bluuebunny/crossref_metadata_2025 huggingface dataset:
Reducing the Risk of Dementia
Authors: Peila Rita , White Lon R. , Masaki Kamal , Petrovitch Helen , Launer Lenore J.
Published: April 2006

Background and Purpose—

The efficacy of treating older persons for hypertension remains controversial. Although clinical trials suggest no short-term harm, or some benefits, there are little data on the effect on cognitive function of long-term antihypertensive treatment. We evaluated the risk of dementia and cognitive decline associated with duration of antihypertensive treatment.

Methods—

Data are from the Honolulu Asia Aging Study on Japanese American men followed since 1965. The subjects included in this analysis were hypertensive from midlife and dementia-free in 1991 (mean age 76.7 years). In 1991, 1994 and 1997, global cognitive function was assessed with the Cognitive Abilities Screening Instrument (CASI) and dementia by a standardized examination using international criteria. The sample was grouped by treatment duration (never-treated hypertensives (NTH), <5 years, 5 to 12 years, >12 years). Normotensive subjects up to 1991 were included in the analysis as a control group.

Results—

For each additional year of treatment there was a reduction in the risk of incident dementia (hazard ratio [HR]=0.94, 95% CI, 0.89 to 0.99). The risk for dementia in subjects with >12 years of treatment was lower compared to NTH (HR for dementia=0.40; 95% CI, 0.22 to 0.75 and for Alzheimer disease HR=0.35; 95% CI, 0.16 to 0.78) and was similar to the normotensives. Nondemented subjects with 5 to 12 years of treatment had lower yearly CASI decline compared to NTH.

Conclusions—

Results suggest that in hypertensive men, the duration of the antihypertensive treatment is associated with a reduced risk for dementia and cognitive decline.
Poststroke C-Reactive Protein Is a Powerful Prognostic Tool Among Candidates for Thrombolysis
Authors: Montaner Joan , Fernandez-Cadenas Israel , Molina Carlos A. , Ribó Marc , Huertas Rafael , Rosell Anna , Penalba Anna , Ortega Laura , Chacón Pilar , Alvarez-Sabín José
Published: April 2006

Background and Purpose—

After acute stroke, an increased level of C-reactive protein (CRP) measured at discharge predicts unfavorable outcome. We sought to investigate whether CRP measured before tissue plasminogen activator (tPA) treatments may add prognostic information to guide stroke thrombolysis.

Methods—

Our target was 151 consecutive patients with an ischemic stroke involving the middle cerebral artery territory who received tPA within 3 hours of symptom onset. High-sensitivity CRP was measured before tPA administration, and CRP gene polymorphisms were determined (G1059C and C1444T). Functional outcome was evaluated by 3-month modified Rankin Scale (mRS).

Results—

A total of 143 tPA-treated patients were valid for analyses after exclusion of those with inflammatory diseases and those probably infected (CRP >6 mg/dL). Patients with history of previous stroke, hypertension, or atrial fibrillation had higher levels of CRP (
P
<0.05). CRP was higher in patients who died after thrombolysis (n=19) than in survivors (0.85 versus 0.53 mg/dL;
P
=0.002). Among the 94 patients with proximal middle cerebral artery occlusions, CRP level was 0.53 for 81 survivors versus 0.81 mg/dL for 13 who died (
P
=0.001). CRP-survival association was found even among patients who recanalized by the end of tPA infusion (
P
=0.007). A correlation between CRP and mRS was found (
r
=0.36,
P
=0.02), although CRP polymorphisms were not related to neurological outcome. In a logistic regression model, CRP (odds ratio=8.51; 95% CI, 2.16 to 33.5;
P
=0.002) and age (odds ratio=6.25; 95% CI, 1.44 to 27.19;
P
=0.015) were the only baseline mortality predictors.

Conclusions—

Admission CRP predicts mortality among tPA-treated stroke patients. Very early recanalization does not ameliorate the negative prognostic impact of elevated CRP.
Increasing Rates of Dementia at Time of Declining Mortality From Stroke
Authors: Ukraintseva Svetlana , Sloan Frank , Arbeev Konstantin , Yashin Anatoly
Published: April 2006

Background and Purpose—

Stroke is associated with increased risk of dementia. There has been a decline in mortality from stroke among persons 65 and over in recent decades in the US. It is not clear, however, how this process has affected incidence of various dementias.

Methods—

We evaluated over time changes in stroke admission rates and survival, and in rates of newly diagnosed dementias (Alzheimer disease, senile, and cerebrovascular disease–related dementia) in persons with and without stroke aged 65 and over, using Medicare inpatient records, 1984 to 2001, linked to the National Long-Term Care Survey (about 380 000 person-years totally).

Results—

Age-adjusted stroke rate increased from 0.0066 to 0.008 (
P
=0.08) from 1984–1990 to 1991–2001. One-year survival after stroke improved from 53% in 1984 to 1990 to 65% in 1991 to 1996 (
P
<0.0001). Age-standardized rate of diagnosed dementias increased from 0.0062 in 1984 to 1990 to 0.0095 in 1991 to 2000 (
P
=0.001). Among stroke patients the rate rose from 0.043 to 0.080. The relative increase in risk was largest for cerebrovascular disease–related dementia (3.68). For senile dementia, the increase was small and not significant. Rates of dementia among persons without stroke rose mainly attributable to Alzheimer disease.

Conclusions—

Mortality from stroke declined mainly because of declining stroke case-fatality. In parallel, the rate of diagnosed dementia increased. The increase was larger for persons with stroke compared with stroke-free population. Improved survival from stroke may contribute to this trend. Other contributing factors may include better diagnostics, an increased propensity to make the diagnosis, and increasing dementia risk attributable to factors other than stroke.
The Politics of Perception: Legislative Images of the Tourism Industry in Virginia and North Carolina
Authors: McGehee Nancy G. , Meng Fang
Published: April 2006

The purpose of this study was to examine politicians' perceptions of the tourism industry, focusing specifically on (1) image and knowledge of the tourism industry, and (2) recommendations regarding lobbying techniques, in part using White's (2001) typology of lobbying techniques. To facilitate mixed method analysis, the survey instrument included both closed- and open-ended questions. Results of this study revealed that legislators held a positive image of tourism in their respective states but were not very knowledgeable about the economic impact of the tourism industry. In regard to lobbying, legislators preferred constituent-based techniques over classic-direct, electronic, or schmoozing techniques and had concerns about perceived attempts to stretch the truth, exaggerate numbers, or oversell the industry. This study concludes with recommendations for a three-pronged approach to lobbying tourism to legislators. The sample population for this study was state legislators in North Carolina and Virginia, United States.
Visitors' Behavior in Heritage Cities: The Case of Girona
Authors: Espelt Nuria Galí , Benito José Antonio Donaire
Published: April 2006

This article presents the results of the study of the behavior of visitors in the monumental city of Girona, Spain. The focus of this study has been the classification of clusters of visitors who show the same behavior. We wanted to define the visitors' hierarchical conglomerates (those internally homogeneous and externally different groups) that will help to appreciate the subtleties in the apparent uniformity of the approach taken to visiting heritage sites. The groups of visitors will show specific needs, ways of looking, and behaviors.
Destination Attractiveness Based on Supply and Demand Evaluations: An Analytical Framework
Authors: Formica Sandro , Uysal Muzaffer
Published: April 2006

This article presents a model to explain and measure the determinants of tourism attractiveness of a destination by measuring supply-and-demand indicators. The guiding principle of this study is that the overall tourism attractiveness of a destination depends on the relationship between the availability of existing attractions and the perceived importance of such attractions. The method used qualitative and quantitative statistical analysis to inventory, group, and measure the existing attraction portfolio and its perceived importance. The findings confirmed that tourism regions are not created equal and reveal significant spatial differences in terms of resource availability and actual perception of these resources. The proposed framework could be used as a decision-making tool in planning, marketing, and developing appropriate resource allocation strategies.
An American Evangelical Pilgrimage to Israel: A Case Study on Politics and Triangulation
Authors: Belhassen Yaniv , Santos Carla Almeida
Published: April 2006

This article examines the political dimensions of American evangelical pilgrimages to Israel by using the methodological technique known as data triangulation. Based on evidence from primary and secondary data, the article illuminates (1) how tourism is used by pilgrims to promote their theological visions that have some political ramifications to the host country and (2) how the political circumstances in the state of Israel engender a noteworthy relationship between an extreme right party from Israel and the pilgrims. The findings regarding the political dimensions are organized around four functions achieved by using data triangulation. In so doing, this article attempts to provide new theoretical insights regarding the philosophical premises and the purposes traditionally related to the use of data triangulation in tourism research.
Editorial: Ethics and Engineering Design
Authors: van de Poel Ibo , Verbeek Peter-Paul
Published: April 2006

Engineering ethics and science and technology studies (STS) have until now developed as separate enterprises. The authors argue that they can learn a lot from each other. STS insights can help make engineering ethics open the black box of technology and help discern ethical issues in engineering design. Engineering ethics, on the other hand, might help STS to overcome its normative sterility. The contributions in this special issue show in various ways how the gap between STS and engineering ethics might be overcome. In this editorial introduction, the authors discuss the various contributions briefly and delve into the way the various authors conceptualize the engineering design process and the consequences of those conceptualizations for what ethical issues become visible. They also discuss the implications for the responsibility of engineers for technological development.
Regulation or Responsibility? Autonomy, Moral Imagination, and Engineering
Authors: Coeckelbergh Mark
Published: April 2006

A prima facie analysis suggests that there are essentially two, mutually exclusive, ways in which risk arising from engineering design can be managed: by imposing external constraints on engineers or by engendering their feelings of responsibility and respect their autonomy. The author discusses the advantages and disadvantages of both approaches. However, he then shows that this opposition is a false one and that there is no simple relation between regulation and autonomy. Furthermore, the author argues that the most pressing need is not more or less regulation but the further development of moral imagination. The enhancement of moral imagination can help engineers to discern the moral relevance of design problems, to create new design options, and to envisage the possible outcomes of their designs. The author suggests a dual program of developing regulatory frameworks that support engineers’ autonomy and responsibility simultaneously with efforts to promote their moral imagination. He describes how some existing institutional changes have started off in this direction and proposes empirical research to take this further.
A Framework for Strategic Network Design Assessment, Decision Making, and Moral Imagination
Authors: Mehalik Matthew M. , Gorman Michael E.
Published: April 2006

This article presents a framework for practitioners who may be interested in maintaining adaptive stability of sociotechnical networks. The framework is developed from assembling several concepts that are useful for assessing and for drawing on appropriate moral reasoning strategies as sociotechnical networks are designed, constructed, and adapted. One such strategy involves the ability to assess degrees of perspective sharing and trading relationships in networks using moral imagination. The article uses the case of the design of an environmentally sustainable fabric to illustrate these strategic concepts. The framework also draws on other examples of cases in which sociotechnical networks have become destabilized to illustrate instances in which the framework may have been useful for decreasing a tendency for destabilization.
Responsibility without Moralism in Technoscientific Design Practice
Authors: Swierstra Tsjalling , Jelsma Jaap
Published: April 2006

While engineering ethics usually addresses the responsibility of engineers in rare cases of whistle blowing, the authors broach the question to what extent engineers can be held responsible in normal practice. For this purpose, they define the conditions under which individuals can be imputable as they prevail in ethics and common sense. From outcomes of science and technology studies research, the authors conclude that these conditions are seldom met in modern technoscientific research practice. By examining such practice in a case study and comparing the results with perceptions of engineers on social responsibility as expressed in interviews, the authors are able to demonstrate that (1) a change in structural characteristics of this practice, such as funding rules, stimulates engineers to attune the inner politics of science to wider societal policies and concerns, and (2) it helps them to overcome the shifting of social responsibility to others as a consequence of the lack of agency they usually perceive.
Materializing Morality
Authors: Verbeek Peter-Paul
Published: April 2006

During the past decade, the “script” concept, indicating how technologies prescribe human actions, has acquired a central place in STS. Until now, the concept has mainly functioned in descriptive settings. This article will deploy it in a normative setting. When technologies coshape human actions, they give material answers to the ethical question of how to act. This implies that engineers are doing “ethics by other means”: they materialize morality. The article will explore the implications of this insight for engineering ethics. It first augments the script concept by developing the notion of technological mediation. After this, it investigates how the concept of mediation could be made fruitful for design ethics. It discusses how the ambition to design behaviorinfluencing technologies raises moral questions itself and elaborates two methods for anticipating technological mediation in the design process: performing mediation analyses and using an augmented version of constructive technology assessment.
Immunoreactivities to Three Circadian Clock Proteins in Two Ground Crickets Suggest Interspecific Diversity of the Circadian Clock Structure
Authors: Shao Qi-Miao , Sehadová Hana , Ichihara Naoyuki , Sehnal František , Takeda Makio
Published: April 2006

The closely related crickets Dianemobius nigrofasciatus and Allonemobius allardi exhibit similar circadian rhythms and photoperiodic responses, suggesting that they possess similar circadian and seasonal clocks. To verify this assumption, antisera to Period (PER), Doubletime (DBT), and Cryptochrome (CRY) were used to visualize circadian clock neurons in the cephalic ganglia. Immunoreactivities referred to as PER-ir, DBT-ir, and CRY-ir were distributed mainly in the optic lobes (OL), pars intercerebralis (PI), dorsolateral protocerebrum, and the subesophageal ganglion (SOG). A system of immunoreactive cells in the OL dominates in D. nigrofasciatus, while immunoreactivities in the PI and SOG prevail in A. allardi. Each OL of D. nigrofasciatus contains 3 groups of cells that coexpress PER-ir and DBT-ir and send processes over the frontal medulla face to the inner lamina surface, suggesting functional linkage to the compound eye. Only 2 pairs of PER-ir cells (no DBT-ir) were found in the OL of A. allardi. Several groups of PER-ir cells occur in the brain of both species. The PI also contains DBT-ir and CRY-ir cells, but in A. allardi, most of the DBT-ir is confined to the SOG. Most immunoreactive cells in the PI and in the dorsolateral brain send their fibers to the contralateral corpora cardiaca and corpora allata. The proximity and, in some cases, proven identity of the PER-ir, DBT-ir, and CRY-ir perikarya are consistent with presumed interactions between the examined clock components. The antigens were always found in the cytoplasm, and no diurnal oscillations in their amounts were detected. The photoperiod, which controls embryonic diapause, the rate of larval development, and the wing length of crickets, had no discernible effect on either distribution or the intensity of the immunostaining.
Drosophila CLOCK Is Constitutively Expressed in Circadian Oscillator and Non-Oscillator Cells
Authors: Houl Jerry H. , Yu Wangjie , Dudek Scott M. , Hardin Paul E.
Published: April 2006

CLOCK (CLK) is a core component of the transcriptional feedback loops that comprise the circadian timekeeping mechanism in Drosophila. As a heterodimer with CYCLE (CYC), CLK binds E-boxes to activate the transcription of rhythmically expressed genes within and downstream of the circadian clock, but this activation unexpectedly occurs at times when CLK is at its lowest levels on Western blots. Recent studies demonstrate that CLK also regulates nonrhythmic gene expression and behaviors. Despite the critical roles CLK plays within and outside the circadian clock, its spatial expression pattern has not been characterized. Using a newly developed CLK antibody, the authors show that CLK is coexpressed with PERIOD (PER) in canonical oscillator cells throughout the head and body. In contrast to PER, however, the levels of CLK immunoreactivity do not cycle in intensity, CLK is detected primarily in the nucleus throughout the circadian cycle, and CLK is expressed in non-oscillator cells within the lateral and dorsal brain, including Kenyon cells, which mediate various forms of learning and memory. These results indicate that constitutive levels of nuclear CLK regulate rhythmic transcription in circadian oscillator cells and suggest that CLK contributes to other behavioral processes by regulating gene expression in non-oscillator cells.
PDF Cycling in the Dorsal Protocerebrum of the Drosophila Brain Is Not Necessary for Circadian Clock Function
Authors: Kula Elzbieta , Levitan Edwin S. , Pyza Elzbieta , Rosbash Michael
Published: April 2006

In Drosophila, the neuropeptide pigment-dispersing factor (PDF) is a likely circadian molecule, secreted by central pacemaker neurons (LNvs). PDF is expressed in both small and large LNvs (sLNvs and lLNvs), and there are striking circadian oscillations of PDF staining intensity in the small cell termini, which require a functional molecular clock. This cycling may be relevant to the proposed role of PDF as a synchronizer of the clock system or as an output signal connecting pacemaker cells to locomotor activity centers. In this study, the authors use a generic neuropeptide fusion protein (atrial natriuretic factor-green fluorescent protein [ANF-GFP]) and show that it can be expressed in the same neurons as PDF itself. Yet, ANF-GFP as well as PDF itself does not manifest any cyclical accumulation in sLNv termini in adult transgenic flies. Surprisingly, the absence of detectable PDF cycling is not accompanied by any detectable behavioral pheno-type, since these transgenic flies have normal morning and evening anticipation in a light-dark cycle (LD) and are fully rhythmic in constant darkness (DD). The molecular clock is also not compromised. The results suggest that robust PDF cycling in sLNv termini plays no more than a minor role in the Drosophila circadian system and is apparently not even necessary for clock output function.
Transcriptional Feedback Oscillators: Maybe, Maybe Not...
Authors: Lakin-Thomas Patricia L.
Published: April 2006

The molecular mechanism of circadian rhythmicity is usually modeled by a transcription/translation feedback oscillator in which clock proteins negatively feed back on their own transcription to produce rhythmic levels of clock protein mRNAs, which in turn cause the production of rhythmic levels of clock proteins. This mechanism has been applied to all model organisms for which molecular data are available. This review summarizes the increasing number of anomalous observations that do not fit the standard molecular mechanism for the model organisms Acetabularia, Synechococcus, Drosophila, Neurospora, and mouse. The anomalies fall into 2 classes: observations of rhythmicity in the organism when transcription of clock genes is held constant, and rhythmicity in the organism when clock gene function is missing in knockout mutants. It is concluded that the weight of anomalies is now so large that the standard transcription/translation mechanism is no longer an adequate model for circadian oscillators. Rhythmic transcription may have other functions in the circadian system, such as participating in input and output pathways and providing robustness to the oscillations. It may be most useful to think in terms of a circadian system that uses a noncircadian oscillator consisting of metabolic feedback loops, which acquires its circadian properties from additional regulatory molecules such as the products of canonical clock genes.
Evolutionary Divergence of Circadian and Photoperiodic Phenotypes in the Pitcher-Plant Mosquito, Wyeomyia smithii
Authors: Mathias Derrick , Reed Laura K. , Bradshaw William E. , Holzapfel Christina M.
Published: April 2006

For decades, chronobiologists have investigated the relationship between the circadian clock that mediates daily activities and the photoperiodic timer that mediates seasonal activities. The main experiment used to infer a circadian basis for photoperiodic time measurement is the Nanda-Hamner protocol (NH). Herein, the authors compare additive and nonadditive (dominance and epistasis) genetic effects that lead to the divergence of populations of the pitcher-plant mosquito, Wyeomyia smithii, for critical photoperiod (CPP) and amplitude of the rhythmic response to NH for 3 temporal-geographic scales: 1) Over geological time between populations in northern and southern clades, 2) over millennial time between populations within the northern clade, and 3) over generational time between lines selected for long and short CPP from within a single population. The authors show that the pattern of additive, dominance, and epistatic effects depends on the time scale over which populations or lines have diverged. Patterns for genetic differences between populations for CPP and response to NH reveal similarities over geological and millennial time scales but differences over shorter periods of evolution. These results, and the observation that neither the period nor amplitude of the NH rhythm are significantly correlated with CPP among populations, lead the authors to conclude that the rhythmic response to NH has evolved independently of photoperiodic response in populations of W. smithii. The implication is that in this species, genetic modification of the circadian clock has not been the basis for the adaptive modification of photoperiodic time measurement over the climatic gradient of North America.
Rethinking the Cost–Benefit Equation of Women's Participation in Community-driven Development in North-western Cameroon
Authors: Fonchingong Charles C. , Ngwa Canute A.
Published: April 2006

This article explores the contributions of women in the community development process in selected rural localities of the Cameroon grasslands. The article situates gender concerns in community participation, rekindled through village development associations—vehicles for the mobilisation of social capital directed at the execution of identified projects. We conclude that women still largely remain on the sidelines on account of the relative lack of the education, tight schedules, anachronistic traditions that reinforce male supremacy, lack of finance and abysmally low representation in village institutional structures.
Gender and the Composition of Corporate Boards
Authors: Amidu Mohammed , Abor Joshua
Published: April 2006

This article examines the gender composition of corporate boards of listed companies in Ghana. Results indicate that women were insignificantly represented and that younger firms had more women on their boards than firms established four decades ago. In addition, the study found that it is only after the initial listing that companies found it necessary to appoint women directors. As firms expand, they tend to employ fewer women on their corporate boards. Also, women were engaged more in the service and financial sectors than the manufacturing and construction industries. Interest-ingly, local companies appointed relatively more women as board members than their multinational counterparts.
Effects of a University Career Development Course on Career Decision-Making Self-Efficacy
Authors: Reese Robert J. , Miller C. Dewayne
Published: April 2006

The effects of a career development course on career decision-making self-efficacy were investigated. The course was primarily designed to help undecided students with career decision making. A pretest-posttest nonequivalent group design compared students who completed the course ( n = 30) with a quasi-control group of students who were enrolled in an introductory psychology course ( n = 66). The results indicated that students who completed the career course showed increased career decision-making self-efficacy overall, specifically in the areas of obtaining occupational information, setting career goals, and career planning. The career course also appeared to lower perceived career decision difficulties. The importance of having a theoretically based career course and the increased need for research in this area are discussed, given the increase in the popularity of career services on college and university campuses. Limitations and future studies are discussed.
Examining Conformity to Masculinity Norms as a Function of RIASEC Vocational Interests
Authors: Mahalik James R. , Perry Justin C. , Coonerty-Femiano Aimee , Catraio Christine , Land Lee N.
Published: April 2006

The authors examined how college men’s conformity to an array of masculinity norms varied as a function of their vocational interests to better understand the gendered context of men’s vocational development. Three hundred ten mostly Caucasian and heterosexual college men completed the Conformity to Masculine Norms Inventory, and their answer to the question “What is your ideal job/career after college?” was classified into one of six high point codes reflecting Holland’s RIASEC interests using the Dictionary of Holland Occupational Titles (1996). Multivariate analysis of variance indicated that college men’s conformity to masculinity norms varied as a function of their vocational interests, and univariate analyses indicated that this was true for 9 of the 11 masculinity norms examined. The discussion addresses the implications of a multidimensional conceptualization of masculinity in understanding men’s vocational development.
The Complicated Pig Speaks: A Reply to Gore and Brown and Tinsley
Authors: Eggerth Donald E.
Published: April 2006

Responses are made to comments regarding Eggerth and Andrew (2006) by Gore and Brown (2006) calling for simplification of the modified C index and by Tinsley (2006) questioning the logic of the modified C index (all articles in this issue).
Distinguishing Developmental From Chronic Career Indecision: Self-Efficacy, Autonomy, and Social Support
Authors: Guay Frédéric , Ratelle Catherine F. , Senécal Caroline , Larose Simon , Deschênes Andrée
Published: April 2006

Career indecision can be divided into two categories: developmental and chronic indecision. The former is generally viewed as a developmentally normal problem resulting from a lack of information on the self and on the world of work, whereas the latter is defined as a pervasive inability to make a decision about one’s career. The goals of the present study were to test the validity of this typology of career indecision and to explain these types of indecision as a function of self-efficacy, autonomy, and support from parents and friends. Based on a 3-year longitudinal design with college students ( N = 325), results provided validity for this typology by revealing the presence of two indecision groups (chronically undecided and developmentally undecided) and a group of students who are decided. In addition, results indicated that self-efficacy and autonomy are important dimensions that make it possible to distinguish between these three groups.
Simpler May Still Be Better: A Reply to Eggerth and Andrew
Authors: Gore Paul A. , Brown Steven D.
Published: April 2006

Eggerth and Andrew (2006 [this issue]) provide a valuable contribution to researchers and practitioners using the C index to measure congruence when person or environment codes contain fewer than three letters. However, the computational procedures outlined by Eggerth and Andrew may be more complex than they need be. A simpler alternative to calculating C under these conditions is suggested that is more theoretically consistent in that it substitutes primary code letters when code letters are missing. Other issues involved in developing accurate estimates of person-environment fit are mentioned, and it is argued that contrary to some opinion in the field, congruence remains an important construct for counseling use and future investigation.
Relative efficacy of intravenous immunoglobulin G in ameliorating thrombocytopenia induced by antiplatelet GPIIbIIIa versus GPIbα antibodies
Authors: Webster Michelle Lee , Sayeh Ebrahim , Crow Min , Chen Pingguo , Nieswandt Bernhard , Freedman John , Ni Heyu
Published: April 2006

Intravenous immunoglobulin G (IVIG) is used to treat idiopathic thrombocytopenic purpura (ITP). Although many patients benefit from IVIG, some are refractory to this therapy. ITP is characterized by platelet clearance mediated primarily by antiplatelet antibodies against GPIIbIIIa and/or the GPIbα complex. These 2 groups of antibodies may induce ITP through different mechanisms. We tested the hypothesis that IVIG may not be equally effective in preventing ITP caused by anti-GPIIbIIIa versus anti-GPIbα antibodies in mice. Thrombocytopenia was induced in BALB/c mice using monoclonal antibodies against either mouse GPIIbIIIa (JON1, JON2, and JON3) or GPIbα (p0p3, p0p4, p0p5, p0p9, and p0p11). Pretreatment with IVIG significantly ameliorated ITP in all anti-GPIIbIIIa–injected animals. Conversely, IVIG failed to prevent ITP in all anti-GPIbα–treated mice, except for p0p4. These results were repeated in C57BL/6 mice, and with different IVIG preparations. These data in mice suggest that patients with ITP mediated by anti-GPIbα antibodies may be less responsive to IVIG treatment.
Targeting self-antigens through allogeneic TCR gene transfer
Authors: de Witte Moniek A. , Coccoris Miriam , Wolkers Monika C. , van den Boom Marly D. , Mesman Elly M. , Song Ji-Ying , van der Valk Martin , Haanen John B. A. G. , Schumacher Ton N. M.
Published: April 2006

Adoptive transfer of T-cell receptor (TCR) genes has been proposed as an attractive approach for immunotherapy in cases where the endogenous T-cell repertoire is insufficient. While there are promising data demonstrating the capacity of TCR-modified T cells to react to foreign antigen encounter, the feasibility of targeting tumor-associated self-antigens has not been addressed. Here we demonstrate that T-cell receptor gene transfer allows the induction of defined self-antigen–specific T-cell responses, even when the endogenous T-cell repertoire is nonreactive. Furthermore, we show that adoptive transfer of T-cell receptor genes can be used to induce strong antigen-specific T-cell responsiveness in partially MHC-mismatched hosts without detectable graft versus host disease. These results demonstrate the feasibility of using a collection of “off the shelf” T-cell receptor genes to target defined tumor-associated self-antigens and thereby form a clear incentive to test this immunotherapeutic approach in a clinical setting.
Human short-term repopulating cells have enhanced telomerase reverse transcriptase expression
Authors: Järås Marcus , Edqvist Anna , Rebetz Johan , Salford Leif G. , Widegren Bengt , Fan Xiaolong
Published: April 2006

Telomerase activity has been suggested to be critically involved in hematopoietic stem cell (HSC) self-renewal. However, it has been unclear whether human HSCs have telomerase activity and how telomerase activity is regulated within the HSC and progenitor pool. Here, we isolated living cord-blood (CB) CD34+ cells with up-regulated human telomerase reverse transcriptase (hTERT) expression by using an hTERT-reporting adenoviral vector encoding destabilized green fluorescent protein (dGFP) driven by the hTERT promoter, and functionally characterized them in comparison with control vector–transduced CD34+ cells expressing GFP. Following a 2-day serum-free transduction protocol, cells were sorted into a dGFP+ and a GFP+ fraction. Cell-cycle analysis revealed that the dGFP+ cells had a greater proportion of cells in S/G2/M phase compared with the GFP+ cells, (56% ± 1.8% vs 35% ± 4.3%; P < .001) and fewer cells in G0 phase (8.1% ± 3.0% vs 20% ± 4.7%; P < .01) However, the colony-forming and short-term nonobese diabetic/severe combined immunodeficient (NOD/SCID) B2m–/– mice bone marrow–repopulating capacities were similar between the dGFP+ and the GFP+ cells. Interestingly, the dGFP+ cells had a 6-fold lower repopulating capacity in NOD/SCID mice compared with the GFP+ cells and lacked secondary NOD/SCID B2m–/– mice bone marrow–repopulating capacity. Thus, up-regulation of hTERT expression within the CB HSC pool is accompanied by decreased self-renewal capacity.
Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation–related imatinib failure
Authors: Jabbour Elias , Cortes Jorge , Kantarjian Hagop M. , Giralt Sergio , Jones Dan , Jones Roy , Giles Francis , Andersson Borje S. , Champlin Richard , de Lima Marcos
Published: April 2006

Resistance to imatinib mesylate is an emerging problem in the treatment of chronic myeloid leukemia (CML), often associated with point mutations in the Bcr-Abl kinase domain. Outcome of patients with such mutations after allogeneic stem cell transplantation (Allo-SCT) is unknown. Ten imatinib-resistant patients with Bcr-Abl kinase mutations received a transplant: 9 had CML (3 in chronic phase, 4 in accelerated phase, and 2 in blast phase) and 1 had Philadelphia-positive acute lymphocytic leukemia (ALL). Patients harbored 9 different protein kinase mutations (T315I mutation, n = 2). Preparative regimens were ablative (n = 7) and nonablative (n = 3). All patients engrafted; there were no treatment-related deaths. Disease response was complete molecular (CMR; n = 7), major molecular (n = 2), and no response (n = 1). Three patients (mutations Q252H, E255K, and T315I) died of relapse after Allo-SCT. Seven patients are alive (6 in CMR) for a median of 19 months. Allo-SCT remains an important salvage option for patients who develop resistance to imatinib through Bcr-Abl mutations.
Regulatory T cells in cancer
Authors: Beyer Marc , Schultze Joachim L.
Published: April 2006

Increasing evidence supports the existence of elevated numbers of regulatory T cells (Treg cells) in solid tumors and hematologic malignancies. Whereas the biology of CD4+CD25+FOXP3+ Treg cells in murine models seems to be rather straightforward, studies in human diseases are more difficult to interpret due to expression of CD25 on activated effector T cells as well as Treg cells. More importantly, early studies in human tumors were mainly focused on CD4+CD25+ Treg cells lacking interrogation of more specific markers such as FOXP3 expression. Although the increase of Treg cells seems to be a characteristic feature in most tumors, little is known about the molecular and cellular mechanisms responsible for the increase and maintenance of elevated levels of Treg cells in cancer. We will discuss earlier data in the context of recent findings in Treg-cell biology with a particular emphasis on CD4+CD25highFOXP3+ Treg cells in human malignancies.
Role of the Glutathione Metabolic Pathway in Lung Cancer Treatment and Prognosis: A Review
Authors: Yang Ping , Ebbert Jon O. , Sun Zhifu , Weinshilboum Richard M.
Published: April 2006

Inherent and acquired drug resistance is a cause of chemotherapy failure, and pharmacogenomic studies have begun to define gene variations responsible for varied drug metabolism, which influences drug efficacy. Platinum-based compounds are the most commonly used chemotherapeutic agents in the treatment of advanced stage lung cancer patients, and the glutathione metabolic pathway is directly involved in the detoxification or inactivation of platinum drugs. Consequently, genotypes corresponding to higher drug inactivation enzyme activity may predict poor treatment outcome. Available evidence is consistent with this hypothesis, although a definitive role for glutathione system genes in lung cancer prognosis needs to be elucidated. We present evidence supporting a role of the glutathione system in acquired and inherited drug resistance and/or adverse effects through the impact of either drug detoxification or drug inactivation, thus adversely effecting lung cancer treatment outcome. The potential application of glutathione system polymorphic genetic markers in identifying patients who may respond favorably, selecting effective antitumor drugs, and balancing drug efficacy and toxicity are discussed.
Characterization of Leptin-Responsive Neurons in the Caudal Brainstem
Authors: Ellacott Kate L. J. , Halatchev Ilia G. , Cone Roger D.
Published: April 2006

The central melanocortin system plays a key role in the regulation of energy homeostasis. Neurons containing the peptide precursor proopiomelanocortin (POMC) are found at two sites in the brain, the arcuate nucleus of the hypothalamus (ARC) and the caudal region of the nucleus of the solitary tract (NTS). ARC POMC neurons, which also express cocaine- and amphetamine-regulated transcript (CART), are known to mediate part of the response to factors regulating energy homeostasis, such as leptin and ghrelin. In contrast, the physiological role(s) of the POMC neurons in the caudal brainstem are not well characterized. However, development of a transgenic mouse expressing green fluorescent protein under the control of the POMC promoter [POMC-enhanced green fluorescent protein (EGFP) mouse] has aided the study of these neurons. Indeed, recent studies have shown significant activation of NTS POMC-EGFP cells by the gut released satiety factor cholecystokinin (CCK). Here we show that peripheral leptin administration induces the expression of phospho-signal transducer and activator of transcription 3 immunoreactivity (pSTAT3-IR), a marker of leptin receptor signaling, in more than 50% of NTS POMC-EGFP neurons. Furthermore, these POMC-EGFP neurons comprise 30% of all pSTAT3-IR cells in the NTS. Additionally, we also show that in contrast to the ARC population, NTS POMC-EGFP neurons do not coexpress CART immunoreactivity. These data suggest that NTS POMC neurons may participate with ARC POMC cells in mediating some of the effects of leptin and thus comprise a novel cell group regulated by both long-term adipostatic signals and satiety factors such as CCK.
Role of Complex Cyclin D1/Cdk4 in Somatostatin Subtype 2 Receptor-Mediated Inhibition of Cell Proliferation of a Medullary Thyroid Carcinoma Cell Line in Vitro
Authors: Tagliati Federico , Zatelli Maria Chiara , Bottoni Arianna , Piccin Daniela , Luchin Andrea , Culler Michael D. , degli Uberti Ettore C.
Published: April 2006

Somatostatin (SRIH) inhibits cell proliferation by interacting with five distinct SRIH receptor subtypes (SSTRs) activating several pathways in many tissues. We previously demonstrated that SRIH, by activating Src homology-2-containing protein, inhibits cell proliferation of the human medullary thyroid carcinoma cell line, TT, which expresses all SSTRs. However, the effects of SRIH on cell cycle proteins have not been investigated so far. We therefore evaluated the effects of SRIH and a selective SSTR2 agonist on cell cycle protein expression, mainly focusing on cyclin D1 and its associated kinases. Our data show that SRIH and the selective SSTR2 agonist, BIM-23120, reduce cell proliferation and DNA synthesis as well as induce a delay of the cell cycle in G2/M phase. Moreover, treatment with both SRIH and BIM-23120 decreases cyclin D1 levels, with a parallel increase in phosphocyclin D1 levels, suggesting protein degradation. Moreover, our data show an increase in glycogen synthase kinase-3β activity, which triggers phosphorylation-dependent cyclin D1 degradation. Indeed, we observed a reduction in cyclin D1 protein half-life under treatment with SRIH or the SSTR2 selective agonist. A reduction in cdk4 protein levels is also observed with a parallel reduction in Rb phosphorylation levels at Ser-780. Our data indicate that the subtype 2 receptor-mediated antiproliferative effect of SRIH on TT cell proliferation may be exerted through a decrease in cyclin D1 levels.
Expression of Adiponectin Receptors and Its Possible Implication in the Human Endometrium
Authors: Takemura Yuri , Osuga Yutaka , Yamauchi Toshimasa , Kobayashi Masaki , Harada Miyuki , Hirata Tetsuya , Morimoto Chieko , Hirota Yasushi , Yoshino Osamu , Koga Kaori , Yano Tetsu , Kadowaki Takashi , Taketani Yuji
Published: April 2006

Adiponectin, a pleiotropic cytokine, exerts its effects via the specific receptors AdipoR1 and AdipoR2. Whereas circulating adiponectin concentrations decrease in women with endometriosis and endometrial cancer, possible effects of adiponectin and the presence of the receptors in the endometrium have not been determined. In this study, we examined the expression of adiponectin receptors AdipoR1 and AdipoR2 in the human endometrium and assessed effects of adiponectin in endometrial cells. Expression of AdipoR1 and AdipoR2 in endometrial tissues was evaluated by real-time quantitative PCR, in situ hybridization, and Western blotting. The effects of adiponectin on phosphorylation of AMP-activated protein kinase, a regulator of energy homeostasis, in cultured endometrial stromal cells (ESCs) and epithelial cells (EECs) were studied by Western blotting. The effects of adiponectin on IL-1β-induced secretion of IL-6, IL-8, and monocyte chemoattractant protein 1 from cultured ESCs were determined using specific ELISAs. The expression of AdipoR1 and AdipoR2 was detected in the endometrium. The expression of both genes was increased in the midluteal phase, the period of embryo implantation. In situ hybridization revealed that both AdipoR1 and AdipoR2 appeared to be equally expressed in the epithelial cells and in the stromal cells. Adiponectin increased phosphorylation of AMP-activated protein kinase in ESCs and EECs. Adiponectin decreased IL-1β-induced secretion of IL-6, IL-8, and monocyte chemoattractant protein 1 from ESCs. These findings suggest that adiponectin exerts energy-homeostatic and antiinflammatory effects in the endometrium, and these effects might be relevant to pathological and physiological endometrium-related events such as implantation and endometriosis.
“Ranging Foresters” And “Women-Like Men”: Physical Accomplishment, Spiritual Power, and Indian Masculinity in Early-Seventeenth-Century New England
Authors: Romero R. Todd
Published: April 2006

Through an examination of seventeenth-century English sources and later Indian folklore, this article illustrates the centrality of religion to defining masculinity among Algonquian-speaking Indians in southern New England. Manly ideals were represented in the physical and spiritual excellence of individual living men like the Penacook sachem-powwow Passaconaway and supernatural entities like Maushop. For men throughout the region, cultivating and maintaining spiritual associations was essential to success in the arenas of life defining Indian masculinity: games, hunting, warfare, governance, and marriage. As is stressed throughout the essay, masculinity was also juxtaposed with femininity in a number of important ways in Indian society.
Dendrimer Complexes Based on Fine-Controlled Metal Assembling
Authors: Yamamoto Kimihisa , Imaoka Takane
Published: April 2006

A series of novel dendrimers composed of dendritic phenylazomethines (DPAs) were synthesized with several types of functional cores. The metal assembling to the DPAs is stepwise by the layers, therefore, they can be used as a scaffold for the precise hybridization between metal ions and organic macromolecules. Because of uniform structure of the dendrimer, there is no structural dispersion in the macromolecule–metal hybrid of the DPAs. Also, the number of metal ions loaded in one dendrimer should have no statistical distribution in principle due to the precise metal assembling. A rigid π-conjugating backbone structure contributes not only to the stepwise metal assembly, but also to the solid-state stability under high temperature. Development of this property without any reduction in solubility in organic media enabled the easy preparation of homogeneous amorphous films in which the metal and macromolecule are precisely hybridized. As a result, the thin solid of the metal-assembling dendrimer acts as an excellent organic semiconductor in the hole-transport layer of a light-emitting diode. Metal-assembling DPAs also enhance the electron-transfer reaction as a protein-like catalyst. The DPA having a cobalt porphyrin core-could catalyze the CO2 reduction at an applied overpotential 1.1 V lower than that needed for the catalysis by a model compound of the porphyrin core (CoTPP). Reversible encapsulation/release of multiple irons is also demonstrated as a mimic of the iron storage protein (Ferritin). The switching between these two coordinating states can be completely controlled by the redox states of the iron (FeII/FeIII). The finding of these unique dendritic ligands will afford new insight into molecular design for finely controlled macromolecule–metal hybrid materials.
Hyperconjugative Electron-Delocalization Mechanism Controlling the Conformational Preference of Fluoroacetaldehyde and Methyl Fluoroacetate
Authors: Sahnoun Riadh , Fujimura Yuichi , Kabuto Kuninobu , Takeuchi Yoshio , Noyori Ryoji
Published: April 2006

We confirmed by both canonical molecular orbital analysis and the orbital deletion procedure (ODP) that a hyperconjugative electron-delocalization mechanism is the main factor controlling the conformational preference for cis and trans conformations of fluoroacetaldehyde (FAA) and methyl fluoroacetate (MFA). The quantitative analysis based on the ODP approach shows that the effects of hyperconjugation are more important in the cis conformation than in trans conformation.
pH-Dependent Reversible Switching of Fluorescence of Water-Soluble Porphyrin Adsorbed on Mesoporous TiO2 Film
Authors: Fujii Yusuke , Tsukahara Yasunori , Wada Yuji
Published: April 2006

Changes of the fluorescence spectra of tetrakis(4-sulfonatophenyl)porphyrin (TPPS) and tetrakis(4-carboxyphenyl)porphyrin (TCPP) chemisorbed on TiO2 film in pH-adjusted water have been investigated. TPPS on TiO2 film in pH 6.5 water showed strong fluorescence, while it hardly emitted in pH 1.6 water, demonstrating a fluorescence switching with dramatic intensity changes in the TPPS–TiO2 system. On the other hand, only small changes in the fluorescence were observed for TCPP adsorbed on TiO2 instead of TPPS, although the changes were reversible. Fluorescence switching observed for TPPS and TCPP only in the adsorbed states on TiO2 are discussed on the basis of quenching of the excitation energy caused by molecular arrangements on TiO2 and photoinduced electron injection of excited porphyrin to TiO2.