bluuebunny/crossref_metadata_2025 huggingface dataset:
Astrocytes as Regulators of Synaptic Function
Authors: Rusakov Dmitri A. , Zheng Kaiyu , Henneberger Christian
Published: May 2011

The emerging role of astrocytes in neural communication represents a conceptual challenge. In striking contrast to the rapid and highly space- and time-constrained machinery of neuronal spike propagation and synaptic release, astroglia appear slow and imprecise. Although a large body of independent experiments documents active signal exchange between astrocytes and neurons, some genetic models have raised doubts about the major Ca2+-dependent molecular mechanism routinely associated with release of “gliotransmitters.” A limited understanding of astrocytic Ca2+ signaling and the imperfect compatibility between physiology and experimental manipulations seem to have contributed to this conceptual bottleneck. Experimental approaches providing mechanistic insights into the diverse mechanisms of intra-astrocyte Ca2+ signaling on the nanoscale are needed to understand Ca2+-dependent astrocytic function in vivo. This review highlights limitations and potential advantages of such approaches from the current methodological perspective.
Excess Costs Attributable to Postoperative Complications
Authors: Carey Kathleen , Stefos Theodore , Shibei Zhao  , Borzecki Ann M. , Rosen Amy K.
Published: May 2011

This article estimates excess costs associated with postoperative complications among inpatients treated in Veterans Health Administration (VA) hospitals. The authors conducted an observational study on 43,822 hospitalizations involving inpatient surgery in one of 104 VA hospitals during fiscal year 2007. Hospitalization-level cost regression analyses were performed to estimate the excess cost of each of 18 unique postoperative complications. The authors used generalized linear modeling techniques to account for the heavily skewed cost distribution. Costs were measured using an activity-based cost accounting system and complications were assessed based on medical chart review conducted by the VA ‘National Surgical Quality Improvement Program. The authors found excess costs associated with postoperative complications ranging from $8,338 for “superficial surgical site infection” to $29,595 for “failure to wean within 24 hours in the presence of respiratory complications.” The results obtained suggest that quality improvement efforts aimed at reducing postoperative complications can contribute significantly to lowering of hospital costs.
Using Consumer Incentives to Increase Well-Child Visits Among Low-Income Children
Authors: Greene Jessica
Published: May 2011

This quasi-experimental study examines the impact of Idaho’s wellness incentive program, which rewards children with CHIP (Children’s Health Insurance Programs) who are up-to-date with well-child visits with $30 in credits per quarter for use toward their CHIP premiums. Between baseline and the second year of implementation, the percentage of CHIP children who were up-to-date with well-child visits increased by 116% (from 23% to 49%), compared with a 13% increase (from 29% to 32%) among children with Medicaid, who were not eligible for the incentive. The incentive program had a greater impact on children who were recommended to have one annual well-child visit compared with those recommended to have two to four annual visits. The program was not, however, more effective for those whose premiums were fully covered by the reward compared with those whose premiums were partially covered. This study provides encouraging evidence to states about using consumer financial incentives for increasing preventive care use.
Differences Between Family Practices in the Associations of Patient Characteristics With Health Care Experiences
Authors: Damman Olga C. , de Boer Dolf , Hendriks Michelle , Meuwissen Liesbeth E. , Rademakers Jany , Delnoij Diana M. J. , Groenewegen Peter P.
Published: May 2011

When comparing health care providers, patient experience data are usually adjusted for case-mix associations to ensure fair comparisons. Previous studies in the United States showed that case-mix associations sometimes vary across health care providers. Such variation could indicate differential provider behavior for patient subgroups, in which case current adjustment techniques might be inappropriate. To see whether this variation is also apparent in a health care system different from the U.S. system, the authors analyzed Dutch patients’ experiences with family practice care. Using multilevel random slope models, the associations between age, general health status, mental health status, education, sex, and ethnicity on one hand and reported experiences on the other hand were assessed across family practices. The authors found only five significant variances between case-mix coefficients, all for outcomes related to health care professionals’ conduct. These findings correspond to previous U.S. findings, suggesting that the case-mix variations reported here and previously constitute a rather robust phenomenon.
Men as Students and Teachers of Feminist Scholarship
Authors: Flood Michael
Published: May 2011

When men participate as students in Women’s and Gender Studies (WGS) classrooms, they undergo feminist change. They adopt more progressive understandings of gender, show greater support for feminism, and increase their involvement in anti-sexist activism. Male students in WGS classrooms benefit to the same degree as female students, showing similar levels of change, although they start with poorer attitudes and thus the gap between them and their female peers persists. At the same time, male students’ presence highlights critical challenges to feminist pedagogy: gendered patterns of interaction, resistance to feminist teaching, and limitations on women’s critical reflections on personal experience. When men teach WGS, typically they are ‘‘graded up’’—evaluated by students as less biased and more competent than female professors. Male professors face distinct dilemmas in teaching about gender inequality from a position of privilege. Yet, like male students, they can adopt traitorous and antipatriarchal social locations and standpoints, developing pedagogies for and by the privileged.
Queer Intersubjectivity: Doing and Undoing Masculinity in Women’s Studies
Authors: Landreau John C.
Published: May 2011

This article uses autobiographical anecdotes to explore the attitudes, decisions, and experience of straight men in Women’s and Gender Studies (WGS) and from this perspective to reflect on the complexities and challenges of queering masculinity for them. In an attempt to focus on the intimate moments of lived gender embodiment, but also to frame a queer ethics grounded in something more tangible that a utopian call for identity disavowal, the article appeals to Jessica Benjamin’s notion of intersubjectivity to enhance the analytical and practical reach of queer theory.
Eco/feminism and rewriting the ending of feminism: From the Chipko movement to Clayoquot Sound
Authors: Moore Niamh
Published: May 2011

This article draws on research at an eco/feminist peace camp set up to facilitate blockades against clear-cut logging in coastal temperate rainforest in Clayoquot Sound on Vancouver Island, British Columbia, in Canada in the early 1990s. The camp was said to be based on feminist principles and sometimes these were even articulated as eco/feminist principles. The slippage between these terms provides a focus for my discussion. Specifically the article explores the apparent paradox of the sheer vitality of this eco/feminist activism, and in particular its insistence on international connections, in contrast to the widely circulating accounts of the end of feminism, and especially the end of global sisterhood, which emerged in the early 1990s. Thus this article is also necessarily about how recent histories of eco/feminism, including tensions between theory and activism, are narrated. I take as a departure point references to the work of Vandana Shiva and the Chipko movement which circulated in accounts of the camp, and explore ways in which eco/feminists might read such utterances as more than evidence of a naive and problematic universalism. I situate eco/feminism’s internationalism genealogically in feminism and eco/feminism and read this as a counter-narrative to the ending of global sisterhood. Through paying attention to various movements, back and forth, between Clayoquot and Chipko, Canada and India, and drawing on Anna Tsing’s notion of ‘friction’, I offer an account of what has been at stake in disavowals of the possibility of reading Chipko as eco/feminist, and suggest the importance of a more generous reading of eco/feminists’ attention to the Chipko movement.
European immigration and Continental feminism: Theories of Rosi Braidotti
Authors: Jusová Iveta
Published: May 2011

This article considers the academic writings and activism of the major Continental feminist philosopher Rosi Braidotti against the background of the growing religiously and racially biased anti-immigration sentiment in Europe. Special attention is paid to Braidotti’s recent response to the post-secular turn in feminism. The article contends that Braidotti’s work highlights and embraces the destabilising structural effects the intensified migration flows have on European identity. It argues that Braidotti charts new models of European subjectivity that would facilitate mutually affirmative and trans-formative relationships between those (self-)perceived as Western feminists and those positioned as immigrant women.
Evaluating the Usability of Personal Digital Assistants to Collect Behavioral Data on Adolescents with Paradata
Authors: McClamroch Kristi J
Published: May 2011

This article analyzes paradata, or data on survey processes, from the 2008 Albany Youth Health Survey to examine the ‘‘usability’’ of personal digital assistants (PDAs) in collecting health and behavioral information among inner-city adolescents. Two parallel sets of data analysis were conducted: one at a subject level and a second at a survey question/item level. Outcomes related to usability issues included difficulty with practice questions, time spent on the survey/item, responding before completion of the audio, and revisiting a question. Overall, participants had relatively few usability issues with the PDAs. At the subject level, participants with lower academic performance were more likely to have difficulty with practice questions, revisit a question, and take more time. The variable-level analysis showed that an increasing level of variable type complexity was negatively associated with a question being revisited and positively associated with completion time. This study suggests that PDAs and other types of handheld computers can be used to collect sensitive data among urban adolescents. Increased practice time to orient certain respondents on certain types of questions on PDA-administered surveys may increase the ability to collect valid and reliable data on sensitive topics.
Television Broadcast Demand in Markets Without Local Teams
Authors: Tainsky Scott , McEvoy Chad D.
Published: May 2011

This article uses television ratings from the 2006 and 2007 National Football League (NFL) seasons to estimate viewer demand in large markets without local teams. The factors that are found to be statistically significant and positively related determinants of television ratings are: team quality and age; the closest team in proximity to the market; late-season contests; and having teams such as the Cowboys and Patriots as participants. Concurrent game telecasts and contests involving unevenly matched teams are negatively related to viewership.
Intrathyroid Adenomas in Primary Hyperparathyroidism
Authors: Herden Uta , Seiler Christian A. , Candinas Daniel , Schmid Stefan W.
Published: May 2011

Background. Ectopic parathyroid adenoma, including intrathyroid adenoma, is a common cause of failed parathyroid operations. The aim of this study was to evaluate the operative strategy/outcome in patients with primary hyperparathyroidism (pHPT), with special regard to intrathyroid adenomas. Method. The authors performed an analysis of all patients receiving operative treatment for pHPT from 2003 through 2005. The operative strategy consisted of systematic perithyroid exploration followed by extended cervical exploration in cases where the adenoma was not found initially. In cases of persistent, high intraoperative parathyroid hormone levels, hemithyroidectomy was performed on the side with higher suspicion of intrathyroid adenoma or with more extended thyroid changes. Results. During the study, 115 patients received surgical treatment for sporadic pHPT. A single parathyroid adenoma (normal parathyroid position) was found in 95 patients (82.6%), ectopic single adenoma was found in 7 patients (6.1%), and double adenomas were found in 10 (8.7%) patients. Operative failure occurred in 3 cases (2.6%). In all, 4 of 7 ectopic single adenomas were intrathyroidal and were removed by hemithyroidectomy according to the authors’ standard protocol. Conclusion. The strategy of ( a) cervical exploration, ( b) extended cervical exploration, and ( c) hemithyroidectomy was highly successful for removing undetectable intrathyroid parathyroid adenomas during primary intervention, thereby reducing the risks associated with reintervention.
Shoplifting: Work, Agency, and Gender
Authors: Caputo Gail A. , King Anna
Published: May 2011

Often described as “pink collar,” shoplifting is crime thought to be dominated by women. While there is evidence of gender discrimination in the crime’s availability to women and that drug addiction as well as personal resources motivate individuals to choose it, the gendered nature of this work (the “how” of the work) is not further elaborated in the literature. The occupational processes of the crime have also largely been omitted from research. The goal of the article is to describe the “job” of shoplifting and how it may be “gendered” by examining the ways individual women talk about the crime.
Comparison of Masculine and Feminine Traits in a National Sample of Male and Female Nursing Students
Authors: Thompson Kenny , Glenn L. Lee , Vertein Daren
Published: May 2011

The stereotype that male nurses are less masculine has existed for generations and spans all age groups. Several studies have investigated masculinity and femininity in nurses using the Bem Sex-Role Inventory, but the results are conflicting and inconclusive. Therefore, a nationwide survey was conducted across the United States that examined the sex-role identity of individuals who chose nursing as a career path. Twenty-eight males and 81 females from 37 states completed the survey. The males and females in the study both had higher mean scores on masculinity and femininity scales when compared with previous studies. The greatest percentage of participants were classified as androgynous, as opposed to masculine, feminine, or undifferentiated, with half of the males and nearly half of the females falling into this category.
‘Don’t mess with Texas!’ Texas Virtual Border Watch Program and the (botched) politics of responsibilization
Authors: Koskela Hille
Published: May 2011

In 2008 the USA launched an interactive Internet site called Texas Virtual Border Watch Program through which the public can participate in the US border control. This paper examines the complex politics of watching and being watched in relation to this scheme, using some lines of contemporary surveillance theory as a theoretical frame. The understanding of surveillance has lately faced a fundamental change, since devices and practices which previously were available only for the authorities are ever more often accessible for anyone. The paper explores the discursive framings by which the authorities have justified the program. It brings up complex issues dealing with voluntary participation and amateur verification and discusses the politics of responsibilization that relate to the border watch program. The Texas Virtual Border Watch Program is evaluated critically also in relation to the contemporary securitization of the Other. Finally, the symbolic value of border control is highlighted and the concept of ‘patriotic voyeurism’ is brought up in order to understand the motivations of the volunteer observers.
Preventive and punitive criminal justice policy support in Trinidad: The media’s role
Authors: Surette Ray , Chadee Derek , Heath Linda , Young Jason R.
Published: May 2011

An unresolved research question regarding crime and justice policy is the relationship between an individual’s media consumption and their support for punitive and preventive criminal justice policies. The relationship between media, crime, and justice is under-examined in countries other than the United States and Britain and the relationship between media and criminal justice policy support remains less than fully understood in all locales. In response, an examination of a media— policy relationship in a Western democracy not previously studied was conducted. Based on data from an October 2005 national telephone survey of Trinidad and Tobago residents, this study measured support for punitive and preventive criminal justice policies in association with crime and justice media consumption and worldviews. Multivariate analysis showed that, for Trinidadians, support for punitive policies was significantly related to perceiving television crime dramas as realistic and crime news as accurate. For preventive policy support, the same media factors plus the level of exposure to crime dramas on television were significant. Overall, media were found to play similar but not especially strong roles in support levels for both punitive and preventive criminal justice policies.
Neo-Nazis and moral panic: The emergence of neo-Nazi youth gangs in Israel
Authors: Sela-Shayovitz Revital
Published: May 2011

The emergence of a neo-Nazi gang is an unprecedented manifestation of deviance in Israel. It has undermined the moral order and shaken the delicate nerves of Israeli society, which lives in the shadow of the Holocaust. Drawing principally on Israeli newspaper coverage, the study examines the dynamics of social discourse among policymakers, the press and pressure groups. The analysis shows that initial formulations of moral panic derived from a profound concern about changes in the social and moral order of society due to immigration. Moreover, conceptually situated within theorizations of moral risk, this moral panic was a temporary rupture in processes of moral regulation and served governing agents, which increased social control by constructing risks and dangers.
Images of torture: Culture, politics and power
Authors: Carrabine Eamonn
Published: May 2011

The digital recording of torture at Abu Ghraib has left pictures which are likely to be the defining images of the war in Iraq. This paper is an attempt to understand the images and why so many critics sought to locate the origins of the cruelty in US popular culture. Internet pornography, reality television and campus humiliation rituals are among the sources said to have inspired the brutality. While such explanations are more than plausible, they ignore the much longer history of violent representation that figures in the European classical art tradition, which all too frequently has justified imperial ambition, colonial conquest, and belief in racial superiority, while eroticizing bodies in pain. In the rush to situate the images well within the terms of a lowly popular culture a fuller understanding of their visual power is lost, as is their place in the cultural politics of torture more generally. The paper begins by outlining influential understandings of photography and atrocity images, before considering the differing explanations of the abuse. In taking a cue from recent scholarship in ‘trauma studies’, the argument is that human suffering should not be reduced to a set of aesthetic concerns, but is fundamentally bound up with the politics of testimony and memory — issues that have been pursued in some of the images produced after Abu Ghraib and which are discussed in the final section of the paper.
ERG promotes T-acute lymphoblastic leukemia and is transcriptionally regulated in leukemic cells by a stem cell enhancer
Authors: Thoms Julie A. I. , Birger Yehudit , Foster Sam , Knezevic Kathy , Kirschenbaum Yael , Chandrakanthan Vashe , Jonquieres Georg , Spensberger Dominik , Wong Jason W. , Oram S. Helen , Kinston Sarah J. , Groner Yoram , Lock Richard , MacKenzie Karen L. , Göttgens Berthold , Izraeli Shai , Pimanda John E.
Published: May 2011

The Ets-related gene (ERG) is an Ets-transcription factor required for normal blood stem cell development. ERG expression is down-regulated during early T-lymphopoiesis but maintained in T-acute lymphoblastic leukemia (T-ALL), where it is recognized as an independent risk factor for adverse outcome. However, it is unclear whether ERG is directly involved in the pathogenesis of T-ALL and how its expression is regulated. Here we demonstrate that transgenic expression of ERG causes T-ALL in mice and that its knockdown reduces the proliferation of human MOLT4 T-ALL cells. We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. This enhancer is not active in normal T cells but in transgenic mice targets expression to fetal liver c-kit+ cells, adult bone marrow stem/progenitors and early CD4−CD8− double-negative thymic progenitors. Taken together, these data illustrate that ERG promotes T-ALL and that failure to extinguish activity of stem cell enhancers associated with regulatory transcription factors such as ERG can contribute to the development of leukemia.
Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score
Authors: Hasford Joerg , Baccarani Michele , Hoffmann Verena , Guilhot Joelle , Saussele Susanne , Rosti Gianantonio , Guilhot François , Porkka Kimmo , Ossenkoppele Gert , Lindoerfer Doris , Simonsson Bengt , Pfirrmann Markus , Hehlmann Rudiger
Published: May 2011

The outcome of chronic myeloid leukemia (CML) has been profoundly changed by the introduction of tyrosine kinase inhibitors into therapy, but the prognosis of patients with CML is still evaluated using prognostic scores developed in the chemotherapy and interferon era. The present work describes a new prognostic score that is superior to the Sokal and Euro scores both in its prognostic ability and in its simplicity. The predictive power of the score was developed and tested on a group of patients selected from a registry of 2060 patients enrolled in studies of first-line treatment with imatinib-based regimes. The EUTOS score using the percentage of basophils and spleen size best discriminated between high-risk and low-risk groups of patients, with a positive predictive value of not reaching a CCgR of 34%. Five-year progression-free survival was significantly better in the low- than in the high-risk group (90% vs 82%, P = .006). These results were confirmed in the validation sample. The score can be used to identify CML patients with significantly lower probabilities of responding to therapy and survival, thus alerting physicians to those patients who require closer observation and early intervention.
Genome-wide analysis of the mouse lung transcriptome reveals novel molecular gene interaction networks and cell-specific expression signatures
Authors: Alberts Rudi , Lu Lu , Williams Robert W , Schughart Klaus
Published: May 2011

Background

The lung is critical in surveillance and initial defense against pathogens. In humans, as in mice, individual genetic differences strongly modulate pulmonary responses to infectious agents, severity of lung disease, and potential allergic reactions. In a first step towards understanding genetic predisposition and pulmonary molecular networks that underlie individual differences in disease vulnerability, we performed a global analysis of normative lung gene expression levels in inbred mouse strains and a large family of BXD strains that are widely used for systems genetics. Our goal is to provide a key community resource on the genetics of the normative lung transcriptome that can serve as a foundation for experimental analysis and allow predicting genetic predisposition and response to pathogens, allergens, and xenobiotics.

Methods

Steady-state polyA+ mRNA levels were assayed across a diverse and fully genotyped panel of 57 isogenic strains using the Affymetrix M430 2.0 array. Correlations of expression levels between genes were determined. Global expression QTL (eQTL) analysis and network covariance analysis was performed using tools and resources in GeneNetwork http://www.genenetwork.org.

Results

Expression values were highly variable across strains and in many cases exhibited a high heri-tability factor. Several genes which showed a restricted expression to lung tissue were identified. Using correlations between gene expression values across all strains, we defined and extended memberships of several important molecular networks in the lung. Furthermore, we were able to extract signatures of immune cell subpopulations and characterize co-variation and shared genetic modulation. Known QTL regions for respiratory infection susceptibility were investigated and several cis-eQTL genes were identified. Numerous cis- and trans-regulated transcripts and chromosomal intervals with strong regulatory activity were mapped. The Cyp1a1 P450 transcript had a strong trans-acting eQTL (LOD 11.8) on Chr 12 at 36 ± 1 Mb. This interval contains the transcription factor Ahr that has a critical mis-sense allele in the DBA/2J haplotype and evidently modulates transcriptional activation by AhR.

Conclusions

Large-scale gene expression analyses in genetic reference populations revealed lung-specific and immune-cell gene expression profiles and suggested specific gene regulatory interactions.
Enhancement of CURB65 score with proadrenomedullin (CURB65-A) for outcome prediction in lower respiratory tract infections: Derivation of a clinical algorithm
Authors: Albrich Werner C , Dusemund Frank , Rüegger Kristina , Christ-Crain Mirjam , Zimmerli Werner , Bregenzer Thomas , Irani Sarosh , Buergi Ulrich , Reutlinger Barbara , Mueller Beat , Schuetz Philipp
Published: May 2011

Background

Proadrenomedullin (ProADM) confers additional prognostic information to established clinical risk scores in lower respiratory tract infections (LRTI). We aimed to derive a practical algorithm combining the CURB65 score with ProADM-levels in patients with community-acquired pneumonia (CAP) and non-CAP-LRTI.

Methods

We used data of 1359 patients with LRTI enrolled in a multicenter study. We chose two ProADM cut-off values by assessing the association between ProADM levels and the risk of adverse events and mortality. A composite score (CURB65-A) was created combining CURB65 classes with ProADM cut-offs to further risk-stratify patients.

Results

CURB65 and ProADM predicted both adverse events and mortality similarly well in CAP and non-CAP-LRTI. The combined CURB65-A risk score provided better prediction of death and adverse events than the CURB65 score in the entire cohort and in CAP and non-CAP-LRTI patients. Within each CURB65 class, higher ProADM-levels were associated with an increased risk of adverse events and mortality. Overall, risk of adverse events (3.9%) and mortality (0.65%) was low for patients with CURB65 score 0-1 and ProADM ≤0.75 nmol/l (CURB65-A risk class I); intermediate (8.6% and 2.6%, respectively) for patients with CURB65 score of 2 and ProADM ≤1.5 nmol/l or CURB classes 0-1 and ProADM levels between 0.75-1.5 nmol/L (CURB65-A risk class II), and high (21.6% and 9.8%, respectively) for all other patients (CURB65-A risk class III). If outpatient treatment was recommended for CURB65-A risk class I and short hospitalization for CURB65-A risk class II, 17.9% and 40.8% of 1217 hospitalized patients could have received ambulatory treatment or a short hospitalization, respectively.

Conclusions

The new CURB65-A risk score combining CURB65 risk classes with ProADM cut-off values accurately predicts adverse events and mortality in patients with CAP and non-CAP-LRTI. Additional prospective cohort or intervention studies need to validate this score and demonstrate its safety and efficacy for the management of patients with LRTI.

Trial Registration

Procalcitonin-guided antibiotic therapy and hospitalisation in patients with lower respiratory tract infections: the prohosp study; isrctn.org Identifier: ISRCTN: ISRCTN95122877
Luminal and basal-like breast cancer cells show increased migration induced by hypoxia, mediated by an autocrine mechanism
Authors: Voss Melanie J , Möller Mischa F , Powe Desmond G , Niggemann Bernd , Zänker Kurt S , Entschladen Frank
Published: May 2011

Background

Some breast cancer patients receiving anti-angiogenic treatment show increased metastases, possibly as a result of induced hypoxia. The effect of hypoxia on tumor cell migration was assessed in selected luminal, post-EMT and basal-like breast carcinoma cell lines.

Methods

Migration was assessed in luminal (MCF-7), post-EMT (MDA-MB-231, MDA-MB-435S), and basal-like (MDA-MB-468) human breast carcinoma cell lines under normal and oxygen-deprived conditions, using a collagen-based assay. Cell proliferation was determined, secreted cytokine and chemokine levels were measured using flow-cytometry and a bead-based immunoassay, and the hypoxic genes HIF-1α and CA IX were assessed using PCR. The functional effect of tumor-cell conditioned medium on the migration of neutrophil granulocytes (NG) was tested.

Results

Hypoxia caused increased migratory activity but not proliferation in all tumor cell lines, involving the release and autocrine action of soluble mediators. Conditioned medium (CM) from hypoxic cells induced migration in normoxic cells. Hypoxia changed the profile of released inflammatory mediators according to cell type. Interleukin-8 was produced only by post-EMT and basal-like cell lines, regardless of hypoxia. MCP-1 was produced by MDA-MB-435 and -468 cells, whereas IL-6 was present only in MDA-MB-231. IL-2, TNF-α, and NGF production was stimulated by hypoxia in MCF-7 cells. CM from normoxic and hypoxic MDA-MB-231 and MDA-MB-435S cells and hypoxic MCF-7 cells, but not MDA-MB-468, induced NG migration.

Conclusions

Hypoxia increases migration by the autocrine action of released signal substances in selected luminal and basal-like breast carcinoma cell lines which might explain why anti-angiogenic treatment can worsen clinical outcome in some patients.
Antigenic repertoire of Plasmodium vivax transmission-blocking vaccine candidates from the Indian subcontinent
Authors: Prajapati Surendra K , Joshi Hema , Dua Virendra K
Published: May 2011

Background

Genetic polymorphism is an inevitable component of a multistage infectious organism, such as the malaria parasite. By means of genetic polymorphism, parasite opts particular polymorph and reveals survival advantage. Pvs25 and pvs28 are sexual stage antigen genes, expressed at the ookinete stage inside the mosquito gut, and considered as potential transmission-blocking vaccine candidates. This study presents sequence variations in two important transmission blocking antigen genes pvs25 and pvs28 in the field isolates of P. vivax from the Indian subcontinent.

Methods

One hundred microscopically diagnosed P. vivax isolates were collected from five geographical regions of India. Pvs25 and pvs28 genes were PCR amplified and sequenced to assess sequence variation among field isolates.

Results

A total of 26 amino acid substitutions were observed in Pvs25 (10) and Pvs28 (16) among field isolates of P. vivax. Tandem repeat polymorphism observed in pvs28 shows 3-6 tandem repeats in the field isolates. Seven and eight novel amino acid substitutions were observed in Pvs25 and Pvs28, respectively in Indian isolates. Comparison of amino acid substitutions suggests that majority of substitutions observed in global isolates were also present in Indian subcontinent. A single haplotype was observed to be major haplotype among isolates of Delhi, Nadiad, Chennai and Panna except in isolates of Kamrup. Further, population comparison analyses suggest that P. vivax isolates inhabiting in north-eastern region (Kamrup) were distantly related with the isolates from remaining parts of the country. Majority of the amino acid substitutions observed in Indian isolates were more identical to the substitutions reported from isolates of Thailand and Bangladesh.

Conclusion

Study uncovered many new amino acid substitutions as well as a predominance of single haplotype in Indian subcontinent except in north-eastern region of the country. The amino acid substitutions data generated in this study from different geographical regions of the Indian subcontinent could be helpful in designing a more effective anti-malarial transmission-blocking vaccine.
MDM2 antagonists boost antitumor effect of androgen withdrawal: implications for therapy of prostate cancer
Authors: Tovar Christian , Higgins Brian , Kolinsky Kenneth , Xia Mingxuan , Packman Kathryn , Heimbrook David C , Vassilev Lyubomir T
Published: May 2011

Background

Hormone therapy is the standard of care for newly diagnosed or recurrent prostate cancers. It uses anti-androgen agents, castration, or both to eliminate cancer promoting effect of testicular androgen. The p53 tumor suppressor controls a major pathway that can block cell proliferation or induce apoptosis in response to diverse forms of oncogenic stress. Activation of the p53 pathway in cancer cells expressing wild-type p53 has been proposed as a novel therapeutic strategy and recently developed MDM2 antagonists, the nutlins, have validated this in preclinical models of cancer. The crosstalk between p53 and androgen receptor (AR) signaling suggest that p53 activation could augment antitumor outcome of androgen ablation in prostate cancer. Here, we test this hypothesis in vitro and in vivo using the MDM2 antagonist, nutlin-3 and the p53 wild-type prostate cancer cell line, LNCaP.

Results

Using charcoal-stripped serum as a cellular model of androgen deprivation, we show an increased apoptotic effect of p53 activation by nutlin-3a in the androgen-dependent LNCaP cells and to a lesser extent in androgen-independent but responsive 22Rv1 cell line. This effect is due, at least in part, to an enhanced downregulation of AR expression by activated p53. In vivo, androgen deprivation followed by two weeks of nutlin administration in LNCaP-bearing nude mice led to a greater tumor regression and dramatically increased survival.

Conclusions

Since majority of prostate tumors express wild-type p53, its activation by MDM2 antagonists in combination with androgen depletion may offer an efficacious new approach to prostate cancer therapy.
Should Global Burden of Disease Estimates Include Depression as a Risk Factor for Coronary Heart Disease?
Authors: Charlson Fiona J , Stapelberg Nicholas JC , Baxter Amanda J , Whiteford Harvey A
Published: May 2011

The 2010 Global Burden of Disease Study estimates the premature mortality and disability of all major diseases and injuries. In addition it aims to quantify the risk that diseases and other factors play in the aetiology of disease and injuries. Mental disorders and coronary heart disease are both significant public health issues due to their high prevalence and considerable contribution to global disease burden. For the first time the Global Burden of Disease Study will aim to assess mental disorders as risk factors for coronary heart disease. We show here that current evidence satisfies established criteria for considering depression as an independent risk factor in development of coronary heart disease. A dose response relationship appears to exist and plausible biological pathways have been proposed. However, a number of challenges exist when conducting a rigorous assessment of the literature including heterogeneity issues, definition and measurement of depression and coronary heart disease, publication bias and residual confounding. Therefore, despite some limitations in the available data, it is now appropriate to consider major depression as a risk factor for coronary heart disease in the new Global Burden of Disease Study.
Antiviral activity of α-helical stapled peptides designed from the HIV-1 capsid dimerization domain
Authors: Zhang Hongtao , Curreli Francesca , Zhang Xihui , Bhattacharya Shibani , Waheed Abdul A , Cooper Alan , Cowburn David , Freed Eric O , Debnath Asim K
Published: May 2011

Background

The C-terminal domain (CTD) of HIV-1 capsid (CA), like full-length CA, forms dimers in solution and CTD dimerization is a major driving force in Gag assembly and maturation. Mutations of the residues at the CTD dimer interface impair virus assembly and render the virus non-infectious. Therefore, the CTD represents a potential target for designing anti-HIV-1 drugs.

Results

Due to the pivotal role of the dimer interface, we reasoned that peptides from the α-helical region of the dimer interface might be effective as decoys to prevent CTD dimer formation. However, these small peptides do not have any structure in solution and they do not penetrate cells. Therefore, we used the hydrocarbon stapling technique to stabilize the α-helical structure and confirmed by confocal microscopy that this modification also made these peptides cell-penetrating. We also confirmed by using isothermal titration calorimetry (ITC), sedimentation equilibrium and NMR that these peptides indeed disrupt dimer formation. In in vitro assembly assays, the peptides inhibited mature-like virus particle formation and specifically inhibited HIV-1 production in cell-based assays. These peptides also showed potent antiviral activity against a large panel of laboratory-adapted and primary isolates, including viral strains resistant to inhibitors of reverse transcriptase and protease.

Conclusions

These preliminary data serve as the foundation for designing small, stable, α-helical peptides and small-molecule inhibitors targeted against the CTD dimer interface. The observation that relatively weak CA binders, such as NYAD-201 and NYAD-202, showed specificity and are able to disrupt the CTD dimer is encouraging for further exploration of a much broader class of antiviral compounds targeting CA. We cannot exclude the possibility that the CA-based peptides described here could elicit additional effects on virus replication not directly linked to their ability to bind CA-CTD.
Inhibition of full length Hepatitis C Virus particles of 1a genotype through small interference RNA
Authors: Ansar Muhammad , Ashfaq Usman Ali , shahid Imran , Sarwar Muhammad Tahir , Javed Tariq , Rehman Sidra , Hassan Sajida , Riazuddin Sheikh
Published: May 2011

Background

Hepatitis C virus (HCV), a member of the Flaviviridae family of viruses, is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Currently, the only treatment available consists of a combination of Pegylated interferon alpha (INF-α) and ribavirin, but only half of the patients treated show a sufficient antiviral response. Thus there is a great need for the development of new treatments for HCV infections. RNA interference (RNAi) represents a new promising approach to develop effective antiviral drugs and has been extremely effective against HCV infection.

Results

This study was design to assess or explore the silencing effect of small interference RNAs (siRNAs) against full length HCV particles of genotype 1a. In the present study six 21-bp siRNAs were designed against different regions of HCV structural genes (Core, E1 and E2). Selected siRNAs were labeled as Csi 301, Csi 29, E1si 52, E1si 192, E2si 86 and E2si 493. Our results demonstrated that siRNAs directed against HCV core gene showed 70% reduction in viral titer in HCV infected liver cells. Moreover, siRNAs against E1 and E2 envelop genes showed a dramatic reduction in HCV viral RNA, E2si 86 exhibited 93% inhibition, while E1si 192, E2si 493 and E1si 52 showed 87%, 80%, and 66% inhibition respectively. No significant inhibition was detected in cells transfected with the negative control siRNA.

Conclusion

Our results suggested that siRNAs targeted against HCV structural genes efficiently silence full length HCV particles and provide an effective therapeutic option against HCV infection.
Primary osteosarcoma of bladder diverticulum mimicking intradiverticular calculus: a case report
Authors: Grubišić Igor , Leniček Tanja , Tomas Davor , Džombeta Tihana , Trnski Davor , Tomašković Igor , Krušlin Božo
Published: May 2011

There is a well-documented relationship between urinary bladder diverticula and intradiverticular neoplasms. The great majorities of these tumors are urothelial carcinomas, but may also be of glandular or squamous type. Sarcomas occurring within bladder diverticula are exceptionally rare and highly malignant lesions, with only 20 well documented cases published in the literature to date (including carcinosarcomas). We report a case of osteosarcoma of the bladder diverticulum in a 68-year old man, which clinically mimicked intradiverticular calculus. To our knowledge, this is the second case described in the literature to date, and the first in English literature.

Virtual Slides

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5205089355246060.
Prospero and Pax2 combinatorially control neural cell fate decisions by modulating Ras- and Notch-dependent signaling
Authors: Charlton-Perkins Mark , Whitaker S Leigh , Fei Yueyang , Xie Baotong , Li-Kroeger David , Gebelein Brian , Cook Tiffany
Published: May 2011

Background

The concept of an equivalence group, a cluster of cells with equal potential to adopt the same specific fate, has served as a useful paradigm to understand neural cell type specification. In the Drosophila eye, a set of five cells, called the 'R7 equivalence group', generates a single photoreceptor neuron and four lens-secreting epithelial cells. This choice between neuronal versus non-neuronal cell fates rests on differential requirements for, and cross-talk between, Notch/Delta- and Ras/mitogen-activated protein kinase (MAPK)-dependent signaling pathways. However, many questions remain unanswered related to how downstream events of these two signaling pathways mediate distinct cell fate decisions.

Results

Here, we demonstrate that two direct downstream targets of Ras and Notch signaling, the transcription factors Prospero and dPax2, are essential regulators of neuronal versus non-neuronal cell fate decisions in the R7 equivalence group. Prospero controls high activated MAPK levels required for neuronal fate, whereas dPax2 represses Delta expression to prevent neuronal fate. Importantly, activity from both factors is required for proper cell fate decisions to occur.

Conclusions

These data demonstrate that Ras and Notch signaling are integrated during cell fate decisions within the R7 equivalence group through the combinatorial and opposing activities of Pros and dPax2. Our study provides one of the first examples of how the differential expression and synergistic roles of two independent transcription factors determine cell fate within an equivalence group. Since the integration of Ras and Notch signaling is associated with many developmental and cancer models, these findings should provide new insights into how cell specificity is achieved by ubiquitously used signaling pathways in diverse biological contexts.
Formation of VEGF isoform-specific spatial distributions governing angiogenesis: computational analysis
Authors: Vempati Prakash , Popel Aleksander S , Mac Gabhann Feilim
Published: May 2011

Background

The spatial distribution of vascular endothelial growth factor A (VEGF) is an important mediator of vascular patterning. Previous experimental studies in the mouse hindbrain and retina have suggested that VEGF alternative splicing, which controls the ability of VEGF to bind to heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM), plays a key role in controlling VEGF diffusion and gradients in tissues. Conversely, proteolysis notably by matrix metalloproteinases (MMPs), plays a critical role in pathological situations by releasing matrix-sequestered VEGF and modulating angiogenesis. However, computational models have predicted that HSPG binding alone does not affect VEGF localization or gradients at steady state.

Results

Using a 3D molecular-detailed reaction-diffusion model of VEGF ligand-receptor kinetics and transport, we test alternate models of VEGF transport in the extracellular environment surrounding an endothelial sprout. We show that differences in localization between VEGF isoforms, as observed experimentally in the mouse hindbrain, as well as the ability of proteases to redistribute VEGF in pathological situations, are consistent with a model where VEGF is endogenously cleared or degraded in an isoform-specific manner. We use our predictions of the VEGF distribution to quantify a tip cell's receptor binding and gradient sensing capacity. A novel prediction is that neuropilin-1, despite functioning as a coreceptor to VEGF165-VEGFR2 binding, reduces the ability of a cell to gauge the relative steepness of the VEGF distribution. Comparing our model to available in vivo vascular patterning data suggests that vascular phenotypes are most consistently predicted at short range by the soluble fraction of the VEGF distributions, or at longer range by matrix-bound VEGF detected in a filopodia-dependent manner.

Conclusions

Isoform-specific VEGF degradation provides a possible explanation for numerous examples of isoform specificity in VEGF patterning and examples of proteases relocation of VEGF upon release.
Effect of Luteinizing Hormone–Releasing Hormone Agonist on Ovarian Function After Modern Adjuvant Breast Cancer Chemotherapy: The GBG 37 ZORO Study
Authors: Gerber Bernd , von Minckwitz Gunter , Stehle Heinrich , Reimer Toralf , Felberbaum Ricardo , Maass Nikolai , Fischer Dorothea , Sommer Harald L. , Conrad Bettina , Ortmann Olaf , Fehm Tanja , Rezai Mahdi , Mehta Keyur , Loibl Sibylle
Published: May 2011

Purpose

Observational studies suggested that luteinizing hormone–releasing hormone agonists (LHRHa) might prevent premature ovarian failure resulting from adjuvant chemotherapy in premenopausal patients. We aimed to test the efficacy of ovarian function preservation with the LHRHa goserelin in patients with breast cancer.

Patients and Methods

In a prospective, randomized, open-label, controlled multicenter study, 60 patients younger than age 46 years with hormone-insensitive breast cancer were allocated to receive anthracycline/cyclophosphamide (with or without taxane) –based neoadjuvant chemotherapy with or without goserelin. The first goserelin injection was administered at least 2 weeks before the first chemotherapy cycle, continuing at 3.6 mg subcutaneously every 4 weeks until the end of the last cycle. The primary objective was the reappearance of normal ovarian function, defined as two consecutive menstrual periods within 21 to 35 days at 6 months after end of chemotherapy.

Results

Fifty-three patients (88.3%) experienced temporary amenorrhea (93.3% with v 83.3% without goserelin). No significant difference was observed regarding the reappearance of menstruation at 6 months after chemotherapy (70.0% with v 56.7% without goserelin; difference of 13.3%; 95% CI, −10.85 to 37.45; P = .284). All but one evaluable patient reported regular menses at 2 years after chemotherapy. Time to restoration of menstruation was 6.8 months (95% CI, 5.2 to 8.4) with goserelin and 6.1 months (95% CI, 5.3 to 6.8) without goserelin (P = .304). Chemotherapy resulted in a decreased ovarian reserve measured by inhibin B and anti-Müllerian hormone during follow-up, supporting the other findings.

Conclusion

Premenopausal patients with breast cancer receiving goserelin simultaneously with modern neoadjuvant chemotherapy did not experience statistically significantly less amenorrhea 6 months after end of chemotherapy compared with those receiving chemotherapy alone.