bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of Urokinase-Type Plasminogen Activator or Matrix Metalloproteinases Prevents Cardiac Injury and Dysfunction During Viral Myocarditis
Authors: Heymans Stephane , Pauschinger Matthias , De Palma Armando , Kallwellis-Opara Angela , Rutschow Susanne , Swinnen Melissa , Vanhoutte Davy , Gao Fangye , Torpai Raimund , Baker Andrew H. , Padalko Elisabeth , Neyts Johan , Schultheiss Heinz-Peter , Van de Werf Frans , Carmeliet Peter , Pinto Yigal M.
Published: August 2006

Background—

Acute viral myocarditis is an important cause of cardiac failure in young adults for which there is no effective treatment apart from general heart failure therapy. The present study tested the hypothesis that increased expression of the proteinases urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) is implicated in cardiac inflammation, injury, and subsequent failure during Coxsackievirus-B3 (CVB3)–induced myocarditis.

Methods and Results—

First, we showed increased expression and activity of uPA and MMP-9 in wild-type mice at 7 days of CVB3-induced myocarditis. Targeted deletion of uPA, which resulted in reduced MMP activity and cytokine expression or inhibition of MMPs by adenoviral gene overexpression of tissue inhibitor of metalloproteinases-1, decreased cardiac inflammation and reduced myocardial necrosis at 7 days and decreased cardiac fibrosis at 35 days after CVB3 infection. Importantly, loss of uPA or MMP activity prevented CVB3-induced cardiac dilatation and dysfunction, as determined by serial echocardiography.

Conclusions—

Loss of uPA or MMP activity reduces the cardiac inflammatory response after CVB3 infection, thereby protecting against cardiac injury, dilatation, and failure during CVB3-induced myocarditis.
Prognostic Utility of Heart-Type Fatty Acid Binding Protein in Patients With Acute Coronary Syndromes
Authors: O’Donoghue Michelle , de Lemos James A. , Morrow David A. , Murphy Sabina A. , Buros Jacqueline L. , Cannon Christopher P. , Sabatine Marc S.
Published: August 2006

Background—

Heart-type fatty acid binding protein (H-FABP) is a cytosolic protein that is released rapidly from the cardiomyocyte in response to myocardial injury. Although it has been investigated as an early marker of acute myocardial infarction, its prognostic utility in acute coronary syndromes has not been established.

Methods and Results—

We measured H-FABP in 2287 patients with acute coronary syndromes from the OPUS-TIMI 16 trial. H-FABP was elevated (>8 ng/mL) in 332 patients (14.5%). Patients with an elevated H-FABP were more likely to suffer death (hazard ratio [HR], 4.1; 95% CI, 2.6 to 6.5), recurrent myocardial infarction (HR, 1.6; 95% CI, 1.0 to 2.5), congestive heart failure (HR, 4.5; 95% CI, 2.6 to 7.8), or the composite of these end points (HR, 2.6; 95% CI, 1.9 to 3.5) through the 10-month follow-up period. H-FABP predicted the risk of the composite end point both in patients who were troponin I negative (HR, 2.1; 95% CI, 1.3 to 3.4) and in those who were troponin I positive (HR, 3.3; 95% CI, 2.0 to 5.3). In a Cox proportional-hazards model that adjusted for baseline variables, including demographics, clinical characteristics, creatinine clearance, ST deviation, index diagnosis, and troponin I, elevated H-FABP remained a significant predictor of the composite end point (HR, 1.9; 95% CI, 1.3 to 2.7), as well as the individual end points of death (HR, 2.7; 95% CI, 1.5 to 4.9) and CHF (HR, 2.4; 95% CI, 1.2 to 5.0). In a multimarker approach, H-FABP, troponin I, and B-type natriuretic peptide provided complementary information.

Conclusions—

Elevation of H-FABP is associated with an increased risk of death and major cardiac events in patients presenting across the spectrum of acute coronary syndromes and is independent of other established clinical risk predictors and biomarkers.
Assyrians in Iraq
Authors: Petrosian Vahram
Published: August 2006

The article examines the question of the Assyrian identity; certain problems pertaining to the history of the Assyrian-Kurdish relationships; the problem of the Assyrian autonomy; the role of the political parties of the Iraqi Assyrians; the status of the Assyrians in Iraqi Kurdistan; the Assyrians after the fall of Saddam Hussein's regime, and several other issues.
Comparison of Wake Model Simulations with Offshore Wind Turbine Wake Profiles Measured by Sodar
Authors: Barthelmie R. J. , Larsen G. C. , Frandsen S. T. , Folkerts L. , Rados K. , Pryor S. C. , Lange B. , Schepers G.
Published: August 2006

This paper gives an evaluation of most of the commonly used models for predicting wind speed decrease (wake) downstream of a wind turbine. The evaluation is based on six experiments where free-stream and wake wind speed profiles were measured using a ship-mounted sodar at a small offshore wind farm. The experiments were conducted at varying distances between 1.7 and 7.4 rotor diameters downstream of the wind turbine. Evaluation of the models compares the predicted and observed velocity deficits at hub height. A new method of evaluation based on determining the cumulative momentum deficit over the profiles is described. Despite the apparent simplicity of the experiments, the models give a wide range of predictions. Overall, it is not possible to establish any of the models as having individually superior performance with respect to the measurements.
A Comparative Study of Rainfall Retrievals Based on Specific Differential Phase Shifts at X- and S-Band Radar Frequencies
Authors: Matrosov Sergey Y. , Cifelli Robert , Kennedy Patrick C. , Nesbitt Steven W. , Rutledge Steven A. , Bringi V. N. , Martner Brooks E.
Published: August 2006

A comparative study of the use of X- and S-band polarimetric radars for rainfall parameter retrievals is presented. The main advantage of X-band polarimetric measurements is the availability of reliable specific differential phase shift estimates, KDP, for lighter rainfalls when phase measurements at the S band are too noisy to produce usable KDP. Theoretical modeling with experimental raindrop size distributions indicates that due to some non-Rayleigh resonant effects, KDP values at a 3.2-cm wavelength (X band) are on average a factor of 3.7 greater than at 11 cm (S band), which is a somewhat larger difference than simple frequency scaling predicts. The non-Rayleigh effects also cause X-band horizontal polarization reflectivity, Zeh, and differential reflectivity, ZDR, to be larger than those at the S band. The differences between X- and S-band reflectivities can exceed measurement uncertainties for Zeh starting approximately at Zeh > 40 dBZ, and for ZDR when the mass-weighted drop diameter, Dm, exceeds about 2 mm. Simultaneous X- and S-band radar measurements of rainfall showed that consistent KDP estimates exceeding about 0.1° km−1 began to be possible at reflectivities greater than ∼26–30 dBZ while at the S band such estimates can generally be made if Zeh > ∼35–39 dBZ. Experimental radar data taken in light-to-moderate stratiform rainfalls with rain rates R in an interval from 2.5 to 15 mm h−1 showed availability of the KDP-based estimates of R for most of the data points at the X band while at the S band such estimates were available only for R greater than about 8–10 mm h−1. After correcting X-band differential reflectivity measurements for differential attenuation, ZDR measurements at both radar frequency bands were in good agreement with each other for Dm < 2 mm, which approximately corresponds to ZDR ≈ 1.6 dB. The ZDR-based retrievals of characteristic raindrop sizes also agreed well with in situ disdrometer measurements.
Intercomparisons and Aerosol Calibrations of 12 Commercial Integrating Nephelometers of Three Manufacturers
Authors: Heintzenberg J. , Wiedensohler A. , Tuch T. M. , Covert D. S. , Sheridan P. , Ogren J. A. , Gras J. , Nessler R. , Kleefeld C. , Kalivitis N. , Aaltonen V. , Wilhelm R-T. , Havlicek M.
Published: August 2006

This study determined measured and Mie-calculated angular signal truncations for total and backscatter TSI, Inc., nephelometers, as a function of wavelength and for particles of known size and composition. Except for the total scattering channels, similar agreements as in a previous study of measured and calculated truncations were derived for submicrometer test aerosols. For the first time, instrument responses were also determined for supermicrometer test aerosols up to 1.9 μm in geometric mean diameter. These supermicrometer data confirm the theoretical predictions of strong angular truncations of the total scatter signals in integrating nephelometers due to the limited range of measured forward scattering angles. Truncations up to 60% were determined for the largest measured particles. Rough empirical truncation corrections have been derived from the calibration data for Radiance Research and Ecotech nephelometers for which no detailed response characteristics exist. Intercomparisons of the nephelometers measuring urban atmospheric aerosols yield average deviations of the slope from a 1:1 relation with a TSI reference nephelometer of less than 7%. Average intercepts range between +0.53 and −0.19 Mm−1. For the Radiance Research and Ecotech nephelometers ambient regressions of the Radiance Research and Ecotech instruments with the TSI nephelometer show larger negative intercepts, which are attributed to their less well characterized optics.
Evaluation of Surface Shortwave Flux Estimates from GOES: Sensitivity to Sensor Calibration
Authors: Wonsick Margaret M. , Pinker Rachel T. , Meng Wen , Nguyen Louis
Published: August 2006

Parameters derived from satellite observations depend on the quality of the calibration method applied to the raw satellite radiance measurements. This study investigates the sensitivity of absolute reflectance, derived cloud cover, and estimated surface shortwave (SW) downward fluxes to two different calibration methods for the visible sensor aboard the eighth Geostationary Operational Environmental Satellite (GOES-8). The first method was developed at NOAA's National Environmental Satellite, Data, and Information Service (NESDIS), and the second at the NASA Langley Research Center. Differences in visible reflectance ranged from −0.5% to 3%. The average difference in monthly mean cloud amount was ∼3%, and the average difference in monthly mean shortwave downward flux was 5 W m−2. Differences in bias and rms of the SW fluxes when evaluated against ground station measurements were less than 3 W m−2. Neither calibration method was shown to consistently outperform the other. This evaluation yields an estimate of the errors in fluxes that can be attributed to calibration.
Optimal Testing With Easy or Difficult Items in Computerized Adaptive Testing
Authors: Eggen Theo J. H. M. , Verschoor Angela J.
Published: August 2006

Computerized adaptive tests (CATs) are individualized tests that, from a measurement point of view, are optimal for each individual, possibly under some practical conditions. In the present study, it is shown that maximum information item selection in CATs using an item bank that is calibrated with the one or the two-parameter logistic model results in each individual answering about 50% of the items correctly. Two item selection procedures giving easier (or more difficult) tests for students are presented and evaluated. Item selection on probability points of items yields good results only with the one-parameter logistic model and not with the two-parameter logistic model. An alternative selection procedure, based on maximum information at a shifted ability level, gives satisfactory results with both models. Index terms: computerized adaptive testing, item selection, item response theory
Equating Error in Observed-Score Equating
Authors: van der Linden Wim J.
Published: August 2006

Traditionally, error in equating observed scores on two versions of a test is defined as the difference between the transformations that equate the quantiles of their distributions in the sample and population of test takers. But it is argued that if the goal of equating is to adjust the scores of test takers on one version of the test to make them indistinguishable from those on another, equating error should be defined as the degree to which the equated scores realize this goal. Two equivalent definitions of equating error based on this criterion are formulated. It is shown how these definitions allow one to evaluate such key quantities as the bias and mean squared error of any equating method if the tests fit a unidimensional response model. Several alternative applications of the ideas for the case in which the tests do not fit a unidimensional response model are discussed. Index terms: bias in equating; local equating; equating error; equipercentile equating; IRT observed-score equating; mean squared error of equating; observed-score equating
“A Lab of Our Own”
Authors: Brown Phil , McCormick Sabrina , Mayer Brian , Zavestoski Stephen , Morello-Frosch Rachel , Altman Rebecca Gasior , Senier Laura
Published: August 2006

There are challenges to the dominant research paradigm in breast cancer science. In the United States, science and social activism create paradigmatic shifts. Using interviews, ethnographic observations, and an extensive review of the literature, we create a three-dimensional model to situate changes in scientific controversy concerning environmental causes of breast cancer. We identify three paradigm challenges posed by activists and some scientists: (1) to move debates about causation upstream to address causes; (2) to shift emphasis from individual to modifiable societal-level factors beyond an individual’s control; and (3) to allow direct lay involvement in research, which may raise new questions and change how questions are approached, the methods used, and the standards of proof. We use our model to examine controversies about doing scientific research, interpreting scientific results, and acting on science. Ultimately, we aim to understand what impedes construction of new methodologies and knowledge about environmental factors in human disease.
Sociotechnical Practices and Difference
Authors: Moser Ingunn
Published: August 2006

In feminist and cultural studies, there is a growing body of work concerned with how people’s lives are subjected to multiple, intersecting axes of differentiation and power. There is growing concern that we seem unable to address more than one difference at a time, thus failing to interrogate enactments of class, race, ethnicity, gender, and sexuality in science, technology, and medicine. This article aims to contribute to the effort to conceptualize the making of and interactions between differences. It explores how differences such as disability, gender, and class are made and unmade in sociotechnical practices. It shows that interactions between enactments of differences are complex, contradictory, unpredictable, and surprising and defy simple conclusions about effects and politics. These patterns of interference need to be investigated in situated practices, and we have to examine carefully how processes of differentiation interact to support and reinforce but also to challenge and undermine each other.
Processes of Inclusion, Cultures of Calculation, Structures of Power
Authors: Goven Joanna
Published: August 2006

The significance of political-economic context for scientific citizenship is argued through an analysis of New Zealand’s Royal Commission on Genetic Modification. My intention is not to provide an account of why the commission came to the decisions it did but to illustrate how the political-economic context and the culture of regulatory science both exacerbate public concerns about unacknowledged uncertainty and commercial influence and make it difficult for those concerns to influence the outcomes of public dialogues. The discursive flexibility of science as alternately predictive and provisional silences concerns about uncertainty, while a further interpretive choice of science as the autonomous activities of individuals unconstrained by political-economic context occludes the nature of concerns about commercial influence. Rather than the increasingly prevalent focus on processes of engagement, I argue that it is essential that researchers in this area attend to how public dialogue is placed in relation to the cultures and structures of regulatory science and neoliberalism.
Authority, Representation, and the Contradictions of Posttraditional Governing
Authors: Catlaw Thomas J.
Published: August 2006

The social, economic, and political transformations of the last 30 years have ushered in a “posttraditional” order in which the institutions and practices of the past are no longer authoritative guides for action and thought. Human experience increasingly is conceived as something to be constructed and decided on without reliance on the authority of tradition. This essay argues that these transformations pose grave challenges to the mechanisms of political representation and administrative legitimacy because they frustrate the coherent production of both recognition of a “We the People” and the conditions for human subjectivity. In doing so, the efficacy of the conventional mechanisms of governmental authority is eroded. An alternative model of administrative practice is outlined that rests on a nonrepresentational mode of authority and a reconceptualization of democracy.
E-Government as an Instrument of Fiscal Accountability and Responsiveness
Authors: Justice Jonathan B. , Melitski James , Smith Daniel L.
Published: August 2006

Fiscal transparency and citizen participation in budgeting processes are widely promoted as means toward the ends of democratic accountability and responsiveness in the allocation and use of public funds. In the past decade, academics and practitioners enthusiastic about e-government have emphasized the potential for using information technology to enhance democratic governance. Putting these two streams of public administration theory and practice together, the authors developed criteria for assessing e-budgeting efforts and applied them to a sample of Web sites operated by state and local governments. Although practitioners are ahead of academics in exploring the potential of e-government for improving fiscal accountability and responsiveness, practice lags behind the relevant basic recommendations of the Government Finance Officers Association. This finding leads to research and practice agendas aimed at enhancing the use of e-government to enhance fiscal transparency and participation.
Path Dependence and Organizational Behavior
Authors: Robinson Scott E. , Meier Kenneth J.
Published: August 2006

A long tradition in public administration describes administrative decision making as incremental. Despite the dominance of incremental models of decision making, few quantitative studies of administrative behavior take the implications of incrementalism seriously. This article introduces two concepts (path dependence and path contingency) to facilitate quantitative models investigating incrementalism in public agencies. The article illustrates the utility of these concepts in model building by analyzing school district promotion policies. The results show that path contingency and path dependence reveal interesting dynamics of promotion standards that traditional analyses would overlook.
Being in Tune With Life
Authors: Nelson Jenenne P.
Published: August 2006

Complementary therapies are commonly used by the public. Increasingly, complementary therapies are being used in hospices for symptom management; however, little research is available on their effect on patient well-being. Purpose: This study explores experiences of 15 hospice residents who received complementary therapies and describes the hospice cultural patterns where complementary therapies were delivered. Method: Ethnography was used to guide data collection. Data were collected by participant observations, formal and informal interviews, and complementary therapy charts in a residential hospice during 9 months. Findings: Three themes of experiencing complementary therapies, reconnecting to life through caring, and presence in relationship were uncovered during data analysis. Implications: Study results suggest that presence may be more important to the patient’s well-being than the physical responses of complementary therapies. Also, a caring culture may influence staff job satisfaction and retention.
The Effects of Nurses’ Practicing of the HeartTouch Technique on Perceived Stress, Spiritual Well-Being, and Hardiness
Authors: Walker Marsha Jelonek
Published: August 2006

Purpose: To test the effects of nurses’ practicing of the HeartTouch technique (internal method of changing thoughts and feelings) on their perceived stress, hardiness, and spiritual well-being. Method: Experimental ( n = 58) and comparison ( n = 40) groups received an education session discussing the effects of thoughts and feelings on stress and health, with the experimental group also learning HeartTouch and practicing it for 1 month. Findings: ANCOVA produced no statisticallysignificant between-group differences. Effect sizes ranged from .14 to .35, indicating practical significance, suggesting that nurses who practiced HeartTouch likely noticed a greater improvement in outcome variables than nurses who did not practice HeartTouch. In the experimental group, statistically significant within-group differences were seen in all variables, with effect sizes ranging from .25 to .89. In the comparison group, statistically significant within-group differences were seen in two variables. Implications: Learning about the power of thoughts and feelings and using HeartTouch to change them can reduce stress and increase hardiness and spiritual well-being.
Considerations for Adolescent Integrative Health Care in Canada
Authors: Francoeur Chera , Patterson Christine , Arthur Heather M. , Noesgaard Charlotte , Swinton Marilyn
Published: August 2006

The increased use of complementary/alternative medicine (CAM) has stimulated practitioners, policy makers, and researchers to examine its integration into mainstream medicine. For adolescents, there is evidence that they are using CAM as an option for health care. However, there is limited information on how adolescent integrative care should be developed in Canada. Practice, practice environments, and education are the three areas identified in which modifications should be made to current adolescent-focused practice in Canada to make it more of an integrative system.
An integrated model of comprehensive care for people with Alzheimer's disease and their caregivers in a primary care setting
Authors: Austrom Mary Guerriero , Hartwell Cora , Moore Patricia , Perkins Anthony J. , Damush Teresa , Unverzagt Frederick W. , Boustani Malaz , Hendrie Hugh C. , Callahan Christopher M.
Published: August 2006

Most people with Alzheimer's disease and their families receive care in primary care. This article describes an integrated model of Alzheimer's disease care in a primary care setting serving a predominantly ethnic minority population. This model included: a comprehensive screening and diagnosis process; a multidisciplinary team approach to care, coordinated by a geriatric advanced practice nurse; and a proactive, longitudinal tracking system. The psychosocial intervention included specific responses to the treatment and management of behavioral and psychological symptoms of dementia, including caregiver directed interventions and pharmacological treatment if needed. Results suggest that this type of model can be implemented in primary care, particularly with the involvement of geriatric advanced practice nurses who can effectively manage the complex nature of Alzheimer's disease.
Family carers' accounts of general practice contacts for their relatives with early signs of dementia
Authors: Downs Murna , Ariss Steven M.B. , Grant Eryk , Keady John , Turner Stephen , Bryans Michelle , Wilcock Jane , Levin Enid , O'carroll Ronan , Iliffe Steve
Published: August 2006

The role of families in supporting people with dementia is widely acknowledged in literature and UK government policy. The role of general practice in ensuring early and effective support for people living with mental health problems including dementia is also enshrined in UK policy. As part of a larger study, a total of 122 carers were asked to rate predefined aspects of the primary care response. For some responses they were also asked to provide a reason for their rating. The purpose of this study was to examine carers' accounts of contacts with general practitioners (GPs) and general practice teams when they were first approached with concerns about their relative. Findings suggest that, on average, carers rate the service as being at least ‘good'. However, their accounts describe a wide variety of experiences and demonstrate that expressed satisfaction does not necessarily reflect a satisfactory service. Both practitioner-related and carer-related issues were cited as reasons for their ratings. Implications for practice and research are discussed.
Self-management for people with early dementia
Authors: Mountain Gail A.
Published: August 2006

This article describes the concept of self-management and how it is being promoted. This is followed by a consideration of why dementia has been largely set aside. Illustrations of how people with early dementia might be enabled to participate are given and the requirements that will help to make this a reality are postulated. These include early disclosure of the diagnosis, support with the consequences of disclosure, a focus upon the needs of the person with dementia, identification of specific interventions that might facilitate self-management, meeting needs for professional education and support and a whole systems approach towards treatment and care. The results of a scoping review of the evidence is given, with an extra factor of meeting needs for lay and patient education being identified in addition to those elements originally postulated. The implications of policy neglect combined with a patchy evidence base and unrecognized service innovations are discussed.
Potential Attenuation of Disease Progression in Recurrent Prostate Cancer With Plant-Based Diet and Stress Reduction
Authors: Saxe Gordon A. , Major Jacqueline M. , Nguyen Jacquelyn Y. , Freeman Karen M. , Downs Tracy M. , Salem Carol E.
Published: August 2006

A rising level of prostate-specific antigen (PSA), after primary surgery or radiation therapy, is the hallmark of recurrent prostate cancer and is often the earliest sign of extraprostatic spread in patients who are otherwise asymptomatic. While hormonal therapy may slightly extend survival in a minority of patients, it is not curative and produces side effects including hot flashes, decreased libido, and loss of bone mass. Alternatively, dietary modification may offer an important tool for clinical management. Epidemiologic studies have associated the Western diet not only with prostate cancer incidence but also with a greater risk of disease progression after treatment. Conversely, many elements of plant-based diets have been associated with reduced risk of progression. However, dietary modification can be stressful and difficult to implement. We therefore conducted a 6-month pilot clinical trial to investigate whether adoption of a plant-based diet, reinforced by stress management training, could attenuate the rate of further PSA rise. Urologists at the University of California, San Diego, and San Diego Veterans Affairs Medical Centers recruited 14 patients with recurrent prostate cancer. A pre-post design was employed in which each patient served as his own control. Rates of PSA rise were ascertained for each patient for the following periods: from the time of posttreatment recurrence up to the start of the study (prestudy) and from the time immediately preceding the intervention (baseline) to the end of the intervention (0-6 months). There was a significant decrease in the rate of PSA rise from prestudy to 0 to 6 months ( P < .01). Four of 10 evaluable patients experienced an absolute reduction in their PSA levels over the entire 6-month study. Nine of 10 had a reduction in their rates of PSA rise and an improvement of their PSA doubling times. Median PSA doubling time increased from 11.9 months (prestudy) to 112.3 months (intervention). These results provide preliminary evidence that adoption of a plant-based diet, in combination with stress reduction, may attenuate disease progression and have therapeutic potential for clinical management of recurrent prostate cancer.
Search Strategies for Retrieving Complementary and Alternative Medicine Clinical Trials in Oncology
Authors: Bardia Aditya , Wahner-Roedler Dietlind L. , Erwin Patricia L. , Sood Amit
Published: August 2006

Purpose: Several Medline search strategies exist to retrieve complementary and alternative medicine (CAM) literature related to oncology. The objective of this study was to compare different search methods to ascertain the most optimal strategy. Methods: All clinical trials with CAM interventions in patients with cancer, published from 1965 to 2004, were abstracted using 4 different approaches. In the CAM filter search, the PubMed complementary medicine filter was used. The Ovid search was performed using a complex search strategy with the Ovid search engine. CAM keyword and not phytogenic searches involved the CAM filter search with the addition of the search terms “AND (complementary OR alternative)” and “NOT (antineoplastic agents, phytogenic), respectively. Articles were evaluated by 3 reviewers to ascertain whether they were clinical trials, the study intervention was related to CAM, and the condition prevented/treated was cancer related (inclusion criteria). Results: The CAM filter search retrieved 10 718 citations, Ovid retrieved 1190, CAM keyword retrieved 2895, and not phytogenic retrieved 1806. Compared to the CAM filter search, all other methods had significantly lower sensitivity (Ovid 48.3% ± 3.2%, CAM keyword 5.8% ± 1.5%, and not phytogenic 77.9% ± 2.7%, P < .001). The specificity of Ovid (38.4% ± 2.8%) and not phytogenic (40.8% ± 2.3%) searches was significantly higher ( P < .001) compared to CAM filter (8.8% ± 0.5%) and CAM keyword searches (1.9% ± 0.5%). Conclusion: The search strategy using PubMed’s complementary medicine filter, although comprehensive, lacks specificity; other methods, although more specific, lack sensitivity. Future indexing of all CAM clinical trials with a common medical subject heading term complementary medicine would enhance efficient retrieval of relevant citations.
The Vav binding site of the non–receptor tyrosine kinase Syk at Tyr 348 is critical for β2 integrin (CD11/CD18)–mediated neutrophil migration
Authors: Schymeinsky Jurgen , Sindrilaru Anca , Frommhold David , Sperandio Markus , Gerstl Ronald , Then Cornelia , Mócsai Attila , Scharffetter-Kochanek Karin , Walzog Barbara
Published: August 2006

Leukocyte adhesion via β2 integrins (CD11/CD18) activates the tyrosine kinase Syk. We found that Syk was enriched at the lamellipodium during N-formyl-Met-Leu-Phe–induced migration of neutrophil-like differentiated HL-60 cells. Here, Syk colocalized with Vav, a guanine nucleotide exchange factor for Rac and Cdc42. The enrichment of Syk at the lamellipodium and its colocalization with Vav were absent upon expression of a Syk kinase-dead mutant (Syk K402R) or a Syk mutant lacking the binding site of Vav (Syk Y348F). Live cell imaging revealed that both mutations resulted in excessive lamellipodium formation and severely compromised migration compared with control cells. Similar results were obtained upon down-regulation of Syk by RNA interference (RNAi) technique as well as in Syk–/– neutrophils from wild-type mice reconstituted with Syk–/– bone marrow. A pivotal role of Syk in vivo was demonstrated in the Arthus reaction, where neutrophil extravasation, edema formation, and hemorrhage were profoundly diminished in Syk–/– bone marrow chimeras compared with those in control animals. In the inflamed cremaster muscle, Syk–/– neutrophils revealed a defect in adhesion and migration. These findings indicate that Syk is critical for β2 integrin–mediated neutrophil migration in vitro and plays a fundamental role in neutrophil recruitment during the inflammatory response in vivo.
MicroRNAs: regulators of gene expression and cell differentiation
Authors: Shivdasani Ramesh A.
Published: August 2006

The existence and roles of a class of abundant regulatory RNA molecules have recently come into sharp focus. Micro-RNAs (miRNAs) are small (approximately 22 bases), non–protein-coding RNAs that recognize target sequences of imperfect complementarity in cognate mRNAs and either destabilize them or inhibit protein translation. Although mechanisms of miRNA biogenesis have been elucidated in some detail, there is limited appreciation of their biological functions. Reported examples typically focus on miRNA regulation of a single tissue-restricted transcript, often one encoding a transcription factor, that controls a specific aspect of development, cell differentiation, or physiology. However, computational algorithms predict up to hundreds of putative targets for individual miRNAs, single transcripts may be regulated by multiple miRNAs, and miRNAs may either eliminate target gene expression or serve to finetune transcript and protein levels. Theoretical considerations and early experimental results hence suggest diverse roles for miRNAs as a class. One appealing possibility, that miRNAs eliminate low-level expression of unwanted genes and hence refine unilineage gene expression, may be especially amenable to evaluation in models of hematopoiesis. This review summarizes current understanding of miRNA mechanisms, outlines some of the important outstanding questions, and describes studies that attempt to define miRNA functions in hematopoiesis.
Expression of interleukin-3 receptor subunits on defined subpopulations of acute myeloid leukemia blasts predicts the cytotoxicity of diphtheria toxin interleukin-3 fusion protein against malignant progenitors that engraft in immunodeficient mice
Authors: Yalcintepe Leman , Frankel Arthur E. , Hogge Donna E.
Published: August 2006

The interleukin-3 receptor (IL-3R) subunits are overexpressed on acute myeloid leukemia (AML) blasts compared with normal hematopoietic cells and are thus potential targets for novel therapeutic agents. Both fluorescence-activated cell sorter (FACS) analysis and quantitative real-time reverse transcription-polymerase chain reaction (QRT-PCR) were used to quantify expression of the IL-3Rα and βc subunits on AML cells. QRT-PCR for both subunits was most predictive of killing of AML colony-forming cells (AML-CFCs) by diphtheria toxin-IL-3 fusion protein (DT388IL3). Among 19 patient samples, the relative level of the IL-3Rα was higher than the IL-3Rβc and highest in CD34+CD38-CD71- cells, enriched for candidate leukemia stem cells, compared with cell fractions depleted of such progenitors. Overall, the amount of IL-3Rβc subunit did not vary among sorted subpopulations. However, expression of both subunits varied by more than 10-fold among different AML samples for all subpopulations studied. The level of IL-3Rβc expression versus glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (set at 1000) ranged from 0.14 to 13.56 in CD34+CD38-CD71- cells from different samples; this value was correlated (r = .76, P = .05) with the ability of DT388IL3 to kill AML progenitors that engraft in β2-microglobin-deficient nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice (n = 7). Thus, quantification of IL-3R subunit expression on AML blasts predicts the effectiveness IL-3R-targeted therapy in killing primitive leukemic progenitors.
Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia
Authors: Kantarjian Hagop , Oki Yasuhiro , Garcia-Manero Guillermo , Huang Xuelin , O'Brien Susan , Cortes Jorge , Faderl Stefan , Bueso-Ramos Carlos , Ravandi Farhad , Estrov Zeev , Ferrajoli Alessandra , Wierda William , Shan Jianqin , Davis Jan , Giles Francis , Saba Hussain I. , Issa Jean-Pierre J.
Published: August 2006

Epigenetic therapy with hypomethylating drugs is now the standard of care in myelodysplastic syndrome (MDS). Response rates remain low, and mechanism-based dose optimization has not been reported. We investigated the clinical and pharmacodynamic results of different dose schedules of decitabine. Adults with advanced MDS or chronic myelomonocytic leukemia (CMML) were randomized to 1 of 3 decitabine schedules: (1) 20 mg/m2 intravenously daily for 5 days; (2) 20 mg/m2 subcutaneously daily for 5 days; and (3) 10 mg/m2 intravenously daily for 10 days. Randomization followed a Bayesian adaptive design. Ninety-five patients were treated (77 with MDS, and 18 with CMML). Overall, 32 patients (34%) achieved a complete response (CR), and 69 (73%) had an objective response by the new modified International Working Group criteria. The 5-day intravenous schedule, which had the highest dose-intensity, was selected as optimal; the CR rate in that arm was 39%, compared with 21% in the 5-day subcutaneous arm and 24% in the 10-day intravenous arm (P < .05). The high dose-intensity arm was also superior at inducing hypomethylation at day 5 and at activating P15 expression at days 12 or 28 after therapy. We conclude that a low-dose, dose-intensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS.
Epstein-Barr virus nuclear antigen 2 inhibits AID expression during EBV-driven B-cell growth
Authors: Tobollik Stephanie , Meyer Linda , Buettner Maike , Klemmer Sandra , Kempkes Bettina , Kremmer Elisabeth , Niedobitek Gerald , Jungnickel Berit
Published: August 2006

Somatic hypermutation and class-switch recombination in germinal centers critically depend on activation-induced cytidine deaminase (AID). Deregulation of AID may lead to the aberrant activation or persistence of both genetic processes, thus contributing to the pathogenesis of B-cell lymphomas by mistargeted mutagenesis or recombination. The Epstein-Barr virus (EBV) establishes an asymptomatic latent infection in more than 90% of the human population, but it has also been linked to lymphomagenesis. A cooperative relationship of EBV and the germinal center reaction during the establishment of viral persistence has been postulated, but the contribution of EBV latent genes to the respective genetic events remains to be investigated in detail. In the present study, we show that activation of the EBV growth program has a clear inhibitory effect on AID expression, due to a negative effect of the master transcription factor of this program, EBNA2. This mechanism may counterbalance AID induction by the LMP1 protein, in order to prevent deleterious genetic changes during EBV-induced B-cell growth. EBNA2-mediated AID inhibition also provides a molecular explanation for the previously observed differences in somatic hypermutation activity in EBV-associated lymphoproliferative diseases, thus pointing to a crucial mechanism of EBV-mediated regulation of genomic integrity.
Suppression of hepcidin during anemia requires erythropoietic activity
Authors: Pak Mihwa , Lopez Miguel A. , Gabayan Victroia , Ganz Tomas , Rivera Seth
Published: August 2006

Hepcidin, the principal iron regulatory hormone, regulates the absorption of iron from the diet and the mobilization of iron from stores. Previous studies indicated that hepcidin is suppressed during anemia, a response that would appropriately increase the absorption of iron and its release from stores. Indeed, in the mouse model, hepcidin-1 was suppressed after phlebotomy or erythropoietin administration but the suppression was reversed by inhibitors of erythropoiesis. The suppression of hepcidin necessary to match iron supply to erythropoietic demand thus requires increased erythropoiesis and is not directly mediated by anemia, tissue hypoxia, or erythropoietin.
CTLA-4 dysregulation of self/tumor-reactive CD8+ T-cell function is CD4+ T-cell dependent
Authors: Gattinoni Luca , Ranganathan Anju , Surman Deborah R. , Palmer Douglas C. , Antony Paul A. , Theoret Marc R. , Heimann David M. , Rosenberg Steven A. , Restifo Nicholas P.
Published: August 2006

Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) maintains peripheral tolerance by suppressing T-cell activation and proliferation but its precise role in vivo remains unclear. We sought to elucidate the impact of CTLA-4 expression on self/tumor-reactive CD8+ T cells by using the glycoprotein (gp) 100–specific T-cell receptor (TCR) transgenic mouse, pmel-1. pmel-1 CLTA-4–/– mice developed profound, accelerated autoimmune vitiligo. This enhanced autoimmunity was associated with a small but highly activated CD8+ T-cell population and large numbers of CD4+ T cells not expressing the transgenic TCR. Adoptive transfer of pmel-1 CLTA-4–/– CD8+ T cells did not mediate superior antitumor immunity in the settings of either large established tumors or tumor challenge, suggesting that the mere absence of CTLA-4–mediated inhibition on CD8+ T cells did not directly promote enhancement of their effector functions. Removal of CD4+ T cells by crossing the pmel-1 CLTA-4–/– mouse onto a Rag-1–/– background resulted in the complete abrogation of CD8+ T-cell activation and autoimmune manifestations. The effects of CD4+ CLTA-4–/– T cells were dependent on the absence of CTLA-4 on CD8+ T cells. These results indicated that CD8+ CLTA-4–/– T-cell–mediated autoimmunity and tumor immunity required CD4+ T cells in which the function was dysregulated by the absence of CTLA-4–mediated negative costimulation.
Rho-kinase regulates tissue morphogenesis via non-muscle myosin and LIM-kinase during Drosophiladevelopment
Authors: Verdier Valerie , Guang-Chao-Chen  , Settleman Jeffrey
Published: August 2006

Background

The Rho-kinases (ROCKs) are major effector targets of the activated Rho GTPase that have been implicated in many of the Rho-mediated effects on cell shape and movement via their ability to affect acto-myosin contractility. The role of ROCKs in cell shape change and motility suggests a potentially important role for Rho-ROCK signaling in tissue morphogenesis during development. Indeed, in Drosophila, a single ROCK ortholog, DRok, has been identified and has been found to be required for establishing planar cell polarity.

Results

We have examined a potential role for DRok in additional aspects of tissue morphogenesis using an activated form of the protein in transgenic flies. Our findings demonstrate that DRok activity can influence multiple morphogenetic processes, including eye and wing development. Furthermore, genetic studies reveal that Drok interacts with multiple downstream effectors of the Rho GTPase signaling pathway, including non-muscle myosin heavy chain, adducin, and Diaphanous in those developmental processes. Finally, in overexpression studies, we determined that Drok and Drosophila Lim-kinase interact in the developing nervous system.

Conclusion

These findings indicate widespread diverse roles for DRok in tissue morphogenesis during Drosophila development, in which multiple DRok substrates appear to be required.
Mismatch repair and treatment resistance in ovarian cancer
Authors: Helleman Jozien , van Staveren Iris L , Dinjens Winand NM , van Kuijk Patricia F , Ritstier Kirsten , Ewing Patricia C , van der Burg Maria EL , Stoter Gerrit , Berns Els MJJ
Published: August 2006

Background

The treatment of ovarian cancer is hindered by intrinsic or acquired resistance to platinum-based chemotherapy. The aim of this study is to determine the frequency of mismatch repair (MMR) inactivation in ovarian cancer and its association with resistance to platinum-based chemotherapy.

Methods

We determined, microsatellite instability (MSI) as a marker for MMR inactivation (analysis of BAT25 and BAT26), MLH1 promoter methylation status (methylation specific PCR on bisulfite treated DNA) and mRNA expression of MLH1, MSH2, MSH3, MSH6 and PMS2 (quantitative RT-PCR) in 75 ovarian carcinomas and eight ovarian cancer cell lines

Results

MSI was detected in three of the eight cell lines i.e. A2780 (no MLH1 mRNA expression due to promoter methylation), SKOV3 (no MLH1 mRNA expression) and 2774 (no altered expression of MMR genes). Overall, there was no association between cisplatin response and MMR status in these eight cell lines.

Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation, however, none of these showed MSI. Forty-six of these patients received platinum-based chemotherapy (11 non-responders, 34 responders, one unknown response). The resistance seen in the eleven non-responders was not related to MSI and therefore also not to MMR inactivation.

Conclusion

No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines as well as the ovarian carcinomas. In the discussion, the results were compared to that of twenty similar studies in the literature including in total 1315 ovarian cancer patients. Although no association between response and MMR status was seen in the primary tumor the possible role of MMR inactivation in acquired resistance deserves further investigation.
Pitting of malaria parasites and spherocyte formation
Authors: Anyona Samuel B , Schrier Stanley L , Gichuki Charity W , Waitumbi John N
Published: August 2006

Background

A high prevalence of spherocytes was detected in blood smears of children enrolled in a case control study conducted in the malaria holoendemic Lake Victoria basin. It was speculated that the spherocytes reflect intraerythrocytic removal of malarial parasites with a concurrent removal of RBC membrane through a process analogous to pitting of intraerythrocytic inclusion bodies. Pitting and re-circulation of RBCs devoid of malaria parasites could be a host mechanism for parasite clearance while minimizing the anaemia that would occur were the entire parasitized RBC removed. The prior demonstration of RBCs containing ring-infected erythrocyte surface antigen (pf 155 or RESA) but no intracellular parasites, support the idea of pitting.

Methods

An in vitro model was developed to examine the phenomenon of pitting and spherocyte formation in Plasmodium falciparum infected RBCs (iRBC) co-incubated with human macrophages. In vivo application of this model was evaluated using blood specimens from patients attending Kisumu Ditrict Hospital. RBCs were probed with anti-RESA monoclonal antibody and a DNA stain (propidium iodide). Flow cytometry and fluorescent microscopy was used to compare RBCs containing both the antigen and the parasites to those that were only RESA positive.

Results

Co-incubation of iRBC and tumor necrosis factor-alpha activated macrophages led to pitting (14% ± 1.31% macrophages with engulfed trophozoites) as opposed to erythrophagocytosis (5.33% ± 0.95%) (P < 0.01). Following the interaction, 26.9% ± 8.1% of the RBCs were spherocytes as determined by flow cytometric reduction in eosin-5-maleimide binding which detects RBC membrane band 3. The median of patient RBCs with pitted parasites (RESA+, PI-) was more than 3 times (95,275/μL) that of RESA+, PI+ RBCs (28,365/μL) (P < 0.01). RBCs with pitted parasites showed other morphological abnormalities, including spherocyte formation.

Conclusion

It is proposed that in malaria holoendemic areas where prevalence of asexual stage parasites approaches 100% in children, RBCs with pitted parasites are re-circulated and pitting may produce spherocytes.