors: Gallo Gianluca
Published: August 2006

Axon guidance is mediated by the effects of attractant and repellent guidance cues on the cytoskeleton of growth cones and axons. During development, axon retraction is an important aspect of the pruning of inappropriately targeted axons in response to repellent guidance cues. I investigated the roles of RhoA-kinase and myosin II in semaphorin-3A-induced growth cone collapse and axon retraction. I report that semaphorin 3A activates myosin II in growth cones and axons. Myosin II activity is required for axon retraction but not growth cone collapse. Furthermore, semaphorin 3A promotes the formation of intra-axonal F-actin bundles in concert with the loss of F-actin in growth cone lamellipodia and filopodia. Formation of axonal F-actin bundles was independent of myosin II, but partially required RhoA-kinase activity. Conversely, RhoA-kinase activity was required to shut down F-actin polymerization underlying protrusive activity. Collectively, these observations suggest that guidance cues cause axon retraction through the coordinated activation of myosin II and the formation of intra-axonal F-actin bundles for myosin-II-based force generation. I suggest that in the context of semaphorin 3A signaling, RhoA-kinase serves as a switch to change the function of the F-actin cytoskeleton from promoting protrusive activity to generating contractile forces.
A computational model of intracellular oxygen sensing by hypoxia-inducible factor HIF1α
Authors: Qutub Amina A. , Popel Aleksander S.
Published: August 2006

Hypoxia-inducible factor-1, HIF1, transcriptionally activates over 200 genes vital for cell homeostasis and angiogenesis. We developed a computational model to gain a detailed quantitative understanding of how HIF1 acts to sense oxygen and respond to hypoxia. The model consists of kinetic equations describing the intracellular variation of 17 compounds, including HIF1, iron, prolyl hydroxylase, oxygen, ascorbate, 2-oxoglutarate, von Hippel Lindau protein and associated complexes. We tested an existing hypothesis of a switch-like change in HIF1 expression in response to a gradual decrease in O2 concentration. Our model predicts that depending on the molecular environment, such as intracellular iron levels, the hypoxic response varies considerably. We show HIF1-activated cellular responses can be divided into two categories: a steep, switch-like response to O2 and a gradual one. Discovery of this dual response prompted comparison of two therapeutic strategies, ascorbate and iron supplementation, and prolyl hydroxylase targeting, to predict under what microenvironments either effectively increases HIF1α hydroxylation. Results provide crucial insight into the effects of iron and prolyl hydroxylase on oxygen sensing. The model advances quantitative molecular level understanding of HIF1 pathways - an endeavor that will help elucidate the diverse responses to hypoxia found in cancer, ischemia and exercise.