bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction of Hepatocyte Growth Factor/Scatter Factor by Fibroblast Clustering Directly Promotes Tumor Cell Invasiveness
Authors: Kankuri Esko , Cholujova Dana , Comajova Monika , Vaheri Antti , Bizik Jozef
Published: November 2005

For determining the malignant behavior of a tumor, paracrine interactions between stromal and cancer cells are crucial. We previously reported that fibroblast clustering induces cyclooxygenase-2 (COX-2), plasminogen activation, and programmed necrosis, all of which were significantly reduced by nonsteroidal anti-inflammatory drugs (NSAID). We have now found that tumor cell–conditioned medium induces similar fibroblast clustering. Activation of the necrotic pathway in clustering fibroblasts, compared with control monolayer cultures, induced a massive >200-fold production of bioactive hepatocyte growth factor/scatter factor (HGF/SF), which made human carcinoma cells spread and invade a collagen lattice. This response occurred only if a functional, properly processed c-Met receptor was present, which was then rapidly phosphorylated. The invasion-promoting activity was inhibited by a neutralizing HGF/SF antibody. NSAIDs, if added early during fibroblast aggregation, inhibited HGF/SF production effectively but had no effect at later stages of cell aggregation. Our results thus provide the first evidence that aggravated progression of tumors with necrotic foci may involve paracrine reciprocal signaling leading to stromal activation by direct cell-cell contact (i.e., nemosis).
HIN-1, an Inhibitor of Cell Growth, Invasion, and AKT Activation
Authors: Krop Ian , Parker Michele Taylor , Bloushtain-Qimron Noga , Porter Dale , Gelman Rebecca , Sasaki Hidefumi , Maurer Matthew , Terry Mary Beth , Parsons Ramon , Polyak Kornelia
Published: November 2005

The HIN-1 gene encoding a small, secreted protein is silenced due to methylation in a substantial fraction of breast, prostate, lung, and pancreatic carcinomas, suggesting a potential tumor suppressor function. The receptor of HIN-1 is unknown, but ligand-binding studies indicate the presence of high-affinity cell surface HIN-1 binding on epithelial cells. Here, we report that HIN-1 is a potent inhibitor of anchorage-dependent and anchorage-independent cell growth, cell migration, and invasion. Expression of HIN-1 in synchronized cells inhibits cell cycle reentry and the phosphorylation of the retinoblastoma protein (Rb), whereas in exponentially growing cells, HIN-1 induces apoptosis without apparent cell cycle arrest and effect on Rb phosphorylation. Investigation of multiple signaling pathways revealed that mitogen-induced phosphorylation and activation of AKT are inhibited in HIN-1–expressing cells. In addition, expression of constitutively activate AKT abrogates HIN-1–mediated growth arrest. Taken together, these studies provide further evidence that HIN-1 possesses tumor suppressor functions, and that these activities may be mediated through the AKT signaling pathway.
An In vivo Tumor Model Exploiting Metabolic Response as a Biomarker for Targeted Drug Development
Authors: Cullinane Carleen , Dorow Donna S. , Kansara Maya , Conus Nelly , Binns David , Hicks Rodney J. , Ashman Leonie K. , McArthur Grant A. , Thomas David M.
Published: November 2005

In vivo models that recapitulate oncogene-dependent tumorigenesis will greatly facilitate development of molecularly targeted anticancer therapies. We have developed a model based on activating mutations in c-KIT in gastrointestinal stromal tumors (GISTs). This model comprises murine tumors of FDC-P1 cell lines expressing c-KIT mutations that render the tumors either responsive (V560G) or resistant (D816V) to the small-molecule c-KIT inhibitor, imatinib. Clinically, GIST response to imatinib is associated with rapid reduction in fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET), preceding changes in conventional response criteria by several weeks. Using the FDC-P1 model in small animal PET, FDG uptake into tumors expressing the c-KIT V560G mutation was significantly reduced as early as 4 hours after imatinib treatment. In contrast, no change in FDG uptake was observed in resistant c-KIT D816V-expressing tumors after 48 hours of imatinib treatment. Consistent with the PET results, expression of the glucose transporter, GLUT1, was significantly reduced in V560G tumors at 4 hours, preceding changes in markers of proliferation by several hours. In vitro, imatinib treatment of V560G cells resulted in a reduction of glucose transporter numbers at the cell surface and decreased glucose uptake well before changes in cell viability. Notably, decreased ambient glucose concentrations enhanced the cytotoxic effect of imatinib. Taken together, these data account for the rapidity and significance of the PET response to imatinib and suggest that metabolic effects may contribute to imatinib cytotoxicity. Further, the FDC-P1 model represents a very useful paradigm for molecularly targeted drug development.
Breath Management: Gender-Based Differences in Classical Singers
Authors: McCoy Scott
Published: November 2005

Fifty-five subjects (38 female, 17 male), consisting of professional operatic singers, singing teachers and advanced classical voice students, were surveyed to explore gender-based differences in breath management strategies for singing. Respondents evaluated extent and significance of thoracic and abdominal movement for inhalation and for control of singing extended phrases. Females were found to concentrate breath efforts lower in the body than did men (hypogastric vs. epigastric regions). Both groups relied heavily on low thoracic activity to provide an antagonistic mechanism for control. Results corroborated a review of standard pedagogical literature, which showed variations in recommended breathing methods that strongly correlate to the gender of the author.
Pegvisomant Treatment in a 4-Year-Old Girl with Neurofibromatosis Type 1
Authors: Main Katharina M. , Sehested Astrid , Feldt-Rasmussen Ulla
Published: November 2005

Background/Aims: Growth hormone (GH) excess in childhood is a rare disorder. Current treatment options such as somatostatin analogues, pituitary surgery or irradiation can have serious side effects. Recently, a GH receptor antagonist, pegvisomant, was introduced for the treatment of adults with acromegaly. We wanted to investigate whether pegvisomant was effective in a child with octreotide-resistant GH excess. Case: A 4-year-old girl with neurofibromatosis type 1 and GH excess associated with optic glioma received pegvisomant injections (10 mg subcutaneously) with increasing intervals from daily to every 4th day. Results: IGF-I and IGFBP-3 decreased from +6.9 and 4.6 standard deviation scores (SDS), respectively, to within normal range. Height velocity dropped from 12.4 SDS to mean –0.7 SDS (range: –5.0 to 5.0) and height SDS decreased from +1.3 to +0.6 (target height: +0.2). Random non-fasting serum GH values were mean 5.0 mlU/l (range: 1.6–9.5). There was no change in fasting blood glucose (4.6–4.7 mmol/l) or glycosylated haemoglobin (5.5%) and no subjective or biochemical side effects. Repeated tests of thyroid, adrenal and gonadal function showed no alterations during the treatment period. Intracranial tumours remained unchanged in size and visual impairment did not deteriorate. Conclusion: Pegvisomant normalized IGF-I and IGFBP-3 levels. Growth velocity was normalized after initial catch-down growth, and it remains to be seen whether this result can be maintained during long-term treatment.
Phytoestrogen Resveratrol Suppresses Steroidogenesis by Rat Adrenocortical Cells by Inhibiting Cytochrome P450 c21-Hydroxylase
Authors: Supornsilchai V. , Svechnikov K. , Seidlova-Wuttke D. , Wuttke W. , Söder O.
Published: November 2005

Background and Aim: The phytoestrogen resveratrol is found in grapes, mulberries and peanuts, all of which are consumed regularly by humans. Resveratrol is also used in chemotherapy against cancer and aging and as a cardioprotectant. The aim of the present study was to characterize the effects of resveratrol on rat adrenal steroidogenesis and to study the underlying mechanism. Methods: Adrenocortical cells were isolated from the adrenal glands of normal male rats (in vitro) and from male rats administered resveratrol in their diet for 12 weeks (ex vivo). Cells from resveratrol-treated and non-treated rats were tested ex vivo for responsiveness to ACTH and cells from normal rats were tested in vitro for responsiveness to ACTH in the presence and absence of resveratrol. Corticosterone and progesterone production were measured by RIA and expression of steroidogenic enzymes analyzed by PAGE/Western blotting. Results: Corticosterone production was inhibited 47% by 50 µM resveratrol in vitro and 20% ex vivo, while progesterone production was elevated to 400% of the control value in in vitro experiments. Resveratrol treatment decreased adrenal cytochrome P450 c21-hydroxylase expression in vivo and cell culture conditions. No changes in cell viability or morphology were caused by exposure to resveratrol in both ex vivo and in vitro experiments. Conclusion: Resveratrol suppresses corticosterone production by primary rat adrenocortical cell cultures in vitro and ex vivo by inhibiting cytochrome P450 c21-hydroxylase.
Myeloperoxidase-Generated Oxidants Modulate Left Ventricular Remodeling but Not Infarct Size After Myocardial Infarction
Authors: Vasilyev Nikolay , Williams Timothy , Brennan Marie-Luise , Unzek Samuel , Zhou Xiaorong , Heinecke Jay W. , Spitz Douglas R. , Topol Eric J. , Hazen Stanley L. , Penn Marc S.
Published: November 2005

Background—

Inflammation after myocardial infarction (MI) heralds worse left ventricular (LV) function and clinical outcomes. However, whether inflammation affects LV function by extending myonecrosis and/or altering LV remodeling remains unknown. We hypothesized that cytotoxic aldehydes generated during oxidative stress may adversely affect remodeling and infarct size. One theoretical source of reactive aldehydes is oxidation of common α-amino acids by myeloperoxidase (MPO) released by leukocytes. However, a role for MPO in formation of aldehydes in vivo and the functional consequences of MPO-generated oxidants in ischemia/reperfusion models of MI have not been established.

Methods and Results—

In studies with cell types found in vascular tissue, MPO-oxidation products of glycine (formaldehyde) and threonine (acrolein) were the most cytotoxic. Mass spectrometry studies of myocardial tissue from murine models of acute MI (both chronic left anterior descending coronary artery ligation and ischemia/reperfusion injury) confirmed that MPO serves as a major enzymatic source in the generation of these cytotoxic aldehydes. Interestingly, although MPO-null mice experienced 35.1% (
P
<0.001) less LV dilation and a 52.2% (
P
<0.0001) improvement in LV function compared with wild-type mice 24 days after ischemia/reperfusion injury, no difference in infarct size between wild-type and MPO-null mice was noted.

Conclusions—

The present data separate inflammatory effects on infarct size and LV remodeling and demonstrate that MPO-generated oxidants do not significantly affect tissue necrosis after MI but rather have a profound adverse effect on LV remodeling and function.
Gene Mutations in Apical Hypertrophic Cardiomyopathy
Authors: Arad Michael , Penas-Lado Manual , Monserrat Lorenzo , Maron Barry J. , Sherrid Mark , Ho Carolyn Y. , Barr Scott , Karim Ahmad , Olson Timothy M. , Kamisago Mitsohiro , Seidman J.G. , Seidman Christine E.
Published: November 2005

Background—

Nonobstructive hypertrophy localized to the cardiac apex is an uncommon morphological variant of hypertrophic cardiomyopathy (HCM) that often is further distinguished by distinct giant negative T waves and a benign clinical course. The genetic relationship between HCM with typical hypertrophic morphology versus isolated apical hypertrophy is incompletely understood.

Methods and Results—

Genetic cause was investigated in 15 probands with apical hypertrophy by DNA sequence analyses of 9 sarcomere protein genes and 3 other genes (
GLA
,
PRKAG2
, and
LAMP2
) implicated in idiopathic cardiac hypertrophy. Six sarcomere gene mutations were found in 7 samples; no samples contained mutations in
GLA
,
PRKAG2
, or
LAMP2
. Clinical evaluations demonstrated familial apical HCM in 4 probands, and in 3 probands disease-causing mutations were identified. Two families shared a cardiac actin Glu101Lys missense mutation; all members of both families with clinical manifestations of HCM (n=16) had apical hypertrophy. An essential light chain missense mutation Met149Val caused apical or midventricular segment HCM in another proband and 5 family members, but 6 other affected relatives had typical HCM morphologies. No other sarcomere gene mutations identified in the remaining probands caused apical HCM in other family members.

Conclusions—

Sarcomere protein gene mutations that cause apical hypertrophy rather than more common HCM morphologies reflect interactions among genetic etiology, background modifier genes, and/or hemodynamic factors. Only a limited number of sarcomere gene defects (eg, cardiac actin Glu101Lys) consistently produce apical HCM.
Robustness of Late Lumen Loss in Discriminating Drug-Eluting Stents Across Variable Observational and Randomized Trials
Authors: Mauri Laura , Orav E. John , Candia Susana C. , Cutlip Donald E. , Kuntz Richard E.
Published: November 2005

Background—

Binary angiographic and clinical restenosis rates can vary widely between clinical studies, even for the same stent, influenced heavily by case-mix covariates that differ among observational and randomized trials intended to assess a given stent system. We hypothesized that mean in-stent late loss might be a more stable estimator of restenosis propensity across such studies.

Methods and Results—

In 46 trials of drug-eluting and bare-metal stenting, increasing mean late loss was associated with higher target lesion revascularization (TLR) rates (
P
<0.001). When the class of bare-metal stents was compared with the class of effective drug-eluting stents, late loss was more discriminating than TLR as measured by the high intraclass correlation coefficient (ρ) (late loss, ρ=0.71 versus TLR, ρ=0.22; 95% CI of difference=0.33, 0.65). When the individual drug-eluting stents and bare-metal stents were compared, late loss was a better discriminator than TLR (0.68 versus 0.19; 95% CI of difference=0.24, 0.60). Greater adjustments of study covariates are needed to stabilize assessments of TLR compared with late loss because of greater influence of reference vessel diameter on TLR than on in-stent late loss. Optimization of late loss with the use of a novel method of standardization according to diabetes prevalence and mean lesion length resulted in minor adjustments in late loss (<0.08 mm for 90% of reported trials) and an ordered array of mean late loss values for the stent systems studied.

Conclusions—

Late loss is more reliable than restenosis rates for discriminating restenosis propensity between new drug-eluting stent platforms across studies and might be the optimum end point for evaluating drug-eluting stents in early, nonrandomized studies.
Union effects on employee relations in Britain
Authors: Bryson Alex
Published: November 2005

I estimate the effects of trade unions on employee and employer perceptions of workplace management-employee relations in Britain using linked employer-employee data from the 1998 Workplace Employee Relations Survey. Associations between these relations and unionization vary with institutional arrangements in relation to bargaining and lay representation. There is support for McCarthy’s view that union lay representatives can act as a ‘lubricant’ assisting with employment relations, but this is apparent from an employer perspective, not an employee perspective. The only union effect common across employers and employees is poorer perceptions of employment relations where union coverage is at the level known to generate a union wage premium.
Toward the construction of a profession’s boundaries: Creating a networking agenda
Authors: Oliver Amalya L. , Montgomery Kathleen
Published: November 2005

Attention to the boundaries of an organization or profession is an essential precursor to facilitating boundary-spanning activities. We follow a four-stage process model of constructing boundaries to delimit a profession’s membership and domain prior to its recognition as an institutionalized entity. A set of networking activities forms the basis of boundary construction, yet identifying and prioritizing which activities to pursue is a challenge that can jeopardize the success of an aspiring group. We use a case study of the emerging Jewish legal profession in pre-state Israel to analyze how an agenda for creating membership and domain boundaries implicitly surfaces through interactions among members of the new group. We employ content analysis of a key meeting transcript and network analytical methods to reveal a shared cognitive map of priorities. The study adds to the literature on professional boundaries and demonstrates the utility of an innovative qualitative-quantitative research approach.
‘In the name of capability’: A critical discursive evaluation of competency-based management development
Authors: Finch-Lees Tim , Mabey Chris , Liefooghe Andreas
Published: November 2005

This article illustrates a number of ways in which competency or capability-based management development (CBMD) can work simultaneously both for and against the interests of organizational agents. It does so by demonstrating how CBMD might usefully be understood as both ideological and quasi-religiously faith-based. These features are shown to provide opportunities for resistance and micro-emancipation alongside those for repression and subordination. The study employs a combination of ‘middle range’ discourse analytical techniques. In the first instance, critical discourse analysis is applied to company documentation to distil the ideological stance of an international organization’s CBMD programme. Critical discursive psychology is then used to assess the ways in which employees’ evaluative accounts both support and resist such stance. The analysis builds upon previous insights from Foucauldian studies of CBMD by foregrounding processes of discursive agency. It also renders more visible and discussible the assumptions and dilemmas that CBMD might imply.
Criminal Prosecution of Domestic Violence Offenses
Authors: Henning Kris , Feder Lynette
Published: November 2005

Whereas significant research has been conducted to identify the legal and extralegal factors that influence police decisions concerning the arrest of domestic violence (DV) offenders, significantly fewer studies have examined prosecutorial and judicial decision making with regard to this offense. Among the few studies available in the extant literature, none have looked at the full range of decisions made during the adjudication process (i.e., pretrial release, prosecution, disposition, and sentencing). Similarly, few of the available studies have included female defendants, despite recent increases in the number of women charged for this offense. Using a sample of 4,178 defendants arrested for a misdemeanor or felony domestic violence offense, this research identified the suspect and offense characteristics that had the greatest effect on court decisions. Explanations for the resulting findings and recommendations for further research are discussed.
Gambling and Problem Gambling Within Forensic Populations
Authors: Williams Robert J. , Royston Jennifer , Hagen Brad F.
Published: November 2005

A review of problem gambling in forensic populations suggests that one third of criminal offenders meet criteria for problem or pathological gambling. This is the highest rate yet found in any population. Approximately 50% of crime by incarcerated problem and pathological gamblers is reportedly committed to support gambling. The prevalence of gambling within correctional facilities (40%) appears lower than in the general population. However, inmates who do gamble tend to do so regularly, and problem and pathological gamblers are disproportionately represented among this group. Inmate screening for problem gambling and provision of specialized treatment are currently lacking in most correctional facilities. In addition to more screening and treatment, there needs to be greater vigilance in detecting gambling and enforcing its prohibition.
Juvenile Delinquency and Adolescent Gambling
Authors: Magoon Maggie E. , Gupta Rina , Derevensky Jeffrey
Published: November 2005

Despite the increasing body of literature that supports the connection between adolescent gambling and risk-taking behavior, participation in criminal or delinquent acts has not been thoroughly addressed. With the established relationship between substance abuse and juvenile delinquency, past research and prevention, intervention, and treatment programs can be used to help guide issues concerning adolescent gambling for youthful offenders. How problem gambling may create a pattern of behavior that includes illegal acts and delinquent behaviors is examined. The role of the juvenile justice system and educational strategies for intervention, treatment, and follow-up efforts are provided. Suggestions for data collection and research using populations in detention centers to garner further information on problem gambling and deviant behaviors are addressed.
Towards a stylistic typology of narrative gaps: knowledge gapping in Flannery O’Connor’s fiction
Authors: Hardy Donald E.
Published: November 2005

This article examines the functions of narrative gaps in the creation and manipulation of knowledge in Flannery O’Connor’s fiction. A distinction is first made between the announced and the unannounced gap, the latter being the general type that occurs most frequently in modern fiction, including that of O’Connor. The form and functions of the announced gap are briefly discussed with reference to 18th-century narratives. The article demonstrates the presence of an attenuated announced gap in O’Connor’s fiction in the use of the indefinite pronoun something. It also makes distinctions between the narrative gap, the ellipsis, and general narrative indeterminacy. The attenuated announced gap and the unannounced gap help to produce involvement of the reader in creating the emotional, spiritual, and rational background for an O’Connor narration. These narrative gaps are stylistically indicative of O’Connor’s prose from her earliest to her latest fiction, both in the particular forms that they take and in their functioning generally to encode concerns with the limitations and possibilities of human knowledge, a thematic concern of heavy significance throughout her fiction. The article is a contribution in the development of a general stylistics of narrative gaps.
Local Responses to Water Resource Degradation in India: Groundwater Farmer Innovations and the Reversal of Knowledge Flows
Authors: Buechler Stephanie , Mekala Gayathri Devi
Published: November 2005

Water is becoming degraded at an increasingly rapid rate, demanding complex, dynamic strategies tailored to local contexts. This study focused on innovative strategies by farmers to reduce risk and increase incomes. The surface and groundwater they used for irrigation was becoming degraded because of inflows of largely untreated urban domestic sewage water and industrial effluent into the Musi River that runs through Hyderabad city, south India. Wastewater flowing into the river is channeled for irrigation in this drought-prone, semi-arid area with falling groundwater tables. Wastewater volumes have increased as more water is supplied to Hyderabad. Paddy farmers engaged in continuous innovation in agricultural and water management strategies in response to deteriorating irrigation water quality yet improved water availability. Findings point to the need for greater recognition and dissemination of local innovations and a reversal of knowledge flows entailing improved linkages between local populations, researchers, managers, development workers, and policy makers.
The International Boundary and Water Commission Under Fire: Policy Prospective for the 21st Century
Authors: Mumme Stephen P.
Published: November 2005

The venerable International Boundary and Water Commission, United States and Mexico, established by the landmark 1944 U.S.-Mexican Water Treaty, has come under fire in the past decade for a range of alleged institutional deficiencies. These deficiencies, ranging from the adequacy of its mandate to its organizational structure and management, are seen as limiting its diplomatic and administrative capacity to promote cooperative solutions to a range of binational water problems including drought, ecological conservation, and planning for sustainable water use and management in the 21st century. This article reviews this recent spate of criticisms and reform recommendations, addressing their feasibility and practicality. It argues that many of these proposals are treaty consistent and have sufficient merit to warrant serious consideration by the two governments.
Recreational Gun Use by California Adolescents
Authors: Vittes Katherine A. , Sorenson Susan B.
Published: November 2005

Most research on adolescents and firearms focuses on urban populations, handguns, and homicide. This study examines the prevalence and correlates of recreational gun use (RGU)—for hunting or target shooting—among 5,801 community-residing 12- to 17-year-old Californians. Data are from the first statewide California Health Interview Survey (CHIS), and person, design, and population weights were applied to the data. About one fifth (22.4%) of California adolescents report that they have gone hunting or target shooting. Nearly two thirds (62.8%) have hunted with a family member, typically (67.3%) their father. Recreational gun use among adolescents appears to be linked to a few basic demographic characteristics; most notably, male adolescents had an adjusted odds ratio of RGU nearly five times that of female adolescents. Some of the variables associated with RGU are consistent with those for violent gun use; differences, however, suggest that separate approaches to preventing firearm-related injury may be warranted.
Australian Adult Consumers’ Beliefs About Plant Foods: A Qualitative Study
Authors: Lea Emma , Worsley Anthony , Crawford David
Published: November 2005

This exploratory qualitative study examined consumers’ perceived barriers and benefits of plant food (fruits, vegetables, grains, legumes, nuts, seeds) consumption and views on the promotion of these foods. Ten focus groups were conducted in Melbourne, Australia. Groups consisted of employees of various workplaces, community group members, university students, and inner-city residents. Health-related benefits predominated, particularly relating to the properties of plant foods (e.g., vitamins). Taste, variety, versatility, and environmental benefits were also considered important. The main barriers to eating plant foods were lack of knowledge and skills and length of preparation time. The poor quality of plant foods was also an issue for consumers. Awareness of the promotion of plant foods was generally high. Participants noted that promotions require a stronger practical emphasis with a focus on quick, easy-to-prepare foods and meals. These findings provide insight into effective ways to promote a higher consumption of plant foods.
Acculturation, Health Protective Sexual Communication, and HIV/AIDS Risk Behavior Among Hispanic Women in a Large Midwestern City
Authors: Rojas-Guyler Liliana , Ellis Nancy , Sanders Stephanie
Published: November 2005

The relationships among acculturation, health protective sexual communication, and HIV/AIDS risk behaviors of Hispanic women are examined. Respondents represented 14 Latin American countries, a mean age of 29.5 years, and relatively low education and income levels. A significant correlation was found between higher non-Hispanic acculturation level and higher sexual communication with new partners. Higher non-Hispanic acculturation levels were also correlated with higher number of sexual partners in the prior 12 months. The higher the score for health protective sexual communication, the higher the reported frequency of condom use with new sexual partners in the past 12 months. Given the low number of sexual partners, HIV/AIDS risk for this group of women appears to be related to not knowing whether their partners had other sexual partners and to low frequency of condom use. Implications for health education are discussed.
Overview of the National Health Educator Competencies Update Project, 1998-2004
Authors: Gilmore Gary David , Olsen Larry K. , Taub Alyson , Connell David
Published: November 2005

The National Health Educator Competencies Update Project (CUP), conducted during 1998-2004, addressed what health educators currently do in practice, the degree to which the role definition of the entry-level health educator is still up-to-date, and the validation of advanced-level competencies. A 19-page questionnaire was sent to a representative sample of health educators in recognized practice settings in all states and the District of Columbia. A total of 4,030 health educators participated in the research (70.6% adjusted response rate) resulting in the largest national data set of its kind, with 1.6 million data points. The model derived from the research was hierarchical (7 areas of responsibility, 35 competencies, and 163 subcompetencies), with three levels of practice (Entry, Advanced 1, and Advanced 2) differentiated by degrees earned and years of experience. The findings affect professional preparation, credentialing, and professional development.
Spectacular Colleges and Spectacular Rankings
Authors: Chang Gordon C. , Osborn J. R.
Published: November 2005

This article applies Guy Debord's theory of the spectacle to the institutional field of contemporary American higher education. Our case study examines the US News & World Report system of college rankings, which has come to acquire a powerful role in determining exchange values among colleges and universities. Based on a document analysis of 12 issues of the USN, we present three processes by which it accomplishes the construction of the rankings spectacle: abstraction, valuation and legitimation. First, the USN abstracts images of colleges and universities in the form of discrete numbers. Second, these numbers are valued, compared and ranked as exchangeable commodities. Finally, we examine the discursive strategies employed by the USN to legitimize its rankings as accurate and useful. As higher education is a unique social institution associated with the notions of truth, knowledge, rationality and science, the widespread consumption and influence of the USN rankings illuminate the degree to which the society of the spectacle has arrived upon today's American society.
Rho GEF Lsc is required for normal polarization, migration, and adhesion of formyl-peptide–stimulated neutrophils
Authors: Francis Sanjeev A. , Shen Xun , Young Jeffrey B. , Kaul Prashant , Lerner Daniel J.
Published: November 2005

Neutrophil migration requires continuous reorganization of the cytoskeleton and cellular adhesion apparatus. Chemoattractants initiate intracellular signals that direct this reorganization. The signaling pathways that link chemoattractant receptors to the cytoskeleton and cellular adhesion apparatus are now being defined. Formyl-peptide chemoattractants released from bacteria stimulate G-protein–linked receptors on the surface of neutrophils and regulate the neutrophil cytoskeleton and adhesion apparatus through RhoA-dependent pathways. Lsc is a RhoA guanine nucleotide exchange factor that binds the heterotrimeric G-protein α-subunits, Gα12 and Gα13. We have disrupted the Lsc gene and demonstrated that formyl-peptide–stimulated Lsc knock-out (KO) neutrophils are unable to generate and sustain a single-dominant pseudopod and migrate with increased speed and reduced directionality. Unexpectedly, we also found that Lsc is required for normal β2- and β1-integrin–dependent neutrophil adhesion. Lsc-deficient mice have a peripheral leukocytosis and extramedullary hematopoiesis, demonstrating that Lsc is required for leukocyte homeostasis. Lsc-deficient neutrophils are recruited normally to sites of bacterial peritonitis and chemical dermatitis, indicating that other signaling pathways compensate for the Lsc deficiency in some forms of inflammation. These results demonstrate that Lsc links formyl-peptide receptors to RhoA signaling pathways that regulate polarization, migration, and adhesion in neutrophils and that Lsc is required for leukocyte homeostasis.
PDZ binding motif of HTLV-1 Tax promotes virus-mediated T-cell proliferation in vitro and persistence in vivo
Authors: Xie Li , Yamamoto Brenda , Haoudi Abdelali , Semmes O. John , Green Patrick L.
Published: November 2005

HTLV-1 cellular transformation and disease induction is dependent on expression of the viral Tax oncoprotein. PDZ is a modular protein interaction domain used in organizing signaling complexes in eukaryotic cells through recognition of a specific binding motif in partner proteins. Tax-1, but not Tax-2, contains a PDZ-binding domain motif (PBM) that promotes the interaction with several cellular PDZ proteins. Herein, we investigate the contribution of the Tax-1 PBM in HTLV-induced proliferation and immortalization of primary T cells in vitro and viral survival in an infectious rabbit animal model. We generated several HTLV-1 and HTLV-2 Tax viral mutants, including HTLV-1ΔPBM, HTLV-2+C22(+PBM), and HTLV-2+ C18(ΔPBM). All Tax mutants maintained the ability to significantly activate the CREB/ATF or NFκB signaling pathways. Microtiter proliferation assays revealed that the Tax-1 PBM significantly increases both HTLV-1– and HTLV-2–induced primary T-cell proliferation. In addition, Tax-1 PBM was responsible for the micronuclei induction activity of Tax-1 relative to that of Tax-2. Viral infection and persistence were severely attenuated in rabbits inoculated with HTLV-1ΔPBM. Our results provide the first direct evidence suggesting that PBM-mediated associations between Tax-1 and cellular proteins play a key role in HTLV-induced cell proliferation and genetic instability in vitro and facilitate viral persistence in vivo.
Repression of human γ-globin gene expression by a short isoform of the NF-E4 protein is associated with loss of NF-E2 and RNA polymerase II recruitment to the promoter
Authors: Zhao Quan , Zhou Wenlai , Rank Gerhard , Sutton Rosemary , Wang Xi , Cumming Helen , Cerruti Loretta , Cunningham John M. , Jane Stephen M.
Published: November 2005

Binding of the stage selector protein (SSP) to the stage selector element (SSE) in the human γ-globin promoter contributes to the preferential expression of the γ-gene in fetal erythroid cells. The SSP contains the transcription factor CP2 and an erythroid-specific partner, NF-E4. The NF-E4 gene encodes a 22-kDa polypeptide employing a non-AUG initiation codon. Antisera specific to NF-E4 detects this species and an additional 14 kDa protein, which initiates from an internal methionine. Enforced expression of p14 NF-E4 in the K562 fetal/erythroid cell line, and in primary erythroid cord blood progenitors, results in repression of γ-gene expression. Biochemical studies reveal that p14 NF-E4 interacts with CP2, resulting in diminished association of CP2 with the SSE in chromatin immunoprecipitation assays. p45 NF-E2 recruitment to the γ-promoter is also lost, resulting in a reduction in RNA polymerase II and TBP binding and a fall in promoter transcriptional activity. This effect is specific, as enforced expression of a mutant form of p14 NF-E4, which fails to interact with CP2, also fails to repress γ-gene expression in K562 cells. These findings provide one potential mechanism that could contribute to the autonomous silencing of the human γ-genes in adult erythroid cells.
Gene-expression patterns predict phenotypes of immune-mediated thrombosis
Authors: Potti Anil , Bild Andrea , Dressman Holly K. , Lewis Deborah A. , Nevins Joseph R. , Ortel Thomas L.
Published: November 2005

Antiphospholipid antibody syndrome (APS) is a complex autoimmune thrombotic disorder with defined clinical phenotypes. Although not all patients with elevated antiphospholipid antibody (aPLA) levels develop complications, the severity of these potential events mandates aggressive and extended lifelong anti-thrombotic therapy. One hundred twenty-nine patients (57 patients with APS and venous thromboembolism [VTE], 32 patients with VTE without aPLA, 32 patients with aPLA only, and 8 healthy patients) were enrolled. RNA from peripheral-blood collection was used for DNA microarray analysis. Patterns of gene expression that characterize APS as well as thrombosis in the presence of aPLA were identified by hierarchical clustering and binary regression methods. Gene-expression profiles identify and predict individuals with APS from patients with VTE without aPLA. Importantly, similar methods identified expression profiles that accurately predicted those patients with aPLA at high risk for thrombotic events. All profiles were validated in independent cohorts of patients. The ability to predict APS, but more importantly, those patients at risk for venous thrombosis, represents a paradigm for a genomic approach that can be applied to other populations of patients with venous thrombosis, providing for more effective clinical management of disease, while also reflecting the possible underlying biologic processes.
Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4+CD25+ immune regulatory network
Authors: de Kleer Ismé , Vastert Bas , Klein Mark , Teklenburg Gijs , Arkesteijn Ger , Yung Gisella Puga , Albani Salvo , Kuis Wietse , Wulffraat Nico , Prakken Berent
Published: November 2005

Despite a rapidly accumulating clinical experience with autologous stem cell transplantation (ASCT) as a treatment for severe refractory autoimmune disease, data on the mechanisms by which ASCT induces immune tolerance are still very scarce. In this study it is shown that ASCT restores immunologic self-tolerance in juvenile idiopathic arthritis (JIA) via 2 mechanisms. First, ASCT induces a restoration of the frequency of FoxP3 expressing CD4+CD25bright regulatory T cells (Tregs) from severely reduced numbers before ASCT to normal levels after ASCT. This recovery is due to a preferential homeostatic expansion of CD4+CD25+ Tregs during the lymphopenic phase of immunereconstitution, as measured by Ki67 and CD44 expression, and to a renewed thymopoiesis of naive mRNA FoxP3 expressing CD4+CD25+ Tregs after ASCT. Second, using artificial antigen-presenting cells to specifically isolate self-reactive T cells, we demonstrate that ASCT induces autoimmune cells to deviate from a proinflammatory phenotype (mRNA interferon-γ [IFN-γ] and T-bet high) to a tolerant phenotype (mRNA interleukin-10 [IL-10] and GATA-3 high). These data are the first to demonstrate the qualitative immunologic changes that are responsible for the induction of immune tolerance by ASCT for JIA: the restoration of the CD4+CD25+ immune regulatory network and reprogramming of autoreactive T cells.
The efficiency of different search strategies in estimating parsimony jackknife, bootstrap, and Bremer support
Authors: Müller Kai F
Published: November 2005

Background

For parsimony analyses, the most common way to estimate confidence is by resampling plans (nonparametric bootstrap, jackknife), and Bremer support (Decay indices). The recent literature reveals that parameter settings that are quite commonly employed are not those that are recommended by theoretical considerations and by previous empirical studies. The optimal search strategy to be applied during resampling was previously addressed solely via standard search strategies available in PAUP*. The question of a compromise between search extensiveness and improved support accuracy for Bremer support received even less attention. A set of experiments was conducted on different datasets to find an empirical cut-off point at which increased search extensiveness does not significantly change Bremer support and jackknife or bootstrap proportions any more.

Results

For the number of replicates needed for accurate estimates of support in resampling plans, a diagram is provided that helps to address the question whether apparently different support values really differ significantly. It is shown that the use of random addition cycles and parsimony ratchet iterations during bootstrapping does not translate into higher support, nor does any extension of the search extensiveness beyond the rather moderate effort of TBR (tree bisection and reconnection branch swapping) plus saving one tree per replicate. Instead, in case of very large matrices, saving more than one shortest tree per iteration and using a strict consensus tree of these yields decreased support compared to saving only one tree. This can be interpreted as a small risk of overestimating support but should be more than compensated by other factors that counteract an enhanced type I error. With regard to Bremer support, a rule of thumb can be derived stating that not much is gained relative to the surplus computational effort when searches are extended beyond 20 ratchet iterations per constrained node, at least not for datasets that fall within the size range found in the current literature.

Conclusion

In view of these results, calculating bootstrap or jackknife proportions with narrow confidence intervals even for very large datasets can be achieved with less expense than often thought. In particular, iterated bootstrap methods that aim at reducing statistical bias inherent to these proportions are more feasible when the individual bootstrap searches require less time.
Aging syndrome genes and premature coronary artery disease
Authors: Low Adrian F , O'Donnell Christopher J , Kathiresan Sekar , Everett Brendan , Chae Claudia U , Shaw Stanley Y , Ellinor Patrick T , MacRae Calum A
Published: November 2005

Background

Vascular disease is a feature of aging, and coronary vascular events are a major source of morbidity and mortality in rare premature aging syndromes. One such syndrome is caused by mutations in the lamin A/C (LMNA) gene, which also has been implicated in familial insulin resistance. A second gene related to premature aging in man and in murine models is the KLOTHO gene, a hypomorphic variant of which (KL-VS) is significantly more common in the first-degree relatives of patients with premature coronary artery disease (CAD). We evaluated whether common variants at the LMNA or KLOTHO genes are associated with rigorously defined premature CAD.

Methods

We identified 295 patients presenting with premature acute coronary syndromes confirmed by angiography. A control group of 145 patients with no evidence of CAD was recruited from outpatient referral clinics. Comprehensive haplotyping of the entire LMNA gene, including the promoter and untranslated regions, was performed using a combination of TaqMan® probes and direct sequencing of 14 haplotype-tagging single nucleotide polymorphisms (SNPs). The KL-VS variant of the KLOTHO gene was typed using restriction digest of a PCR amplicon.

Results

Two SNPs that were not in Hardy Weinberg equilibrium were excluded from analysis. We observed no significant differences in allele, genotype or haplotype frequencies at the LMNA or KLOTHO loci between the two groups. In addition, there was no evidence of excess homozygosity at the LMNA locus.

Conclusion

Our data do not support the hypothesis that premature CAD is associated with common variants in the progeroid syndrome genes LMNA and KLOTHO.
Evaluation of the profile of alopecia areata and the prevalence of thyroid function test abnormalities and serum autoantibodies in Iranian patients
Authors: Seyrafi Hassan , Akhiani Maryam , Abbasi Hamed , Mirpour Sahar , Gholamrezanezhad Ali
Published: November 2005

Background

The study aimed at evaluating the prevalence of thyroid function abnormalities in patients with alopecia areata (AA) and its association with other autoimmune diseases and various autoimmune antibodies.

Method

We retrospectively analyzed medical records of 123 patients with AA. The main site of involvement, pattern, and extent of alopecia as well as presence of the similar disease in first-degree family members and serologic status of patients were recorded.

Results

Participating in the study were 57 males and 66 females (6 to 59 years old). In the majority of patients (69.9%) the disease was manifested in the first two decades of life. Patients with family members having alopecia were recorded in 24.4%. Thyroid function abnormalities were found in 8.9% of patients. Positive autoimmune antibodies were associated with AA in 51.4% of patients with no significant association between the severity and duration of disease and presence of these antibodies.

Conclusion

The incidence of positive auto-immune antibodies in Iranian patients is higher than previous reports. Concerning the female:male ratio, thyroid function tests and the prevalence of alopecia in first-degree relatives, our results are compatible with previous data obtained from different ethnic populations. Previous reports documented that a greater severity and longer duration of AA were seen in the early onset forms; however our result are relatively different which could be explained by differences in genetic factors.
Is it worth offering a routine laparoscopic cholecystectomy in developing countries? A Thailand case study
Authors: Teerawattananon Yot , Mugford Miranda
Published: November 2005

Objective

The study aims to investigate whether laparoscopic cholecystectomy (LC) is a cost-effective strategy for managing gallbladder-stone disease compared to the conventional open cholecystectomy(OC) in a Thai setting.

Design and Setting

Using a societal perspective a cost-utility analysis was employed to measure programme cost and effectiveness of each management strategy. The costs borne by the hospital and patients were collected from Chiang Rai regional hospital while the clinical outcomes were summarised from a published systematic review of international and national literature. Incremental cost per Quality Adjusted Life Year (QALY) derived from a decision tree model.

Results

The results reveal that at base-case scenario the incremental cost per QALY of moving from OC to LC is 134,000 Baht under government perspective and 89,000 Baht under a societal perspective. However, the probabilities that LC outweighed OC are not greater than 95% until the ceiling ratio reaches 190,000 and 270,000 Baht per QALY using societal and government perspective respectively.

Conclusion

The economic evaluation results of management options for gallstone disease in Thailand differ from comparable previous studies conducted in developed countries which indicated that LC was a cost-saving strategy. Differences were due mainly to hospital costs of post operative inpatient care and value of lost working time. The LC option would be considered a cost-effective option for Thailand at a threshold of three times per capita gross domestic product recommended by the committee on the Millennium Development Goals.