bluuebunny/crossref_metadata_2025 huggingface dataset:
Children Talking: Emerging Perspectives and Experiences of Cigarette Smoking
Authors: Treacy Margaret (Pearl) , Hyde Abbey , Boland Jennie , Whitaker Teresa , Abaunza Pilar Santos , Stewart-Knox Barbara J.
Published: January 2007

Despite efforts to prevent the onset of smoking, the rate among older children remains high. In this article, the authors report on a longitudinal, qualitative study of 11 to 16-year-old children describing children's construction of what it means to be a smoker, the reasons given for children smoking, and their views of smoking behavior. Findings indicate that children adopt broad interpretations of what constitutes smoking behavior; although they strongly disapprove of children who smoke, they are less disapproving of older children or adult smokers and are increasingly tolerant of smoking behavior as they get older. Children's disapproval of smoking acts as a protective mechanism against smoking for younger participants. Participants' broad interpretation of what it means to be a cigarette smoker, their association of smoking with adulthood, and their increasing tolerance of and exposure to smoking behavior as they move into adolescence appears to increase susceptibility to becoming cigarette smokers.
Community Social Support for Cuban Refugees in Texas
Authors: Barnes Donelle M. , Aguilar Rocio
Published: January 2007

Social support has been linked to positive health outcomes for many populations across multiple health issues. The interactional approach defines social support as a complex, transactional process between the person and his or her social environment. Being part of a community enhances the likelihood of social bonding, leading to increased perceived support. In this study, the authors describe recently arrived adult Cuban refugees' perceptions of community-level support in Texas. Practical and emotional support needs included jobs and companionship away from everyday problems. The two major sources of practical support were resettlement agencies and other Cubans. The two major sources of emotional support were other Cubans and English-speaking friends. There were no local Cuban clubs or associations where Cubans could meet. Besides receiving support, many Cubans were also supporting other Cubans locally and in Cuba, and some experienced discrimination.
Confidentiality and Autonomy: The Challenge(s) of Offering Research Participants a Choice of Disclosing Their Identity
Authors: Giordano James , O'Reilly Michelle , Taylor Helen , Dogra Nisha
Published: January 2007

In this article, the authors present one of the key ethical features of research: confidentiality as maintained by nondis-closure of participants' identities. In light of (a) the contingency that certain participants might vest interest in research studies through their identity and (b) the concept of respect for participants' autonomy, the authors consider the possibilities of offering research participants the choice of nonconfidentiality, afforded as an autonomous (negative) right of refusal of nondisclosure of identity. They address the issue that this possibility generates within the context(s) of current codes of ethics related to health research and the manifest responsibilities of the institutional review process. In this way, they attempt to elucidate potential benefits and consequences that arise from confidentiality and nonconfidentiality.
Learning From the Grandmothers: Incorporating Indigenous Principles Into Qualitative Research
Authors: Loppie Charlotte
Published: January 2007

In this article, the author describes the process she undertook to incorporate Indigenous principles into her doctoral research about the midlife health experiences of elder Aboriginal women in Nova Scotia, Canada. By employing qualitative methods within the context of an Indigenous worldview, she gained knowledge of and developed competence in Aboriginal health research. The emergent partnership among Aboriginal community research facilitators, participating Mi'kmaq women, and the researcher provided many opportunities for the researcher to incorporate the paradigmatic and methodological traditions of Western science and Indigenous cultures. The application of these principles to this study might provide a useful example for other health researchers who are attempting to incorporate diverse methodological principles.
Yet Another Solution to Galton's Problem
Authors: Denton Trevor
Published: January 2007

For half a century, Galton's problem has been a thorn in the side of cultural anthropologists, agitating them to print. Galton's problem motivated the creators of all the major cross-cultural sampling frames to advocate selection of a single ethnographic description from each of up to hundreds of internally homogeneous culture areas. Why this happened is perplexing. Galton's problem disappears when it is thought of as a theoretical issue of correct specification of a theoretical model. There are implications for the construction of new cross-cultural samples.
Unit of Observation in Cross-Cultural Research
Authors: Denton Trevor
Published: January 2007

The unit of observation in all current cross-cultural research is a culture or society. There are two consequences. First, if the unit of analysis is also a culture or society, demonstrable face or content validity must establish that the units of observation in a sample of cultures or societies are a random sample from the population from which the sample is deemed to be drawn. Second, where units of analysis (e.g., individuals) are aggregated into units of observation (i.e., cultures or societies), appropriate data analysis must be used. Unless these conditions are met, two varieties of error may result: The sample used may not be a valid, representative subset of the population, or analysis of aggregated data as if they were nonaggregated may distort results. Examples are given using the Standard Cross-Cultural Sample (SCCS). Validity appears to be greater for the SCCS as a sample of societies than a sample of cultures. A method for drawing new samples is suggested.
Female Status Predicts Female Mate Preferences Across Nonindustrial Societies
Authors: Moore Fhionna R. , Cassidy Clare
Published: January 2007

Most studies demonstrating the contribution of economic constraints on women to sex differences in mate preferences have used samples from postindustrial societies with similar social structures. The authors investigate the effects of female status on female mate preferences in a subsection of the Standard Cross-Cultural Sample. Whyte's (1978) codes provide indicators of female status, and mate preferences are obtained through qualitative analysis of ethnographic data in the Human Relations Area Files. Two measures of female status are found to relate to the relative importance of physical appearance to access to resources in attraction to a partner: Domestic authority is associated with greater importance placed on appearance relative to resources, whereas ritualized female solidarity is associated with lower importance of appearance relative to resources. Results are discussed in the context of the contribution of social and economic constraints on women to sex differences.
The Soul of Sorrow Work
Authors: Moules Nancy J. , Simonson Kari , Fleiszer Andrea R. , Prins Mark , Glasgow Rev. Bob
Published: January 2007

The courage and willingness to walk alongside families in grief calls forth particular beliefs and practices in nurses and other health care professionals. In this second phase of a study on grief and grief interventions, the researchers examine experiences of bereaved family members who received care in a grief support program and explore program clinicians'explanations of the work that they do with the bereaved. Findings of this interpretive study suggest that it is not so much models of grief intervention but maps that most guide the clinicians—maps that are drawn out of experience and with awareness of their limitations. The family members and the clinicians bring us to an understanding that, often, it is the willingness to step off of the map that makes for the best traveling companion in the spiritual walk of grief.
Imposing Order
Authors: Hall Wendy A.
Published: January 2007

This study investigated how English and Canadian families with preschool children used strategies to impose varying levels of order to manage day-to-day activities. This grounded theory study is a secondary analysis of 55 hours of participant observation and interviews with 58 individuals and 29 couples. Constant comparative analysis and theoretical sampling were used to construct categories. To attempt to impose order, strategies used by families included organizing and planning, establishing routines, setting limits, setting standards, purchasing services and technology, and delegating tasks. Most families used these strategies successfully; costs outweighed benefits where families concentrated inflexibly on a few strategies in particular spheres of activity or had difficulty using strategies. Families using a variety of strategies flexibly were better at balancing personal and family goals, promoting fulfillment, health, and happiness for each family member, and fostering family development and commitment. Imposing order links everyday family dynamics and concerns to long-term goals.
In Defense of Being “Native”: The Case for Insider Academic Research
Authors: Brannick Teresa , Coghlan David
Published: January 2007

Within organizational research, the subject of insider academic research has received relatively little consideration. By insider research, we mean research by complete members of organizational systems in and on their own organizations. Insider research can be undertaken within any of the three major research paradigms—positivism, hermeneutics, and action research—selected and presented in this article. First, we revisit some of the established research paradigms to see what position they might have on insider research. Second, we explore the dynamics of insider research under the headings of access, preunderstanding, role duality, and managing organizational politics. Our conclusion is that within each of the main streams of research, there is no inherent reason why being native is an issue and that the value of insider research is worth reaffirming.
Using Indices of Group Agreement in Multilevel Construct Validation
Authors: Meade Adam W. , Eby Lillian T.
Published: January 2007

This article illustrates the role of group-agreement indices in the process of multilevel construct validation. A two-step process is outlined that includes multitrait-multimethod confirmatory factor analysis (CFA) and the use of a dispersion model to examine correlates of consensus of multilevel constructs. The role of dispersion models for providing discriminant validity evidence for similar constructs, as well as providing insight as to why some teams share perceptions more strongly than others, is illustrated using three efficacy-related constructs.
Using a Random-Effects Model to Test Differing Conceptualizations of Multidimensional Constructs
Authors: Sturman Michael C. , Carraher Shawn M.
Published: January 2007

Previous work investigating the dimensionality of psychological constructs has assumed a fixed-effects model, in which one true correlation describes the relationship between two given dimensions. We challenge this assumption by showing how a random-effects model may aid in representing individual perceptions of multidimensional constructs. Using the Pay Satisfaction Questionnaire (PSQ), we demonstrate that the relationships that individuals hold between the (purported) dimensions of the PSQ are predictable by cognitive complexity, pay level satisfaction, pay level, and interactions; we also show how between-dimension variation assists in establishing criterion-related validity.
Using Multilevel Random Coefficient Modeling to Investigate Rater Effects in Performance Ratings
Authors: Lahuis David M. , Avis John M.
Published: January 2007

There has been recent interest in how rater attributes lead to systematic variance in ratings of job performance. Although numerous rater characteristics have been proposed to affect performance ratings, there has been little empirical research studying them. We suggest this has been because of methodological problems with levels of analysis and propose multilevel random coefficient (MRC) modeling as a solution. We present a multilevel model of rater effects in which ratees are nested within raters. We also present two examples of applying MRC modeling to criterion-related validity data to study how rater-level variables influence performance ratings and the relationships selection assessments have with those ratings.
Integrating Implicit and Explicit Social Cognitions for Enhanced Personality Assessment: A General Framework for Choosing Measurement and Statistical Methods
Authors: Bing Mark N. , LeBreton James M. , Davison H. Kristl , Migetz Debrah Z. , James Lawrence R.
Published: January 2007

The current article advocates integrating implicit and explicit social cognitions for enhanced personality assessment in organizational contexts (e.g., personnel selection settings). Several methods for measuring implicit cognitions are reviewed, and their strengths and limitations are discussed. The most widely used method for measuring explicit cognitions, the self-report questionnaire, also is described along with its strengths and limitations. Implicit and explicit cognitions then are integrated to form a general model of personality prototypes. The authors describe several mechanisms by which implicit and explicit cognitions may operate (e.g., coact, interact) to predict criteria, depending on the nature of the personality construct assessed and the outcome of interest. These different operations implicate different statistical methodologies. The authors then present specific examples of this integrative procedure for enhancing personality assessment using the construct of achievement motivation. They conclude by discussing how future research could extend and apply this general framework for use with other personality constructs.
Exploring Perspectives on Human Resource Development: An Introduction
Authors: Garavan Thomas N. , O'Donnell David , McGuire David , Watson Sandra
Published: January 2007

The problem and the solution. This issue overview presents a brief justification for adopting a multiperspectival approach to theory and practice in human resource development (HRD). It is argued that such an approach has the potential to add theoretical depth and breadth to HRD discourse as well as contributing to reflective HRD practice.The contributions are then briefly introduced.
HRD From a Functionalist Perspective:The Views of Line Managers Sandra Watson
Authors: Watson Sandra , Maxwell Gillian A.
Published: January 2007

The problem and the solution. Previous research has indicated that line managers play a critical role in facilitating organizational and individual learning. However, short-term pressures, work overload, and lack of specialist expertise, for example, have been identified as inhibiting line manager involvement in human resource development (HRD). Based on a sample of 328 line managers from the Hilton hotel group in the United Kingdom, this article considers line managers' under-standing of their HRD roles and responsibilities, the key HRD activities they engage in, and the challenges they face in relation to their HRD roles. It concludes that line managers appear to have embraced their HRD roles, with support from HRD professionals.
Psychodynamic and Critical Perspectives on Leadership Development
Authors: Trehan Kiran
Published: January 2007

The problem and the solution. Increasing attention is focusing on the value of critical approaches to enhancing human resource development (HRD). This article examines how critical HRD and psychoanalytic processes can be harnessed to produce valuable learning through reflection. Psychodynamic perspectives not only explore underlying power and control issues but actively engage in an examination of political and cultural processes affecting the development process. Such perspectives enable one to move beyond purely instrumentalist approaches toward embracing the complexity of leadership development.
Discursive Struggle and the Ambiguous World of HRD
Authors: Francis Helen
Published: January 2007

The problem and the solution. In this article, the author draws on a discourse perspective to explore the role of the human resource development (HRD) function in shaping organizational change within a large manufacturing firm moving toward a flatter team-based organizational structure. In support of an emerging “critical” strand of HRD, the author gives special consideration to how HRD specialists worked with colleagues from the personnel function to strategically draw on a complex mix of discursive constructions to promote a supportive learning environment and enhanced worker participation.Treating language as social practice, the author shows how this ability to act strategically was shaped by a variety of discursive practices at corporate level and beyond.
Human Resource Development from a Holistic Perspective
Authors: Lee Monica
Published: January 2007

The problem and the solution. In an increasing complex world, a holistic perspective on HRD examines the inter-relatedness of the global and local; economic and social; individual and community and considers the role of professional bodies, the development of ethical approaches, and the need to guard and enhance notions of identity.
Metaperspectives and HRD: Lessons for Research and Practice
Authors: McGuire David , Garavan Thomas N. , O'Donnell David , Watson Sandra
Published: January 2007

The problem and the solution. Reviewing the contributions, four metaperspectives on HRD are proposed: language, community/ societal, system, and psychological. Each suggests a particular conception of HRD and some implications of each metaperspective for theory and practice are presented.Academics and practitioners are challenged to incorporate multiperspectival views into theory,method, and practice.
TLR ligands differentially affect uptake and presentation of cellular antigens
Authors: Weck Markus Michael , Grünebach Frank , Werth Daniela , Sinzger Christian , Bringmann Anita , Brossart Peter
Published: January 2007

Dendritic cells (DCs) have the unique ability to efficiently present T-cell epitopes from exogenous antigens on MHC class I molecules, a process called cross-presentation. In our study we demonstrate that stimulation of monocyte-derived DCs with Toll-like receptor (TLR) ligands differentially affects the uptake and cross-presentation of cellular antigens. Activation of DCs with TLR3 or TLR4 but not with TLR2 or TLR7/8 ligands inhibited phagocytosis of apoptotic tumor cells and resulted in a reduced cross-presentation of pp65-derived T-cell epitopes on MHC class I molecules upon engulfment of cytomegalovirus (CMV)–infected fibroblasts. These results have an important impact on the understanding of the interactions between the immune system and pathogens and the development of vaccination strategies to treat malignant diseases.
MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825
Authors: Nguyen Tri K. , Rahmani Mohamed , Harada Hisashi , Dent Paul , Grant Steven
Published: January 2007

Interactions between MEK1/2 inhibitors and the dual Abl/Src kinase inhibitor dasatinib (BMS-354825) were examined in chronic myeloid leukemia (CML) cell lines and primary specimens. Cotreatment of K562 or LAMA cells with subtoxic or marginally toxic concentrations of PD184352 (or U0126) and dasatinib synergistically potentiated mitochondrial damage, caspase activation, and apoptosis. Similar interactions were observed in CD34+ cells from one CML patient–derived but not in a normal human CD34+ bone marrow cell specimen. These interactions were associated with multiple perturbations in survival signaling pathways, including inactivation of Bcr/Abl, STAT5, and ERK1/2; down-regulation of Bcl-xL and Mcl-1; and dephosphorylation/activation of Bim. They were also associated with BAX/BAK conformational change, mitochondrial dysfunction, and caspase activation. Bim knockdown by shRNA suppressed BAX and BAK conformational change and protected cells from dasatinib/PD184352 lethality. Conversely, K562 cells ectopically expressing Mcl-1 or Bcl-xL were significantly less susceptible to dasatinib/PD184352 toxicity. Notably, the dasatinib/PD184352 regimen was active against leukemic cells exhibiting various forms of imatinib mesylate resistance, including Bcr/Abl overexpression, Lyn activation, and several Bcr/Abl kinase domain mutations (eg, E255K, M351T), but not T315I. Together, these findings suggest that strategies combining dasatanib with MEK1/2 inhibitors warrant further investigation in Bcr/Abl+ malignancies, particularly in the setting of imatinib mesylate–resistant disease.
Reciprocal regulation of human natural killer cells and macrophages associated with distinct immune synapses
Authors: Nedvetzki Shlomo , Sowinski Stefanie , Eagle Robert A. , Harris James , Vély Frédéric , Pende Daniela , Trowsdale John , Vivier Eric , Gordon Siamon , Davis Daniel M.
Published: January 2007

Natural killer (NK) cells directly lyse tumor or viral-infected cells but also an important role for NK cell cytotoxicity in regulating the extent of immune responses is emerging. Here, we show that autologous human macrophages activated NK cell proliferation and cytokine secretion, increased expression of activating receptors, and primed NK cell cytotoxicity against susceptible target cells. Ligation of NK cell 2B4, and not NKp30 (known to be important for DC-mediated NK cell activation), is critical for this macrophage-mediated NK cell activation. Reciprocally, however, NK cells regulated macrophage activity by directly killing macrophages stimulated by high doses of LPS. Cytolysis was triggered by NKG2D recognition of stress-inducible class I major histocompatibility complex (MHC)–like ligands on macrophages: high doses of LPS induced transcription and surface expression of ULBP1, ULBP2, and ULBP3 and surface expression of constitutively transcribed MICA. Thus, these data suggest a new function for NK cell cytotoxicity in eliminating overstimulated macrophages. Additionally, these interactions define, for the first time, 2 distinct activating NK cell synapses: lytic and nonlytic. Triggering NK cell proliferation and cytokine secretion, but not cytolysis, specifically associated with synaptic accumulation of macrophage F-actin and NK cell 2B4, while macrophages were killed when NK cell F-actin and macrophage ICAM-1 accumulated around a central cluster of NK cell NKG2D/DAP10.
Genomewide identification of prednisolone-responsive genes in acute lymphoblastic leukemia cells
Authors: Tissing Wim J. E. , den Boer Monique L. , Meijerink Jules P. P. , Menezes Renee X. , Swagemakers Sigrid , van der Spek Peter J. , Sallan Stephen E. , Armstrong Scott A. , Pieters Rob
Published: January 2007

Glucocorticoids are keystone drugs in the treatment of childhood acute lymphoblastic leukemia (ALL). To get more insight in signal transduction pathways involved in glucocorticoid-induced apoptosis, Affymetrix U133A GeneChips were used to identify transcriptionally regulated genes on 3 and 8 hours of prednisolone exposure in leukemic cells of 13 children as compared with nonexposed cells. Following 3 hours of exposure no significant changes in gene expression could be identified. Following 8 hours of exposure, 51 genes were differentially expressed (P < .001 and false discovery rate < 10%) with 39 genes being up-regulated (median, 2.4-fold) and 12 genes were down-regulated (median, 1.7-fold). Twenty-one of those genes have not been identified before to be transcriptionally regulated by prednisolone. Two of the 3 most highly up-regulated genes were tumor suppressor genes, that is, thioredoxin-interacting protein (TXNIP; 3.7-fold) and zinc finger and BTB domain containing 16 (ZBTB16; 8.8-fold). About 50% of the differentially expressed genes were functionally categorized in 3 major routes, namely MAPK pathways (9 genes), NF-κB signaling (11 genes), and carbohydrate metabolism (5 genes). Biologic characterization of these genes and pathways might elucidate the action of glucocorticoids in ALL cells, possibly suggesting causes of glucocorticoid resistance and new potential targets for therapy.
In silico panning for a non-competitive peptide inhibitor
Authors: Yagi Yukiko , Terada Kotaro , Noma Takahisa , Ikebukuro Kazunori , Sode Koji
Published: January 2007

Background

Peptide ligands have tremendous therapeutic potential as efficacious drugs. Currently, more than 40 peptides are available in the market for a drug. However, since costly and time-consuming synthesis procedures represent a problem for high-throughput screening, novel procedures to reduce the time and labor involved in screening peptide ligands are required. We propose the novel approach of 'in silico panning' which consists of a two-stage screening, involving affinity selection by docking simulation and evolution of the peptide ligand using genetic algorithms (GAs). In silico panning was successfully applied to the selection of peptide inhibitor for water-soluble quinoprotein glucose dehydrogenase (PQQGDH).

Results

The evolution of peptide ligands for a target enzyme was achieved by combining a docking simulation with evolution of the peptide ligand using genetic algorithms (GAs), which mimic Darwinian evolution. Designation of the target area as next to the substrate-binding site of the enzyme in the docking simulation enabled the selection of a non-competitive inhibitor. In all, four rounds of selection were carried out on the computer; the distribution of the docking energy decreased gradually for each generation and improvements in the docking energy were observed over the four rounds of selection. One of the top three selected peptides with the lowest docking energy, 'SERG' showed an inhibitory effect with K
i value of 20 μM. PQQGDH activity, in terms of the V
max value, was 3-fold lower than that of the wild-type enzyme in the presence of this peptide. The mechanism of the SERG blockage of the enzyme was identified as non-competitive inhibition. We confirmed the specific binding of the peptide, and its equilibrium dissociation constant (K
D) value was calculated as 60 μM by surface plasmon resonance (SPR) analysis.

Conclusion

We demonstrate an effective methodology of in silico panning for the selection of a non-competitive peptide inhibitor from small virtual peptide library. This study is the first to demonstrate the usefulness of in silico evolution using experimental data. Our study highlights the usefulness of this strategy for structure-based screening of enzyme inhibitors.
Wnt/β-catenin signaling is required for development of the exocrine pancreas
Authors: Wells James M , Esni Farzad , Boivin Gregory P , Aronow Bruce J , Stuart William , Combs Chelsea , Sklenka Angela , Leach Steven D , Lowy Andrew M
Published: January 2007

Background

β-catenin is an essential mediator of canonical Wnt signaling and a central component of the cadherin-catenin epithelial adhesion complex. Dysregulation of β-catenin expression has been described in pancreatic neoplasia. Newly published studies have suggested that β-catenin is critical for normal pancreatic development although these reports reached somewhat different conclusions. In addition, the molecular mechanisms by which loss of β-catenin affects pancreas development are not well understood. The goals of this study then were; 1] to further investigate the role of β-catenin in pancreatic development using a conditional knockout approach and 2] to identify possible mechanisms by which loss of β-catenin disrupts pancreatic development. APdx1-cremouse line was used to delete a floxedβ-cateninallele specifically in the developing pancreas, and embryonic pancreata were studied by immunohistochemistry and microarray analysis.

Results

Pdx1-crefloxedβ-cateninanimals were viable but demonstrated small body size and shortened median survival. The pancreata from knockout mice were hypoplastic and histologically demonstrated a striking paucity of exocrine pancreas, acinar to duct metaplasia, but generally intact pancreatic islets containing all lineages of endocrine cells. In animals with extensive acinar hypoplasia, putative hepatocyte transdifferention was occasionally observed. Obvious and uniform pancreatic hypoplasia was observed by embryonic day E16.5. Transcriptional profiling ofPdx1-crefloxedβ-cateninembryonic pancreata at E14.5, before there was a morphological phenotype, revealed significant decreases in the β-catenin target geneN-myc, and the basic HLH transcription factorPTF1, and an increase of several pancreatic zymogens compared to control animals. By E16.5, there was a dramatic loss of exocrine markers and an increase inHoxb4, which is normally expressed anterior to the pancreas.

Conclusion

We conclude that β-catenin expression is required for development of the exocrine pancreas, but is not required for development of the endocrine compartment. In contrast, β-catenin/Wnt signaling appears to be critical for proliferation of PTF1+ nascent acinar cells and may also function, in part, to maintain an undifferentiated state in exocrine/acinar cell precursors. Finally, β-catenin may be required to maintain positional identity of the pancreatic endoderm along the anterior-posterior axis. This data is consistent with the findings of frequentβ-cateninmutations in carcinomas of acinar cell lineage seen in humans.
Prostaglandin I2 enhances cough reflex sensitivity to capsaicin in the asthmatic airway
Authors: Ishiura Yoshihisa , Fujimura Masaki , Nobata Kouichi , Oribe Yoshitaka , Abo Miki , Myou Shigeharu
Published: January 2007

Inflammatory mediators are involved in the pathogenesis of airway inflammation, but the role of prostaglandin I2 (PGI2) remains obscure. This study was designed to investigate the role of PGI2 in cough reflex sensitivity of the asthmatic airway, which is characterized by chronic eosinophilic airway inflammation. The effect of beraprost, a chemically and biologically stable analogue of PGI2, on cough response to inhaled capsaicin was examined in 21 patients with stable asthma in a randomized, placebo-controlled cross over study. Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was measured as an index of airway cough reflex sensitivity. The cough threshold was significantly (p < 0.05) decreased after two weeks of treatment with beraprost [17.8 (GSEM 1.20) μM] compared with placebo [30.3 (GSEM 1.21) μM]. PGI2 increases cough reflex sensitivity of the asthmatic airway, suggesting that inhibition of PGI2 may be a novel therapeutic option for patients with asthma, especially cough predominant asthma.
Interferon alpha therapy for hepatitis C: treatment completion and response rates among patients with substance use disorders
Authors: Huckans Marilyn S , Loftis Jennifer M , Blackwell Aaron D , Linke Alex , Hauser Peter
Published: January 2007

Background

Individuals with substance use disorders (SUDs) are at increased risk for hepatitis C viral infection (HCV), and few studies have explored their treatment responses empirically. The objective of this study was to assess interferon alpha therapy (IFN) completion and response rates among patients with HCV who had a history of comorbid SUDs. More data is needed to inform treatment strategies and guidelines for these patients. Using a medical record database, information was retrospectively collected on 307,437 veterans seen in the Veterans Integrated Service Network 20 (VISN 20) of the Veterans Healthcare Administration (VHA) between 1998 and 2003. For patients treated with any type of IFN (including regular or pegylated IFN) or combination therapy (IFN and ribavirin) who had a known HCV genotype, IFN completion and response rates were compared among patients with a history of SUD (SUD+ Group) and patients without a history of SUD (SUD- Group).

Results

Odds ratio analyses revealed that compared with the SUD- Group, the SUD+ Group was equally likely to complete IFN therapy if they had genotypes 2 and 3 (73.1% vs. 68.0%), and if they had genotypes 1 and 4 (39.5% vs. 39.9%). Within the sample of all patients who began IFN therapy, the SUD- and SUD+ groups were similarly likely to achieve an end of treatment response (genotypes 2 and 3, 52.8% vs. 54.3%; genotypes 1 and 4, 24.5% vs. 24.8%) and a sustained viral response (genotypes 2 and 3, 42.6% vs. 41.1%; genotypes 1 and 4: 16.0% vs. 22.3%).

Conclusion

Individuals with and without a history of SUD responded to antiviral therapy for HCV at similar rates. Collectively, these findings suggest that patients who have co-morbid SUD and HCV diagnoses can successfully complete a course of antiviral therapy.
A comparative study of the complications of surgical tracheostomy in morbidly obese critically ill patients
Authors: El Solh Ali A , Jaafar Wafaa
Published: January 2007

Introduction

There is little objective comparative information about the postoperative complications of tracheostomy in morbidly obese patients. The aim of this study was to determine the incidence and severity of complications associated with open tracheostomy in critically ill morbidly obese patients during hospitalization.

Methods

During a six year period, all consecutive morbidly obese patients (body mass index [BMI] of greater than or equal to 40 kg/m2) who underwent an elective open tracheostomy were compared to a control group (BMI of less than 40 kg/m2) of the same institution. Variables examined included age, gender, BMI, Charlson index, and reasons for tracheostomy. All postoperative tracheotomy-related complications that occurred during hospitalization, including death, were recorded.

Results

A tracheostomy was performed in 89 morbidly obese patients out of 427 critically ill patients. A total of 27 complications were recorded in 22 morbidly obese patients (25%) compared to 65 complications in 49 patients (14%) of the control group (p = 0.03). The majority of these complications were minor in origin. Overall, nine serious events were responsible for two deaths in the morbidly obese compared to seven cases and two deaths in the control group (p = 0.001). Life-threatening complications were attributed to tube obstruction and malpositioning of the tracheostomy after being dislodged. In multivariate analysis, morbid obesity (odds ratio 4.4, 95% confidence interval 2.1 to 11.7) was independently associated with increased risk of tracheostomy-related complications.

Conclusion

In the present series, morbid obesity is associated with increased frequency and life-threatening complications from conventional tracheostomy. Special techniques and operative policies must be applied to overcome loss of airway control.
Managing an effective treatment for neuroleptic malignant syndrome
Authors: Reulbach Udo , Dütsch Carmen , Biermann Teresa , Sperling Wolfgang , Thuerauf Norbert , Kornhuber Johannes , Bleich Stefan
Published: January 2007

Introduction

Neuroleptic malignant syndrome (NMS) is a rare, but sometimes fatal, adverse reaction to neuroleptics characterized principally by fever and rigor. The aim of this study was to prove the efficacy of different NMS treatment strategies, focusing on the efficacy of dantrolene.

Methods

Altogether, 271 case reports were included. These cases were categorized into four treatment groups and compared to each other according to effectiveness of therapy within 24 hours, mortality, complete time of remission in days, effectiveness due to increase of dosage, relapse on the basis of decrease of dosage, and improvement of symptoms.

Results

Between the four treatment groups, the complete time of remission was significantly different (analysis of variance, F = 4.02; degrees of freedom = 3; p = 0.008). In a logistic regression with adjustment for age, gender, and severity code, no significant predictor of the treatment for the complete time of remission (dichotomized by median) could be found. However, if the premedication was a monotherapy with neuroleptics, the complete time of remission was significantly shorter with dantrolene monotherapy (t = -2.97; p = 0.004).

Conclusion

The treatment of NMS with drugs that are combined with dantrolene is associated with a prolongation of clinical recovery. Furthermore, treatment of NMS with dantrolene as monotherapy seems to be associated with a higher overall mortality. Therefore, dantrolene does not seem to be the evidence-based treatment of choice in cases of NMS but might be useful if premedication consisted of a neuroleptic monotherapy.
Sequential gene profiling of basal cell carcinomas treated with imiquimod in a placebo-controlled study defines the requirements for tissue rejection
Authors: Panelli Monica C , Stashower Mitchell E , Slade Herbert B , Smith Kina , Norwood Christopher , Abati Andrea , Fetsch Patricia , Filie Armando , Walters Shelley-Ann , Astry Calvin , Aricó Eleonora , Zhao Yingdong , Selleri Silvia , Wang Ena , Marincola Francesco M
Published: January 2007

Background

Imiquimod is a Toll-like receptor-7 agonist capable of inducing complete clearance of basal cell carcinoma (BCC) and other cutaneous malignancies. We hypothesized that the characterization of the early transcriptional events induced by imiquimod may provide insights about immunological events preceding acute tissue and/or tumor rejection.

Results

We report a paired analysis of adjacent punch biopsies obtained pre- and post-treatment from 36 patients with BCC subjected to local application of imiquimod (n = 22) or vehicle cream (n = 14) in a blinded, randomized protocol. Four treatments were assessed (q12 applications for 2 or 4 days, or q24 hours for 4 or 8 days). RNA was amplified and hybridized to 17.5 K cDNA arrays. All treatment schedules similarly affected the transcriptional profile of BCC; however, the q12 × 4 days regimen, associated with highest effectiveness, induced the most changes, with 637 genes unequivocally stimulated by imiquimod. A minority of transcripts (98 genes) confirmed previous reports of interferon-α involvement. The remaining 539 genes portrayed additional immunological functions predominantly involving the activation of cellular innate and adaptive immune-effector mechanisms. Importantly, these effector signatures recapitulate previous observations of tissue rejection in the context of cancer immunotherapy, acute allograft rejection and autoimmunity.

Conclusion

This study, based on a powerful and reproducible model of cancer eradication by innate immune mechanisms, provides the first insights in humans into the early transcriptional events associated with immune rejection. This model is likely representative of constant immunological pathways through which innate and adaptive immune responses combine to induce tissue destruction.
Increased Notch 1 Expression and Attenuated Stimulatory G Protein Coupling to Adenylyl Cyclase in Osteonectin-Null Osteoblasts
Authors: Kessler Catherine B. , Delany Anne M.
Published: January 2007

Osteonectin, or secreted protein acidic and rich in cysteine, is one of the most abundant noncollagen matrix components in bone. This matricellular protein regulates extracellular matrix assembly and maturation in addition to modulating cell behavior. Mice lacking osteonectin develop severe low-turnover osteopenia, and in vitro studies of osteonectin-null osteoblastic cells showed that osteonectin supports osteoblast formation, maturation, and survival. The present studies demonstrate that osteonectin-null osteoblastic cells have increased expression of Notch 1, a well-documented regulator of cell fate in multiple systems. Furthermore, osteonectin-null cells are more plastic and less committed to osteoblastic differentiation, able to pursue adipogenic differentiation given the appropriate signals. Notch 1 transcripts are down-regulated by inducers of cAMP in both wild-type and osteonectin-null osteoblasts, suggesting that the mutant osteoblasts may have a defect in generation of cAMP in response to stimuli. Indeed, many bone anabolic agents signal through increased cAMP. Wild-type and osteonectin-null osteoblasts generated comparable amounts of cAMP in response to forskolin, a direct stimulator of adenylyl cyclase. However, the ability of osteonectin-null osteoblasts to generate cAMP in response to cholera toxin, a direct stimulator of Gs, was attenuated. These data imply that osteonectin-null osteoblasts have decreased coupling of Gs to adenylyl cyclase. Because osteonectin promotes G protein coupling to an effector, our studies support the concept that low-turnover osteopenia can result from reducing G protein coupled receptor activity.
Alteration of Cerebellar Neurotropin Messenger Ribonucleic Acids and the Lack of Thyroid Hormone Receptor Augmentation by staggerer-Type Retinoic Acid Receptor-Related Orphan Receptor-α Mutation
Authors: Qiu Chun-Hong , Shimokawa Noriaki , Iwasaki Toshiharu , Parhar Ishwar S. , Koibuchi Noriyuki
Published: January 2007

The mutant mouse staggerer (sg) harbors a deletion within the gene encoding the retinoic acid receptor-related orphan receptor-α (RORα). Homozygotes show aberrant cerebellar development. However, the mechanisms responsible for the cerebellar defect are still poorly understood. In the present study, the involvement of neurotropins (NTs), including nerve growth factor, brain-derived neurotropic factor, NT-3 and NT-4/5, and their receptors, which play a crucial role in brain development, on the cerebellar defects of sg mice was studied by semiquantitative RT-PCR and in situ hybridization histochemistry. An evident alteration of these mRNA levels was observed in both heterozygotes and homozygotes. Such difference was most evident in the internal granule cell layer. Because the changes in NT expression as well as morphological alterations in sg cerebellum are similar to those in hypothyroid animals, the effect of mutant RORα (RORsg) on transcriptional regulation through the thyroid hormone (TH) response element or the ROR response element (RORE) was then studied. RORsg neither activated the transcription through RORE nor suppressed RORα-induced transcription, indicating that it does not function as a dominant negative inhibitor. On the other hand, although wild-type RORα augmented TH receptor (TR)α1/β1-mediated transcription through various TH response elements, RORsg was not effective in augmenting TR action. These results suggest that the cerebellar defect of the sg mouse is partly caused by the altered expression of NTs and the lack of augmentation of TR-mediated transcription by RORα as well as the absence of RORα action through RORE.
Effects of Prenatal Dexamethasone Treatment on Postnatal Physical, Endocrine, and Social Development in the Common Marmoset Monkey
Authors: Hauser Jonas , Dettling-Artho Andrea , Pilloud Sonia , Maier Claudia , Knapman Alana , Feldon Joram , Pryce Christopher R.
Published: January 2007

The prophylactic treatment of diagnosed preterm delivery with synthetic glucocorticoids, such as dexamethasone (DEX), is commonplace. Long-term effects of such treatment are not well understood. In the present study, we exposed pregnant common marmosets (Callithrix jacchus), small-bodied monkeys that are therefore advantageous for long-term primate studies, to daily repeated DEX (5 mg/kg orally) either during early (d 42–48) or late (d 90–96) pregnancy (gestation period of 144 d). Relative to control, we investigated DEX effects in terms of maternal endocrinology (plasma cortisol and estrogen titers) and offspring physical growth, plasma and urinary ACTH and cortisol titers, and social and maintenance behaviors from birth to weaning. Both DEX treatments resulted in markedly reduced maternal plasma cortisol titers during treatment and reduced estimated gestation period. Both treatments were without effects on neonate morphometric measurements and basal hypothalamic-pituitary-adrenal axis activity. Early DEX treatment resulted in increased infant body weight at postnatal d 56 and 84, co-occurring at the behavioral level with increased time spent in eating solid food, a mobile state, solitary play, and exhibiting tail hair piloerection. The constellation of physical and behavioral effects of early DEX suggests interesting parallels with the human metabolic syndrome, providing primate support that the latter is causally associated with the fetal environment, including prenatal programming. This novel primate in vivo evidence for postnatal effects of prenatal synthetic glucocorticoid exposure indicates the importance of improved understanding of this acute clinical treatment in terms of its long-term effects on offspring well-being.
From Persistent Triplet Carbenes to Persistent High-Spin Polycarbenes
Authors: Itoh Tetsuji , Hirai Katsuyuki , Tomioka Hideo
Published: January 2007

Triplet carbenes are regarded as one of the most effective spin sources for organic ferromagnetic materials since the magnitude of the exchange coupling between the neighboring centers is large. However, those systems have two disadvantages that prevent their use as practical magnetic materials. First, a triplet carbene unit is highly unstable and lacks the stability for practical applications under ambient conditions. Second, diazo groups, which are precursors for triplet carbenes, are generally labile and, hence, cannot be used as building blocks to prepare a more complicated poly(diazo) compound. After great efforts to stabilize the triplet carbenes, we have succeeded in preparing fairly stable triplet carbenes that survive for days. We found that a diazo precursor for a persistent triplet carbene was also persistent and, hence, can be further modified into a more complicated diazo compound that can generate persistent high-spin polycarbenes. In this account, we would like to summarize our efforts along this line. We employed the following three approaches to prepare poly(diazo) compounds; (1) synthesis of dendritic molecules having peripheral diazo groups starting from diazo compounds, (2) preparation of a poly(phenylacetylene) with a diazo unit using Rh-complex-catalyzed polymerization of diazo compounds with p-ethynyl substituents, and (3) preparation of a polymer chain as a result of complexation of the pyridine ligand on diazo compounds with coordinatively unsaturated metal ions. We also characterized the magnetic properties of photoproducts obtained by photolysis of those poly(diazo) compounds. Although spin-states observed for those photoproducts were not so high, the results suggest that our approach using persistent triplet carbenes will eventually lead us to a persistent high-spin polycarbenes by taking advantage of the stability of our diazo compounds.
Interaction of a Coordinatively Unsaturated Transition-Metal Center with Small Molecules: DFT Studies on W(CO)5L (L = None, C2H4, and NH3)
Authors: Kawakami Kenta , Nakazawa Hirotaka , Kinoshita Toshimichi , Ishikawa Yo-ichi
Published: January 2007

DFT calculations were performed in order to investigate the interactions between coordinatively unsaturated sites on W(CO)5 and C2H4 as a typical π-acceptor and NH3 as a typical σ-donor. B3LYP-based DFT calculations with ECPs (LANL2DZ) on W and 6-311G(d,p) all-electron basis sets on H, C, N, and O reproduced the characteristic shifts in vibrational frequency of carbonyls that have been experimentally observed for the successive processes W(CO)6 (− CO) → W(CO)5 (+ L) → W(CO)5L (L = C2H4 and NH3). Based on the calculations, C2H4 coordinates to the coordinatively unsaturated site of W atom in a side-on fashion with a 23.1 kcal mol−1 bond dissociation enthalpy (BDE), where the center of the C=C double bond was 2.39 Å from W atom, and NH3 coordinates with a BDE of 31.9 kcal mol−1 and a distance of 2.37 Å. As well, the C=C bond length (1.38 Å) in C2H4 was found to be slightly longer than that of free C2H4 (1.33 Å).