bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancing Generalizability: Moving From an Intimate to a Political Voice
Authors: Groleau Danielle , Zelkowitz Phyllis , Cabral Ivone Evangelista
Published: February 2009

Weak external validity of qualitative data has been a subject of debate outside and within the field of qualitative health research. Though some narratives have the power to reveal universal existential issues and inform theoretical development, each story remains unique and cannot be generalized. If the goal of qualitative researchers is to have narrative knowledge effect social change, we are faced with a pervasive problem. Our main objective with this article is methodological; that is, to argue and illustrate that a sequential—consensual qualitative design can yield data with adequate external validity to influence clinicians and public health programming. We seek to contribute to the debate on the generalizability of qualitative research in the health field and provide a methodological template for this type of qualitative design so researchers can apply it to future projects to transfer and translate popular knowledge in a way that can influence social change.
“Who Do They Think We Are, Anyway?”: Perceptions of and Responses to Poverty Stigma
Authors: Reutter Linda I. , Stewart Miriam J. , Veenstra Gerry , Love Rhonda , Raphael Dennis , Makwarimba Edward
Published: February 2009

In this article, we report on qualitative findings pertaining to low-income people's perceptions of and responses to “poverty stigma,” a key component of social exclusion with important implications for health and well-being. Our findings are drawn from a multimethod study designed to investigate experiences of social exclusion and social isolation among people living on low incomes. We conducted semistructured individual interviews ( n = 59) and group interviews (total n = 34) with low-income residents of two large Canadian cities. Data were analyzed using thematic content analysis techniques. Participants overwhelmingly thought that other members of society tend to view them as a burden to society—as lazy, disregarding of opportunities, irresponsible, and opting for an easy life. Low-income people responded to perceived stigma with a variety of cognitive and behavioral strategies that reflected their efforts to reconcile their perceived “social” and “personal” identities. These strategies included confronting discrimination directly, disregarding responses from others, helping other low-income people, withdrawing and isolating themselves from others, engaging in processes of cognitive distancing, and concealing their financial situation.
To Survive Out-of-Hospital Cardiac Arrest: A Search for Meaning and Coherence
Authors: Bremer Anders , Dahlberg Karin , Sandman Lars
Published: February 2009

The primary responsibility of prehospital emergency personnel at out-of-hospital cardiac arrests (OHCA) is to provide lifesaving care. Ethical considerations, decisions, and actions should be based in the patient's beliefs about health and well-being. In this article, we describe patients' experiences of surviving OHCA. By using a phenomenological approach, we focus on how OHCA influences patients' well-being over time. Nine survivors were interviewed. Out-of-hospital cardiac arrest is described as a sudden and elusive threat, an awakening in perplexity, and the memory gap as a loss of coherence. Survival means a search for coherence with distressing and joyful understanding, as well as existential insecurity exposed by feelings of vulnerability. Well-being is found through a sense of coherence and meaning in life. The study findings show survivors' emotional needs and a potential for prehospital emergency personnel to support them as they try to make sense of what has happened to them.
A Passion for Giving, a Passion for Sharing
Authors: Berthoin Antal Ariane , Richebé Nathalie
Published: February 2009

This contribution explores knowledge-based interactions among academics through the lens of gift exchange theory. Drawing from interviews conducted in France and Germany, it first reviews the diversity of contexts and reasons for knowledge sharing, then analyzes the processes and the implicit rules that govern them. The use of gift exchange theory brings to light several paradoxes inherent in interactions among members of the academic community, and it offers a fresh way of looking at power, status, and emotions in exchange processes.
Raging Against or With the Private Marketplace?
Authors: Mars Matthew M. , Lounsbury Michael
Published: February 2009

The rise of market logics and the spread of neoliberal policies over the past couple of decades have led to resistance and countermobilization efforts by a variety of activists and concerned citizens—recall the vivid 1999 World Trade Organization (WTO) protests in Seattle. However, contemporary modernity is more complicated than such simple movement—countermovement imageries, and instead of witnessing a leveling of previous institutional configurations with new market-oriented ones, the blending or coexistence of multiple competing and/or complementary logics has become de rigeuer. Hence, in some cases, market logics can provide a foundation for action that supports the arguments and interests of those who stand opposed on principle to market creep. Highlighting how the environmental movement has come to embrace the market as well as activism via an exploration of student eco-entrepreneurship in university settings, we argue that both researchers and skeptics need to go beyond ideological commitments to appreciate the complicated diversity of action and empirical reality that exists at the interface of business and society.
The Expression and Clinical Significance of TGF-β1 and MMP2 in Human Renal Clear Cell Carcinoma
Authors: Yang Shu-dong , Sun Rong-chao , Mu Hui-jun , Xu Zhuo-qun , Zhou Zhi-yi
Published: February 2009

The expression and clinical significance of transforming growth factor β1 (TGF-β1) and matrix metalloproteinase-2 (MMP2) in human renal clear cell carcinoma (RCCC) were investigated. The intensity of TGF-β1 and MMP2 expression in RCCC kidneys was significantly higher than that in normal kidneys. Expression of TGF-β1 and MMP2 in RCCC tissues was positively correlated with pathological grade and clinical stage. There was also a significant correlation between TGF-β1 and Msshese analyses indicate that upregulation of TGF-β1 and MMP2 expression may occur during the progression of RCCC. Thus, TGF-β1 and MMP2 may be useful molecular markers for evaluating prognosis in RCCC patients.
Inflammation of Ectopic Pancreatic Tissue in a Meckel’s Diverticulum Causing Acute Abdominal Symptoms: A Case Report and Review of the Literature
Authors: Zarand Attila , Bajtai Attila , Baranyai Zsolt , Dede Kristof , Jakab Ferenc
Published: February 2009

An unusual case of acute abdomen was caused by the inflammation of ectopic pancreatic tissue in a Meckel’s diverticulum. A 49-year-old man presented with acute abdominal pain, and the clinical diagnosis of acute appendicitis was established. During laparotomy, a normal appendix of unusual localization near the gallbladder and a Meckel’s diverticulum with an inflamed tip were found. Histological examination showed acute inflammation of heterotopic pancreatic tissue along with normal ectopic gastric and duodenal mucosa within the wall of the diverticulum. Fat necrosis was also ascertained. The authors believe that this is the first report of acute inflammation of ectopic pancreatic tissue and the presence of normal ectopic gastric and duodenal tissue in the same Meckel’s diverticulum.
Mastocytosis of the Female Breast
Authors: Setia Namrata , Crisi Giovanna M. , Pantanowitz Liron
Published: February 2009

A subset of patients with systemic mastocytosis may manifest with extracutaneous involvement. To the best of our knowledge, mastocytosis of the human breast has not been described. This study reports a case with mastocytosis involving the breasts of a 33-year-old woman associated with mammary hypertrophy (breast mastocytosis). The potential for infiltrating mast cells to mimic lobular carcinoma is emphasized and the relationship to breast hypertrophy in this case is discussed.
JAK2V617F and Prothrombin G20210A Gene Mutations in a Patient With Budd-Chiari Syndrome and Essential Thrombocythemia
Authors: Musallam Khaled M. , Aoun Elie G. , Mahfouz Rami A. , Khalife Mohamad , Taher Ali T.
Published: February 2009

Myeloproliferative disorders and the inherited thrombophilias have been described as the main causes underlying the Budd-Chiari syndrome. Moreover, the presence of the JAK2V617F was associated with a higher frequency of Budd-Chiari syndrome in patients who have overt or even latent myeloproliferative disorder. We herein describe a 28-year-old woman who was diagnosed with Budd-Chiari syndrome and later developed an overt myeloproliferative disorder. The patient was found to carry both the JAK2V617F and the prothrombin G20210A mutation in the heterozygous form. The significance of the chronology of diagnosis is highlighted.
Temporal Patterns of Hospital Admissions for Transient Ischemic Attack: A Retrospective Population-based Study in the Emilia-Romagna Region of Italy
Authors: Manfredini Roberto , Manfredini Fabio , Boari Benedetta , Malagoni Anna Maria , Gamberini Susanna , Salmi Raffaella , Gallerani Massimo
Published: February 2009

Acute cerebrovascular events are not randomly distributed over time but show specific temporal patterns of occurrence. However, most studies focused stroke and little is known about transient ischemic attack. This study aimed to explore the existence of a temporal pattern of transient ischemic attack and the possible influence by the most common risk factors. The analysis included all hospital admissions with the ICD9-CM code for TIA, recorded in the database of the Emilia Romagna region of Italy (1998-2006; n = 43642, mean age 76.8 ± 11.5 years, 45.5% males). Transient ischemic attack was most frequent in autumn and winter and less common in spring and summer (P < 0.0001), with the highest number of cases in October and the lowest in February, and also most frequent on Monday (P < 0.0001). This study shows a seasonal and weekly pattern in occurrence of transient ischemic attack, independent of sex and the presence of the most common risk factors.
Improving the Outcome of In-Hospital Cardiac Arrest: The Importance of Being EARNEST
Authors: Dichtwald Sara , Matot Idit , Einav Sharon
Published: February 2009

Cardiopulmonary resuscitation techniques were introduced more than 50 years ago, yet the rate of survival from cardiac arrest, particularly in the hospital setting, remains dismally low. This article reviews the prevalence, etiology, and outcome of in-hospital cardiac arrest, with a focus on the determinants of outcome that are amenable to improvement. These include principally components of basic life support that may be supported by either prompting or mechanical assistance (eg, chest compression, ventilation, and defibrillation). Also reviewed are preevent and postevent effectors such as medical staff skills and recognition of impending arrest, induction of mild hypothermia, and stabilization after return of spontaneous circulation.
Dynamic Component Extension: a Strategy for Performance Improvement in Multicomponent Applications
Authors: Sivagama Sundari M. , Vadhiyar Sathish S. , Nanjundiah Ravi S.
Published: February 2009

Multicomponent application paradigms have gained prominence in many significant multidisciplinary scientific applications. In this work, we propose a software strategy called dynamic component extension for multicomponent applications to improve application performance by minimizing processor idling. In this strategy, the processor space of a component is dynamically extended to include the processors of other components during certain computationally intensive phases of the component. We demonstrate its use in improving the performance of one of the most prominent multicomponent applications, the community climate system model (CCSM). In this application, we dynamically extend the atmosphere component to minimize the idling in other components caused by large periodic temporal load imbalances in the atmosphere component. By means of experiments on different parallel platforms with different numbers of processors, we show that using our strategy can lead to about 15% reduction and savings of several days in execution times of CCSM for 1000-year simulation runs.
Phyllanthus amarus Inhibits Cell Growth and Induces Apoptosis in Dalton's Lymphoma Ascites Cells Through Activation of Caspase-3 and Downregulation of Bcl-2
Authors: Harikumar Kuzhuvelil B. , Kuttan Girija , Kuttan Ramadasan
Published: February 2009

The authors found in an earlier study that Phyllanthus amarus extract could significantly inhibit the solid and ascites tumor development in mice induced by Dalton's lymphoma ascites (DLA) cells. In the present study, the apoptotic effects of P.amarus against DLA cells in culture was evaluated. P.amarus produced significant reduction in cell viability as determined by the MTT assay. It also induces the formation of apoptotic bodies with characteristic features like plasma membrane invagination, elongation, fragmentation, and chromatin condensation. P.amarus at concentrations of 100 and 200 µg/mL is shown to induce DNA fragmentation. Gene expression analysis reveals that P.amarus induces the expression of caspase-3 and inhibits the expression of Bcl-2, which is an antiapoptotic protein. So the present study provides some insights into the possible mechanism by which P.amarus brings about apoptosis and growth inhibition in DLA cells.
Carotid Artery Pseudo-occlusion: Does End-diastolic Velocity Suggest Need for Treatment?
Authors: Bowman Jonathan N. , Olin Jeffrey W. , Teodorescu Victoria J. , Carroccio Alfio , Ellozy Sharif H. , Marin Michael L. , Faries Peter L.
Published: February 2009

Objective: We reviewed our institution’s experience with carotid artery pseudo-occlusion (CAPO), to investigate whether internal carotid artery (ICA) end-diastolic velocity (EDV) as measured by duplex ultrasonography, was a predictor of need for further intervention. Methods: From February 2003 to January 2008, 7478 patients underwent duplex ultrasonographic evaluation of their carotid arteries. Diagnosis of CAPO included the appearance of a narrow flow jet (string sign) on power doppler images, low velocities in the ICA and additional criteria listed below. Results: Ten patients (0.13%) were identified as having a CAPO. All patients were asymptomatic and had an EDV < 78cm/s. Occlusion or functional occlusion was identified in nine patients on contrast imaging studies. Eight of these patients were treated medically without neurologic complication on follow-up. Two patients were treated with interventions and were asymptomatic at follow up. The mean follow up for the entire group was 12 months. Conclusions: Although this is a low volume study, there is evidence to suggest that asymptomatic patients with low EDV in the setting of carotid artery pseudo-occlusion found of duplex, may be safely managed medically.
Are Biologic Grafts Effective for Hernia Repair?
Authors: Hiles Michael , Record Ritchie Rae D. , Altizer Alicia M.
Published: February 2009

Biologic grafts for hernia repair are a relatively new development in the world of surgery. A thorough search of the Medline database for uses of various biologic grafts in hernia shows that the evidence behind their application is plentiful in some areas (ventral, inguinal) and nearly absent in others (parastomal). The assumption that these materials are only suited for contaminated or potentially contaminated surgical fields is not borne out in the literature, with more than 4 times the experience being reported in clean fields and the average success rates being higher (93% vs 87%). Outcomes prove to be highly dependent on material source, processing methods and implant scenarios with failure rates ranging from zero to more than 30%. Small intestinal submucosa (SIS) grafts have an aggregate failure rate of 6.7% at 19 months whereas acellular human dermis (AHD) grafts have a failure rate of 13.6% at 12 months. Chemically cross-linked grafts have much less published data than the non-cross-linked materials. In particular, the search found 33 articles for SIS, 32 for AHD, and 13 for cross-linked porcine dermis. Furthermore, the cumulative level of evidence for each graft material was fairly low (2.6 to 2.9), and only 1 material (SIS) had level 1 evidence reported in any hernia type (inguinal and hiatal). Together, biologic grafts have published evidence showing success rates better than 90% overall and more than 2000 years of cumulative implant time. Improvements in materials, techniques, and patient selection are likely to improve these numbers as this field of surgery matures.
School Physical Education: The Pill Not Taken
Authors: McKenzie Thomas L. , Lounsbery Monica A. F.
Published: February 2009

Physical education programs in schools have the potential to promote healthy, active lifestyles by providing children with some of their recommended physical activity, increasing their physical fitness levels, and teaching them generalizable movement and behavioral skills. If “exercise is medicine,” physical education is the pill not taken. Numerous barriers, including limited curriculum time allocations, low subject status, and inadequate resources hinder physical education from playing a major role in providing and promoting physical activity. This article profiles physical education as it relates to physical activity, describes its current status from both historical and contextual standpoints, and concludes with recommendations for improving it.
Microstructures formed from mixed solders on copper substrate
Authors: Snugovsky L. , Snugovsky P. , Perovic D. D. , Bagheri S. , Rutter J. W.
Published: February 2009

With the development and use of a variety of Pb free solders, it is probable that some solder joints in electronic assemblies may be made with solders of two different compositions. To investigate possible microstructures resulting from such procedure, samples were prepared using small balls of four different Sn–Ag–Cu (SAC) Pb free solders, as well as Sn–Zn–Al solder, melted together with eutectic Pb–Sn solder paste and also various SAC solder pastes, on a copper substrate. It was observed that using eutectic Pb–Sn solder paste with an SAC solder ball introduced some Pb–Sn eutectic microstructure and changed the ternary eutectic present from Ag3Sn–Cu6Sn5–Sn to Ag3Sn–Pb–Sn. Use of an SAC solder paste with Sn–Zn–Al solder introduced an apparent Ag–Cu–Zn ternary compound, replacing Zn lamellae of the Sn–Zn eutectic. With eutectic Pb–Sn solder paste, the Pb–Sn–Zn ternary eutectic was formed. It was noted that use of a high Sn solder results in rapid dissolution of the copper substrate.
Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation
Authors: Nakayama Masafumi , Akiba Hisaya , Takeda Kazuyoshi , Kojima Yuko , Hashiguchi Masaaki , Azuma Miyuki , Yagita Hideo , Okumura Ko
Published: February 2009

Phagocytes such as macrophages and dendritic cells (DCs) engulf apoptotic cells to maintain peripheral immune tolerance. However, the mechanism for the recognition of dying cells by phagocytes is not fully understood. Here, we demonstrate that T-cell immunoglobulin mucin-3 (Tim-3) recognizes apoptotic cells through the FG loop in the IgV domain, and is crucial for clearance of apoptotic cells by phagocytes. Whereas Tim-4 is highly expressed on peritoneal resident macrophages, Tim-3 is expressed on peritoneal exudate macrophages, monocytes, and splenic DCs, indicating distinct Tim-mediated phagocytic pathways used by different phagocytes. Furthermore, phagocytosis of apoptotic cells by CD8+ DCs is inhibited by anti–Tim-3 mAb, resulting in a reduced cross-presentation of dying cell-associated antigens in vitro and in vivo. Administration of anti–Tim-3 as well as anti–Tim-4 mAb induces autoantibody production. These results indicate a crucial role for Tim-3 in phagocytosis of apoptotic cells and cross-presentation, which may be linked to peripheral tolerance.
Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus–prone B6.Sle1.Yaa animals
Authors: Maeda Kenichiro , Malykhin Alex , Teague-Weber Brittany N. , Sun Xiao-Hong , Farris A. Darise , Coggeshall K. Mark
Published: February 2009

We previously reported the inhibitory action of interleukin-6 (IL-6) on B lymphopoiesis with SHIP−/− mice and showed that IL-6 biases lineage commitment toward myeloid cell fates in vitro and in vivo. Because elevated IL-6 is a feature of chronic inflammatory diseases, we applied an animal model of systemic lupus erythematosus (SLE) to determine whether IL-6 has similar effects on hematopoiesis. We found that IL-6 levels were elevated in the B6.Sle1.Yaa mice, and the increase was accompanied by losses of CD19+ B cells and more primitive B-lymphoid progenitors in bone marrow. Both the CD19+ B-cell population and their progenitors recovered in an IL-6−/− background. The uncommitted progenitors, containing precursors for both lymphoid and myeloid fates, expressed IL-6 receptor-α chain and responded to IL-6 by phosphorylation of STAT3. IL-6 stimulation caused uncommitted progenitors to express the Id1 transcription factor, which is known to inhibit lymphopoiesis and elevate myelopoiesis, and its expression was MAPK dependent. We conclude that chronic inflammatory conditions accompanied by increased IL-6 production bias uncommitted progenitors to a myeloid fate by inducing Id1 expression.
Genome-wide identification of Xenopus matrix metalloproteinases: conservation and unique duplications in amphibians
Authors: Fu Liezhen , Das Biswajit , Mathew Smita , Shi Yun-Bo
Published: February 2009

Background

Matrix metalloproteinases (MMPs) are members of the superfamily of Zn2+ dependent extracellular or membrane-bound endopeptidases which have been implicated to play critical roles in vertebrate development and human pathogenesis. A number of MMP genes have been found to be upregulated in some or all organs during frog metamorphosis, suggesting that different MMPs may have different functions in various organs/tissues. The recent advances in EST (expressed sequence tag) sequencing and the completion of the genome of Xenopus (X.) tropicalis prompted us to systematically analyze the existence of MMPs in the Xenopus genome.

Results

We examined X. laevis and X. tropicalis ESTs and genomic sequences for MMPs and obtained likely homologs for 20 out of the 25 MMPs known in higher vertebrates. Four of the five missing MMPs, i.e. MMPs 8, 10, 12 and 27, were all encoded on human Chromosome 11 and the other missing MMP, MMP22 (a chicken MMP), was also absent in human genome. In addition, we identified several novel MMPs which appears to be derived from unique duplications over evolution, are present in the genomes of both Xenopus species.

Conclusion

We identified the homologs of most of the mammalian MMPs in Xenopus and discovered a number of novel MMPs. Our results suggest that MMP genes undergo dynamic changes over evolution. It will be of interest in the future to investigate whether MMP expression and functions during vertebrate development are conserved. The sequence information reported here should facilitate such an endeavor in the near future.
Using cell fate attractors to uncover transcriptional regulation of HL60 neutrophil differentiation
Authors: Huang Albert C , Hu Limei , Kauffman Stuart A , Zhang Wei , Shmulevich Ilya
Published: February 2009

Background

The process of cellular differentiation is governed by complex dynamical biomolecular networks consisting of a multitude of genes and their products acting in concert to determine a particular cell fate. Thus, a systems level view is necessary for understanding how a cell coordinates this process and for developing effective therapeutic strategies to treat diseases, such as cancer, in which differentiation plays a significant role. Theoretical considerations and recent experimental evidence support the view that cell fates are high dimensional attractor states of the underlying molecular networks. The temporal behavior of the network states progressing toward different cell fate attractors has the potential to elucidate the underlying molecular mechanisms governing differentiation.

Results

Using the HL60 multipotent promyelocytic leukemia cell line, we performed experiments that ultimately led to two different cell fate attractors by two treatments of varying dosage and duration of the differentiation agent all-trans-retinoic acid (ATRA). The dosage and duration combinations of the two treatments were chosen by means of flow cytometric measurements of CD11b, a well-known early differentiation marker, such that they generated two intermediate populations that were poised at the apparently same stage of differentiation. However, the population of one treatment proceeded toward the terminally differentiated neutrophil attractor while that of the other treatment reverted back toward the undifferentiated promyelocytic attractor. We monitored the gene expression changes in the two populations after their respective treatments over a period of five days and identified a set of genes that diverged in their expression, a subset of which promotes neutrophil differentiation while the other represses cell cycle progression. By employing promoter based transcription factor binding site analysis, we found enrichment in the set of divergent genes, of transcription factors functionally linked to tumor progression, cell cycle, and development.

Conclusion

Since many of the transcription factors identified by this approach are also known to be implicated in hematopoietic differentiation and leukemia, this study points to the utility of incorporating a dynamical systems level view into a computational analysis framework for elucidating transcriptional mechanisms regulating differentiation.
Comparison of effective stiffness and compliance for characterizing cracked rocks
Authors: Hu Yanrong , McMechan George A.
Published: February 2009

The noninteraction approximation (NIA) is commonly used for prediction of the anisotropic elastic stiffnesses of cracked rocks. At large crack density, the NIA has a desirable nonlinear stiffness behavior; however, this is inconsistent with the dilute crack assumption. The nonlinear behavior of stiffness predicted by the NIA at high crack density is produced by defining compliance to be a linear function of crack density and then inverting the compliance tensor to stiffness. The linear behavior of compliance is strictly valid only when there is no crack interaction (at low crack density), so the resulting nonlinear stiffnesses at high crack density are unconstrained extrapolations. Comparison of results from the NIA method, an effective stiffness (T-matrix) method, and numerical modeling shows that: (1) first-order compliance methods are not better than first-order stiffness methods; they are equivalent and valid only under the noninteraction (or dilute crack) assumption; and (2) it is misleading to use the NIA at high crack density; crack interactions (shielding and amplification) should not be assumed to cancel for all crack distributions, so they require explicit consideration, for example, with a high-order T-matrix formulation. Examples of unreliable predictions of the NIA at high crack density include nonzero stiffnesses at 100% porosity for a model with dry cracks, and errors in relative stiffnesses in the isotropic limit.
This issue of GEOPHYSICS
Authors: Wapenaar Kees
Published: February 2009

In this article, the Editor of Geophysics provides an overview of all technical articles in this issue of the journal.
Retrospective Evaluation of the Clinical and Radiographic Risk Factors Associated With Severe Pulmonary Hemorrhage in First-Line Advanced, Unresectable Non–Small-Cell Lung Cancer Treated With Carboplatin and Paclitaxel Plus Bevacizumab
Authors: Sandler Alan B. , Schiller Joan H. , Gray Robert , Dimery Isaiah , Brahmer Julie , Samant Meghna , Wang Lisa I. , Johnson David H.
Published: February 2009

Purpose

Severe (grade ≥ 3) pulmonary hemorrhage (PH) in advanced non–small-cell lung cancer was observed in two prospective, randomized, phase II (N = 99) and phase III (N = 878) trials of bevacizumab plus carboplatin and paclitaxel. Retrospective case-control and cohort analyses were conducted to identify associated radiographic and clinical risk factors for PH.

Patients and Methods

Six patients with PH from the phase II trial, 15 potential PH patients with hemorrhage at any site from the phase III trial, and their matched controls were evaluated with review of baseline and on-treatment radiographs by an independent radiology facility, blinded to patient/control status. Patients with severe (grade ≥ 3) PH from each trial were matched with up to three controls based on sex, age group, histology (phase II), or sex and age group (phase III).

Results

Seven PH patients in the phase III trial were identified as severe PH. Six of the patients were early onset (occurred < 150 days of initiating bevacizumab) and one was late onset. Baseline tumor cavitation, not tumor location, was identified as the only potential risk factor for patients with early onset. Combined analysis of severe PH patients from the phase II and phase III trials (n = 13), compared with their pooled matched controls (n = 42), did not identify any additional baseline radiographic or clinical variables associated with PH.

Conclusion

PH was an uncommon event. Based on these analyses, baseline tumor cavitation may be a potential risk factor for PH. No other baseline clinical variables were predictive for PH although the number of events was small.
Identification of Leptomeningeal Disease in Aggressive B-Cell Non-Hodgkin's Lymphoma: Improved Sensitivity of Flow Cytometry
Authors: Quijano Sandra , López Antonio , Manuel Sancho Juan , Panizo Carlos , Debén Guillermo , Castilla Cristina , Antonio García-Vela José , Salar Antonio , Alonso-Vence Natalia , González-Barca Eva , Peñalver Francisco Javier , Plaza-Villa Josefa , Morado Marta , García-Marco José , Arias Jesús , Briones Javier , Ferrer Secundino , Capote Javier , Nicolás Concepción , Orfao Alberto
Published: February 2009

Purpose

Here, we evaluate the sensitivity and specificity of a new 11-parameter flow cytometry (FCM) approach versus conventional cytology (CC) for detecting neoplastic cells in stabilized CSF samples from newly diagnosed aggressive B-cell non-Hodgkin's lymphoma (B-NHL) at high risk of CNS relapse, using a prospective, multicentric study design.

Patients and Methods

Moreover, we compared the distribution of different subpopulations of CSF leukocytes and the clinico-biologic characteristics of CSF+ versus CSF−, patients, in an attempt to define new algorithms useful for predicting CNS disease.

Results

Overall, 27 (22%) of 123 patients showed infiltration by FCM, while CC was positive in only seven patients (6%), with three other cases being suspicious (2%). CC+/FCM+ samples typically had more than 20% neoplastic B cells and/or ≥ one neoplastic B cell/μL, while FCM+/CC− samples showed lower levels (P < .0001) of infiltration. Interestingly, in Burkitt lymphoma, presence of CNS disease by FCM could be predicted with a high specificity when increased serum β2-microglobulin and neurological symptoms coexisted, while peripheral blood involvement was the only independent parameter associated with CNS disease in diffuse large B-cell lymphoma, with low predictive value.

Conclusion

FCM significantly improves the sensitivity of CC for the identification of leptomeningeal disease in aggressive B-NHL at higher risk of CNS disease, particularly in paucicellular samples.
High Numbers of Tumor-Infiltrating Programmed Cell Death 1–Positive Regulatory Lymphocytes Are Associated With Improved Overall Survival in Follicular Lymphoma
Authors: Carreras Joaquim , Lopez-Guillermo Armando , Roncador Giovanna , Villamor Neus , Colomo Lluis , Martinez Antonio , Hamoudi Rifat , Howat William J. , Montserrat Emili , Campo Elias
Published: February 2009

Purpose

Tumor microenvironment influences the behavior of follicular lymphoma (FL), although the specific cell subsets involved are not well known. The aim of this study was to determine the impact of programmed cell death 1 (PD-1) –positive inhibitory immunoregulatory lymphoid cells in the clinicobiologic features and outcome of patients with FL.

Patients and Methods

We examined samples from 100 patients (53 men and 47 women; median age, 54 years) at diagnosis, as well as in 32 patients at first relapse, with a recently generated monoclonal antibody against PD-1. The cells were quantified using computerized image analysis. Additional analysis consisted of double immunofluorescence and flow cytometry.

Results

PD-1 expression was alternative to FOXP3 in lymphoid cells from both reactive tonsils and FL. At diagnosis, the median percentage of PD-1–positive cells was 14% (range, 0.1% to 74%). Patients with grade 3 FL, poor performance status, and high serum lactate dehydrogenase showed lower numbers of PD-1–positive cells. After a median follow-up of 6.2 years, patients with PD-1–positive cells ≤ 5% (n = 25), 6% to 33% (n = 50), and more than 33% (n = 25) had a 5-year progression-free survival rate of 20%, 46%, and 48% (P = .038) and overall survival (OS) of 50%, 77%, and 95% (P = .004), respectively. PD-1 and FL International Prognostic Index maintained prognostic value for OS in multivariate analysis. Patients with PD-1–positive cells ≤ 5% showed a higher risk of histologic transformation. At that time, transformed diffuse large B-cell lymphomas had lower percentage of PD-1–positive cells than FL.

Conclusion

A high content of PD-1–positive cells predicted favorable outcome of FL patients, whereas a marked reduction is observed in transformation.
HLA-Identical Sibling Compared With 8/8 Matched and Mismatched Unrelated Donor Bone Marrow Transplant for Chronic Phase Chronic Myeloid Leukemia
Authors: Arora Mukta , Weisdorf Daniel J. , Spellman Stephen R. , Haagenson Michael D. , Klein John P. , Hurley Carolyn K. , Selby George B. , Antin Joseph H. , Kernan Nancy A. , Kollman Craig , Nademanee Auayporn , McGlave Philip , Horowitz Mary M. , Petersdorf Effie W.
Published: February 2009

Purpose

Transplantation of hematopoietic stem cells from an unrelated donor (URD) is an option for many patients who do not have an HLA-identical sibling donor (MSD). Current criteria for the selection of URDs include consideration for HLA alleles determined by high resolution typing methods, with preference for allele-matched donors. However, the utility and outcome associated with transplants from URDs compared with those from MSDs remains undefined.

Patients and Methods

We examined clinical outcome after patients received bone marrow transplants (BMTs) from MSDs; HLA-A, -B, -C, and DRB1 allele-matched URDs (8/8); and HLA-mismatched URDs in a homogeneous population of patients with chronic myeloid leukemia (CML) in first chronic phase (CP1) where a strong allogeneic effect and hence a lower risk of relapse is anticipated. Transplantation outcomes were compared between 1,052 URD and 3,514 MSD BMT recipients with CML in CP1.

Results

Five-year overall survival and leukemia-free survival (LFS) after receipt of BMTs from 8/8 matched URDs were worse than those after receipt of BMTs from MSDs (5-year survival, 55% v 63%; RR, 1.35; 95% CI, 1.17 to 1.56; P < .001; LFS, 50% v 55%; RR, 1.21; 95% CI, 1.06 to 1.40; P = .006). Survival was progressively worse with greater degrees of mismatch. Similar and low risk of relapse were observed after receipt of transplant from either MSD or URD.

Conclusion

In this homogeneous cohort of good risk patients with CML in CP1, 5-year overall survival and LFS after receipt of transplant from 8/8 allele-matched donors were modestly though significantly worse than those after receipt of transplant from MSDs. Additive adverse effects of multilocus mismatching are not well tolerated and should be avoided if possible.
Developing an In-Training Examination for Fellows: The Experience of the American Society of Clinical Oncology
Authors: Collichio Frances A. , Kayoumi Karen M. , Hande Kenneth R. , Hawkins Richard E. , Hawley Janine L. , Adelstein David J. , D'Angelo Jean M. , Stewart James A.
Published: February 2009

The American Society of Clinical Oncology (ASCO) developed its own test—the Medical Oncology In-Training Examination (MedOnc ITE)—as a tool to assess trainees' knowledge of the clinical oncology subspecialty, establish consistency in educational standards across training programs, identify areas of strength and weakness in individual programs, and stimulate intraprogrammatic reading and discussion. The Accreditation Council for Graduate Medical Education Outcome Project provided additional incentive for ASCO to develop an ITE. The examination was developed in 4 years. The concept of the examination and the budget were approved by the ASCO governing board. The National Board of Medical Examiners was selected to work with ASCO. Fellowship programs were contacted to determine if they had the information technology support to hold the examination. A blueprint for the examination was developed. The test format, including the number of questions and the selection of case-based single best answers, was determined. Physician volunteers to write the questions were solicited from among program directors, various ASCO committees, and disease experts. A workshop was held to teach volunteers how to write proper case-based questions. From this pool, a smaller group of physicians was selected to develop the test and review all test questions. The final examination was developed and administered in February 2008, with scores provided to fellows and program directors in April 2008. Feedback received after the examination will be helpful for developing future MedOnc ITEs. The process ASCO went through to develop the MedOnc ITE serves as a model for other subspecialties interested in developing their own ITEs.
Social Outcomes in the Childhood Cancer Survivor Study Cohort
Authors: Gurney James G. , Krull Kevin R. , Kadan-Lottick Nina , Nicholson H. Stacy , Nathan Paul C. , Zebrack Brad , Tersak Jean M. , Ness Kirsten K.
Published: February 2009

Difficulties with negotiating and achieving desired social outcomes in life may be exacerbated by the experience of childhood cancer, including adverse effects from therapies used to achieve a cure. This review of previous publications from the Childhood Cancer Survivor Study (CCSS) and other relevant literature provides insight into the prevalence of, and risk factors for, poor educational attainment, less than optimal employment status, and interpersonal relationship issues among long-term survivors of childhood cancer. The impacts of emotional health and physical disability on social outcomes are also examined. Study results suggest that childhood cancer survivors generally have similar high school graduation rates, but are more likely to require special education services than sibling comparison groups. Survivors are slightly less likely than expected to attend college, and are more likely to be unemployed and not married as young adults. Cancers and treatments that result in impairment to the CNS, particularly brain tumors, or that impact sensory functioning, such as hearing loss, are associated with greater risk for undesirable social outcomes, as are emotional health problems and physical disability. This review of relevant data from CCSS and other studies provides information on risk factors for social problems into adulthood. A greater understanding of the long-term social impacts from the diagnosis and treatment of childhood cancer is critically important for developing targeted interventions to prevent or ameliorate adverse psychosocial effects.
Modified-Release Hydrocortisone to Provide Circadian Cortisol Profiles
Authors: Debono Miguel , Ghobadi Cyrus , Rostami-Hodjegan Amin , Huatan Hiep , Campbell Michael J. , Newell-Price John , Darzy Ken , Merke Deborah P. , Arlt Wiebke , Ross Richard J.
Published: February 2009

Context: Cortisol has a distinct circadian rhythm regulated by the brain’s central pacemaker. Loss of this rhythm is associated with metabolic abnormalities, fatigue, and poor quality of life. Conventional glucocorticoid replacement cannot replicate this rhythm.

Objectives: Our objectives were to define key variables of physiological cortisol rhythm, and by pharmacokinetic modeling test whether modified-release hydrocortisone (MR-HC) can provide circadian cortisol profiles.

Setting: The study was performed at a Clinical Research Facility.

Design and Methods: Using data from a cross-sectional study in healthy reference subjects (n = 33), we defined parameters for the cortisol rhythm. We then tested MR-HC against immediate-release hydrocortisone in healthy volunteers (n = 28) in an open-label, randomized, single-dose, cross-over study. We compared profiles with physiological cortisol levels, and modeled an optimal treatment regimen.

Results: The key variables in the physiological cortisol profile included: peak 15.5 μg/dl (95% reference range 11.7–20.6), acrophase 0832 h (95% confidence interval 0759–0905), nadir less than 2 μg/dl (95% reference range 1.5–2.5), time of nadir 0018 h (95% confidence interval 2339–0058), and quiescent phase (below the mesor) 1943–0531 h. MR-HC 15 mg demonstrated delayed and sustained release with a mean (sem) maximum observed concentration of 16.6 (1.4) μg/dl at 7.41 (0.57) h after drug. Bioavailability of MR-HC 5, 10, and 15 mg was 100, 79, and 86% that of immediate-release hydrocortisone. Modeling suggested that MR-HC 15–20 mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels.

Conclusion: By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol.
Ran on tracks – cytoplasmic roles for a nuclear regulator
Authors: Yudin Dmitry , Fainzilber Mike
Published: February 2009

The GTPase Ran is best known for its crucial roles in the regulation of nucleocytoplasmic transport in interphase cells and in the organization of the spindle apparatus during mitosis. A flurry of recent reports has now implicated Ran in diverse cytoplasmic events, including trafficking of an ephrin receptor homolog in nematode oocytes, control of neurite outgrowth in Drosophila and mammalian neurons, and retrograde signaling in nerve axons after injury. Striking findings suggest that the guanine-nucleotide state of Ran can be regulated by local translation of the Ran-binding protein RanBP1 in axons, and that an additional Ran-binding protein, RanBP10, can act as a microtubule-binding cytoplasmic guanine-nucleotide exchange factor for Ran (RanGEF) in megakaryocytes. Thus, the Ran GTPase system can act as a spatial regulator of importin-dependent transport and signaling in distal cytoplasm, and as a regulator of cytoskeletal dynamics at sites that are distant from the nucleus.
A nuclear-envelope bridge positions nuclei and moves chromosomes
Authors: Starr Daniel A.
Published: February 2009

Positioning the nucleus is essential for the formation of polarized cells, pronuclear migration, cell division, cell migration and the organization of specialized syncytia such as mammalian skeletal muscles. Proteins that are required for nuclear positioning also function during chromosome movement and pairing in meiosis. Defects in these processes lead to human diseases including laminopathies. To properly position the nucleus or move chromosomes within the nucleus, the cell must specify the outer surface of the nucleus and transfer forces across both membranes of the nuclear envelope. KASH proteins are specifically recruited to the outer nuclear membrane by SUN proteins, which reside in the inner nuclear membrane. KASH and SUN proteins physically interact in the perinuclear space, forming a bridge across the two membranes of the nuclear envelope. The divergent N-terminal domains of KASH proteins extend from the surface of the nucleus into the cytoplasm and interact with the cytoskeleton, whereas the N-termini of SUN proteins extend into the nucleoplasm to interact with the lamina or chromatin. The bridge of SUN and KASH across the nuclear envelope functions to transfer forces that are generated in the cytoplasm into the nucleoplasm during nuclear migration, nuclear anchorage, centrosome attachment, intermediate-filament association and telomere clustering.
Study on the Structure and Vibrational Dynamics of Functional Molecules and Molecular Clusters by Double Resonance Vibrational Spectroscopy
Authors: Ebata Takayuki
Published: February 2009

Structure and dynamics of gas-phase molecules and their clusters formed in a supersonic jet has been a great interest to many researchers. Studies on these simple systems provide us with the fundamental concept of many physical and chemical phenomena observed in bulk systems. These studies are also important for the verification of theoretical prediction and quantum chemical calculations. Especially molecular clusters have been thought to be a good model for molecular level understanding of intermolecular interaction and relaxation in condensed phase. However, until the beginning of 1990, studies of molecular clusters mainly concentrated on electronic spectroscopy and very few studies were reported for vibrational spectroscopy. On the other hand, vibrational spectroscopy is essential in condensed phase, and there has been a gap between cluster science and condensed phase science. In 1993 we first reported infrared (IR)–ultraviolet (UV) double resonance spectroscopy of the OH stretching vibration of phenol and its hydrated clusters in a supersonic jet. The observed vibrational spectra showed a characteristic feature of the H-bonding, that is a larger frequency shift as well as broadening of the OH stretching band, and the structures were unambiguously determined with the aid of quantum chemical calculation. It is not too much to say that the combination of double resonance vibrational spectroscopy and quantum chemical calculation has become a very popular method in cluster science. In this paper, we describe various double resonance vibrational spectroscopies in frequency domain. Typical examples of application are shown; determination of H-bonded clusters of benzonitrile, conformer selective vibrational spectroscopy for l-phenylalanine and its hydrated cluster, and study of the encapsulation structure of guest atom and molecules by functional molecules, calixarene and crown ether. Finally, time-domain studies for the dynamics of the vibrations are described. Picosecond IR–UV pump–probe spectroscopy is applied to study the vibrational energy relaxation (VER) of the OH stretching vibration of isolated aromatic molecules and the H-bonded clusters.
Molecular Structure of Chlorocycloheptane in Inclusion Compound with 9,9′-Bianthryl and Gelation during Crystallization
Authors: Toyota Shinji , Okamoto Yohei , Ishikawa Takeharu , Iwanaga Tetsuo , Yamada Masanori
Published: February 2009

9,9′-Bianthryl formed an inclusion compound with chlorocycloheptane in a 2:1 ratio. X-ray analysis revealed that two guest molecules were accommodated in a cavity surrounded by eight host molecules. The guest molecules were conformationally fixed in each cavity into either of two twist-chair forms that differed in the position of the chloro group. These conformations were compared with the calculated ones for chlorocycloheptane itself by DFT calculation. When the inclusion compound was prepared from a concentrated solution of 9,9′-bianthryl in chlorocycloheptane, the gelation was followed by crystallization. This phenomenon is unusual for relatively small molecules lacking strong intermolecular interactions.