bluuebunny/crossref_metadata_2025 huggingface dataset:
A Systematic Community-Based Participatory Approach to Refining an Evidence-Based Community-Level Intervention
Authors: Rhodes Scott D. , Daniel Jason , Alonzo Jorge , Duck Stacy , García Manuel , Downs Mario , Hergenrather Kenneth C. , Alegría-Ortega José , Miller Cindy , Boeving Allen Alex , Gilbert Paul A. , Marsiglia Flavio F.
Published: October 2012

Our community-based participatory research partnership engaged in a multistep process to refine a culturally congruent intervention that builds on existing community strengths to promote sexual health among immigrant Latino men who have sex with men (MSM). The steps were the following: (1) increase Latino MSM participation in the existing partnership, (2) establish an Intervention Team, (3) review the existing sexual health literature, (4) explore needs and priorities of Latino MSM, (5) narrow priorities based on what is important and changeable, (6) blend health behavior theory with Latino MSM’s lived experiences, (7) design an intervention conceptual model, (8) develop training modules and (9) resource materials, and (10) pretest and (11) revise the intervention. The developed intervention contains four modules to train Latino MSM to serve as lay health advisors known as Navegantes. These modules synthesize locally collected data with other local and national data; blend health behavior theory, the lived experiences, and cultural values of immigrant Latino MSM; and harness the informal social support Latino MSM provide one another. This community-level intervention is designed to meet the expressed sexual health priorities of Latino MSM. It frames disease prevention within sexual health promotion.
Predictors of Clinically Significant Weight Loss and Participant Retention in an Insurance-Sponsored Community-Based Weight Management Program
Authors: Abildso Christiaan G. , Zizzi Sam , Fitzpatrick Sean J.
Published: October 2012

Health insurance providers are a logical partner in providing third-party payment for behavioral weight loss programming, but little evidence of predictors of improved outcomes or retention in large, insurance-sponsored lifestyle programming is available. The purpose was to determine predictors of weight loss and retention in an insurance-sponsored, community-based weight management program. Current and former participants ( N = 2,106) were recruited to complete a program evaluation survey. Respondents’ survey and objective outcome data ( n = 766) were analyzed using logistic regression procedures to understand the factors predictive of clinically-significant (5%) weight loss and program retention (>6 months). Clinically significant weight loss was predicted by completing more than 6 months of the program, positive ratings of staff interaction, and social support from friends on success. Ratings of positive impact of site hours of operation, nurse calls, and availability of safe places to be active and feeling comfortable at the site were predictive of program retention. Modifiable intervention, social factors, and site-level factors were predictive of clinically significant weight loss and program retention, providing fodder for further study and dissemination to current providers and to a broader network of health promotion professionals.
Advanced (Measurement) Applications of Curriculum-Based Measurement in Reading
Authors: Petscher Yaacov , Cummings Kelli Dawn , Biancarosa Gina , Fien Hank
Published: October 2012

The purpose of this article is to provide a commentary on the current state of several measurement issues pertaining to curriculum-based measures of reading (R-CBM1). We begin by providing an overview of the utility of R-CBM, followed by a presentation of five specific measurements considerations: (a) the reliability of R-CBM oral reading fluency (ORF), (b) issues pertaining to form effects, (c) the generalizability of scores from R-CBM, (d) measurement error, and (e) linearity of growth in R-CBM. We then conclude with a presentation of the purpose for this issue and broadly introduce the articles in the special issue. Because ORF is one of the most common measures of R-CBM, much of the review is focused on this particular type of assessment; however, the issues presented extend to other assessments of R-CBM.
An Adaptation of the Coping Cat Program
Authors: Michael Kurt D. , Payne Lucinda O. , Albright Abby E.
Published: October 2012

Generalized anxiety disorder (GAD) during childhood is a common condition with negative implications. This case study describes the successful cognitive-behavioral treatment of a 6-year-old boy with excessive worry and sleep disturbances. Because of the patient’s age, treatment methods were adapted for an early reader. The frequency and intensity of his symptoms (e.g., physiologic arousal, apprehensive expectations, sleep disturbances) were measured over the course of treatment and at 3 and 7 years after treatment. Recommendations are provided for clinicians and students who aim to treat young children with GAD. The results of this intervention suggest a durable and meaningful reduction in GAD-related symptoms.
Metric driven mobility modeling in tactical networks
Authors: Ray Sucharita , La Porta Thomas , Basu Prithwish , Cao Guohong , Shaffer Scott , Dent Dave
Published: October 2012

Mobility management is a key aspect of designing and evaluating protocols for Mobile Ad Hoc Networks (MANETs). The high mobility of nodes in a MANET constantly causes the network topology to change. Mobility patterns of nodes have a direct effect on fundamental network characteristics, such as path length, neighborhood size, and link stability. Consequently, the network performance is strongly affected by the nature of mobility patterns. While evaluating protocols for a specific MANET application, it becomes imperative to use a mobility model that is able to capture the movement of nodes in an accurate manner. The objective of this work is to produce mobility models that are able to describe tactical mobility in military applications of MANETs. We provide models of four tactical scenarios, show that these models are accurate compared to synthetic traces, and that when used to evaluate network protocols, they provide different conclusions than when using generic mobility models.
Comparative Assessment of 3D Surface Scanning Systems in Breast Plastic and Reconstructive Surgery
Authors: Patete Paolo , Eder Maximilian , Raith Stefan , Volf Alexander , Kovacs Laszlo , Baroni Guido
Published: October 2012

In this work, we compared accuracy, repeatability, and usability in breast surface imaging of 2 commercial surface scanning systems and a hand-held laser surface scanner prototype coupled with a patient’s motion acquisition and compensation methodology. The accuracy of the scanners was assessed on an anthropomorphic phantom, and to evaluate the usability of the scanners on humans, thorax surface images of 3 volunteers were acquired. Both the intrascanner repeatability and the interscanner comparative accuracy were assessed. The results showed surface-to-surface distance errors inferior to 1 mm and to 2 mm, respectively, for the 2 commercial scanners and for the prototypical one. Moreover, comparable performances of the 3 scanners were found when used for acquiring the breast surface. On the whole, this study demonstrated that handheld laser surface scanners coupled with subject motion compensation methods lend themselves as competitive technologies for human body surface modeling.
A Meta-analysis Comparing Lightweight Meshes With Heavyweight Meshes in Lichtenstein Inguinal Hernia Repair
Authors: Zhong Chunlin , Wu Bo , Yang Zhili , Deng Xianzhao , Kang Jie , Guo Bomin , Fan Youben
Published: October 2012

Background. To evaluate the influence of lightweight and heavyweight mesh on postoperative recovery in Lichtenstein inguinal hernia repair. Methods. PubMed, EMBASE, and the Cochrane library were used to search for published clinical randomized controlled trials (RCTs), which compared lightweight meshes with heavyweight meshes in Lichtenstein inguinal hernia repair. Two independent reviewers assessed the trials for eligibility and quality, and all the related data matching our standards were abstracted for meta-analysis by RevMan 5.0 software. The evaluation criteria included recurrence, pain, seroma, hematoma, the sensation of a foreign body, wound infection, urine retention, and testicular atrophy. Results. A total of 2231 hernias from 11 RCTs were included. Compared with a heavyweight polypropylene mesh, the lightweight mesh led to less postoperative chronic pain (odds ratio [OR] = 0.64, 95% confidence interval (CI) = 0.51-0.82; P < .05) and less sensation of a foreign body (OR = 0.56; 95% CI = 0.40-0.78; P < .05), regardless of whether the mesh was made of partially absorbable or nonabsorbable material. There was no significant difference in postoperative recurrence, seroma, hematoma, wound infection, urine retention, and testicular atrophy. Conclusion. Current evidence suggests that the use of a lightweight mesh is associated with less postoperative pain and less sensation of a foreign body, without increasing the incidence of recurrence. Further high-quality, long-term follow-up RCTs are needed to provide more reliable evidence.
Moving Beyond the Prostate
Authors: Wenger Lisa M. , Oliffe John L.
Published: October 2012

As researchers recognize the value in considering gender dynamics within the cancer experience, a majority of the masculinities work has centered on men with prostate cancer. This focus has positioned prostate cancer as the flagship of men’s cancer (and perhaps men’s health). There is value in this research. However, as 78% of men experience cancers of a different type, a narrow focus on prostate cancer does not necessarily account for broader intersections of cancer and masculinity. Argued here are the benefits to expanding the focus of research on men’s cancer experiences. As researchers consider patterns and diversities among men managing an array of cancers, there is opportunity to broaden understanding of the challenges “cancer” can present for men, disrupt assumptions that the study of men’s gendered experience of cancer must be tethered to male sex–specific biology, and enhance the relevance and impact of psychosocial interventions for men living with cancer.
Privacy and Democracy: What the Secret Ballot Reveals
Authors: Lever Annabelle
Published: October 2012

Does the rejection of pure proceduralism show that we should adopt Brettschneider’s value theory of democracy? The answer, this article suggests, is “no.” There are a potentially infinite number of incompatible ways to understand democracy, of which the value theory is, at best, only one. The article illustrates and substantiates its claims by looking at what the secret ballot shows us about the importance of privacy and democracy. Drawing on the reasons to reject Mill’s arguments for open voting, in a previous article by A. Lever, it argues that people’s claims to privacy have a constitutive, as well as an instrumental, importance to democratic government, which is best seen by attending to democracy as a practice, and not merely as a distinctive set of values.
On the Co-originality of Liberalism and Democracy: Rationalist vs. Paradoxicalist Perspectives
Authors: Green Jeffrey Edward
Published: October 2012

When the commitment to liberal rights conflicts with the commitment to democratic procedures, which side ought to prevail? Whereas rights foundationalists hold that rights trump procedures and democratic positivists hold that procedures trump rights, theorists of co-originality affirm both rights and procedures as coeval, equally valid commitments within a liberal democracy. But the notion of co-originality itself can be interpreted in two different ways: either in a rationalist form (as the idea that rights and procedures can be reconciled, so that those rights which limit democratic majorities are understood as being required by the very meaning of democracy itself) or in a paradoxicalist form (as the idea that rights and procedures do inescapably conflict, with neither side having primacy, but such conflicts are understood as conducive to salutary democratic goods like diversity and ongoing activism). Taking Corey Brettschneider and Chantal Mouffe as key exponents of the rationalist and paradoxicalist forms of co-originality, respectively, this article examines how these two renderings of co-originality ought to be understood in relation to each other. After elaborating the implicit critique each account makes of the other, my ultimate point is that one should understand Brettschneider and Mouffe’s alternate forms of co-originality as themselves being co-original. On the one hand, I demonstrate how Brettschneider’s rationalism and Mouffe’s paradoxicalism remain in permanent tension, with each side opposed to – yet nonetheless unable to dispense with – the other. On the other hand, I show how their two divergent notions of co-originality, when viewed not in abstract terms as rival political epistemologies but as practical guides for how actual citizens ought to operate within liberal democracies, can work in tandem with each other without necessarily involving direct conflict.
Revolution and Reform in Elizabeth Gaskell’s Fiction
Authors: Frank Cathrine O.
Published: October 2012

This article provides a reading of Elizabeth Gaskell’s social novel North and South and later historical fiction in the context of nineteenth-century debates about individual liberty and the authority of the state. Focused on the novel’s depiction of modes of dissent and the significance of Gaskell’s turn from contemporary to historical subjects, the article concludes with a reflection on the encounter with history and literature as imaginative and transformative experiences.
Use of the Kolmogorov–Smirnov test for gamma process
Authors: Grall-Maës Edith
Published: October 2012

This article deals with the use of the Kolmogorov–Smirnov test for comparing an observed gamma process with a reference process or for comparing two observed gamma processes. In the case of observed processes with periodic inspections, the Kolmogorov–Smirnov test can be applied directly. It is pointed out that, from the power of test point of view, the length of monitoring is more important than the number of observations. In the case of observed processes with aperiodic inspections, a method for building an empirical cumulative distribution required for the test is proposed. It consists of generating equal time increment observations from the original sample thanks to the gamma bridge. A sort of the original observations for improving the power of the test is proposed. Simulations have proved the feasibility of the approach and shown that when the variance of the time increments increases, the power of the test decreases only a little. An illustrative example showing the interest of such a test for maintenance is described.
Uncertainty assessment of reliability estimates for safety-instrumented systems
Authors: Jin Hui , Lundteigen Mary Ann , Rausand Marvin
Published: October 2012

Reliability estimates play a crucial role in decision making related to the design and operation of safety-instrumented systems. A safety-instrumented system is often a complex system whose performance is seldom fully understood. The safety-instrumented system reliability estimation is influenced by several simplifications and assumptions, both about the safety-instrumented system and its operating context, and therefore subject to uncertainty. If the decision makers are not aware of the level of uncertainty, they may misinterpret the results and select a safety-instrumented system design that is either too complex or too simple, or with an inadequate testing strategy, to provide the required risk reduction. This article elucidates the uncertainties related to safety-instrumented system reliability estimation. The article is limited to safety-instrumented systems that are operated in a low-demand mode, for which the probability of failure on demand is the standard reliability measure. The uncertainty of the probability of failure on demand estimate is classified as completeness uncertainty, model uncertainty, and parameter uncertainty and each category is thoroughly discussed. It is argued that the completeness uncertainty is the most important for safety-instrumented system reliability analyses, followed by parameter and model uncertainty. It is further argued that uncertainty assessment should be an integrated part of any safety-instrumented system reliability analysis, and that the analyst should communicate her judgment about the uncertainty to the decision-makers as part of the analysis results.
Magnetic Resonance Imaging as a Predictor of Return to Play Following Syndesmosis (High) Ankle Sprains in Professional Football Players
Authors: Howard Daniel R. , Rubin David A. , Hillen Travis J. , Nissman Daniel B. , Lomax James , Williams Tyler , Scott Reggie , Cunningham Byron , Matava Matthew J.
Published: October 2012

Background:

Syndesmosis ankle sprains cause greater disability and longer duration of recovery than lateral ankle sprains.

Objective:

To describe the severity of syndesmosis sprains using several accepted magnetic resonance imaging (MRI) criteria and to assess the interrater reliability of diagnosing syndesmosis injury using these same criteria in professional American football players.

Hypothesis:

There is a high degree of interrater reliability of MRI findings in American football players with syndesmosis ankle sprains. These radiographic findings will correlate with time lost to injury, indicating severity of the sprain.

Study Design:

Uncontrolled retrospective review.

Methods:

Player demographics and time lost to play were recorded among professional football players who had sustained a syndesmosis ankle sprain and underwent standardized ankle MRI. Each image was independently read by 3 blinded musculoskeletal radiologists.

Results:

Seventeen players met study criteria. There was almost perfect agreement among the radiologists for diagnosing injury to the syndesmotic membrane; substantial agreement for diagnosing injury to the posterior inferior tibiofibular ligament (PITFL) and in determining the proximal extent of syndesmotic edema/injury; but only fair agreement for diagnosing injury to the anterior inferior tibiofibular ligament and in determining the width of syndesmotic separation. There was a significant correlation between the width of syndesmotic separation and time lost, but no significant correlation between individual syndesmotic ligament injury or proximal extent of syndesmotic edema/injury and time lost.

Conclusion:

While ankle MRI can identify syndesmotic disruption with a high degree of interobserver agreement, no association was demonstrated between the extent of injury on MRI and the time to return to play following a high ankle sprain.

Clinical Relevance:

In athletes with suspected high ankle sprains, MRI may help confirm diagnosis or suggest alternative diagnoses when the syndesmotic supporting structures are intact. However, the severity of ligamentous and syndesmotic disruption on MRI cannot help predict recovery times.
Pitfalls of appropriating prestigious theories to frame conceptual arguments
Authors: Schaubroeck John M.
Published: October 2012

Researchers are often encouraged to shape an existing theoretical framework around their arguments to make them more convincing to readers. This can improve the coherence of their narratives and better ground them in existing literature. However, overarching theoretical frameworks can in many cases serve to insulate the author’s unique and presumably novel arguments from criticism concerning omitted variables and ambiguous causal direction. After discussing reasons authors appropriate external theoretical frameworks into their papers I suggest that relying on a small number of prestigious overarching theories as explanatory, rather than simply organizational frameworks may have subtle and pernicious influences on inquiry by (a) restricting the boundaries of the phenomena that are considered relevant, (b) introducing barriers to changing or supplanting theories, (c) biasing estimation of relationships due to omitted variables, (d) encouraging authors to exclude contradictory evidence and insights from their narratives, and (e) limiting how scholars evaluate theoretical contributions.
Key Characteristics of Major Depressive Disorder Occurring in Childhood, Adolescence, Emerging Adulthood, and Adulthood
Authors: Rohde Paul , Lewinsohn Peter M. , Klein Daniel N. , Seeley John R. , Gau Jeff M.
Published: October 2012

This article summarizes characteristics of major depressive disorder (MDD) in the Oregon Adolescent Depression Project, using data from 816 participants (56% female; 89% White). Contrasting four developmental periods (childhood, 5.0–12.9 years of age; adolescence, 13.0–17.9; emerging adulthood, 18.0–23.9; adulthood, 24–30), we examine MDD incidence/recurrence, gender, comorbidity, duration, and suicide attempts across periods. MDD first incidence was lower in childhood compared to subsequent periods and higher in emerging adulthood than in adulthood. Cumulative incidence was 51%. Recurrence was lower during childhood than remaining periods, which did not differ. Female gender predicted first-incident MDD in all four periods but was unassociated with recurrence. Comorbidity rates were comparable across periods. MDD duration was greater in childhood than in remaining periods. Suicide attempt rates were significantly higher during adolescence than during either emerging adulthood or adulthood. Depression research should focus on MDD during emerging adulthood, adolescent suicidal behavior, the continuing role of gender into adulthood, and the ubiquity of MDD.
Transforming Asia: Realizing the Asian Century through Good Governance
Authors: Nag Rajat M.
Published: October 2012

As developing Asia seeks to cement the gains from a decades-long economic boom and sustain its growth momentum, it will need to take bold action to address the plethora of governance challenges facing the region. Failure to address these challenges will lead to widened governance deficit in government, businesses and institutions.

Policy prescriptions for good governance abound, but true change will need to come from within the region. There is no short-cut to building good governance. We believe that endogenous factors—changing demographics, increasing urbanization, an expanding middle class—will drive demand for good governance in the region. It is hoped that the new aspirations accompanying the prospect of realizing the Asian Century and attaining higher living standards as well quality of life will transform governance across the region.
Challenges in the Sustainability of a Targeted Health Care Initiative in India
Authors: Balooni Kulbhushan , Gangopadhyay Kausik , Turakhia Sudeep , Karthik R.G.
Published: October 2012

In this article, we raise sustainability issues in a targeted health initiative, namely the Rashtriya Swasthya Bima Yojana. This unique health insurance initiative targets the poor population to address the iniquity in healthcare in the Indian societal context. We analyze this initiative because it is a unique case of a public–private partnership in the development sector arena in India being used as an instrument for improving the health care system on a large scale. The initial success stories from this initiative include improved hospitalization rates for the targeted population, a reduction in their out-of-pocket health care spending, and a reasonable incentive encouraging the participation of insurance companies. The sustainability of this initiative, however, is threatened mainly by a lack of information, heterogeneity in access, institutional shortcomings and the long-run escalation of costs. While the government is employing a public–private partnership to implement this initiative, there is need to simultaneously use this model to augment the existing health infrastructure to make this initiative sustainable and effective.
‘Fiat and Forbearance’: The Challenge of Capturing Plurality and Diversity in Environmental Governance
Authors: Damodaran A.
Published: October 2012

A close reading of India’s Constitution indicates that the ideals of pluralism and diversity underpin our basic approach to environmental issues. All the same, the past record of environmental governance in the country suggests that the twin ideals have not been adequately captured through appropriate policies and programmes. Part of the reason for this situation has been the predominant use of command and control instruments for realizing environmental goals. This article argues that the future of environmental governance in India lies in pursuing the principles of pluralism and diversity through balanced approaches to issues. This would imply having an open mind towards ‘command and control’ and ‘market based instruments’, pursuing economic and social development within the ambit of environmental policies, conserving the diversity of landscapes and nurturing a network of public spheres that can create plural viewpoints on environmental issues. In the light of the current environmental scenario in the country, where local commons and global commons fight for space, it is argued that an enlightened ‘fiat and forbearance regime’ that balances the ‘global’ with the ‘local’ offers the best hope for promoting plurality and diversity in environmental governance. The article unfolds the architecture of an enlightened fiat and forbearance regime for India in its local, regional, national and global dimensions. It is argued that a multi-level, multi-stakeholder governance system, if backed by certain enabling principles, can help India realize the paradigm of ‘enlightened fiat and forbearance regime’ in the realm of environment.
Accountability, Transparency and Sustainability in Governance: Can Rural Broadband be a Game-changer?
Authors: Gopalakrishnan R.
Published: October 2012

Transparency and accountability is crucial to sustainability of any system. Transparency of a governance structure is ensured if there are robust and reliable processes of information sharing. Accountability comes with effective feedback and redressal mechanisms. In this context, use of technology by way of rural broadband connectivity can greatly help in making rural governance system more transparent, accountable and hence more sustainable. This article details various methods of using rural broadband for deepening the democratic processes through Panchayati Raj in India. The use of rural broadband to communicate, train, educate, deliver, mobilize and finally evaluate can truly play a transformational role in India’s rural governance systems.
Role of Ti and N in line pipe steel welds
Authors: Zhu Z X , Kuzmikova L , Marimuthu M , Li H J , Barbaro F
Published: October 2012

High strength line pipe steels exhibit a combination of excellent toughness and high strength achieved through microalloy additions and thermomechanical controlled processing. During welding, severe thermal cycles experienced by the heat affected zone (HAZ) result in precipitate coarsening/dissolution and subsequent grain growth. This significantly reduces toughness in this region. It is well known that small Ti additions are utilised to control grain growth in the HAZ through grain boundary pinning action of TiN precipitates. Because of a lack of systematic and controlled study, it has been difficult to quantify the effect of TiN in the variety of steels. Hence, the optimum levels proposed in the literature are inconsistent and even contradict each other when compared. This paper mainly reviews the effect of different levels of Ti, N and Ti/N ratios on steels and pipes manufactured using different processes, with particular focus on the HAZ toughness.
Modelling hot cracking in 6061 aluminium alloy weld metal with microstructure based criterion
Authors: Niel A , Bordreuil C , Deschaux-Beaume F , Fras G
Published: October 2012

Hot cracking in welding is a complex phenomenon due to coupling between process, metallurgy and mechanical loading. A methodology based on process simulation, simple microstructural prediction and a pressure model along columnar grains is developed in order to integrate all factors that influence hot cracking. The model is based on some developments of Rappaz, Drezet and Gremaud and takes into account the influences of grain morphology, mechanical and welding thermal loading, on hot cracking. The model based on the microstructure behaviour is able to predict crack onset location in columnar grains on 6061 aluminium alloy.
The high Nrf2 expression in human acute myeloid leukemia is driven by NF-κB and underlies its chemo-resistance
Authors: Rushworth Stuart A. , Zaitseva Lyubov , Murray Megan Y. , Shah Niraj M. , Bowles Kristian M. , MacEwan David J.
Published: October 2012

NF-E2–related factor 2 (Nrf2) transcription factor regulates a range of cytoprotective transcriptional responses, preventing further cellular injury by removing biochemical damage and renewing tissue. Here we show that acute myeloid leukemia (AML) cells possess greater constitutive nuclear levels of Nrf2 than normal control CD34+ cells because of an imbalance between mRNA expression levels of Nrf2 and its inhibitor Keap1 but not through their somatic mutation. Elevated Nrf2 was reduced by NF-κB inhibitors. Using promoter assays, ChIP and siRNA knockdown, we demonstrated NF-κB subunits p50 and p65 induce transcription of Nrf2 in AML cells at a specific promoter κB-site and that long-term lentiviral miRNA-knockdown of Nrf2 significantly reduced clonogenicity of AML patient cells and improved their chemotherapeutic responsiveness. Normal physiologic Nrf2 protects cells from damage, but here we have exposed aberrant continuous nuclear activation of Nrf2 in AML that allows cell survival, even against cytotoxic chemotherapeutics. We show for the first time that Nrf2, an important regulator of several biologic processes involved in the progression of cancer, has abnormal NF-κB–driven constitutive expression in AML. Such a mechanism allows for a greater cytoprotective response in human AML cells and encourages their evasion of chemotherapy-induced cytotoxicity, which is necessary for improved clinical outcomes.
Identification of functionally important residues in TFPI Kunitz domain 3 required for the enhancement of its activity by protein S
Authors: Ahnström Josefin , Andersson Helena M. , Hockey Verity , Meng Yiran , McKinnon Thomas A. J. , Hamuro Tsutomu , Crawley James T. B. , Lane David A.
Published: October 2012

Protein S is a cofactor for tissue factor pathway inhibitor (TFPI) that critically reduces the inhibition constant for FXa to below the plasma concentration of TFPI. TFPI Kunitz domain 3 is required for this enhancement to occur. To delineate the molecular mechanism underlying enhancement of TFPI function, in the present study, we produced a panel of Kunitz domain 3 variants of TFPI encompassing all 12 surface-exposed charged residues. Thrombin-generation assays in TFPI-depleted plasma identified a novel variant, TFPI E226Q, which exhibited minimal enhancement by protein S. This was confirmed in purified FXa inhibition assays in which no protein S enhancement of TFPI E226Q was detected. Surface plasmon resonance demonstrated concentration-dependent binding of protein S to wild-type TFPI, but almost no binding to TFPI E226Q. We conclude that the TFPI Kunitz domain 3 residue Glu226 is essential for TFPI enhancement by protein S.
Frat2 mediates the oncogenic activation of Rac by MLL fusions
Authors: Walf-Vorderwülbecke Vanessa , de Boer Jasper , Horton Sarah J. , van Amerongen Renée , Proost Natalie , Berns Anton , Williams Owen
Published: October 2012

Mixed lineage leukemia (MLL) fusion genes arise from chromosomal translocations and induce acute myeloid leukemia through a mechanism involving transcriptional deregulation of differentiation and self-renewal programs. Progression of MLL-rearranged acute myeloid leukemia is associated with increased activation of Rac GTPases. Here, we demonstrate that MLL fusion oncogenes maintain leukemia-associated Rac activity by regulating Frat gene expression, specifically Frat2. Modulation of FRAT2 leads to concomitant changes in Rac activity, and transformation of Frat knockout hematopoietic progenitor cells by MLL fusions results in leukemias displaying reduced Rac activation and increased sensitivity to chemotherapeutic drugs. FRAT2 activates Rac through a signaling mechanism that requires glycogen synthase kinase 3 and DVL. Disruption of this pathway abrogates the leukemogenic activity of MLL fusions. This suggests a rationale for the paradoxical requirement of canonical Wnt signaling and glycogen synthase kinase 3 activity for MLL fusion oncogenicity and identifies novel therapeutic targets for this disease.
The biology of nematode- and IL4Rα-dependent murine macrophage polarization in vivo as defined by RNA-Seq and targeted lipidomics
Authors: Thomas Graham D. , Rückerl Dominik , Maskrey Benjamin H. , Whitfield Phillip D. , Blaxter Mark L. , Allen Judith E.
Published: October 2012

Alternatively activated macrophages (AAMφ) are a major component of the response to helminth infection; however, their functions remain poorly defined. To better understand the helminth-induced AAMφ phenotype, we performed a systems-level analysis of in vivo derived AAMφ using an established mouse model. With next-generation RNA sequencing, we characterized the transcriptomes of peritoneal macrophages from BALB/c and IL4Rα−/− mice elicited by the nematode Brugia malayi, or via intraperitoneal thioglycollate injection. We defined expression profiles of AAMφ-associated cytokines, chemokines, and their receptors, providing evidence that AAMφ contribute toward recruitment and maintenance of eosinophilia. Pathway analysis highlighted complement as a potential AAMφ-effector function. Up-regulated mitochondrial genes support in vitro evidence associating mitochondrial metabolism with alternative activation. We mapped macrophage transcription start sites, defining over-represented cis-regulatory motifs within AAMφ-associated promoters. These included the binding site for PPAR transcription factors, which maintain mitochondrial metabolism. Surprisingly PPARγ, implicated in the maintenance of AAMφ, was down-regulated on infection. PPARδ expression, however, was maintained. To explain how PPAR-mediated transcriptional activation could be maintained, we used lipidomics to quantify AAMφ-derived eicosanoids, potential PPAR ligands. We identified the PPARδ ligand PGI2 as the most abundant AAMφ-derived eicosanoid and propose a PGI2-PPARδ axis maintains AAMφ during B malayi implantation.
Unique small RNA signatures uncovered in the tammar wallaby genome
Authors: Lindsay James , Carone Dawn M , Brown Judy , Hall Laura , Qureshi Sohaib , Mitchell Sarah E , Jannetty Nicholas , Hannon Greg , Renfree Marilyn , Pask Andrew , O’Neill Michael , O’Neill Rachel
Published: October 2012

Background

Small RNAs have proven to be essential regulatory molecules encoded within eukaryotic genomes. These short RNAs participate in a diverse array of cellular processes including gene regulation, chromatin dynamics and genome defense. The tammar wallaby, a marsupial mammal, is a powerful comparative model for studying the evolution of regulatory networks. As part of the genome sequencing initiative for the tammar, we have explored the evolution of each of the major classes of mammalian small RNAs in an Australian marsupial for the first time, including the first genome-scale analysis of the newest class of small RNAs, centromere repeat associated short interacting RNAs (crasiRNAs).

Results

Using next generation sequencing, we have characterized the major classes of small RNAs, micro (mi) RNAs, piwi interacting (pi) RNAs, and the centromere repeat associated short interacting (crasi) RNAs in the tammar. We examined each of these small RNA classes with respect to the newly assembled tammar wallaby genome for gene and repeat features, salient features that define their canonical sequences, and the constitution of both highly conserved and species-specific members. Using a combination of miRNA hairpin predictions and co-mapping with miRBase entries, we identified a highly conserved cluster of miRNA genes on the X chromosome in the tammar and a total of 94 other predicted miRNA producing genes. Mapping all miRNAs to the tammar genome and comparing target genes among tammar, mouse and human, we identified 163 conserved target genes. An additional nine genes were identified in tammar that do not have an orthologous miRNA target in human and likely represent novel miRNA-regulated genes in the tammar. A survey of the tammar gonadal piRNAs shows that these small RNAs are enriched in retroelements and carry members from both marsupial and tammar-specific repeat classes. Lastly, this study includes the first in-depth analyses of the newly discovered crasiRNAs. These small RNAs are derived largely from centromere-enriched retroelements, including a novel SINE.

Conclusions

This study encompasses the first analyses of the major classes of small RNAs for the newly completed tammar genome, validates preliminary annotations using deep sequencing and computational approaches, and provides a foundation for future work on tammar-specific as well as conserved, but previously unknown small RNA progenitors and targets identified herein. The characterization of new miRNA target genes and a unique profile for crasiRNAs has allowed for insight into multiple RNA mediated processes in the tammar, including gene regulation, species incompatibilities, centromere and chromosome function.
Enhancement of carotenoid production by disrupting the C22-sterol desaturase gene (CYP61) in Xanthophyllomyces dendrorhous
Authors: Loto Iris , Gutiérrez María Soledad , Barahona Salvador , Sepúlveda Dionisia , Martínez-Moya Pilar , Baeza Marcelo , Cifuentes Víctor , Alcaíno Jennifer
Published: October 2012

Background

Xanthophyllomyces dendrorhous is a basidiomycetous yeast that synthesizes astaxanthin, which is a carotenoid with a great biotechnological impact. The ergosterol and carotenoid synthesis pathways are derived from the mevalonate pathway, and in both pathways, cytochrome P450 enzymes are involved.

Results

In this study, we isolated and described the X. dendrorhous CYP61 gene, which encodes a cytochrome P450 involved in ergosterol biosynthesis. This gene is composed of nine exons and encodes a 526 amino acid polypeptide that shares significant percentages of identity and similitude with the C22-sterol desaturase, CYP61, from other fungi. Mutants derived from different parental strains were obtained by disrupting the CYP61 gene with an antibiotic selection marker. These mutants were not able to produce ergosterol and accumulated ergosta-5,8,22-trien-3-ol and ergosta-5,8-dien-3-ol. Interestingly, all of the mutants had a more intense red color phenotype than their respective parental strains. The carotenoid composition was qualitatively and quantitatively analyzed by RP-HPLC, revealing that the carotenoid content was higher in the mutant strains without major changes in their composition. The expression of the HMGR gene, which encodes an enzyme involved in the mevalonate pathway (3-hydroxy-3-methylglutaryl-CoA reductase), was analyzed by RT-qPCR showing that its transcript levels are higher in the CYP61 mutants.

Conclusions

These results suggest that in X. dendrorhous, ergosterol regulates HMGR gene expression by a negative feedback mechanism and in this way; it contributes in the regulation of the carotenoid biosynthesis.
Temporal profile of body temperature in acute ischemic stroke: relation to stroke severity and outcome
Authors: Karaszewski Bartosz , Thomas Ralph GR , Dennis Martin S , Wardlaw Joanna M
Published: October 2012

Background

Pyrexia after stroke (temperature ≥37.5°C) is associated with poor prognosis, but information on timing of body temperature changes and relationship to stroke severity and subtypes varies.

Methods

We recruited patients with acute ischemic stroke, measured stroke severity, stroke subtype and recorded four-hourly tympanic (body) temperature readings from admission to 120 hours after stroke. We sought causes of pyrexia and measured functional outcome at 90 days. We systematically summarised all relevant previous studies.

Results

Amongst 44 patients (21 males, mean age 72 years SD 11) with median National Institute of Health Stroke Score (NIHSS) 7 (range 0–28), 14 had total anterior circulation strokes (TACS). On admission all patients, both TACS and non-TACS, were normothermic (median 36.3°C vs 36.5°C, p=0.382 respectively) at median 4 hours (interquartile range, IQR, 2–8) after stroke; admission temperature and NIHSS were not associated (r2=0.0, p=0.353). Peak temperature, occurring at 35.5 (IQR 19.0 to 53.8) hours after stroke, was higher in TACS (37.7°C) than non-TACS (37.1°C, p<0.001) and was associated with admission NIHSS (r2=0.20, p=0.002). Poor outcome (modified Rankin Scale ≥3) at 90 days was associated with higher admission (36.6°C vs. 36.2°C p=0.031) and peak (37.4°C vs. 37.0°C, p=0.016) temperatures. Sixteen (36%) patients became pyrexial, in seven (44%) of whom we found no cause other than the stroke.

Conclusions

Normothermia is usual within the first 4 hours of stroke. Peak temperature occurs at 1.5 to 2 days after stroke, and is related to stroke severity/subtype and more closely associated with poor outcome than admission temperature. Temperature-outcome associations after stroke are complex, but normothermia on admission should not preclude randomisation of patients into trials of therapeutic hypothermia.
Colloid cyst of the third ventricle, hypothalamus, and heart: a dangerous link for sudden death
Authors: Turillazzi Emanuela , Bello Stefania , Neri Margherita , Riezzo Irene , Fineschi Vittorio
Published: October 2012

Colloid cysts are rare congenital, intracranial neoplasms, commonly located in the third ventricle. Colloid cysts are endodermal congenital malformations. The cysts commonly range in size from 1–2 cm in diameter, although large cysts >3 cm in size have been reported. The components of the cyst include an outer fibrous capsule over an inner epithelium. The epithelium is usually a single layer of mucin-producing or ciliated cells. Such cysts contain mucoid and gelatinous material, which is positive for both Periodic acid Schiff (PAS) and mucicarmen staining. Although colloid cysts usually represent histopathologically benign neoplasms, they can result in sudden, unexpected and potentially lethal complications. The mechanism(s) of death is still a controversial subject and several mechanisms have been postulated to explain the sudden onset of severe symptoms and of fatal rapid deterioration in patients with colloid cysts. In this case, macroscopic and histological findings addressed the diagnosis of colloid cyst of the third ventricle with diffuse myocardial injury (coagulative myocytolysis or contraction band necrosis, CBN) and led us to conclude that acute cardiac arrest due to hypothalamus stimulation in the context of colloid cyst of the third ventricle was the cause of death. As the hypothalamic structures which are involved in neuroendocrine and autonomic regulation playing a key role in cardiovascular control are located close to the walls of the third ventricle which is the most frequent anatomical site of colloid cyst, this may suggest that reflex cardiac effects due to the compression of the hypothalamic cardiovascular regulatory centers by the cyst explain the sudden death in patients harboring a colloid cyst when signs of hydrocephalus or brain herniation are lacking.

Virtual slides

The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/4915842848034158
Radiotherapy is associated with significant improvement in local and regional control in Merkel cell carcinoma
Authors: Kang Susan H , Haydu Lauren E , Goh Robin Yeong Hong , Fogarty Gerald B
Published: October 2012

Introduction

Merkel cell carcinoma (MCC) is a rare tumour of skin. This study is a retrospective audit of patients with MCC from St Vincent’s and Mater Hospital, Sydney, Australia. The aim of this study was to investigate the influence of radiotherapy (RT) on the local and regional control of MCC lesions and survival of patients with MCC.

Method

The data bases in anatomical pathology, RT and surgery. We searched for patients having a diagnosis of MCC between 1996 and 2007. Patient, tumour and treatment characteristics were collected and analysed. Univariate survival analysis of categorical variables was conducted with the Kaplan-Meier method together with the Log-Rank test for statistical significance. Continuous variables were assessed using the Cox regression method. Multivariate analysis was performed for significant univariate results.

Results

Sixty seven patients were found. Sixty two who were stage I-III and were treated with radical intent were analysed. 68% were male. The median age was 74 years. Forty-two cases (68%) were stage I or II, and 20 cases (32%) were stage III. For the subset of 42 stage I and II patients, those that had RT to their primary site had a 2-year local recurrence free survival of 89% compared with 36% for patients not receiving RT (p<0.001). The cumulative 2-year regional recurrence free survival for patients having adjuvant regional RT was 84% compared with 43% for patients not receiving this treatment (p<0.001). Immune status at initial surgery was a significant predictor for OS and MCCSS. In a multivariate analysis combining macroscopic size (mm) and immune status at initial surgery, only immune status remained a significant predictor of overall survival (HR=2.096, 95% CI: 1.002-4.385, p=0.049).

Conclusions

RT is associated with significant improvement in local and regional control in Merkel cell carcinoma. Immunosuppression is an important factor in overall survival.
The viral transactivator HBx protein exhibits a high potential for regulation via phosphorylation through an evolutionarily conserved mechanism
Authors: Hernández Sergio , Venegas Mauricio , Brahm Javier , Villanueva Rodrigo A
Published: October 2012

Background

Hepatitis B virus (HBV) encodes an oncogenic factor, HBx, which is a multifunctional protein that can induce dysfunctional regulation of signaling pathways, transcription, and cell cycle progression, among other processes, through interactions with target host factors. The subcellular localization of HBx is both cytoplasmic and nuclear. This dynamic distribution of HBx could be essential to the multiple roles of the protein at different stages during HBV infection. Transactivational functions of HBx may be exerted both in the nucleus, via interaction with host DNA-binding proteins, and in the cytoplasm, via signaling pathways. Although there have been many studies describing different pathways altered by HBx, and its innumerable binding partners, the molecular mechanism that regulates its different roles has been difficult to elucidate.

Methods

In the current study, we took a bioinformatics approach to investigate whether the viral protein HBx might be regulated via phosphorylation by an evolutionarily conserved mechanism.

Results

We found that the phylogenetically conserved residues Ser25 and Ser41 (both within the negative regulatory domain), and Thr81 (in the transactivation domain) are predicted to be phosphorylated. By molecular 3D modeling of HBx, we further show these residues are all predicted to be exposed on the surface of the protein, making them easily accesible to these types of modifications. Furthermore, we have also identified Yin Yang sites that might have the potential to be phosphorylated and O-β-GlcNAc interplay at the same residues.

Conclusions

Thus, we propose that the different roles of HBx displayed in different subcellular locations might be regulated by an evolutionarily conserved mechanism of posttranslational modification, via phosphorylation.