bluuebunny/crossref_metadata_2025 huggingface dataset:
A Content Analysis of Nutrition Education Curricula Used With Low-Income Audiences
Authors: Hernández-Garbanzo Yenory , Griffin Sarah , Cason Katherine L. , Loberger Ginger , Williams Joel , Baker Susan , Coffee Aubrey , Linton Brittney , Hall Trisha , Hayden Victoria
Published: November 2012

In developing recommendations for core measures/items for the evaluation of the Youth Expanded Food and Nutrition Education Program (EFNEP), three nutrition education curricula, implemented by land grant universities, were content analyzed. Selection criteria included the following: Curriculum content must include all EFNEP core content areas and must be implemented in more than one state with school children in third through fifth grades. Content analysis strategies were employed to identify and describe common areas/themes and mediators of behaviors addressed across the selected curricula. Content analysis coding was based on a list of behavioral mediators, which have empirical associations with nutrition, physical activity, and food safety. The most evident approaches identified across the three curricula were to enhance motivation, teach cognitive knowledge, and practice behavioral skills. The presence of self-regulation and environmental theory–based strategies was limited in all three curricula. In addition, multiple themes for nutrition, physical activity, and food safety were commonly addressed across curricula with multiple educational strategies. Based on these findings, recommendations for developing content appropriate measures and items for an outcome evaluation tool for Youth EFNEP are provided.
Using Photovoice as a Participatory Evaluation Tool in Kaiser Permanente’s Community Health Initiative
Authors: Kramer Leila , Schwartz Pamela , Cheadle Allen , Rauzon Suzanne
Published: November 2012

Photovoice is a community-based participatory research method that provides participants who traditionally have little voice in community policy decisions, with training in photography, ethics, critical dialogue, photo captioning, and policy advocacy. Photovoice has been used primarily as a needs assessment and advocacy tool and only rarely as a pre-/postintervention evaluation method. This article describes the use of Photovoice as a participatory evaluation method in the Community Health Initiative, a 6-year, multisite community-based obesity prevention initiative, sponsored by Kaiser Permanente. Fifty community participants (including six youth) from six Community Health Initiative communities used photos and captions to identify, from their perspective, the most significant accomplishments from the initiative at both baseline and follow-up. Accomplishments identified included increased access to fresh/healthy food in local neighborhoods; policy changes supporting a “healthy eating, active living” community; increased access to physical activity; changes to the built environment creating increased neighborhood walkability/safety; and leadership development.
Development of STEADI
Authors: Stevens Judy A. , Phelan Elizabeth A.
Published: November 2012

Falls among people aged ≥65 years are the leading cause of both injury deaths and emergency department visits for trauma. Research shows that many falls are preventable. In the clinical setting, an effective fall intervention involves assessing and addressing an individual’s fall risk factors. This individualized approach is recommended in the American and British Geriatrics Societies’ (AGS/BGS) practice guideline. This article describes the development of STEADI (Stopping Elderly Accidents, Deaths, and Injuries), a fall prevention tool kit that contains an array of health care provider resources for assessing and addressing fall risk in clinical settings. As researchers at the Centers for Disease Control and Prevention’s Injury Center, we reviewed relevant literature and conducted in-depth interviews with health care providers to determine current knowledge and practices related to older adult fall prevention. We developed draft resources based on the AGS/BGS guideline, incorporated provider input, and addressed identified knowledge and practice gaps. Draft resources were reviewed by six focus groups of health care providers and revised. The completed STEADI tool kit, Preventing Falls in Older Patients—A Provider Tool Kit, is designed to help health care providers incorporate fall risk assessment and individualized fall interventions into routine clinical practice and to link clinical care with community-based fall prevention programs.
Australian Blue-Collar Men’s Health and Well-Being
Authors: Du Plessis Karin , Cronin David , Corney Tim , Green Emma
Published: November 2012

In Australia, blue-collar workers are predominantly male and form a unique and large (approximately 30%) subset of the Australian workforce. They exhibit particular health-related issues and, in comparison to other groups, often a lack of health promoting behavior. This article briefly discusses the Australian context and some of the key health issues blue-collar men face, in particular as it relates to construction workers. It reviews the impact of gender and socioeconomic factors in designing workplace health promotion interventions. This article considers practice strategies for health promoters in a specific workplace setting: it looks at meta-factors and industry-based contextual factors, including barriers to implementation and participation, while addressing common misconceptions about Australian blue-collar workers.
Linking Physical Education With Community Sport and Recreation
Authors: Casey Meghan , Mooney Amanda , Eime Rochelle , Harvey Jack , Smyth John , Telford Amanda , Payne Warren
Published: November 2012

The engagement of adolescent girls in physical activity (PA) is a persistent challenge. School-based PA programs have often met with little success because of the lack of linkages between school and community PA settings. The Triple G program aimed to improve PA levels of secondary school girls (12-15 years) in regional Victoria, Australia. The program included a school-based physical education (PE) component that uniquely incorporated student-centered teaching and behavioral skill development. The school component was conceptually and practically linked to a community component that emphasized appropriate structures for participation. The program was informed by ethnographic fieldwork to understand the contextual factors that affect girls’ participation in PA. A collaborative intervention design was undertaken to align with PE curriculum and coaching and instructional approaches in community PA settings. The theoretical framework for the intervention was the socioecological model that was underpinned by both individual-level (social cognitive theory) and organizational-level (building organizational/community capacity) strategies. The program model provides an innovative conceptual framework for linking school PE with community sport and recreation and may benefit other PA programs seeking to engage adolescent girls. The objective of this article is to describe program development and the unique theoretical framework and curriculum approaches.
The Effects of an Aerobic and Resistance Exercise Training Program on Cognition Following Stroke
Authors: Marzolini Susan , Oh Paul , McIlroy William , Brooks Dina
Published: November 2012

Background. Cognitive benefits obtained from exercise in healthy populations support the idea that aerobic and resistance training (AT+RT) would confer benefit for poststroke recovery. However, there is little evidence regarding the effectiveness of such programs. Objective. To evaluate the effects of a 6-month exercise program of AT+RT on cognition in consecutively enrolled patients with motor impairments ≥10 weeks poststroke. Methods. Outcomes were measured before and after 6 months of AT+RT on 41 patients. Cognition was measured by the Montreal Cognitive Assessment (MoCA). Secondary measures included evaluation of gas exchange anaerobic threshold (ATge), body composition by dual energy X-ray absorptiometry, and depressive symptoms by questionnaire. Results. There were significant improvements in overall MoCA scores (22.5 ± 4.5 to 24.0 ± 3.9, P < .001) as well as in the subdomains of attention/concentration (4.7 ± 1.7 to 5.2 ± 1.3, P = .03) and visuospatial/executive function (3.4 ± 1.1 to 3.9 ± 1.1, P = .002). There was a significant reduction in the proportion of patients meeting the threshold criteria for mild cognitive impairment (MCI) at baseline compared with posttraining (65.9% vs 36.6%, P < .001). In a linear regression model, there was a positive association between change in cognitive function and change in fat-free mass of the nonaffected limbs (β = .002; P = .005) and change in attention/concentration and change in ATge (β = .383; P ≤ .001), independent of age, sex, time from stroke, and change in fat mass and depression score. Conclusion. A combined training model (AT+RT) resulted in improvements in cognitive function and a reduction in the proportion of patients meeting the threshold criteria for MCI. Change in cognition was positively associated with change in fat-free mass and ATge.
Motor Representations in the Intact Hemisphere of the Rat Are Reduced After Repetitive Training of the Impaired Forelimb
Authors: Barbay Scott , Guggenmos David J. , Nishibe Mariko , Nudo Randolph J.
Published: November 2012

Background. During recovery from a unilateral cortical stroke, spared cortical motor areas in the contralateral (intact) cerebral cortex are recruited. Preclinical studies have demonstrated that compensation with the less-impaired limb may have a detrimental inhibitory effect on the intact cortical hemisphere and could impede recovery of the more-impaired limb. However, evidence from detailed neurophysiological mapping studies in animal models is lacking. Objectives. The present study examines neurophysiological changes in the intact hemisphere of the rat following a unilateral ischemic infarct to cortical forelimb motor areas. Methods. A total of 8 rats were trained for 2 weeks on a reach and retrieval task prior to an ischemic infarct induced by the vasoconstrictor endothelin-1 injected into the cortical gray matter encompassing the 2 forelimb motor representations: the caudal forelimb area (CFA) and the rostral forelimb area (RFA). Animals were randomly assigned to an infarct/training group (n = 4) or an infarct/no-training group (ie, spontaneous recovery, n = 4). After a 5-week postinfarct period, motor areas of the intact hemisphere (CFA and RFA) were characterized using intracortical microstimulation techniques. The resulting maps of evoked movements were compared with maps derived from CFA and RFA in normal rats (normal, n = 5; normal/training, n = 4). Results. Compared with the normal/no-training group, CFA representations were significantly smaller in the infarct/training group but not in the infarct/no-training group. No significant differences were found in RFA. Conclusions. Repetitive training of the more-impaired forelimb during the postinfarct recovery period reduces the size of motor representations in the intact hemisphere.
Meeting the Leadership Challenge of Employee Well-Being Through Relationship PsyCap and Health PsyCap
Authors: Luthans Fred , Youssef Carolyn M. , Sweetman David S. , Harms Peter D.
Published: November 2012

Increasing recognition is being given to the role that employee overall well-being plays in desired outcomes of today’s organizations. To help organizational leaders searching for understanding and answers, we propose that the positive core construct of psychological capital (or simply PsyCap), consisting of the positive psychological resources of hope, efficacy, resiliency, and optimism can be extended into the well-being domain. Although PsyCap has been clearly demonstrated to be related to employee attitudes, behaviors, and performance, linking it with other life domains relevant to overall well-being has yet to be tested. After first building a comprehensive conceptual foundation for extending PsyCap into the well-being domain, we empirically found that a cross section of employees’ ( N = 523) “Relationship PsyCap” and “Health PsyCap” were related to both their respective satisfaction appraisals and desired objective outcomes. In addition, these two extended life satisfactions, along with the already well-established work satisfaction, combined to relate to the appraisal of the study participants’ overall well-being. This well-being was in turn found to be related to their overall level of PsyCap. These findings have implications for helping leaders meet the challenges they face in both understanding and helping develop the overall well-being of their employees.
No Sex Please, We Are Finite State Machines
Authors: Gallagher Rob
Published: November 2012

Despite the fact that most players of video games are now adults, the medium continues to shy away from the question of sex. This article considers some of the reasons for this reticence, offering close readings of a number of games in which sex’s absence seems especially significant. Attending to these absences can, I argue, throw light on some prevalent misconceptions regarding the nature of video games and the appeal of play. Debates concerning games and sex reveal that commentators, critics, and game developers alike are, by and large, still too ready to judge games using standards developed in relation to other media forms. In doing so they tend both to ignore games’ unique characteristics and to misrepresent their potential as vehicles for creative expression—a potential suggested by the ways in which the medium has already begun to explore how technology is altering our understanding of sex.
Impact of prior systemic corticosteroid use in patients admitted with community-acquired pneumonia
Authors: Malave Adriel , Laserna Elena , Sibila Oriol , Mortensen Eric M. , Anzueto Antonio , Restrepo Marcos I.
Published: November 2012

Background and objective:

Limited information is available regarding the impact of prior outpatient use of systemic corticosteroids (SCS) in patients subsequently developing community-acquired pneumonia (CAP). We investigate the effects of prior SCS on severity of illness, microbiology and clinical outcomes for patients hospitalized with CAP.

Methods:

A retrospective cohort study of subjects with CAP (according to International Classification of Diseases, 9th edition codes) was conducted over a 3-year period at two tertiary teaching hospitals. Subjects were considered to be SCS users if they received oral corticosteroids prior to admission. Primary outcomes were severity of illness, microbiology and 30-day mortality.

Results:

Data were abstracted on 698 patients [prior SCS users, 75 (10.7%) versus prior non-SCS users 623 (89.3%)]. Prior SCS users were more likely to have chronic obstructive pulmonary disease. No differences were found in severity of disease at admission, microbiological etiology including opportunistic and drug-resistant pathogens and clinical outcomes, including 30-day mortality, intensive care unit admission, length of hospital stay, need for mechanical ventilation and need for vasopressors.

Conclusion:

Prior SCS use is not associated with increased 30-day mortality for patients hospitalized with CAP. In addition, no differences were found in either the severity of the disease at the time of presentation or in the presence of the resistant or opportunistic pathogens among groups.
Applying the Loyalty Matrix to Evaluate Casino Loyalty Programs
Authors: Tanford Sarah , Baloglu Seyhmus
Published: November 2012

A well-established loyalty matrix classifies customers into four quadrants based on their frequency of purchase and attitude toward a hospitality business. These quadrants represent four distinct types of loyalty, according to combinations of patronage frequency and attitude favorability: true, latent, spurious, and low. Using a sample of casino reward club members, we applied cluster analysis to classify customers based on behavioral loyalty, defined as player gaming worth and visitation frequency; and on attitudinal loyalty, defined as emotional commitment and trust. We obtained empirical support for the existence of all four quadrants, and validated these quadrants on additional loyalty-related attributes. Truly loyal customers have high attitudinal and behavioral loyalty on all indicators, whereas customers with latent loyalty have favorable attitudes but low levels of visitation and gaming behavior, possibly due to income limitations. Spuriously loyal customers have high behavioral loyalty but very low attitudinal loyalty. These customers place a high value on reward program benefits, suggesting that such benefits are driving their behavior. Customers with low loyalty are low in both attitudes and behaviors.
In vitro chondrogenic differentiation of human adipose-derived stem cells with silk scaffolds
Authors: Kim Hyeon Joo , Park Sang-Hyug , Durham Jennah , Gimble Jeffrey M , Kaplan David L , Dragoo Jason L
Published: November 2012

Human adipose-derived stem cells have shown chondrogenic differentiation potential in cartilage tissue engineering in combination with natural and synthetic biomaterials. In the present study, we hypothesized that porous aqueous-derived silk protein scaffolds would be suitable for chondrogenic differentiation of human adipose-derived stem cells. Human adipose-derived stem cells were cultured up to 6 weeks, and cell proliferation and chondrogenic differentiation were investigated and compared with those in conventional micromass culture. Cell proliferation, glycosaminoglycan, and collagen levels in aqueous-derived silk scaffolds were significantly higher than in micromass culture. Transcript levels of SOX9 and type II collagen were also upregulated in the cell–silk constructs at 6 weeks. Histological examination revealed that the pores of the silk scaffolds were filled with cells uniformly distributed. In addition, chondrocyte-specific lacunae formation was evident and distributed in the both groups. The results suggest the biodegradable and biocompatible three-dimensional aqueous-derived silk scaffolds provided an improved environment for chondrogenic differentiation compared to micromass culture.
Health Policy and Ethics: A Catholic Contribution in a Pluralistic Society
Authors: Flaman Paul
Published: November 2012

Health policy generally seeks to improve the overall health of people in society. Since public health policy involves human values, decisions, and actions, it is inescapably ethical. In recent years there has been a growing awareness of the need for a systematic approach to the ethical analysis of public policy. Some government health-policy statements attempt to provide ethical frameworks. In our pluralistic societies, however, these tend to be pragmatic and lack a solid grounding in an adequate understanding of the human person. This could lead to justifying what is popular rather than what is ethical. This article attempts to show how a Catholic moral approach, which provides a solid foundation for ethics, can make a significant contribution to a discussion of health-policy ethics in a pluralistic society.
Current Medical Research Summer–Fall 2009
Authors: Fehring Richard J.
Published: November 2012

Note that the “Current Medical Research” feature focuses on issues relevant to natural family planning and the beginning of life. This piece is complemented by medical reviews published in The National Catholic Bioethics Quarterly, which focus more on other areas of general medical interest including end-of-life issues.—Ed.
Catholic Moral Teaching and the Conceivex Conception Kit Infertility Treatment Method
Authors: Rivet Edward L.
Published: November 2012

Catholic moral teaching with regard to infertility treatment and assisted reproductive technologies continues to evolve. Still, some uncertainties remain as to the licitness of various technologies. A new FDA-cleared product, the Conception Kit, developed by Conceivex, Inc., is a coital-based method of fertility enhancement designed such that the spouses remain sole agents of their procreative actions, in the privacy of their own home. This article provides a review and analysis of current Catholic moral teaching and how the Conception Kit relates to that teaching.
Sexual Abuse of Minors by Catholic Clergy
Authors: Fitzgibbons Richard , O'Leary Dale
Published: November 2012

The reports The Nature and Scope of Sexual Abuse of Minors by Catholic Priests and Deacons in the United States 1950–2002 and the Supplementary Data Analysis, and The Causes and Context study (2011) by the John Jay College of Criminal Justice, commissioned by the U.S. Conference of Catholic Bishops, concluded that the childhood and adolescent sexual abuse committed by clergy was totally unrelated to homosexuality. The latest John Jay attempt to explain the deliberate homosexual predation and abuse of adolescent males, the primary victims in the crisis, as a crime of opportunity ignores the severe psychological conflicts and grooming behaviors in priests who offended against minors. This article discusses why the studies used to support the view of the abuse of minors as being not related to homosexuality are not applicable to the problem of clergy childhood sexual abuse. The data in the John Jay reports strongly suggests that homosexual abuse of adolescent males is at the heart of the crisis. The psychological causes of homosexual attraction in men to adolescent males are presented. A number of well-designed studies have found that men with SSA are more likely to have psychiatric and substance abuse disorders and STDs than heterosexual males, and are more likely to have a positive attitude to sexual relations between adult and adolescent males. Competent mental-health professionals should offer a second opinion about the causes of the crisis in regard to the psychological conflicts in the priests. Also, priests and seminarians with deep-seated homosexual tendencies have a serious responsibility to pursue appropriate treatment and spiritual direction in order to protect adolescent males, in particular, and the Church from further damage.
Disease-associated missense mutations in the EVH1 domain disrupt intrinsic WASp function causing dysregulated actin dynamics and impaired dendritic cell migration
Authors: Worth Austen J. J. , Metelo Joao , Bouma Gerben , Moulding Dale , Fritzsche Marco , Vernay Bertrand , Charras Guillaume , Cory Giles O. C. , Thrasher Adrian J. , Burns Siobhan O.
Published: November 2012

Wiskott Aldrich syndrome (WAS), an X-linked immunodeficiency, results from loss-of-function mutations in the human hematopoietic cytoskeletal regulator gene WAS. Many missense mutations in the Ena Vasp homology1 (EVH1) domain preserve low-level WAS protein (WASp) expression and confer a milder clinical phenotype. Although disrupted binding to WASp-interacting protein (WIP) leads to enhanced WASp degradation in vivo, the intrinsic function of EVH1-mutated WASp is poorly understood. In the present study, we show that, despite mediating enhanced actin polymerization compared with wild-type WASp in vitro, EVH1 missense mutated proteins did not support full biologic function in cells, even when levels were restored by forced overexpression. Podosome assembly was aberrant and associated with dysregulated lamellipodia formation and impaired persistence of migration. At sites of residual podosome-associated actin polymerization, localization of EVH1-mutated proteins was preserved even after deletion of the entire domain, implying that WIP-WASp complex formation is not absolutely required for WASp localization. However, retention of mutant proteins in podosomes was significantly impaired and associated with reduced levels of WASp tyrosine phosphorylation. Our results indicate that the EVH1 domain is important not only for WASp stability, but also for intrinsic biologic activity in vivo.
Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature
Authors: Kleinschnitz Christoph , Kraft Peter , Dreykluft Angela , Hagedorn Ina , Göbel Kerstin , Schuhmann Michael K. , Langhauser Friederike , Helluy Xavier , Schwarz Tobias , Bittner Stefan , Mayer Christian T. , Brede Marc , Varallyay Csanad , Pham Mirko , Bendszus Martin , Jakob Peter , Magnus Tim , Meuth Sven G. , Iwakura Yoichiro , Zernecke Alma , Sparwasser Tim , Nieswandt Bernhard , Stoll Guido , Wiendl Heinz
Published: November 2012

We have recently identified T cells as important mediators of ischemic brain damage, but the contribution of the different T-cell subsets is unclear. Forkhead box P3 (FoxP3)–positive regulatory T cells (Tregs) are generally regarded as prototypic anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. In the present study, we examined the role of Tregs after experimental brain ischemia/reperfusion injury. Selective depletion of Tregs in the DEREG mouse model dramatically reduced infarct size and improved neurologic function 24 hours after stroke and this protective effect was preserved at later stages of infarct development. The specificity of this detrimental Treg effect was confirmed by adoptive transfer experiments in wild-type mice and in Rag1−/− mice lacking lymphocytes. Mechanistically, Tregs induced microvascular dysfunction in vivo by increased interaction with the ischemic brain endothelium via the LFA-1/ICAM-1 pathway and platelets and these findings were confirmed in vitro. Ablation of Tregs reduced microvascular thrombus formation and improved cerebral reperfusion on stroke, as revealed by ultra-high-field magnetic resonance imaging at 17.6 Tesla. In contrast, established immunoregulatory characteristics of Tregs had no functional relevance. We define herein a novel and unexpected role of Tregs in a primary nonimmunologic disease state.
IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors
Authors: Cieri Nicoletta , Camisa Barbara , Cocchiarella Fabienne , Forcato Mattia , Oliveira Giacomo , Provasi Elena , Bondanza Attilio , Bordignon Claudio , Peccatori Jacopo , Ciceri Fabio , Lupo-Stanghellini Maria Teresa , Mavilio Fulvio , Mondino Anna , Bicciato Silvio , Recchia Alessandra , Bonini Chiara
Published: November 2012

Long-living memory stem T cells (TSCM) with the ability to self-renew and the plasticity to differentiate into potent effectors could be valuable weapons in adoptive T-cell therapy against cancer. Nonetheless, procedures to specifically target this T-cell population remain elusive. Here, we show that it is possible to differentiate in vitro, expand, and gene modify in clinically compliant conditions CD8+ TSCM lymphocytes starting from naive precursors. Requirements for the generation of this T-cell subset, described as CD62L+CCR7+CD45RA+CD45R0+IL-7Rα+CD95+, are CD3/CD28 engagement and culture with IL-7 and IL-15. Accordingly, TSCM accumulates early after hematopoietic stem cell transplantation. The gene expression signature and functional phenotype define this population as a distinct memory T-lymphocyte subset, intermediate between naive and central memory cells. When transplanted in immunodeficient mice, gene-modified naive-derived TSCM prove superior to other memory lymphocytes for the ability to expand and differentiate into effectors able to mediate a potent xenogeneic GVHD. Furthermore, gene-modified TSCM are the only T-cell subset able to expand and mediate GVHD on serial transplantation, suggesting self-renewal capacity in a clinically relevant setting. These findings provide novel insights into the origin and requirements for TSCM generation and pave the way for their clinical rapid exploitation in adoptive cell therapy.
The constitutive androstane receptor is a novel therapeutic target facilitating cyclophosphamide-based treatment of hematopoietic malignancies
Authors: Wang Duan , Li Linhao , Yang Hui , Ferguson Stephen S. , Baer Maria R. , Gartenhaus Ronald B. , Wang Hongbing
Published: November 2012

Cyclophosphamide (CPA) is one of the most widely used chemotherapeutic prodrugs that undergoes hepatic bioactivation mediated predominantly by cytochrome P450 (CYP) 2B6. Given that the CYP2B6 gene is primarily regulated by the constitutive androstane receptor (CAR, NR1I3), we hypothesize that selective activation of CAR can enhance systemic exposure of the pharmacologically active 4-hydroxycyclophosamide (4-OH-CPA), with improved efficacy of CPA-based chemotherapy. In this study, we have developed a unique human primary hepatocyte (HPH)–leukemia cell coculture model; the chemotherapeutic effects of CPA on leukemia cells can be directly investigated in vitro in a cellular environment where hepatic metabolism was well maintained. Our results demonstrated that activation of CAR preferentially induces the expression of CYP2B6 over CYP3A4 in HPHs, although endogenous expression of these enzymes in leukemia cells remains negligible. Importantly, coadministration of CPA with a human CAR activator led to significantly enhanced cytotoxicity in leukemia cells by inducing the apoptosis pathways, without concomitant increase in the off-target hepatotoxicity. Associated with the enhanced antitumor activity, a time and concentration-dependent increase in 4-OH-CPA formation was observed in the coculture system. Together, our findings offer proof of concept that CAR as a novel molecular target can facilitate CPA-based chemotherapy by selectively promoting its bioactivation.
Myelopoiesis is regulated by osteocytes through Gsα-dependent signaling
Authors: Fulzele Keertik , Krause Daniela S. , Panaroni Cristina , Saini Vaibhav , Barry Kevin J. , Liu Xiaolong , Lotinun Sutada , Baron Roland , Bonewald Lynda , Feng Jian Q. , Chen Min , Weinstein Lee S. , Wu Joy Y. , Kronenberg Henry M. , Scadden David T. , Divieti Pajevic Paola
Published: November 2012

Key Points

Deletion of Gsα in osteocytes induces severe osteopenia and a dramatic expansion of cells of the myeloid lineage. Osteocytes regulate hematopoiesis and specifically contribute to myelopoiesis by secreting proliferative factors such as G-CSF.
Distinct severity of HLH in both human and murine mutants with complete loss of cytotoxic effector PRF1, RAB27A, and STX11
Authors: Sepulveda Fernando E. , Debeurme Franck , Ménasché Gaël , Kurowska Mathieu , Côte Marjorie , Pachlopnik Schmid Jana , Fischer Alain , de Saint Basile Geneviève
Published: November 2012

Inherited defects of granule-dependent cytotoxicity led to the life-threatening immune disorder hemophagocytic lymphohistiocytosis (HLH), characterized by uncontrolled CD8 T-cell and macrophage activation. In a cohort of HLH patients with genetic abnormalities expected to result in the complete absence of perforin, Rab27a, or syntaxin-11, we found that disease severity as determined by age at HLH onset differed significantly, with a severity gradient from perforin (early onset) > Rab27a > syntaxin-11 (late onset). In parallel, we have generated a syntaxin-11–deficient (Stx11−/−) murine model that faithfully reproduced the manifestations of HLH after lymphocytic choriomeningitis virus (LCMV) infection. Stx11−/− murine lymphocytes exhibited a degranulation defect that could be rescued by expression of human syntaxin-11 but not expression of a C-terminal–truncated mutant. Comparison of the characteristics of LCMV infection-induced HLH in the murine counterparts of the 3 human conditions revealed a similar gradient in the phenotypic severity of HLH manifestations. Strikingly, the severity of HLH was not correlated with the LCMV load and not fully with differences in the intensity of cytotoxic activity. The capacity of antigen presentation differed in vivo between Rab27a- and Syntaxin-11–deficient mutants. Our data indicate that cytotoxic effectors may have other immune-regulatory roles in addition to their role in controlling viral replication.
Incremental value in outcome prediction with gene expression–based signatures in diffuse large B-cell lymphoma
Authors: Hong Fangxin , Kahl Brad S. , Gray Robert
Published: November 2012

Multiple gene expression–based signatures have been identified in diffuse large B-cell lymphoma that are predictive for survival outcomes. Most studies assess predictive significance based on P values from multivariable Cox regression. Few investigations have evaluated the incremental usefulness of these signatures. Recent developments in statistical methodology extend the use of concordance measures on censored survival data. We applied these methods to evaluate the added value in survival risk prediction from 3 published gene-based signatures on 2 sets of patients with diffuse large B-cell lymphoma treated with CHOP or R-CHOP. Our results indicate these gene-based signatures are inferior to clinical factors and provide little added value in risk assessment. To develop highly discriminating risk prediction models, we need to use appropriate approaches and consider more than gene expression. However, the study of gene expression and clinical outcomes retains considerable potential to enhance understanding of disease mechanisms and uncover new therapeutic targets.
Heat shock protein 70 regulates Tcl1 expression in leukemia and lymphomas
Authors: Gaudio Eugenio , Paduano Francesco , Ngankeu Apollinaire , Lovat Francesca , Fabbri Muller , Sun Hui-Lung , Gasparini Pierluigi , Efanov Alexey , Peng Yong , Zanesi Nicola , Shuaib Mohammed A. , Rassenti Laura Z. , Kipps Thomas J. , Li Chenglong , Aqeilan Rami I. , Lesinski Gregory B. , Trapasso Francesco , Croce Carlo M.
Published: November 2012

T-cell leukemia/lymphoma 1 (TCL1) is an oncogene overexpressed in T-cell prolymphocytic leukemia and in B-cell malignancies including B-cell chronic lymphocytic leukemia and lymphomas. To date, only a limited number of Tcl1-interacting proteins that regulate its oncogenic function have been identified. Prior studies used a proteomic approach to identify a novel interaction between Tcl1 with Ataxia Telangiectasia Mutated. The association of Tcl1 and Ataxia Telangiectasia Mutated leads to activation of the NF-κB pathway. Here, we demonstrate that Tcl1 also interacts with heat shock protein (Hsp) 70. The Tcl1-Hsp70 complex was validated by coimmunoprecipitation experiments. In addition, we report that Hsp70, a protein that plays a critical role in the folding and maturation of several oncogenic proteins, associates with Tcl1 protein and stabilizes its expression. The inhibition of the ATPase activity of Hsp70 results in ubiquitination and proteasome-dependent degradation of Tcl1. The inhibition of Hsp70 significantly reduced the growth of lymphoma xenografts in vivo and down-regulated the expression of Tcl1 protein. Our findings reveal a functional interaction between Tcl1 and Hsp70 and identify Tcl1 as a novel Hsp70 client protein. These findings suggest that inhibition of Hsp70 may represent an alternative effective therapy for chronic lymphocytic leukemia and lymphomas via its ability to inhibit the oncogenic functions of Tcl1.
Some Hermite-Hadamard type inequalities for n-time differentiable "Equation missing" -convex functions
Authors: Bai Shu-Ping , Wang Shu-Hong , Qi Feng
Published: November 2012

In the paper, the famous Hermite-Hadamard integral inequality for convex functions is generalized to and refined as inequalities for n-time differentiable functions which are

(
α
,
m
)

-convex.

MSC: 26D15, 26A51, 41A55.
A standard numbering scheme for thiamine diphosphate-dependent decarboxylases
Authors: Vogel Constantin , Widmann Michael , Pohl Martina , Pleiss Jürgen
Published: November 2012

Background

Standard numbering schemes for families of homologous proteins allow for the unambiguous identification of functionally and structurally relevant residues, to communicate results on mutations, and to systematically analyse sequence-function relationships in protein families. Standard numbering schemes have been successfully implemented for several protein families, including lactamases and antibodies, whereas a numbering scheme for the structural family of thiamine-diphosphate (ThDP) -dependent decarboxylases, a large subfamily of the class of ThDP-dependent enzymes encompassing pyruvate-, benzoylformate-, 2-oxo acid-, indolpyruvate- and phenylpyruvate decarboxylases, benzaldehyde lyase, acetohydroxyacid synthases and 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexadiene-1-carboxylate synthase (MenD) is still missing.

Despite a high structural similarity between the members of the ThDP-dependent decarboxylases, their sequences are diverse and make a pairwise sequence comparison of protein family members difficult.

Results

We developed and validated a standard numbering scheme for the family of ThDP-dependent decarboxylases. A profile hidden Markov model (HMM) was created using a set of representative sequences from the family of ThDP-dependent decarboxylases. The pyruvate decarboxylase from S. cerevisiae (PDB: 2VK8) was chosen as a reference because it is a well characterized enzyme. The crystal structure with the PDB identifier 2VK8 encompasses the structure of the Sc PDC mutant E477Q, the cofactors ThDP and Mg2+ as well as the substrate analogue (2S)-2-hydroxypropanoic acid. The absolute numbering of this reference sequence was transferred to all members of the ThDP-dependent decarboxylase protein family. Subsequently, the numbering scheme was integrated into the already established Thiamine-diphosphate dependent Enzyme Engineering Database (TEED) and was used to systematically analyze functionally and structurally relevant positions in the superfamily of ThDP-dependent decarboxylases.

Conclusions

The numbering scheme serves as a tool for the reliable sequence alignment of ThDP-dependent decarboxylases and the unambiguous identification and communication of corresponding positions. Thus, it is the basis for the systematic and automated analysis of sequence-encoded properties such as structural and functional relevance of amino acid positions, because the analysis of conserved positions, the identification of correlated mutations and the determination of subfamily specific amino acid distributions depend on reliable multisequence alignments and the unambiguous identification of the alignment columns. The method is reliable and robust and can easily be adapted to further protein families.
PHB granules are attached to the nucleoid via PhaM in Ralstonia eutropha
Authors: Wahl Andreas , Schuth Nora , Pfeiffer Daniel , Nussberger Stephan , Jendrossek Dieter
Published: November 2012

Background

Poly(3-hydroxybutyrate) (PHB) granules are important storage compounds of carbon and energy in many prokaryotes which allow survival of the cells in the absence of suitable carbon sources. Formation and subcellular localization of PHB granules was previously assumed to occur randomly in the cytoplasm of PHB accumulating bacteria. However, contradictionary results on subcellular localization of PHB granules in Ralstonia eutropha were published, recently.

Results

Here, we provide evidence by transmission electron microscopy that PHB granules are localized in close contact to the nucleoid region in R. eutropha during growth on nutrient broth. Binding of PHB granules to the nucleoid is mediated by PhaM, a PHB granule associated protein with phasin-like properties that is also able to bind to DNA and to phasin PhaP5. Over-expression of PhaM resulted in formation of many small PHB granules that were always attached to the nucleoid region. In contrast, PHB granules of ∆phaM strains became very large and distribution of granules to daughter cells was impaired. Association of PHB granules to the nucleoid region was prevented by over-expression of PhaP5 and clusters of several PHB granules were mainly localized near the cell poles.

Conclusion

Subcellular localization of PHB granules is controlled in R. eutropha and depends on the presence and concentrations of at least two PHB granule associated proteins, PhaM and PhaP5.
PTENgenomic deletion predicts prostate cancer recurrence and is associated with low AR expression and transcriptional activity
Authors: Choucair Khalil , Ejdelman Joshua , Brimo Fadi , Aprikian Armen , Chevalier Simone , Lapointe Jacques
Published: November 2012

Background

Prostate cancer (PCa), a leading cause of cancer death in North American men, displays a broad range of clinical outcome from relatively indolent to lethal metastatic disease. Several genomic alterations have been identified in PCa which may serve as predictors of progression. PTEN, (10q23.3), is a negative regulator of the phosphatidylinositol 3-kinase (PIK3)/AKT survival pathway and a tumor suppressor frequently deleted in PCa. The androgen receptor (AR) signalling pathway is known to play an important role in PCa and its blockade constitutes a commonly used treatment modality. In this study, we assessed the deletion status of PTEN along with AR expression levels in 43 primary PCa specimens with clinical follow-up.

Methods

Fluorescence In Situ Hybridization (FISH) was done on formalin fixed paraffin embedded (FFPE) PCa samples to examine the deletion status of PTEN. AR expression levels were determined using immunohistochemistry (IHC).

Results

Using FISH, we found 18 cases of PTEN deletion. Kaplan-Meier analysis showed an association with disease recurrence (P=0.03). Concurrently, IHC staining for AR found significantly lower levels of AR expression within those tumors deleted for PTEN (P<0.05). To validate these observations we interrogated a copy number alteration and gene expression profiling dataset of 64 PCa samples, 17 of which were PTEN deleted. We confirmed the predictive value of PTEN deletion in disease recurrence (P=0.03). PTEN deletion was also linked to diminished expression of PTEN (P<0.01) and AR (P=0.02). Furthermore, gene set enrichment analysis revealed a diminished expression of genes downstream of AR signalling in PTEN deleted tumors.

Conclusions

Altogether, our data suggest that PTEN deleted tumors expressing low levels of AR may represent a worse prognostic subset of PCa establishing a challenge for therapeutic management.
Use of and factors associated with self-treatment in China
Authors: Yuefeng Li , Keqin Rao , Xiaowei Ren
Published: November 2012

Background

When an individual is ill or symptomatic, they have the options of seeking professional health care, self-treating or doing nothing. In China, some studies suggest that the number of individuals opting to self-treat has been rapidly increasing in recent years. Therefore, the aim of this study was to analyze the trends of and factors related to self-treatment in China.

Methods

Self-treatment was measured based the concept and data of the China National Health Survey (CNHS), which covers 802,454 individuals. We used CNHS data from 1993, 1998, 2003, and 2008, and a Multinomial Logit Selection Model to estimate the factors influencing the decision to self-treat.

Results

The prevalences of self-treatment with a recall period of two-weeks were significantly higher in urban compared with rural areas (31.2% vs 14.9% in 1993, 43.5% vs 21.4% in 1998, 47.2% vs 31.4% in 2003, 31.0% vs 25.3% in 2008) in China. Economic (per capita income, TV, sanitary water) and individual (education, profession, family members, exercise) factors, as well as accessibility to drugs had a positive association with the probability of self-treating. Different illness symptoms, severity, and duration show a negative association with the probability of self-treating, showing a degree of rationality in decision-making. Different insurance systems were also found to have an effect on self-treatment decision-making.

Conclusions

Self-treatment and professional medical services have shared the incremental medical needs of residents in recent years in China. Self-perceived illness status, economic circumstances, and education play important roles in health care decision-making.
Specialist trainees on rotation cannot replace dedicated consultant clinicians for antimicrobial stewardship of specialty disciplines
Authors: Yeo Chay Leng , Wu Jia En , Chung Gladys Wei-Teng , Chan Douglas Su-Gin , Fisher Dale , Hsu Li Yang
Published: November 2012

Our prospective-audit-and-feedback antimicrobial stewardship (AS) program for hematology and oncology inpatients was switched from one led by dedicated clinicians to a rotating team of infectious diseases trainees in order to provide learning opportunities and attempt a “de-escalation” of specialist input towards a more protocol-driven implementation. However, process indicators including the number of recommendations and recommendation acceptance rates fell significantly during the year, with accompanying increases in broad-spectrum antibiotic prescription. The trends were reversed only upon reverting to the original setup. Dedicated clinicians play a crucial role in AS programs involving immunocompromised patients. Structured training and adequate succession/contingency planning is critical for sustainability.
HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation
Authors: Liao Yi-Hsiang , Lin Yi-Chieh , Tsao Shih-Ting , Lin Ying-Cing , Yang Ai-Jen , Huang Chen-Tsung , Huang Kuo-Chin , Lin Wan Wan
Published: November 2012

Statin-induced caspase-1 activation and IL-1β release are due to unmask the anti-inflammatory action of isoprenoids by activating P2X7.

Recent studies have demonstrated the stimulatory effects of HMG-CoA reductase inhibitors, statins, on IL-1β secretion in monocytes and suggest a crucial role for isoprenoids in the inhibition of caspase-1 activity. In this study, we further elucidated the molecular mechanisms underlying the stimulatory effects of statins on caspase-1. Three commonly recognized mechanistic models for NLRP3 inflammasome activation (i.e., ATP/P2X7/K+ efflux, ROS production, and lysosomal rupture) were investigated in statin-stimulated human THP-1 monocytes. We found that fluvastatin and lovastatin can synergize with LPS to trigger inflammasome activation. Moreover, statin-induced caspase-1 activation and IL-1β production in LPS-primed THP-1 cells are dependent on GGPP deficiency and P2X7 activation. In particular, increased ATP release accounts for the action of statins in P2X7 activation. We also provide evidence that statin-induced moderate ROS elevation is involved in this event. Moreover, the cathepsin B inhibitor was shown to reduce statin-induced IL-1β secretion. Consistently statins can induce cathepsin B activation and lysosomal rupture, as evidenced by LysoTracker staining. Statins also increase intracellular ATP secretion and IL-1β release in primary human monocytes and murine macrophages. Notably, exogenous ATP-elicited P2X7 activation and consequent IL-1β release, an index of direct NLRP3 inflammasome activation, were not altered by statins. Taken together, statin-induced enhancement of inflammasome activation in monocytes and macrophages covers multiple mechanisms, including increases in ATP release, ROS production, and lysosomal rupture. These data not only shed new insight into isoprenylation-dependent regulation of caspase-1 but also unmask mechanisms for statin-elicited inflammasome activation.