bluuebunny/crossref_metadata_2025 huggingface dataset:
The Sustainability of Innovative Schools as Learning Organizations and Professional Learning Communities During Standardized Reform
Authors: Giles Corrie , Hargreaves Andy
Published: January 2006

Background: Implicitly, innovative schools have historically contained some (but not usually all) of the properties of learning organizations and professional learning communities but have a weak record of sustaining success over time. Can innovative schools that self-consciously establish themselves as learning organizations and professional learning communities sustain their early promise of success in the face of the predictable cycle of the “attrition of change”; of pressure and envy in the surrounding district, profession, and community; and of the historically specific and recent pressure of standardized reform?

Purpose : This article explores the impact of these influences on three innovative schools and their sustainability over time. It concentrates in particular on the promise and viability of one of these schools, which has been consciously modeled as a learning organization and professional learning community.

Conclusions: Although further research is required, the article concludes that the learning organization and professional learning community model may provide a more robust resistance to conventional processes of the attrition of change and of surrounding change forces, but much like other innovative schools, it also shows signs of defaulting to conventional patterns of schooling in the face of standardized reform.
Gender and Age Differences in Same-Sex Aggregation and Social Behavior
Authors: Munroe Robert L. , Romney A. Kimball
Published: January 2006

Children's tendencies to aggregate with same-sex others and to increase spatial experience with age are investigated among 3- to 9-year-olds in four non-Western communities. Also investigated are genderspecific social behaviors, labeled by Eleanor Maccoby as male-styleand female-styleplay. Analysis of naturalistic observations of daily activities indicate that during free time in all cultures, older children (7- and 9-year-olds) are much more involved in both same-sex aggregation and away-from-home spatial experience than are younger children (3- and 5-year-olds) and that older boys are more strongly involved in these events than are older girls. Older boys also display a marked degree of same-sex aggregation when enacting the male-style behaviors of physicality and attention seeking, but girls do not display a similar same-sex aggregation for any category of social behavior. Children's levels of gender understanding are unrelated to the outcomes.
Collectivism and Governmentally Initiated Restrictions
Authors: Conway Lucian Gideon , Sexton Shannon M. , Tweed Roger G.
Published: January 2006

This article provides evidence for a link between cultural collectivism and indexes of governmentally initiated restriction both across nations and within one nation, both cross-sectionally and longitudinally. In Investigation 1, across U.S. states, an index of legislative restriction is positively related to an index of collective behaviors. In Investigation 2, across nations, an index of political restriction is positively related to measures of national cultural collectivism. In Investigation 3, longitudinal analyses suggest that cultural measures predict restriction better than vice versa, although this evidence is stronger and more consistent across nations than across states. The present findings are discussed in terms of their contribution to understanding the relationship between culture and politics.
Autocratic Leadership Around the Globe
Authors: Van de Vliert Evert
Published: January 2006

Common autocratic leader characteristics in a country's organizations are conceptualized here as cultural adaptations to noncultural components of the national environment, such as the harshness of cold or hot climate and the level of wealth. A secondary analysis of managerial survey data gathered in 61 cultures is used to retest the recently formulated theory that climatic demands matched by wealth-based resources are positively linked to democratic leadership, whereas climatic demands unmatched by wealth-based resources are negatively linked to democratic leadership. In further support of this cultural leadership theory, autocratic leadership, as the opposite of democratic leadership, is seen as less effective in richer countries with more demanding climates but as more effective in poorer countries with more demanding climates.
A World of Lies
Authors:   The Global Deception Research Team
Published: January 2006

This article reports two worldwide studies of stereotypes about liars. These studies are carried out in 75 different countries and 43 different languages. In Study 1, participants respond to the open-ended question “How can you tell when people are lying?” In Study 2, participants complete a questionnaire about lying. These two studies reveal a dominant pan-cultural stereotype: that liars avert gaze. The authors identify other common beliefs and offer a social control interpretation.
Culture and Counterfactuals
Authors: Chen Jing , Chiu Chi-Yue , Roese Neal J. , Tam Kim-Pong , Lau Ivy Yee-Man
Published: January 2006

Past research, with its emphasis on affective regulatory processes, has failed to find cross-cultural differences in counterfactual thoughts. In the current study, the authors examine the tendency to generate additive counterfactuals (those that focus on the addition of new aspects that were not in fact present) and subtractive counterfactuals (those that focus on subtraction of factual aspects) among Mainland Chinese and European American university students in five life domains: schoolwork, romantic relationships, family relationships, friendships, and life in general. As in previous studies, the authors find an overall main effect, in which additive counterfactuals predominate over subtractive counterfactuals within both cultural groups. However, they also find systematic cultural differences in the likelihood of generating additive and subtractive counterfactuals in the domains of schoolwork and family. These findings are discussed in terms of their implications for understanding the nature of cultural differences.
Developmental Tasks of Adolescents of Native or Foreign Origin in France and Germany
Authors: Schleyer-Lindenmann Alexandra
Published: January 2006

The developmental task concept has been useful to study adolescent development for more than 50 years. However, some facets of this concept remain unexplored. In this article, the author presents a cross-cultural and intercultural study comparing the developmental tasks of adolescents of native and foreign origin in France (French and North African origin) and Germany (German and Turkish origin). The results suggest that developmental tasks are not identical for adolescents in the national cultures (France and Germany) and furthermore that they are not the same depending on the acculturation framework to which adolescents of foreign origin are exposed in these two European countries.
Child-Parent Agreement in the Assessment of Young Children's Fears
Authors: Lahikainen Anja Riitta , Kraav Inger , Kirmanen Tiina , Taimalu Merle
Published: January 2006

Finnish and Estonian parents' assessments of their 5- to 6-year-old children's fears (selected items of the Ollendick Fear Survey Schedule) were compared with children's self-reported fears in a semistructured interview that included a picture-aided section. Representative samples from Finland and Estonia consisted of 330 child-parent pairs. The level of agreement between the informants'assessmentswas lowin both countries. Children reported more fears than did their parents in comparable items. Parents in both countries seem to underestimate children's fears. These findings suggest that children should be primary informants of their fears. In addition, the same types of differences in children's fears were revealed between the countries irrespective of the informant. Finnish children expressed more fears related to issues of mental overexcitation; the fears of Estonian children more often concerned concrete people's behavior.
Adapting a Tourism Crime Typology: Classifying Outdoor Recreation Crime
Authors: Tynon Joanne F. , Chavez Deborah J.
Published: January 2006

Using a qualitative approach, the authors tested a crime typology developed for tourism destinations in a U.S. National Forest recreation setting. Specific objectives were to classify the attributes of crime and violence, examine the effects of crime and violence on visitor demand, and suggest methods of prevention and recovery. A key modification to the crime typology prior to data collection was to anchor it to crime And violence-activity categories revealed from an earlier study. Several recommendations are given, with the understanding that they derived from the first run of the crime typology in a U.S. National Forest setting. These include refinements of key typology measures of motivations, victims, severity, frequency, and riots.
Experiencing Cultural Tourism: Visitors at the Maori Arts and Crafts Institute, New Zealand
Authors: Ryan Chris , Higgins Opal
Published: January 2006

This study reports results derived from semistructured interviews with 40 visitors to the Maori Arts and Crafts Institute in Rotorua, New Zealand. The article discusses briefly the mode of data capture used and adopts an approach of identifying classifications of a primarily functional nature to list reasons why people visit such a site and what it is they seek. In general, visitors reported high levels of satisfaction, yet the cultural component of their experience was primarily reported in terms of the visit being informative and entertaining. Additionally, whereas modest levels of interest in things Maori seemed to motivate visits to other Maori sites, the actual list of other locations being nominated was few in number. The impression results that visits are made to Maori sites because this is a “done thing” when visiting New Zealand, but overall, the level of interest shown by most visitors in indigenous culture is modest.
Time Series Analyses of UK Outbound Travel by Air
Authors: Coshall John
Published: January 2006

Time series models are applied to outbound travel flows by air from the United Kingdom to 20 destinations. Objective assessments are made as to whether seasonal components in ARIMA processes should be modeled additively or multiplicatively. A selection strategy is presented to differentiate between the difference filters applicable to additive and multiplicative ARIMA models. The strategy inherently incorporates the possibility of increasing stochastic or deterministic seasonal variation. It is shown that neither logarithmic transformations nor a large number of difference filters are required. Selected ARIMA models tend to outperform Holt-Winters and Naïve models in terms of goodness of fit and forecasting accuracy.
Heritage Site Perceptions and Motivations to Visit
Authors: Poria Yaniv , Reichel Arie , Biran Avital
Published: January 2006

The present study has two main objectives: (1) to further explore the motivations of potential visitors to a heritage site, and (2) to explore whether the relationships among the tourists’ perceptions of the site relative to their own heritage are related to their motivations for the visit. The sample is composed of potential visitors to Anne Frank House in Amsterdam. The results reveal the existence of motives often ignored in previous studies, including emotional involvement and bequeathal of the site's narrative. The findings also indicate a distinct relationship between tourists’ perceptions of a site relative to their own heritage and the motivations for visiting the site. The study contributes to the understanding of tourist behaviors relative to heritage settings along with implications for the marketing of heritage settings.
Repeat Visitation in Mature Sun and Sand Holiday Destinations
Authors: Alegre Joaquín , Cladera Magdalena
Published: January 2006

European sun and sand holiday destinations that emerged in the Mediterranean in the 1960s are currently facing competition from both new destinations and new tourist demands. One of the main characteristics of these destinations is the phenomenon of repeat visitation. This article analyzes the effect that repeat visitation rates have on the intention to revisit the destination and on tourists’ level of satisfaction. The results show firstly that despite the fact that repeat visitors are more likely to make a further visit to a destination, its main determinant is a high level of satisfaction. Secondly, the repeat visitation rate has only a limited effect on overall satisfaction. The study's conclusions also point to a tourists’ continued interest in sun and sand products, as well as highlight a need for the product's basic components to offer high quality levels to maintain client loyalty.
Identifying the Success Factors of Web-Based Marketing Strategy: An Investigation of Convention and Visitors Bureaus in the United States
Authors: Wang Youcheng , Fesenmaier Daniel R.
Published: January 2006

American convention and visitors bureaus are trying to adjust their marketing strategy to incorporate the Internet but have achieved mixed results. This study examines the factors affecting the success of Web-based marketing strategies by American convention and visitors bureaus. The results of this study indicate that successful Web marketing strategies require the integration and coordination of three complementary aspects of the Internet marketing efforts as well as favorable organization and technology environment and innovative approaches. Discussion and implications are provided based on the results of the study.
The Distribution Mix For Tourism Attractions in Rotorua, New Zealand
Authors: Pearce Douglas G. , Tan Raewyn
Published: January 2006

Based on in-depth interviews with 20 providers, this article-examines the distribution mix for tourism attractions in Rotorua, a major New Zealand destination. It seeks to establish the balance between direct and indirect distribution channels, to identify the different forms of distribution involved, and to examine the factors influencing their use. The distribution mix was found to be very mixed, the percentage of direct sales ranging from 95% to 20%. Little systematic variation was evident, with the exception of an inverse relationship between the percentage of direct sales and the proportion of business from group tours. Variation was also found in the structure of direct and indirect channels and in the reasons given for using each of these. Factors influencing the overall distribution mix include the segments targeted, the characteristics of the attractions, and the perceived advantages and disadvantages of different channels with respect to yield, control, and seasonality.
Likelihood of Cruise Ship Passenger Return to a Visited Port: The Case of Bar Harbor, Maine
Authors: Gabe Todd M. , Lynch Colleen P. , McConnon James C.
Published: January 2006

Cruise ship visits provide an often overlooked benefit of showcasing port communities to thousands of potential repeat tourists. Using data from a survey conducted in 2002, this study examines the factors that affect a cruise ship passenger's intention of returning to Bar Harbor, Maine. Survey results indicate that one-third of the respondents plan to return to town in the two years following their cruise ship visit. Empirical results suggest that the distance between a respondent's place of residence and Bar Harbor has a negative effect on the likelihood of return. The total number of visits a passenger has made to Bar Harbor and the amount of time spent in port during the one-day visit have a positive effect on the likelihood of return. Finally, household income and the experience of taking a cruise-line-sponsored tour do not have a significant effect on a passenger's intention of returning to a visited port.
Assessing Gay Men and Lesbian Women's Hotel Experiences: An Exploratory Study of Sexual Orientation in the Travel Industry
Authors: Poria Yaniv
Published: January 2006

This study examines the hotel experiences of gay men and lesbians, using qualitative interviews of 54 self-identified lesbians and gay men in the United Kingdom and Israel. The findings show that participants are highly affected by the symbolic meanings they assign to specific elements of the hotel experience. Results indicate that it is important for gay men and lesbians to feel accepted and welcome when their sexual orientation is known. Specifically, they wish to be treated in the same way they believe heterosexuals are treated. Critical elements of the hotel experience focus on the behavior of hotel staff, hotel attributes, and the environment of the hotel. The findings may assist in shaping service provision for, and service delivery to, lesbians and gay men.
The Utilization of Critical Incident Technique to Examine Cruise Passengers’ Repurchase Intentions
Authors: Petrick James F. , Tonner Catherine , Quinn Christina
Published: January 2006

Recent passenger figures suggest that although the cruise industry is growing, so is the competition. This growth has made it imperative for the industry to retain its current clientele to thrive. Research has revealed that service experiences can be severely altered, either positively or negatively, by one single “moment of truth.” This study examined cruise passengers’ moments of truth using critical incident technique to better understand cruise passengers’ overall satisfaction, perceived value, word of mouth, and repurchase intentions. Results imply that analyzing critical incidents can be an effective management tool for cruise line management and that these “moments of truth” are relevant to visitor retention. It was also found that negative incidents have a much greater effect on cruise passengers’ post hoc cruise evaluations than positive incidents. Opportunities for future research are also discussed.
Advancing Ecological Systems Theory in Lifestyle, Leisure, and Travel Research
Authors: Woodside Arch G. , Caldwell Marylouise , Spurr Ray
Published: January 2006

Ecological systems theory and research focus on describingand explaining the thoughts and actions of individuals and groups within specific contexts of their lives. This article applies ecological systems theory to examine the contextual facilitating and constraining factors in the thoughts and actions of individuals regarding work, leisure, and travel alternatives. The article presents the results of a case research study of five Australian households with thought protocol data on these households’ lived experiences in work, leisure, and travel, and learning how they compare “ noncomparable” leisure expenditure options; the discussion leads to advancing macroecological and microecological systems theory in leisure travel behavior. The article includes suggestions for future research and implications for tourism marketing strategy.
An Analysis of the Differences between State Welcome Center Users and Local Visitor Center Users: A Profile of Louisiana Travelers
Authors: Dimanche Frederic , Taylor Marlise Moody
Published: January 2006

The purpose of this study was to contribute to the existing body of highway visitor research by investigating differences between visitors to state welcome centers and visitors to local welcome centers. More than 3,000 self-administered questionnaires collected in state and local visitor centers throughout Louisiana were used to differentiate automobile travelers. State visitor center users significantly differed from local center visitors for most behavioral trip characteristics. This study confirms previous findings that users of state welcome centers are not representative of all automobile travelers. States that want to conduct visitor profile studies at welcome centers should include local welcome centers in their studies.
Statistical Inference for Measures of Inequality With a Cross-National Bootstrap Application
Authors: Moran Timothy Patrick
Published: January 2006

The problem of statistical inference in inequality research has persisted despite the solutions long suggested by asymptotic theory. This article provides a thorough analysis of the theoretical and practical aspects of conducting statistical inference in the context of inequality data. Using the income surveys of the Luxembourg Income Study, the article outlines in detail the new bootstrap procedures, assesses their performance, and demonstrates their effectiveness in evaluating levels and trends in cross-national inequality. It provides an analytical evaluation of current advancements in inequality measurement and for the first time applies these methods in the context of comparative research, but it also can be used as practical guide for handling the problems of statistical inference in more general social scientific settings.
An Introduction to Ensemble Methods for Data Analysis
Authors: Berk Richard A.
Published: January 2006

This article provides an introduction to ensemble statistical procedures as a special case of algorithmic methods. The discussion begins with classification and regression trees (CART) as a didactic device to introduce many of the key issues. Following the material on CART is a consideration of cross-validation, bagging, random forests, and boosting. Major points are illustrated with analyses of real data.
Factorial Survey Methods for Studying Beliefs and Judgments
Authors: Jasso Guillermina
Published: January 2006

This article develops a unified framework, based on Rossi's factorial survey method, for studying positive beliefs and normative judgments. The framework enables estimation of individuals' positive-belief and normative-judgment equations, leading to analysis of the components of beliefs and judgments, assessment of interpersonal variability in the components, and estimation of two further equations, representing, respectively, the determinants and consequences of the components. We describe procedures for data collection, assemble a set of tools for estimating the positive-belief and normative-judgment equations and carrying out the corresponding homogeneity tests, and propose ways of estimating the determinants and consequences equations. To illustrate the framework, we investigate both a positive-belief equation (describing adolescents' views concerning determination of marital happiness) and a normative-judgment equation (describing judgments of the justice of earnings). This article thus provides a guide to contemporary factorial survey analysis, and points the way to its further development.
Prevalence and Symptoms of Delirium Superimposed on Dementia
Authors: Voyer Philippe , Cole Martin G. , McCusker Jane , Belzile Éric
Published: January 2006

Delirium is a frequent syndrome among patients who are elderly. People who are older with cognitive impairment who are institutionalized are at increased risk of developing delirium when hospitalized. In addition, their prior cognitive impairment makes detecting their delirium a challenge. This study goal was to describe the effect of severity of prior cognitive impairment on delirium prevalence and symptom presentation among patients who were older and were newly admitted to an acute care hospital. A total of 104 were included in this descriptive study and screened for delirium. The results showed that the prevalence of delirium increased according to the severity of the patients’ prior cognitive impairment. Except for disorganized thinking, all symptoms of delirium were similar among patients with mild, moderate, and severe prior cognitive impairment. The study concluded that training nurses to recognize subtle changes in mental status among those patients who were older with prior cognitive impairment may prevent the underdetection of delirium.
Family Caregivers and Transition to Long-Term Care
Authors: Strang Vicki R. , Koop Priscilla M. , Dupuis-Blanchard Suzanne , Nordstrom Marlene , Thompson Betty
Published: January 2006

This study’s purpose was to explore family caregivers’ experiences while they waited placement of family members with dementia in long-term care and how they coped during this period of waiting and transition. In this exploratory descriptive qualitative study, interviews were conducted with 29 caregivers at entry to the placement wait-list and at 3 to 4-month intervals thereafter. Final interviews, with 15 caregivers, were conducted shortly after admission to long-term care. When “the waiting begins,” the themes of crisis as initiator, synchronicity, control, and reciprocity emerged. “After placement” included the themes of deeply bonded relationships, attempting continuity, and sorting out the change. The findings provide new insight into family caregiver experiences during and after placement of a family member with dementia in long-term care. Clinicians must recognize that wherever services are provided, at home before placement or in institutions after placement, family caregivers must be incorporated as full partners in care.
Health Care Workers’ Hand Decontamination Practices
Authors: Creedon Sile A.
Published: January 2006

The primary purpose of this quasi-experimental research is to observe health care workers’ compliance with hand-hygiene guidelines during patient care in an intensive care unit in Ireland before (pretest) and after (posttest) implementation of a multifaceted hand-hygiene program. Health care workers’ attitudes, beliefs, and knowledge in relation to compliance with handwashing guidelines were also investigated. A convenience sample of nurses, doctors, physiotherapists, and care assistants ( n = 73 observational participants, n = 62 questionnaire respondents) was used. Data ( N = 314 observations, 62 questionnaires) were analyzed descriptively and cross-tabulated using chi-square (Pearson’s) and Mann-Whitney statistical tests. Results revealed that a significant shift (32%) occurred in health care workers’ compliance with handwashing guidelines (pretest 51%, posttest 83%, p < .001) following the interventional hand-hygiene program. Significant changes were also found in relation to health care workers’ attitudes, beliefs, and knowledge ( p < .05).
Pilot Using World Wide Web to Prevent Diabetes in Adolescents
Authors: Long JoAnn D. , Armstrong Myrna L. , Amos Elizabeth , Shriver Brent , Roman-Shriver Carmen , Feng Du , Harrison LaNell , Luker Scott , Nash Anita , Blevins Monica Witcher
Published: January 2006

This pilot study tested the effects of an interactive nutrition education Web site on fruit, vegetable, and fat consumption in minority adolescents genetically at risk for Type 2 diabetes. A one-group nonexperimental pretest, posttest focus group design was used. Twenty-one sixth-grade to eighth-grade junior high adolescents who were minorities volunteered to participate. Participants received 5 hours of Web-based nutrition education over 3 weeks. A significant difference in fat consumption was supported from the computerized dietary assessment. No difference was found in fruit or vegetable consumption. Comparative data indicated a rise in body mass index (BMI) percentile from 88.03 (1999) to 88.40 (2002; boys) and 88.25 (1999) to 91.2 (2002; girls). Focus group responses supported the satisfaction of adolescents in the study with the use of the Web-based intervention for nutrition education. Healthy eating interventions using Web-based nutrition education should be further investigated with adolescents.
A family with Papillon-Lefèvre syndrome reveals a requirement for cathepsin C in granzyme B activation and NK cell cytolytic activity
Authors: Meade Josephine L. , de Wynter Erika A. , Brett Peter , Sharif Saghira Malik , Woods C. Geoffrey , Markham Alexander F. , Cook Graham P.
Published: January 2006

Activation of granzyme B, a key cytolytic effector molecule of natural killer (NK) cells, requires removal of an N-terminal pro-domain. In mice, cathepsin C is required for granzyme processing and normal NK cell cytolytic function, whereas in patients with Papillon-Lefèvre syndrome (PLS), loss-of-function mutations in cathepsin C do not affect lymphokine activated killer (LAK) cell function. Here we demonstrate that resting PLS NK cells do have a cytolytic defect and fail to induce the caspase cascade in target cells. NK cells from these patients contain inactive granzyme B, indicating that cathepsin C is required for granzyme B activation in unstimulated human NK cells. However, in vitro activation of PLS NK cells with interleukin-2 restores cytolytic function and granzyme B activity by a cathepsin C-independent mechanism. This is the first documented example of a human mutation affecting granzyme B activity and highlights the importance of cathepsin C in human NK cell function.
Induction of the plasminogen activator inhibitor-2 in cells expressing the ZNF198/FGFR1 fusion kinase that is involved in atypical myeloproliferative disease
Authors: Kasyapa Chitta S. , Kunapuli Padmaja , Hawthorn Lesleyann , Cowell John K.
Published: January 2006

The ZNF198/FGFR1 fusion kinase associated with an atypical myeloproliferative disease is constitutively activated and regulates several STAT transcription factors. We used oligonucleotide microarrays to compare the gene-expression profiles between HEK-293 cells that stably express either the ZNF198/FGFR1 chimeric protein or the wild-type ZNF198 gene. Expression of the plasminogen activator inhibitor-2 (PAI-2/SERPINB2) was highly increased in cells expressing the fusion gene. Western blot analysis demonstrated that HEK-293 cells do not express PAI-2 endogenously, but in ZNF198/FGFR1-expressing cells 2 molecular forms of PAI-2, which were 47 kDa and 32 kDa, were expressed intracellularly, and a 60-kDa form was secreted. Similarly, expression of ZNF198/FGFR1 in BaF/3 mouse hematopoietic cells also induced the expression of the PAI-2 protein. Immunoprecipitation analysis revealed that both intracellular forms of PAI-2 bind to the ZNF198/FGFR1 kinase. Treatment of HEK-293 and BaF/3 cells with TNF-α in the presence of cycloheximide, induced apoptosis in both cases. In contrast, HEK-293 and BaF/3 cells expressing ZNF198/FGFR1 were resistant to TNF-α-induced apoptosis. These observations suggest that expression of the ZNF198/FGFR1 fusion gene is associated with specific PAI-2-mediated resistance to apoptosis which may contribute to the highly malignant nature of leukemic cells carrying this fusion kinase gene.
Implication of the folate-methionine metabolism pathways in susceptibility to follicular lymphomas
Authors: Niclot Sidonie , Pruvot Quentin , Besson Caroline , Savoy Daniel , Macintyre Elisabeth , Salles Gilles , Brousse Nicole , Varet Bruno , Landais Paul , Taupin Pierre , Junien Claudine , Baudry-Bluteau Dominique
Published: January 2006

The incidence of follicular lymphoma (FL) in industrialized countries has been increasing since the 1950s. Polymorphisms in genes encoding key enzymes controlling folate-methionine metabolism, including methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MS or MTR), serine hydroxymethyltransferase (SHMT), and thymidylate synthase (TS or TYMS), modify the risk of various cancers and possibly FL. This study specifically looks for an association between MTHFR, MTR, TYMS, and SHMT polymorphisms and the risk of FL. We carried out a case-control study with 172 patients diagnosed with FL and 206 control subjects. We report that the risk of FL was doubled by the association of one mutant allele at both MTHFR polymorphisms. Individuals with MTR 2756AA had 2-fold higher risk of FL, and subjects not having at least one TYMS 2R allele showed a 2-fold higher risk of FL. The MTR 2756AA genotype conferred a greater multivariate-adjusted relative risk of FL, and the risk was multiplied by almost 5 in the TYMS2R(-)/MTR 2756AA combination. In conclusion, common polymorphisms in key enzymes of the folate-methionine metabolism pathway result in an increased risk of FL and suggest that inadequate intake of dietary folate and other methyl donor nutrients may contribute to the development of this malignancy. (Blood. 2006;108:278-285)
Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML
Authors: Reindl Carola , Bagrintseva Ksenia , Vempati Sridhar , Schnittger Susanne , Ellwart Joachim W. , Wenig Katja , Hopfner Karl-Peter , Hiddemann Wolfgang , Spiekermann Karsten
Published: January 2006

In acute myeloid leukemia (AML), two clusters of activating mutations are known in the FMS-like tyrosine kinase-3 (FLT3) gene: FLT3-internal tandem duplications (FLT3-ITDs) in the juxtamembrane (JM) domain in 20% to 25% of patients, and FLT3 point mutations in the tyrosine-kinase domain (FLT3-TKD) in 7% to 10% of patients, respectively. Here, we have characterized a new class of activating point mutations (PMs) that cluster in a 16-amino acid stretch of the juxtamembrane domain of FLT3 (FLT3-JM-PMs). Expression of 4 FLT3-JM-PMs in interleukin-3 (IL-3)-dependent Ba/F3 cells led to factor-independent growth, hyperresponsiveness to FLT3 ligand, and resistance to apoptotic cell death. FLT3-JM-PM receptors were autophosphorylated and showed a higher constitutive dimerization rate compared with the FLT3-wild-type (WT) receptor. As a molecular mechanism, we could show activation of STAT5 and up-regulation of Bcl-x(L) by all FLT3-JM-PMs. The FLT3 inhibitor PKC412 abrogated the factor-independent growth of FLT3-JM-PM-expressing cells. Compared with FLT3-ITD and FLT3-TKD mutants, the FLT3-JM-PMs showed a weaker transforming potential related to lower autophosphorylation of the receptor and its downstream target STAT5.

Mapping of the FLT3-JM-PMs on the crystal structure of FLT3 showed that these mutations reduce the stability of the autoinhibitory JM domain, and provides a structural basis for the transforming capacity of this new class of gain-of-function mutations of FLT3.
Host factors that impact the biodistribution and persistence of multipotent adult progenitor cells
Authors: Tolar Jakub , O'Shaughnessy Matthew J. , Panoskaltsis-Mortari Angela , McElmurry Ron T. , Bell Scott , Riddle Megan , McIvor R. Scott , Yant Stephen R. , Kay Mark A. , Krause Diane , Verfaillie Catherine M. , Blazar Bruce R.
Published: January 2006

Multipotent adult progenitor cells (MAPCs) are marrow-derived pluripotent stem cells with a broad differentiation potential. We sought to identify factors that affect adoptively transferred MAPCs. In vitro, MAPCs expressed low levels of major histocompatibility complex (MHC) antigens, failed to stimulate CD4+ and CD8+ T-cell alloresponses, and were targets of NK cytolysis. To study in vivo biodistribution, we labeled MAPCs with luciferase for sequential quantification of bioluminescence and DsRed2 for immunohistochemical analysis. C57BL /6 MAPCs were infused intravenously into C57BL /6, Rag-2–/– (T- and B-cell–deficient), and Rag-2–/–/IL-2Rγc–/– (T-, B-, and NK-cell–deficient) mice. In C57BL /6 mice, MAPCs were transiently detected only in the chest compared with long-term persistence in T- and B-cell–deficient mice. NK depletion reduced MAPC elimination. Because the lungs were the major uptake site after intravenous injection, intra-arterial injections were tested and found to result in more widespread biodistribution. Widespread MAPC biodistribution and long-term persistence were seen in irradiated recipients given allogeneic marrow and MAPCs; such MAPCs expressed MHC class I antigens in tissues. Our data indicate that the biodistribution and persistence of reporter gene–labeled MAPCs are maximized after intra-arterial delivery or host irradiation and that T cells, B cells, and NK cells contribute to in vivo MAPC rejection.
AIDS-related non-Hodgkin lymphoma: final analysis of 485 patients treated with risk-adapted intensive chemotherapy
Authors: Mounier Nicolas , Spina Michele , Gabarre Jean , Raphael Martine , Rizzardini Giuliano , Golfier Jean-Baptiste , Vaccher Emanuela , Carbone Antonino , Coiffier Bertrand , Chichino Guido , Bosly Andre , Tirelli Umberto , Gisselbrecht Christian ,   for the French-Italian cooperative group
Published: January 2006

We aimed to compare AIDS risk–adapted intensive chemotherapy in AIDS-related lymphoma (ARL) patients before and after the advent of highly active antiretroviral therapy (HAART). A total of 485 patients aged from 18 to 67 years were randomly assigned to chemotherapy after stratification according to an HIV score based on performance status, prior AIDS, and CD4+ cell counts below 0.10 × 109/L (100/mm3). A total of 218 good-risk patients (HIV score 0) received ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisolone) or CHOP (doxorubicin, cyclophosphamide, vincristine, and prednisolone); 177 intermediate-risk patients (HIV score 1), CHOP or low-dose CHOP (Ld-CHOP); and 90 poor-risk patients (HIV score 2-3), Ld-CHOP or VS (vincristine and steroid). The 5-year overall survival (OS) in the good-risk group was 51% for ACVBP versus 47% for CHOP (P = .85); in the intermediate-risk group, 28% for CHOP versus 24% for Ld-CHOP (P = .19); and in the poor-risk group, 11% for Ld-CHOP versus 3% for VS (P = .14). The time-dependent Cox model demonstrated that the only significant factors for OS were HAART (relative risk [RR] 1.6, P < .001), HIV score (RR 1.7, P < .001), and the International Prognostic Index (IPI) score (RR 1.5, P < .001) but not chemotherapy regimen. Our findings indicate that in ARL patients, HIV score, IPI score, and HAART affect survival but not the intensity of the CHOP-based chemotherapy.
In vivo peripheral expansion of naive CD4+CD25highFoxP3+ regulatory T cells in patients with multiple myeloma
Authors: Beyer Marc , Kochanek Matthias , Giese Thomas , Endl Elmar , Weihrauch Martin R. , Knolle Percy A. , Classen Sabine , Schultze Joachim L.
Published: January 2006

In solid tumors, leukemias, and lymphomas, increased frequencies of functional CD4+CD25high regulatory T cells (Treg cells) have been previously demonstrated. In healthy individuals, Treg cells consist not only of memory but also of naive T cells, which can undergo peripheral expansion and are characterized by a relative enrichment for autoreactive T-cell receptors. Here, we demonstrate in patients with premalignant monoclonal gammopathy of undetermined significance and patients with multiple myeloma that functional FoxP3+ Treg cells of naive, central, and effector memory phenotype as determined by CCR7 and CD45RA expression are significantly expanded. Low frequencies of T-cell receptor excision circles in naive Treg cells in both healthy controls and multiple myeloma patients point to peripheral expansion as the prominent mechanism of increased frequencies of naive Treg cells in these cancer patients. These findings strongly suggest that the increase of functional Treg cells in cancer patients is a response to the process of malignant transformation.
Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response
Authors: Fujita Shigeharu , Seino Ken-ichiro , Sato Kaori , Sato Yumiko , Eizumi Kawori , Yamashita Naohide , Taniguchi Masaru , Sato Katsuaki
Published: January 2006

Bacterial infection triggers host inflammation through the activation of immune cells, leading to the elimination of bacteria. However, the regulatory mechanisms of the host inflammatory response remain unknown. Here we report that a subset of potent tolerogenic dendritic cells (DCs), regulatory DCs (DCregs), control the systemic inflammatory response. Unlike normal DCs, which produced proinflammatory cytokines in response to bacterial lipopolysaccharide (LPS), DCregs produced fewer proinflammatory cytokines and instead preferentially produced interleukin-10 (IL-10), and these events involved the expression of IκBNS and Bcl-3 as well as cyclic AMP (cAMP)-mediated activation of protein kinase A (PKA). In addition, DCregs not only suppressed LPS-induced production of proinflammatory cytokines in macrophages, but also reduced their serum levels in mice. Furthermore, DCregs protected mice against the lethality induced by experimental endotoxemia and bacterial peritonitis. The inhibitory effect of DCregs against inflammatory responses involved the production of IL-10. On the other hand, naturally existing tolerogenic DC subsets producing IL-10, CD11clowCD45RBhigh DCs, also suppressed LPS-induced host inflammatory responses. Thus, a subset of tolerogenic DCs act as potential regulators of the host inflammatory response, and they might have preventive and therapeutic potential for the treatment of systemic as well as local inflammatory diseases.
Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation
Authors: Lan Ping , Tonomura Noriko , Shimizu Akira , Wang Shumei , Yang Yong-Guang
Published: January 2006

Studies of the human immune system have been limited by the lack of an appropriate in vivo model. For this reason, efforts have been made to develop murine models with a functional human immune system. We report here that cotransplantation of human fetal thymus/liver tissues and CD34+ hematopoietic stem/progenitor cells led to the development of sustained human hematopoiesis and a functional human immune system in immunodeficient NOD/SCID mice. The humanized mice showed systemic repopulation with a comprehensive array of human lymphohematopoietic cells, including T cells, B cells, and dendritic cells, and the formation of secondary lymphoid organs. Furthermore, these mice produce high levels of human IgM and IgG antibodies and mediate strong immune responses in vivo as demonstrated by skin xenograft rejection. Thus, the humanized NOD/SCID mice described in this paper provide a powerful model system to study human immune function.
Severe pulmonary complications in Japanese patients after bortezomib treatment for refractory multiple myeloma
Authors: Miyakoshi Shigesaburo , Kami Masahiro , Yuji Koichiro , Matsumura Tomoko , Takatoku Masaaki , Sasaki Makoto , Narimatsu Hiroto , Fujii Takeshi , Kawabata Masateru , Taniguchi Shuichi , Ozawa Keiya , Oshimi Kazuo
Published: January 2006

Bortezomib is a novel proteasome inhibitor with significant antimyeloma activity. Its frequent adverse effects are manageable, including gastrointestinal symptoms, peripheral neuropathy, and thrombocytopenia. Severe lung toxicity has not previously been reported. Between June 2004 and September 2005, 13 Japanese patients with multiple myeloma were treated with bortezomib in Toranomon Hospital, Juntendo University School of Medicine, and Jichi Medical School. Four of them developed severe pulmonary complications, and 2 died of respiratory failure without progression of underlying disease. To our knowledge, this is the first report on life-threatening pulmonary adverse effects after bortezomib therapy. Previous clinical studies on bortezomib, mostly in the United States and Europe, have shown low incidences of pulmonary adverse effects. Our study suggests that bortezomib can cause serious lung injury, and that its incidence might vary among different ethnicities. Clinicians need to be alert to the possibility.
Galanin-Like Peptide Stimulates Food Intake via Activation of Neuropeptide Y Neurons in the Hypothalamic Dorsomedial Nucleus of the Rat
Authors: Kuramochi Motoki , Onaka Tatsushi , Kohno Daisuke , Kato Satoshi , Yada Toshihiko
Published: January 2006

Galanin-like peptide (GALP), a 29-amino-acid neuropeptide, is located in the hypothalamic arcuate nucleus (ARC), binds to galanin receptor subtype 2, and induces food intake upon intracerebroventricular (icv) injection in rats. However, neural mechanisms underlying its orexigenic action remain unclear. We aimed to identify the nuclei and neuron species that mediate the food intake in response to icv GALP injection. Intracerebroventricular injection of GALP, as powerfully as that of neuropeptide Y (NYP), increased food intake for the initial 2 h. GALP injected focally into the dorsomedial nucleus (DMN), but not the ARC, lateral hypothalamus, or paraventricular nucleus (PVN), stimulated food intake for 2 h after injection. In contrast, galanin injected into the DMN had no effect. DMN-lesion rats that received icv GALP injection showed attenuated feeding compared with control rats. Intracerebroventricular GALP injection increased c-Fos expression in NPY-containing neurons in the DMN, but not the ARC. GALP increased the cytosolic calcium concentration ([Ca2+]i) in NPY-immunoreactive neurons isolated from the DMN, but not the ARC. Furthermore, both anti-NPY IgG and NPY antagonists, when preinjected, counteracted the feeding induced by GALP injection. These data show that icv GALP injection induces a potent short-term stimulation of food intake mainly via activation of NPY-containing neurons in the DMN.
Hyperinsulinemia, But Not Other Factors Associated with Insulin Resistance, Acutely Enhances Colorectal Epithelial Proliferation in Vivo
Authors: Tran Thien T. , Naigamwalla Dinaz , Oprescu Andrei I. , Lam Loretta , McKeown-Eyssen Gail , Bruce W. Robert , Giacca Adria
Published: January 2006

The similarity in risk factors for insulin resistance and colorectal cancer (CRC) led to the hypothesis that markers of insulin resistance, such as elevated circulating levels of insulin, glucose, fatty acids, and triglycerides, are energy sources and growth factors in the development of CRC. The objective was thus to examine the individual and combined effects of these circulating factors on colorectal epithelial proliferation in vivo. Rats were fasted overnight, randomized to six groups, infused iv with insulin, glucose, and/or Intralipid for 10 h, and assessed for 5-bromo-2-deoxyuridine labeling of replicating DNA in colorectal epithelial cells. Intravenous infusion of insulin, during a 10-h euglycemic clamp, increased colorectal epithelial proliferation in a dose-dependent manner. The addition of hyperglycemia to hyperinsulinemia did not further increase proliferation. Intralipid infusion alone did not affect proliferation; however, the combination of insulin, glucose, and Intralipid infusion resulted in greater hyperinsulinemia than the infusion of insulin alone and further increased proliferation. Insulin infusion during a 10-h euglycemic clamp decreased total IGF-I levels and did not affect insulin sensitivity. These results provide evidence for an acute role of insulin, at levels observed in insulin resistance, in the proliferation of colorectal epithelial cells in vivo.
Luteinizing Hormone Receptors Translocate to Plasma Membrane Microdomains after Binding of Human Chorionic Gonadotropin
Authors: Smith Steven M. L. , Lei Ying , Liu Jingjing , Cahill Mary E. , Hagen Guy M. , Barisas B. George , Roess Deborah A.
Published: January 2006

Receptor-mediated signal transduction by G protein-coupled receptors can involve redistribution of plasma membrane receptors into membrane structures that are characterized by insolubility in Triton X-100 and low buoyant density in sucrose gradients. Here we describe the translocation of wild-type (wt) rat LH receptors (LHR-wt) from the bulk membrane into membrane microdomains (rafts) after the binding of human chorionic gonadotropin (hCG). In sucrose gradient ultracentrifugation of plasma membranes from cells stably expressing FLAG-tagged LHR-wt, receptors were located in high-density membrane fractions before binding of hormone and in low-density fractions after hCG treatment. Receptor translocation to low-density sucrose fractions did not occur when cells were pretreated with 1% methyl-β-cyclodextrin, which reduces membrane cholesterol and disrupts rafts. Single-particle tracking of individual FLAG-LHR-wt receptors showed that hCG-treated receptors become confined in small compartments with a diameter of 86 ± 36 nm, significantly smaller than 230 ± 79 nm diameter regions accessed by the untreated receptor. Receptors were no longer confined in these small compartments after disruption of rafts by methyl-β-cyclodextrin, a treatment that also decreased levels of cAMP in response to hCG. Finally, translocation of LHR into rafts required a functional hormone-receptor complex but did not occur after extensive receptor cross-linking that elevated cAMP levels. Thus, retention of LHR in rafts or small membrane compartments is a characteristic of functional, hormone-occupied LHR-wt. Although raft translocation was not essential for cAMP production, it may be necessary for optimizing hormone-mediated signaling.