bluuebunny/crossref_metadata_2025 huggingface dataset:
New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects
Authors: Aparicio-Gallego Guadalupe , Blanco Moisés , Figueroa Angélica , García-Campelo Rosario , Valladares-Ayerbes Manuel , Grande-Pulido Enrique , Antón-Aparicio Luis
Published: December 2011

The introduction of targeted therapy represents a major advance in the treatment of tumor progression. Targeted agents are a novel therapeutic approach developed to disrupt different cellular signaling pathways. The tyrosine kinase inhibitor sunitinib specifically blocks multiple tyrosine kinase receptors that are involved in the progression of many tumors. Sunitinib is the current standard of care in first-line treatment of advanced renal cell carcinoma, and it is approved in imatinib-intolerant and imatinib-refractory gastrointestinal stromal tumors. However, it is increasingly evident that sunitinib may display collateral effects on other proteins beyond its main target receptors, eliciting undesirable and unexpected adverse events. A better understanding of the molecular mechanisms underlying these undesirable sunitinib-associated side effects will help physicians to maximize efficacy of sunitinib and minimize adverse events. Here, we focus on new insights into molecular mechanisms that may mediate sunitinib-associated adverse events. Mol Cancer Ther; 10(12); 2215–23. ©2011 AACR.
The E6 Oncoprotein from HPV16 Enhances the Canonical Wnt/β-Catenin Pathway in Skin Epidermis In Vivo
Authors: Bonilla-Delgado José , Bulut Gülay , Liu Xuefeng , Cortés-Malagón Enoc M. , Schlegel Richard , Flores-Maldonado Catalina , Contreras Rubén G. , Chung Sang-Hyuk , Lambert Paul F. , Üren Aykut , Gariglio Patricio
Published: December 2011

The contribution of the Wnt signaling pathway to human papilloma virus (HPV)-induced carcinogenesis is poorly understood. In high-grade dysplastic lesions that are caused by high-risk HPVs (HR-HPV), β-catenin is often located in the cell nucleus, which suggests that Wnt pathway may be involved in the development of HPV-related carcinomas. Most of the oncogenic potential of HR-HPVs resides on the PDZ-binding domain of E6 protein. We hypothesized that the PDZ-binding domain of the HPV16-E6 oncoprotein induces the nuclear accumulation of β-catenin due to its capacity to degrade PDZ-containing cellular targets. To test this hypothesis, we evaluated the staining pattern of β-catenin in the skin epidermis of transgenic mice expressing the full-length E6 oncoprotein (K14E6 mice) and measured LacZ gene expression in K14E6 mice that were crossed with a strain expressing LacZ that was knocked into the Axin2 locus (Axin2+/LacZ mice). Here, we show that the E6 oncoprotein enhances the nuclear accumulation of β-catenin, the accumulation of cellular β-catenin–responsive genes, and the expression of LacZ. None of these effects were observed when a truncated E6 oncoprotein that lacks the PDZ-binding domain was expressed alone (K14E6ΔPDZ mice) or in combination with Axin2+/LacZ. Conversely, cotransfection with either E6 or E6ΔPDZ similarly enhanced canonical Wnt signaling in short-term in vitro assays that used a luciferase Wnt/β-catenin/TCF-dependent promoter. We propose that the activation of canonical Wnt signaling could be induced by the HPV16-E6 oncoprotein; however, the participation of the E6 PDZ-binding domain seems to be important in in vivo models only. Mol Cancer Res; 10(2); 250–8. ©2011 AACR.
Influence of Maternal Dental Anxiety on the Child’s Dental Caries Experience
Authors: Goettems M.L. , Ardenghi T.M. , Romano A.R. , Demarco F.F. , Torriani D.D.
Published: December 2011

This study assessed the influence of maternal dental anxiety-related behavior on the child’s caries experience. A cross-sectional study with 608 mother-child dyads during the Children’s National Immunization Campaign in Pelotas, Brazil was performed. Mothers were asked to answer a questionnaire and dental examination of the children was performed (dmft). The association assessment used Poisson regression. Children from anxious mothers were more likely to present untreated caries even after covariate adjustment. Boys, older children and low-income family children presented a higher dmft mean. Preventive strategies should focus not only on child and family characteristics, but also on maternal dental anxiety-related behaviors.
Empirical Risk Minimization for Probabilistic Grammars: Sample Complexity and Hardness of Learning
Authors: Cohen Shay B. , Smith Noah A.
Published: December 2011

Probabilistic grammars are generative statistical models that are useful for compositional and sequential structures. They are used ubiquitously in computational linguistics. We present a framework, reminiscent of structural risk minimization, for empirical risk minimization of probabilistic grammars using the log-loss. We derive sample complexity bounds in this framework that apply both to the supervised setting and the unsupervised setting. By making assumptions about the underlying distribution that are appropriate for natural language scenarios, we are able to derive distribution-dependent sample complexity bounds for probabilistic grammars. We also give simple algorithms for carrying out empirical risk minimization using this framework in both the supervised and unsupervised settings. In the unsupervised case, we show that the problem of minimizing empirical risk is NP-hard. We therefore suggest an approximate algorithm, similar to expectation-maximization, to minimize the empirical risk.
A Test of the Routine Activities and Neighborhood Attachment Explanations for Bias in Disorder Perceptions
Authors: Wallace Danielle
Published: December 2011

“Neighborhood disorder” refers to how people perceive neighborhoods as unsafe and disorganized. However, certain disorder cues may indicate disorder to some residents but not to others. There are many explanations for disorder perception bias, though few have been tested. This article uses data on 4,721 residents in 100 neighborhoods in Seattle to assess two explanations for biases: neighborhood attachment and routine activities. Using fixed-effect models, this article shows that neighborhood attachment and routine activities provide additional insight into disorder perceptions. Hanging out with teens and engaging in protective neighborhood activities, like watching neighbors’ property, have a strong positive influence on disorder perceptions. This study concludes by discussing alternative explanations for disorder perception bias and their impact on disorder theory as a whole.
Efficiency assessment of real estate cadastral offices using DEA
Authors: Ferrera José Manuel Cordero , Chaparro Francisco Pedraja , Jiménez Javier Salinas
Published: December 2011

This article describes an approach to measuring efficiency of a set of units operating in an administrative public service context, namely real estate cadastral offices, a venue which has not been analysed previously in the reported literature. This study was madepossible thanks to the dataset provided by the Directorate General of Real Estate Cadastral Assessment and includes relevant information on regional cadastral offices in Spain over the time period 2000 to 2005. Data Envelopment Analysis and Malmquist indices were used to estimate the efficiency levels of these units. The results of these analyses revealed the existence of significant differences between average efficiency levels and the identification of efficient units throughout the period under consideration, although it is possible to detect a substantial improvement in technical efficiency for the last two years of the data collection period, when the new regulation about real estate evaluation came into effect. Likewise, the estimation of a second stage model based on bootstrap techniques highlights the importance of collaborating with other public sector agents to enhance efficiency levels.

Points for practitioners

This article provides an empirical analysis of units providing cadastral services in Spain using Data Envelopment Analysis. This technique is an excellent tool for professionals working in public management and administration since it is easy to implement and allows identifying the best performers among producers operating in a field, which can be considered as benchmarks for other units searching to improve their results. Ourresults confirm that the units collaborating with other public sector agents (mainly councils and notaries) accomplish enhanced performances in terms of efficiency. This evidence can be useful for policy-makers interested in reducing costs and improving the organization of administrative units.
Assessing the effects of an Intelligence Performance Regime: Quebec's Municipal Management Indicators, 1999–2010
Authors: Charbonneau Étienne
Published: December 2011

Quebec's Municipal Management Indicators embodies what Hood (2007) described as an intelligence regime. This research tries to determine if the design of the municipal intelligence performance regime in Quebec, Canada, delivered the expected results. To answer that question, publicly available official documents, minutes of meetings, and survey data are used. The story of Quebec's regime offers a counter-example to Pollitt and colleagues’ (2010) theory that once in place, performance regimes follow a logic of escalation. The municipal intelligence regime in Quebec never moved from formative to summative; from intelligence to targets and rankings. The experience in that Canadian province offers support to Hood's (2007) model about the shortcomings of intelligence regimes.

Points for practitioners

The case study of a performance regime details an effort with few demands on participants. It is argued that the documented shortcomings are the result of the strategic path initially taken by decision makers, not the result of their later decisions and adjustments. Shielded from public scrutiny and without sanctions from the provincial government, most municipal managers chose not to use the indicators, not to include them in budgets and annual reports, not to compare themselves to others, and not to set targets for themselves. In a mandated regime with bottom-up and voluntary approaches, most municipalities effectively opted out.
Whose Liberation? A Partly-Forgotten Left Critique of ANC Strategy and Its Contemporary Implications
Authors: Friedman Steven
Published: December 2011

At the beginning of the 1980s, a group of left intellectuals and activists sought to press the then-exiled African National Congress (ANC) to adopt a change of strategy which would have given priority to the organized collective action of workers and the poor: they were expelled and their proposed remedies ignored. But, while it had little impact on political practice at the time, the implied debate between the dissidents and the ANC raised issues crucial to understanding the challenges which face South African democracy today. Although the dissidents’ approach was based on a flawed analysis of the processes which produce social change, it did highlight an aspect of anti-apartheid resistance strategy which has made achieving a more egalitarian and democratic South African more difficult.
“The Kids Still Come First”
Authors: Sano Yoshie , Manoogian Margaret M. , Ontai Lenna L.
Published: December 2011

This qualitative study examined the nature of partnerships among 28 rural low-income mothers who experienced partnership transitions across three waves of annual interviews. Guided by lens of uncertainty and boundary ambiguity theory, the authors specifically explored (a) how low-income mothers in rural communities experience partnership transitions over time and (b) how rural, low-income mothers create stability for themselves and their children in the midst of partnership transitions. The narratives of rural, low-income mothers not only featured the uncertainty, unreliability, and instability of their lives but also underscored their resilience and ability to adapt to an impoverished environment. Their decisions to enter into, stay, and leave partnerships, in most cases, were part of their flexible responses to the structural constraints imposed by unemployment, lack of resources, and rural contexts.
Synergistic integration of computational fluid dynamics and experimental fluid dynamics for ground effect aerodynamics studies
Authors: Barber T J , Doig G , Beves C , Watson I , Diasinos S
Published: December 2011

This article highlights the ‘synergistic’ use of experimental fluid dynamics (EFD) and computational fluid dynamics (CFD), where the two sets of simulations are performed concurrently and by the same researcher. In particular, examples from the area of ground effect aerodynamics are discussed, where the major facility used was also designed through a combination of CFD and EFD. Three examples are than outlined, to demonstrate the insight that can be obtained from the integration of CFD and EFD studies. The case studies are the study of dimple flow (to enhance aerodynamic performance), the analysis of a Formula-style front wing and wheel, and the study of compressible flow ground effect aerodynamics. In many instances, CFD has been used to not only provide complementary information to an experimental study, but to design the experiments. Laser-based, non-intrusive experimental techniques were used to provide an excellent complement to CFD. The large datasets found from both experimental and numerical simulations have required a new methodology to correlate the information; a new post-processing method has been developed, making use of the kriging and co-kriging estimators, to develop correlations between the often disparate data types.
Severity estimation and effect of operational parameters for civil aircraft jet engines
Authors: Hanumanthan H , Stitt A , Laskaridis P , Singh R
Published: December 2011

Engine maintenance costs for civil aircraft largely depend on the life consumption of critical parts like high-pressure turbine blade and disk. Severity (defined as a measure of relative damage) can be used to characterize the degree of life consumption for the parts subjected to low cycle fatigue, creep, and oxidation as predominant life-limiting modes under normal engine operation. In this context, a numerical tool has been developed to study the impact of engine-aircraft operational parameters on engine severity. This is accomplished by combining aircraft performance, gas turbine performance, component sizing, heat transfer calculation, thermal analysis, structural analysis, life and severity estimation for the high-pressure turbine, and the disk components of jet engines. Operational parameters such as take-off (TO) derate, climb derate, outside air temperature, and airport altitude have been studied for lower thrust and larger thrust engines. The observations from the study show that TO derate and outside air temperature are dominant parameters in terms of engine severity. The use of climb derate also lowers the severity and is more beneficial for larger thrust engines, while airport altitude effects could be minimized by the use of suitable TO derate. The severity characteristics estimated through the numerical tool can provide an enhanced perspective on aircraft engine maintenance.
Extended state observer-based robust pitch autopilot design for tactical missiles
Authors: Godbole A A , Libin T R , Talole S E
Published: December 2011

In this article, a new design based on the extended state observer (ESO) technique for the pitch autopilot of a tail-controlled, skid-to-turn missile is proposed. The pitch-plane dynamics with the angle of attack as output is significantly uncertain. The ESO simultaneously estimates the state and the uncertainty. The estimated uncertainty is used to robustify the input–output–linearization-based controller designed for the nominal system. Closed-loop stability of the observer–controller combination is proved. The notable feature of the proposed design is that it neither requires accurate plant model nor any information about the uncertainty. The effectiveness of the ESO in estimation of the uncertainties and states and in meeting the specified tracking performance in the presence of significant uncertainties is illustrated by simulation. Finally, to demonstrate the efficacy of the proposed design, comparison of its performance with some of the well-known existing controllers is presented.
Aging and the experience of ‘remembered’ time: A biopsychosocial exploration
Authors: Chernus Linda A.
Published: December 2011

Though considerable research has been conducted on the subjective experience of time periods of short duration, little has been written about acceleration of long intervals of remembered time with age. The author reviews and assesses psychosocial, biological, and mathematical considerations contributing toward a comprehensive understanding of why the years seem to ‘fly by’ increasingly more rapidly. In particular, it is suggested that the powerful impact of social acceleration on our subjective sense of the passage of time may affect us differently at various stages in the life cycle.
Empowering Preservice Music Teachers Through the Dialogue-Centered Methods Class
Authors: Scheib John W.
Published: December 2011

The front-loaded lecture can be a dangerous thing. It creates passivity among students and disengages them in the teaching learning process. Many teachers believe frontal lecturing to be the most efficient way to deliver content—the path of least resistance. Unfortunately, these teachers do not view course content as an inquiry; rather they see content as an established body of knowledge solely possessed by the teacher. In contrast, arguably some of the greatest educational thinkers of our time view the classroom and course content quite differently. As well, understandings developed through learning theory and best practice related research also are at odds with this traditional model. Through the use of problem-posing, student-led debates, small group cooperative learning projects, journaling, field experiences, peer teachings, and portfolio assessment, a methods class can be transformed into an empowering vehicle for student learning as well as help students foster a greater sense of ownership in their future profession.
Creating a Survey to Assess Physicians’ Adoption of Health Information Technology
Authors: Baier Rosa R. , Gardner Rebekah L. , Buechner Jay S. , Harris Yael , Viner-Brown Samara , Gifford Deidre S.
Published: December 2011

Information on state-level health information technology (HIT) adoption will become increasingly important with the implementation of incentive payments to accelerate uptake. Recognizing this, the Rhode Island Department of Health selected physician HIT adoption as a subject for its legislatively mandated quality reporting program. This article discusses the state’s process for developing HIT adoption measures, including the importance of stakeholder involvement in the development of a survey and the difficulty of accurately defining electronic medical record (EMR) adoption. This article describes the challenges in defining “true” EMRs, which may be addressed, in part, by ensuring local consensus about EMR measures and by piloting the survey and measures, prior to public reporting or the calculation of a statewide baseline. It also presents results from the 2009 administration of this survey to all 3,883 Rhode Island–licensed physicians providing direct patient care.
(Un)Natural and contractual international society: A conceptual inquiry
Authors: Roshchin Evgeny
Published: December 2011

This article offers a critical perspective on one of the central concepts of IR and the English School of IR in particular, namely the concept of international society. It argues that the moral agency of international society and its ‘naturalness’ were affirmed simultaneously with the marginalization of the concept of societas designating contractual political relations. The article traces the concept of contracted societas back to the work of Hugo Grotius, an acclaimed founder of the ‘international society’ tradition. By placing Grotius’ use of the concept in the context of ancient and early modern discussion of political alliances and partnerships, it demonstrates that politically contracted societas was no less conventional and important than the Stoic universal human society. However, this alternative societas had to be abandoned in the debates over the rival theories of social contract and the law of nations. The inherent sociability arguments, which were used to undermine a Hobbesian explanation for social contract or to question the very idea that society results from contract, found no place for societas contracted for a particular political purpose. The identification of such contingency in the history of the concept provides grounds for reopening the closure of the present conceptualizations of international society.
The Othering of Food in Touristic Eatertainment: A Netnography
Authors: Mkono Muchazondida
Published: December 2011

Adjectives such as ‘scary’, ‘yucky’ and ‘bizarre’, used in connection with food in touristic experience, illustrate tourists’ propensity to ‘Other’. In this paper, I use netnographic tourist reviews of two cultural restaurants to explore tourists’ self-interpretation of the Other as represented in food. The findings are organized under four themes, namely, ‘scary, unusual food’, ‘eating the authentic Other’ and ‘the reassurance in mixing familiar with unfamiliar’. It is recommended that future research on food in tourism experience should explore contexts that have not previously been viewed as culinary destinations to create more ‘situated’ knowledge. Further, netnography offers a novel approach which could reveal tourists’ subjective realities that are provided more candidly than in traditional qualitative methods.
HERS Institutes
Authors: White Judith S.
Published: December 2011

The Problem.

At this critical time, higher education needs more women prepared to assume senior leadership roles, both to fill the openings from anticipated presidential retirements and to provide higher quality decision making through more diverse perspective at all levels of leadership.

The Solution.

Higher Education Resource Services (HERS), founded in 1972, has provided leadership development opportunities for more than 4,300 women faculty and administrators sponsored by 1,100 institutions in the United States and abroad. HERS has recently implemented significant revisions of its signature HERS Institutes to address the new circumstances and challenges women leaders will face in guiding institutions in the decade ahead. This article examines the historical development of HERS, recent revisions, and future plans for expanding programs.

The Stakeholders.

Revisions to HERS Institutes suggestimplications for those developing women in HRD, conducting research on leadership development, or concerned about higher education as a new leadership cadre faces the demands of the future.
Meaningful Work, Employee Engagement, and Other Key Employee Outcomes
Authors: Fairlie Paul
Published: December 2011

The Problem.

Meaningful work is underrepresented in current models and measures of work characteristics. Ironically, past research suggests that meaningful work may have substantive impacts on employee outcomes. The current study addresses this problem by demonstrating the value of meaningful work in human resource development (HRD) practices involving employee engagement.

The Solution.

A web-based survey of employed North Americans ( n = 574) was conducted. Meaningful work characteristics were compared to other work characteristics as correlates and predictors of employee engagement, burnout, job satisfaction, organizational commitment, and turnover cognitions. Meaningful work characteristics had the strongest relative correlations with multiple employee outcomes. They also predicted substantive variance in employee engagement while controlling for other work characteristics in regression analyses.

The Stakeholders.

Since meaningful work contains themes of human development (e.g., self-actualization, social impact), this variable represents an opportunity for human resource development (HRD) practitioners to increase levels of employee engagement as a strategic leverage point within organizations.
Indirect Presidential Influence, State-Level Approval, and Voting in the U.S. Senate
Authors: Dwyer Caitlin E. , Treul Sarah A.
Published: December 2011

In the current era of polarization, bipartisanship between a president and senators of the opposite party seems unlikely. Yet, we expect that given a senator’s desire to please his constituents and ensure reelection, if a president is popular with constituents in a senator’s home state, he can have an indirect influence on the senator’s votes. We test this relationship using state-level presidential approval data, which are a district level cue for senators. The results suggest that when a president is popular with a senator’s constituents, the senator becomes increasingly likely to cast a vote in support of the president’s agenda regardless of partisanship. In fact, as approval in an opposite party senator’s state increases, his agreement rate increases by a greater margin than it does for senators of the president’s party. We also test the effect of reelection and determine that it tempers the bipartisanship a popular president can incite.
An Investigation of Neighborhood Disadvantage, Low Self-Control, and Violent Victimization Among Youth
Authors: Gibson Chris L.
Published: December 2011

This research combines social disorganization and self-control perspectives to understand personal victimization among youth. In doing so, several research questions are investigated to explore the independent and interactive influences on violent victimization risk. Using data from the Longitudinal Cohort Study in the Project on Human Development in Chicago Neighborhoods (PHDCN-LCS), results from several multivariate models show that, independent of various situational and lifestyle choices made by adolescents, low self-control increases the likelihood of violent victimization. Further analysis shows that this association varies across levels of neighborhood concentrated disadvantage; low self-control’s influence in the most disadvantaged neighborhoods dissipates while it is amplified for those living in the least disadvantaged neighborhoods. The implications of these findings are discussed.
A capillary blood ammonia bedside test following glutamine load to improve the diagnosis of hepatic encephalopathy in cirrhosis
Authors: Ditisheim Saskia , Giostra Emiliano , Burkhard Pierre R , Goossens Nicolas , Mentha Gilles , Hadengue Antoine , Spahr Laurent
Published: December 2011

Background

Hepatic encephalopathy (HE) is a frequent and severe complication of cirrhosis. A single determination of ammonia in venous blood correlates poorly with neurological symptoms. Thus, a better biological marker is needed.

Aim

To make a diagnosis of HE, we explored the value of ammonia in capillary blood, an equivalent to arterial blood, measured at bedside following an oral glutamine challenge.

Methods

We included 57 patients (age 56 yrs; M/F: 37/20) with cirrhosis (alcoholic = 42; MELD score 13.8 [7-29], esophageal varices = 38) and previous episodes of HE (n = 19), but without neurological deficits at time of examination, and 13 healthy controls (age 54 yrs). After psychometric tests and capillary (ear lobe) blood ammonia measurements, 20 gr of glutamine was administered orally. Tests were repeated at 60 minutes (+ blood ammonia at 30'). Minimal HE was diagnosed if values were > 1.5 SD in at least 2 psychometric tests. Follow-up lasted 12 months.

Results

The test was well tolerated (nausea = 1; dizziness = 1). Patients showed higher values of capillary blood ammonia over time as compared to controls (0'-30'-60 minutes: 75, 117, 169 versus 52, 59, 78 umol/L, p < 0.05). At baseline, 25 patients (44%) had minimal HE, while 38 patients (67%) met the criteria for HE at 60 minutes (chi2: p < 0.01). For the diagnosis of minimal HE, using the ROC curve analysis, baseline capillary blood ammonia showed an AUC of 0.541 (CI: 0.38-0.7, p = 0.6), while at 60 minutes the AUC was 0.727 (CI: 0.58-0.87, p < 0.006). During follow-up, 18 patients (31%) developed clinical episodes of HE. At multivariate analysis, the MELD score (1.12 [1.018-1.236]), previous episodes of HE (3.2[1.069-9.58]), but not capillary blood ammonia, were independent predictors of event.

Conclusions

In patients with cirrhosis and normal neurological examination, bedside determination of ammonia in capillary blood following oral glutamine load is well tolerated and achieves a better diagnostic performance for minimal HE than basal capillary ammonia levels. However, capillary blood ammonia is a poor predictor of development of clinically overt HE.
Nocardia transvalensis keratitis: an emerging pathology among travelers returning from Asia
Authors: Trichet Elodie , Cohen-Bacrie Stéphan , Conrath John , Drancourt Michel , Hoffart Louis
Published: December 2011

Background

The incidence rate of Nocardia keratitis is increasing, with new species identified thanks to molecular methods. We herein report a case of Nocardia transvalensis keratitis, illustrating this emerging pathology among travellers returning from Asia.

Case presentation

A 23-year-old man presented with a 10-week history of ocular pain, redness, and blurred vision in his right eye following a projectile foreign body impacting the cornea while motor biking in Thaïland. At presentation, a central epithelial defect with a central whitish stromal infiltrate associated with pinhead satellite infiltrates was observed. Identification with 16S rRNA PCR sequencing and microbiological culture of corneal scraping and revealed N. transvalensis as the causative organism. Treatment was initiated with intensive topical amikacin, oral ketoconazole and oral doxycycline. After a four-week treatment period, the corneal infiltrate decreased so that only a faint subepithelial opacity remained.

Conclusion

Nocardia organisms should be suspected as the causative agent of any case of keratitis in travelers returning from Asia. With appropriate therapy, Nocardia keratitis resolves, resulting in good visual outcome.
Bone resorption and environmental exposure to cadmium in children: a cross - sectional study
Authors: Sughis Muhammad , Penders Joris , Haufroid Vincent , Nemery Benoit , Nawrot Tim S
Published: December 2011

Background

Exposure to cadmium has been associated with osteoporosis and fracture risk in women and elderly, but studies in children are lacking. In the present study we investigate the association between markers of bone demineralization [urinary calcium (Ca) and deoxypyridinoline (DPD) excretion] and urinary cadmium (Cd) excretion (as an index of lifetime body burden).

Methods

155 schoolchildren from 2 elementary schools in Lahore, Pakistan were included. Urinary Cd was measured as an index of lifetime exposure. We assessed the multivariate-adjusted association of exposure with markers of bone resorption, urinary DPD as well as with Ca excretion.

Results

Urinary Cd averaged 0.50 nmol/mmol creatinine and was not influenced by age, height, weight and socio-economic status (SES). Independent of gender, age, height, weight and SES a doubling of urinary Cd was associated with a 1.72 times (p < 0.0001) increase in urinary DPD and, a 1.21 times (p = 0.02) increase in urinary Ca. Additional adjustment for urinary Ca revealed still significant associations between urinary Cd and urinary DPD. The shape of the association was linear without evidence of a threshold.

Conclusions

Even in young children, low-level environmental exposure to cadmium is associated with evidence of bone resorption, suggesting a direct osteotoxic effect with increased calciuria. These findings might have clinical relevance at older age.
Adaptive Müller cell responses to microglial activation mediate neuroprotection and coordinate inflammation in the retina
Authors: Wang Minhua , Ma Wenxin , Zhao Lian , Fariss Robert N , Wong Wai T
Published: December 2011

Purpose

Microglia and Müller cells are prominent participants in retinal responses to injury and disease that shape eventual tissue adaptation or damage. This investigation examined how microglia and Müller cells interact with each other following initial microglial activation.

Methods

Mouse Müller cells were cultured alone, or co-cultured with activated or unactivated retinal microglia, and their morphological, molecular, and functional responses were evaluated. Müller cell-feedback signaling to microglia was studied using Müller cell-conditioned media. Corroborative in vivo analyses of retinal microglia-Müller cell interactions in the mouse retina were also performed.

Results

Our results demonstrate that Müller cells exposed to activated microglia, relative to those cultured alone or with unactivated microglia, exhibit marked alterations in cell morphology and gene expression that differed from those seen in chronic gliosis. These Müller cells demonstrated in vitro (1) an upregulation of growth factors such as GDNF and LIF, and provide neuroprotection to photoreceptor cells, (2) increased pro-inflammatory factor production, which in turn increased microglial activation in a positive feedback loop, and (3) upregulated chemokine and adhesion protein expression, which allowed Müller cells to attract and adhere to microglia. In vivo activation of microglia by intravitreal injection of lipopolysaccharide (LPS) also induced increased Müller cell-microglia adhesion, indicating that activated microglia may translocate intraretinally in a radial direction using Müller cell processes as an adhesive scaffold.

Conclusion

Our findings demonstrate that activated microglia are able to influence Müller cells directly, and initiate a program of bidirectional microglia-Müller cell signaling that can mediate adaptive responses within the retina following injury. In the acute aftermath following initial microglia activation, Müller cell responses may serve to augment initial inflammatory responses across retinal lamina and to guide the intraretinal mobilization of migratory microglia using chemotactic cues and adhesive cell contacts. Understanding adaptive microglia-Müller cell interactions in injury responses can help discover therapeutic cellular targets for intervention in retinal disease.
Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer
Authors: West Nathan R , Milne Katy , Truong Pauline T , Macpherson Nicol , Nelson Brad H , Watson Peter H
Published: December 2011

Introduction

Infiltration of breast tumors by tumor-infiltrating lymphocytes (TIL) has been associated with sensitivity to anthracycline-based chemotherapy. However, it is unclear whether this is true within the estrogen receptor-alpha (ER)-negative subset of breast tumors that frequently manifest high TIL levels.

Methods

The association of TIL with short-term and long-term clinical response to anthracycline-based therapy was assessed in two independent ER-negative breast cancer cohorts in which patients were categorized as TIL-high or TIL-low. We defined an eight-gene lymphocyte mRNA expression signature (including CD19, CD3D, CD48, GZMB, LCK, MS4A1, PRF1, and SELL) and used unsupervised hierarchical clustering to examine the association between TIL and short-term response to neoadjuvant chemotherapy in a previously published cohort of ER-negative tumors (n = 113). We also examined the association between TIL and long-term chemotherapeutic efficacy in a second cohort of ER-negative tumors (n = 255) with longer than 6 years of median follow-up by using tissue microarrays and immunohistochemistry (IHC) for detection of CD3, CD8, CD4, CD20, and TIA-1.

Results

In patients with ER-negative tumors treated with neoadjuvant anthracycline-based chemotherapy, pathologic complete responses (pCRs) were achieved by 23 (74%) of 31 TIL-high patients and 25 (31%) of 80 TIL-low patients (odds ratio (OR), 6.33; 95% confidence interval (CI), 2.49 to 16.08; P < 0.0001). Multivariate logistic regression with standard clinicopathologic features demonstrated that only tumor size (P = 0.037) and TIL status (P = 0.001) were independent predictors of anthracycline response. In the second cohort, adjuvant anthracycline-based therapy was associated with increased disease-free survival (DFS) only in patients with high levels of intraepithelial CD3+ TIL (P = 0.0023). In contrast, outcomes after CMF treatment (cyclophosphamide, methotrexate, and fluorouracil) showed no association with CD3 status. In both cohorts, cytotoxic T-cells were the primary TIL subtype associated with anthracycline sensitivity. Finally, TIL significantly predicted anthracycline sensitivity for both the Her2-positive and triple-negative tumor phenotypes.

Conclusions

ER-negative breast cancers with high levels of TIL have heightened sensitivity to anthracycline-based chemotherapy, as assessed by the immediate response to neoadjuvant therapy and long-term outcome following adjuvant therapy. Investigations of TIL-based predictive tests to identify patients likely to benefit from anthracycline-based treatments are warranted.
Short women with severe sepsis-related acute lung injury receive lung protective ventilation less frequently: an observational cohort study
Authors: Han SeungHye , Martin Greg S , Maloney James P , Shanholtz Carl , Barnes Kathleen C , Murray Stacey , Sevransky Jonathan E
Published: December 2011

Introduction

Lung protective ventilation (LPV) has been shown to improve survival and the duration of mechanical ventilation in acute lung injury (ALI) patients. Mortality of ALI may vary by gender, which could result from treatment variability. Whether gender is associated with the use of LPV is not known.

Methods

A total of 421 severe sepsis-related ALI subjects in the Consortium to Evaluate Lung Edema Genetics from seven teaching hospitals between 2002 and 2008 were included in our study. We evaluated patients' tidal volume, plateau pressure and arterial pH to determine whether patients received LPV during the first two days after developing ALI. The odds ratio of receiving LPV was estimated by a logistic regression model with robust and cluster options.

Results

Women had similar characteristics as men with the exception of lower height and higher illness severity, as measured by Acute Physiology and Chronic Health Evaluation (APACHE) II score. 225 (53%) of the subjects received LPV during the first two days after ALI onset; women received LPV less frequently than men (46% versus 59%, P < 0.001). However, after adjustment for height and severity of illness (APACHE II), there was no difference in exposure to LPV between men and women (P = 0.262).

Conclusions

Short people are less likely to receive LPV, which seems to explain the tendency of clinicians to adhere to LPV less strictly in women. Strategies to standardize application of LPV, independent of differences in height and severity of illness, are necessary.
Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? An observational study
Authors: Johansson Pär I , Sørensen Anne Marie , Perner Anders , Welling Karen Lise , Wanscher Michael , Larsen Claus F , Ostrowski Sisse R
Published: December 2011

Introduction

It is debated whether early trauma-induced coagulopathy (TIC) in severely injured patients reflects disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype, acute coagulopathy of trauma shock (ACoTS) or yet other entities. This study investigated the prevalence of overt DIC and ACoTS in trauma patients and characterized these conditions based on their biomarker profiles.

Methods

An observational study was carried out at a single Level I Trauma Center. Eighty adult trauma patients (≥18 years) who met criteria for full trauma team activation and had an arterial cannula inserted were included. Blood was sampled a median of 68 minutes (IQR 48 to 88) post-injury. Data on demography, biochemistry, injury severity score (ISS) and mortality were recorded. Plasma/serum was analyzed for biomarkers reflecting tissue/endothelial cell/glycocalyx damage (histone-complexed DNA fragments, Annexin V, thrombomodulin, syndecan-1), coagulation activation/inhibition (prothrombinfragment 1+2, thrombin/antithrombin-complexes, antithrombin, protein C, activated protein C, endothelial protein C receptor, protein S, tissue factor pathway inhibitor, vWF), factor consumption (fibrinogen, FXIII), fibrinolysis (D-dimer, tissue-type plasminogen activator, plasminogen activator inhibitor-1) and inflammation (interleukin (IL)-6, terminal complement complex (sC5b-9)). Comparison of patients stratified according to the presence or absence of overt DIC (International Society of Thrombosis and Hemostasis (ISTH) criteria) or ACoTS (activated partial thromboplastin time (APTT) and/or international normalized ratio (INR) above normal reference).

Results

No patients had overt DIC whereas 15% had ACoTS. ACoTS patients had higher ISS, transfusion requirements and mortality (all P < 0.01) and a biomarker profile suggestive of enhanced tissue, endothelial cell and glycocalyx damage and consumption coagulopathy with low protein C, antithrombin, fibrinogen and FXIII levels, hyperfibrinolysis and inflammation (all P < 0.05). Importantly, in non-ACoTS patients, apart from APTT/INR, higher ISS correlated with biomarkers of enhanced tissue, endothelial cell and glycocalyx damage, protein C activation, coagulation factor consumption, hyperfibrinolysis and inflammation, that is, resembling that observed in patients with ACoTS.

Conclusions

ACoTS and non-ACoTS may represent a continuum of coagulopathy reflecting a progressive early evolutionarily adapted hemostatic response to the trauma hit and both are parts of TIC whereas DIC does not appear to be part of this early response.
Rv2468c, a novelMycobacterium tuberculosisprotein that costimulates human CD4+ T cells through VLA-5
Authors: Li Qing , Ding Xuedong , Thomas Jeremy J , Harding Clifford V , Pecora Nicole D , Ziady Assem G , Shank Samuel , Boom W Henry , Lancioni Christina L , Rojas Roxana E
Published: December 2011

Mtb regulates many aspects of the host immune response, including CD4+ T lymphocyte responses that are essential for protective immunity to Mtb, and Mtb effects on the immune system are paradoxical, having the capacity to inhibit (immune evasion) and to activate (adjuvant effect) immune cells. Mtb regulates CD4+ T cells indirectly (e.g., by manipulation of APC function) and directly, via integrins and TLRs expressed on T cells. We now report that previously uncharacterized Mtb protein Rv2468c/MT2543 can directly regulate human CD4+ T cell activation by delivering costimulatory signals. When combined with TCR stimulation (e.g., anti-CD3), Rv2468c functioned as a direct costimulator for CD4+ T cells, inducing IFN-γ secretion and T cell proliferation. Studies with blocking antibodies and soluble RGD motifs demonstrated that Rv2468c engaged integrin VLA-5 (α5β1) on CD4+ T cells through its FN-like RGD motif. Costimulation by Rv2468c induced phosphorylation of FAKs and Pyk2. These results reveal that by expressing molecules that mimic host protein motifs, Mtb can directly engage receptors on CD4+ T cells and regulate their function. Rv2468c-induced costimulation of CD4+ T cells could have implications for TB immune pathogenesis and Mtb adjuvant effect.
Students Study Up the University
Authors: Hunter Gina
Published: December 2011

College students often use the campus as a venue for their course-based research activities. More often than not, however, the university is simply a locus of research, not a subject of student inquiry. In this article, I consider what can be gained when students “study up” the university as an institution. I draw on data from my undergraduate students' research process in an ethnographic methods course at Illinois State University. I argue that an institutional focus provides an especially effective approach for teaching ethnographic methods — one that differs from standard introductory textbook instruction in ethnography and that helps students avoid routine pitfalls of beginning ethnographic research. In particular, I argue that the university focus enables novice students to analyze fine-grained ethnographic data within a middle-range institutional context without macrosocial theories and frameworks that are likely beyond the scope of their semester-long projects. I also argue that an institutional focus can help students become more engaged, critical stakeholders in the university community.
Critical Editing and Close Reading in the Undergraduate Classroom
Authors: Kelemen Erick
Published: December 2011

Textual criticism, often ignored or confined to graduate study, is academic writing based on close reading and therefore is ideal for undergraduate study because it teaches readers to be more careful and skeptical. Critical editing assignments require students to negotiate historical evidence and aesthetic judgment for themselves, addressing questions of literary value.
Anatomy of right superior septal artery demonstrated on the coronary CT scan
Authors: Takeguchi Takaya , Ibukuro Kenji , Fukuda Hozumi , Tobe Kimiko , Abe Shoko
Published: December 2011

Background

A coronary CT scan allows for non-invasive visualization of the anatomy of a coronary artery in three dimensions compared to the two dimensions afforded by conventional angiography. The septal artery, the main blood source of the interventricular septum, is usually derived from the left anterior descending artery; however, it is occasionally derived from the right coronary artery.

Purpose

To analyze the prevalence, origin, diameter, and length of the right superior septal artery (RSSA) demonstrated on a coronary CT scan.

Material and Methods

The right superior septal artery was retrospectively reviewed on the reconstructed axial scan images (0.5-mm thickness, 0.25-mm interval) in 1290 consecutive patients who underwent coronary CT scans. All patients were scanned on a 320-row CT scanner. The images were transferred to a workstation to trace the vessel to analyze the origin, diameter, and length. We also compared the length of the RSSA between patients with and without coronary artery stenosis.

Results

The RSSA was identified in 51 (3.9%) of 1290 patients. The origin was the proximal portion of the right coronary artery ( n = 40) or the right sinus of Valsalva ( n = 11). The artery co-existed with the conus artery in 15 (29%) of 51 patients. The length was 16–62 mm (mean 31.2 mm ± 10.5), and the diameter was 0.8–2.0 mm (mean 1.3 mm ± 0.2). Longer RSSAs tended to be demonstrated in the patients with coronary artery stenosis rather than with normal coronary arteries ( P < 0.05).

Conclusion

The right superior septal artery and its anatomical variant could be analyzed with a coronary CT scan. The ability to demonstrate this artery on the coronary CT scan was the same as with coronary angiography. The recognition of this vessel is useful for physicians managing with the diagnosis and treatment of the coronary artery disease.