bluuebunny/crossref_metadata_2025 huggingface dataset:
The influence of parental support on the community service learning experiences of American college students
Authors: Seider Scott
Published: August 2012

This mixed methods study considered the relationship between the civic development of college students participating in the Serve Program at Ignatius University and the influence of these students’ parents. The Serve Program is a community service learning program that combines coursework in philosophy and theology with a year-long service project. Analyses of pre-post survey data revealed that students whose parents were highly supportive of their participation in the program demonstrated the greatest increases in public service motivation and expected political participation. Qualitative interviews with Serve participants revealed that highly supportive parents provided students with additional opportunities for reflection upon the readings, lectures and service projects they were encountering through the Serve Program.
Is Irony Good for America? The Threat of Nihilism, the Importance of Romance, and the Power of Cultural Forms
Authors: Guhin Jeffrey
Published: August 2012

This paper examines three discussions in the American public sphere between 1998 and 2008 about whether irony is good for America: the response to a 1999 book against irony, the declared ‘death of irony’ after the events of September 11, 2001, and concerns about the ironic nature of The Daily Show with Jon Stewart. After reviewing the literature on irony from various academic disciplines, the author shows how ‘knockers’ worried that irony was a counter-narrative that would distract from romantic progress, while ‘boosters’ claimed irony was a trope that could only strengthen the romantic story of the nation. Rather than answering the title question, the author uses the evidence of these ‘ironic crises’ to show how such questions reveal the cultural forms and reflexivity that structure the American public sphere.
Contemporary Progressive Christianity and Its Symbolic Ramifications
Authors: Edles Laura Desfor
Published: August 2012

In the last decade, progressive Christians have been mounting an increasingly perceptible challenge to the ‘Christian right’ in the United States. New organizations and websites are cropping up, a wellspring of books are being published, and long-standing progressive writers and theologians are garnering more attention and support than ever before. Despite significant advances, however, the impact of the ‘religious left’ in the American public sphere is still limited. In this paper, I ask why. Based on participant observation, discourse analysis, and in-depth interviews, and using a multidimensional culturalist perspective rooted in Durkheimian and Weberian ideas, I explore the symbolic dynamics of the Christian ‘left’. I argue that in addition to their structural disadvantages, progressive Christians face thorny dilemmas regarding authority/legitimacy, rationalization, de-mystification, disenchantment, charisma (or the lack thereof), and profanation that, though not insurmountable, are not easily resolved.
‘Small, but Very Determined’: A Novel Theorization of Children’s Consumption of Clothing
Authors: Pilcher Jane
Published: August 2012

Childhood and consumption are each firmly established as substantive topics in sociology, yet the relationship between them remains narrowly considered. In this paper I attempt to deepen sociological understanding of one aspect of children’s consumption (their clothing) through reimagining the structure and agency problematic via a novel theorization centred on the concept of determinativity. I do this by engaging in a critical evaluation and adaptive use of existing theories, and by using data from an empirical study to illustrate and strengthen the theoretical claims I make. Children are argued to be exceptional consumers, in that what they come to wear on their bodies is subject to a different set of social processes than is the case for adults. At the same time, the theorization offered in this paper suggests ways forward for rethinking how individuals at all stages of the life course interactively engage in consumer societies.
Making Globalization Visible? The Oil Assemblage, the Work of Sociology and the Work of Art
Authors: Stewart Janet
Published: August 2012

This article sets out to rethink the relationship between the work of art and the work of sociology, drawing on Jacques Ranciere’s writing on the work of art to provide the basis for recognizing affinities and differences between these two processes. In juxtaposing the sociology of globalization with the art of globalization, beginning with their common desire to understand globalization through rendering invisible forces visible, the article suggests ways in which artistic practice might be said to be ‘proto-sociological’, while also considering the role that aesthetic categories play in producing sociological knowledge. These questions are approached through a detailed case study that focuses on the cultural response to the oil industry offered by Ursula Biemann in her film essay, Black Sea Files (2005). The article argues that to grasp a phenomenon as complex as globalization, collaborative work between different forms of knowledge construction plays a crucial role.
The Suffering of Symbols: Giotto Frescoes and the Cultural Trauma of Objects
Authors: Debs Mira
Published: August 2012

The loss of iconic buildings and artifacts can result in public mourning which may even overshadow the loss of human life. Cultural trauma theory examines how such processes are socially constructed, but has focused on events of great human suffering, ignoring the power of objects. Discourse analysis of two months of Italian media coverage following the 1997 Umbria-Marche earthquake and local interviews in Assisi show that a cultural trauma was articulated around the damaged Basilica of St Francis of Assisi and its fragmented Giotto frescoes. In addition to factors specific to Italy, I compare ten recent worldwide cases of artistic loss, some of which became cultural traumas while others did not, in order to determine the critical factors in creating a cultural trauma of objects: the comparative loss of human life, the object’s totemic significance to the collective, and the time-frame until the object can be repaired.
Racial Differences in Effects of Religiosity and Mastery on Psychological Distress
Authors: Oates Gary L. , Goode Jennifer
Published: August 2012

This research engages nationally representative longitudinal data and a multipopulation LISREL model to investigate variation among black and white Americans in the impact of religiosity and mastery on psychological distress. Guided by the stress and coping perspective and prominent theorizing about how religiosity influences mental health, the model assesses not only direct effects of religiosity and mastery on distress but also the possibility of religiosity and mastery inhibiting distress indirectly (via effects on other coping resources or stressors) and attenuating the distress-inducing properties of individual stressors. Findings solidly support the endorsed proposition of religiosity’s being particularly beneficial to blacks’ emotional well-being and moderately support the prediction of mastery’s being primarily helpful to whites’. Public religiosity substantially eclipses private and subjective religiosity as a facilitator of blacks’ emotional well-being, and although main effects dominate, there are significant mediation and moderation effects of religiosity or mastery within each race.
Altered microtubule equilibrium and impaired thrombus stability in mice lacking RanBP10
Authors: Meyer Imke , Kunert Stefan , Schwiebert Silke , Hagedorn Ina , Italiano Joseph E. , Dütting Sebastian , Nieswandt Bernhard , Bachmann Sebastian , Schulze Harald
Published: August 2012

The crucial function of blood platelets in hemostasis is to prevent blood loss by stable thrombus formation. This process is driven by orchestrated mechanisms including several signal transduction cascades and morphologic transformations. The cytoplasmic microtubule modulator RanBP10 is a Ran and β1-tubulin binding protein that is essential for platelet granule release and mice lacking RanBP10 harbor a severe bleeding phenotype. In this study, we demonstrate that RanBP10-nullizygous platelets show normal adhesion on collagen and von Willebrand factor under flow conditions. However, using a ferric chloride-induced arterial thrombosis model, the formation of stable thrombi was significantly impaired, preventing vessel occlusion or leading to recanalization and thromboembolization. Delta-granule secretion was normal in mutant mice, whereas platelet shape change in aggregometry was attenuated. Lack of RanBP10 leads to increased β1-tubulin protein, which drives α-monomers into polymerized microtubules. In mutant platelets agonists failed to contract the peripheral marginal band or centralize granules. Pretreatment of wild-type platelets with taxol caused microtubule stabilization and phenocopied the attenuated shape change in response to collagen, suggesting that RanBP10 inhibits premature microtubule polymerization of β1-tubulin and plays a pivotal role in thrombus stabilization.
Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40
Authors: Yang Yan , Liu Chengwen , Peng Weiyi , Lizée Gregory , Overwijk Willem W. , Liu Yang , Woodman Scott E. , Hwu Patrick
Published: August 2012

Targeted and immune-based therapies are thought to eradicate cancer cells by different mechanisms, and these approaches could possibly complement each other when used in combination. In this study, we report that the in vivo antitumor effects of the c-KIT inhibitor, dasatinib, on the c-KIT mutant P815 mastocytoma tumor were substantially dependent on T cell–mediated immunity. We found that dasatinib treatment significantly decreased levels of Tregs while specifically enhancing tumor antigen-specific T-cell responses. We sought to further enhance this therapy with the addition of anti-OX40 antibody, which is known to provide a potent costimulatory signal to T cells. The combination of dasatinib and anti-OX40 antibody resulted in substantially better therapeutic efficacy compared with either drug alone, and this was associated with enhanced accumulation of tumor antigen-specific T cells in the tumor microenvironment. Furthermore, the combination regimen inhibited the function of Tregs and also resulted in significantly up-regulated expression of the IFN-γ–induced chemokines CXCL9, 10, and 11 in the tumor microenvironment, which provides a feasible mechanism for the enhanced intratumoral CTL infiltration. These studies delineate a strategy by which targeted therapy and immunotherapy may be combined to achieve superior antitumor responses in cancer patients.
Kruppel-like factor 7 overexpression suppresses hematopoietic stem and progenitor cell function
Authors: Schuettpelz Laura G. , Gopalan Priya K. , Giuste Felipe O. , Romine Molly P. , van Os Ronald , Link Daniel C.
Published: August 2012

Increased expression of Kruppel-like factor 7 (KLF7) is an independent predictor of poor outcome in pediatric acute lymphoblastic leukemia. The contribution of KLF7 to hematopoiesis has not been previously described. Herein, we characterized the effect on murine hematopoiesis of the loss of KLF7 and enforced expression of KLF7. Long-term multilineage engraftment of Klf7−/− cells was comparable with control cells, and self-renewal, as assessed by serial transplantation, was not affected. Enforced expression of KLF7 results in a marked suppression of myeloid progenitor cell growth and a loss of short- and long-term repopulating activity. Interestingly, enforced expression of KLF7, although resulting in multilineage growth suppression that extended to hematopoietic stem cells and common lymphoid progenitors, spared T cells and enhanced the survival of early thymocytes. RNA expression profiling of KLF7-overexpressing hematopoietic progenitors identified several potential target genes mediating these effects. Notably, the known KLF7 target Cdkn1a (p21Cip1/Waf1) was not induced by KLF7, and loss of CDKN1A does not rescue the repopulating defect. These results suggest that KLF7 is not required for normal hematopoietic stem and progenitor function, but increased expression, as seen in a subset of lymphoid leukemia, inhibits myeloid cell proliferation and promotes early thymocyte survival.
Combined treatment with lenalidomide and epoetin alfa in lower-risk patients with myelodysplastic syndrome
Authors: Komrokji Rami S. , Lancet Jeffrey E. , Swern Arlene S. , Chen Nianhang , Paleveda Jennifer , Lush Richard , Saba Hussain I. , List Alan F.
Published: August 2012

The erythropoietic effects of lenalidomide are cytokine dependent, suggesting that the erythroid hematologic improvement (HI-E) rate may be augmented by combined treatment (CT) with recombinant human erythropoietin (rhu-EPO) in myelodysplastic syndrome (MDS). In the present study, we explored the benefits of CT and the relationship between lenalidomide pharmacokinetics and hematologic toxicity in transfusion-dependent patients with low- to intermediate-1–risk MDS who failed prior rhu-EPO. In stage I, patients received 10 or 15 mg/d of lenalidomide monotherapy. At week 16, erythroid nonresponders (NRs) were eligible for CT with rhu-EPO 40 000 U/wk. Among 39 patients, HI-E response rate to monotherapy was 86% (6 of 7) in del(5q) and 25% (8 of 32) in non-del(5q) patients (10 mg, 17.7%; 15 mg, 33.3%). Twenty-three patients proceeded to CT, with 6 (26.0%) achieving HI-E. In 19 non-del(5q) patients, 4 (21.1%) showed HI-E. Mean baseline serum EPO in non-del(5q) patients was lower in monotherapy and CT responders than in NR (not statistically significant). Thrombocytopenia was significantly correlated with lenalidomide area under the plasma concentration-time curve (P = .0015), but severity of myelosuppression did not. The benefits of lenalidomide plus rhu-EPO are currently under investigation in a phase 3 Eastern Cooperative Oncology Group (ECOG)–sponsored intergroup study. This study is registered at www.clinicaltrials.gov as NCT00910858.
HIF-1α is a negative regulator of plasmacytoid DC development in vitro and in vivo
Authors: Weigert Andreas , Weichand Benjamin , Sekar Divya , Sha Weixiao , Hahn Christina , Mora Javier , Ley Stephanie , Essler Silke , Dehne Nathalie , Brüne Bernhard
Published: August 2012

Hypoxia-inducible factors (HIFs) regulate hematopoiesis in the embryo and maintain hematopoietic stem cell function in the adult. How hypoxia and HIFs contribute to hematopoietic lineage differentiation in the adult is ill defined. Here we provide evidence that HIF-1 limits differentiation of precursors into plasmacytoid dendritic cells (pDCs). Low oxygen up-regulated inhibitor of DNA binding 2 (ID2) and suppressed Flt3-L–induced differentiation of bone marrow cells to pDCs in wild-type but not HIF-1αfl/fl LysM-Cre bone marrow cells. Moreover, pDC differentiated normally in hypoxic ID2−/− bone marrow cultures. Finally, we observed elevated pDC frequencies in bone marrow, blood, and spleen of HIF-1αfl/fl LysM-Cre and ID2−/−, but not HIF-2αfl/fl LysM-Cre mice. Our data indicate that the low oxygen content in the bone marrow might limit pDC development. This might be an environmental mechanism to restrict the numbers of these potentially autoreactive cells.
Formation of a PKCζ/β-catenin complex in endothelial cells promotes angiopoietin-1–induced collective directional migration and angiogenic sprouting
Authors: Oubaha Malika , Lin Michelle I. , Margaron Yoran , Filion Dominic , Price Emily N. , Zon Leonard I. , Côté Jean-François , Gratton Jean-Philippe
Published: August 2012

Angiogenic sprouting requires that cell-cell contacts be maintained during migration of endothelial cells. Angiopoietin-1 (Ang-1) and vascular endothelial growth factor act oppositely on endothelial cell junctions. We found that Ang-1 promotes collective and directional migration and, in contrast to VEGF, induces the formation of a complex formed of atypical protein kinase C (PKC)-ζ and β-catenin at cell-cell junctions and at the leading edge of migrating endothelial cells. This complex brings Par3, Par6, and adherens junction proteins at the front of migrating cells to locally activate Rac1 in response to Ang-1. The colocalization of PKCζ and β-catenin at leading edge along with PKCζ-dependent stabilization of cell-cell contacts promotes directed and collective endothelial cell migration. Consistent with these results, down-regulation of PKCζ in endothelial cells alters Ang-1–induced sprouting in vitro and knockdown in developing zebrafish results in intersegmental vessel defects caused by a perturbed directionality of tip cells and by loss of cell contacts between tip and stalk cells. These results reveal that PKCζ and β-catenin function in a complex at adherens junctions and at the leading edge of migrating endothelial cells to modulate collective and directional migration during angiogenesis.
Transcriptome sequencing in Sézary syndrome identifies Sézary cell and mycosis fungoides-associated lncRNAs and novel transcripts
Authors: Lee Carolyn S. , Ungewickell Alexander , Bhaduri Aparna , Qu Kun , Webster Dan E. , Armstrong Randall , Weng Wen-Kai , Aros Cody J. , Mah Angela , Chen Richard O. , Lin Meihong , Sundram Uma , Chang Howard Y. , Kretz Markus , Kim Youn H. , Khavari Paul A.
Published: August 2012

Sézary syndrome (SS) is an aggressive cutaneous T-cell lymphoma (CTCL) of unknown etiology in which malignant cells circulate in the peripheral blood. To identify viral elements, gene fusions, and gene expression patterns associated with this lymphoma, flow cytometry was used to obtain matched pure populations of malignant Sézary cells (SCs) versus nonmalignant CD4+ T cells from 3 patients for whole transcriptome, paired-end sequencing with an average depth of 112 million reads per sample. Pathway analysis of differentially expressed genes identified mis-regulation of PI3K/Akt, TGFβ, and NF-κB pathways as well as T-cell receptor signaling. Bioinformatic analysis did not detect either nonhuman transcripts to support a viral etiology of SS or recurrently expressed gene fusions, but it did identify 21 SC-associated annotated long noncoding RNAs (lncRNAs). Transcriptome assembly by multiple algorithms identified 13 differentially expressed unannotated transcripts termed Sézary cell-associated transcripts (SeCATs) that include 12 predicted lncRNAs and a novel transcript with coding potential. High-throughput sequencing targeting the 3′ end of polyadenylated transcripts in archived tumors from 24 additional patients with tumor-stage CTCL confirmed the differential expression of SC-associated lncRNAs and SeCATs in CTCL. Our findings characterize the SS transcriptome and support recent reports that implicate lncRNA dysregulation in human malignancies.
Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia
Authors: Shi Aibin , Murai Marcelo J. , He Shihan , Lund George , Hartley Thomas , Purohit Trupta , Reddy Gireesh , Chruszcz Maksymilian , Grembecka Jolanta , Cierpicki Tomasz
Published: August 2012

Menin functions as a critical oncogenic cofactor of mixed lineage leukemia (MLL) fusion proteins in the development of acute leukemias, and inhibition of the menin interaction with MLL fusion proteins represents a very promising strategy to reverse their oncogenic activity. MLL interacts with menin in a bivalent mode involving 2 N-terminal fragments of MLL. In the present study, we reveal the first high-resolution crystal structure of human menin in complex with a small-molecule inhibitor of the menin-MLL interaction, MI-2. The structure shows that the compound binds to the MLL pocket in menin and mimics the key interactions of MLL with menin. Based on the menin–MI-2 structure, we developed MI-2-2, a compound that binds to menin with low nanomolar affinity (Kd = 22nM) and very effectively disrupts the bivalent protein-protein interaction between menin and MLL. MI-2-2 demonstrated specific and very pronounced activity in MLL leukemia cells, including inhibition of cell proliferation, down-regulation of Hoxa9 expression, and differentiation. Our results provide the rational and essential structural basis to design next generation of inhibitors for effective targeting of the menin-MLL interaction in leukemia and demonstrate a proof of concept that inhibition of complex multivalent protein-protein interactions can be achieved by a small-molecule inhibitor.
Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation
Authors: Langhauser Friederike , Göb Eva , Kraft Peter , Geis Christian , Schmitt Joachim , Brede Marc , Göbel Kerstin , Helluy Xavier , Pham Mirko , Bendszus Martin , Jakob Peter , Stoll Guido , Meuth Sven G. , Nieswandt Bernhard , McCrae Keith R. , Kleinschnitz Christoph
Published: August 2012

Thrombosis and inflammation are hallmarks of ischemic stroke still unamenable to therapeutic interventions. High-molecular-weight kininogen (KNG) is a central constituent of the contact-kinin system which represents an interface between thrombotic and inflammatory circuits and is critically involved in stroke development. Kng−/− mice are protected from thrombosis after artificial vessel wall injury and lack the proinflammatory mediator bradykinin. We investigated the consequences of KNG deficiency in models of ischemic stroke. Kng−/− mice of either sex subjected to transient middle cerebral artery occlusion developed dramatically smaller brain infarctions and less severe neurologic deficits without an increase in infarct-associated hemorrhage. This protective effect was preserved at later stages of infarction as well as in elderly mice. Targeting KNG reduced thrombus formation in ischemic vessels and improved cerebral blood flow, and reconstitution of KNG-deficient mice with human KNG or bradykinin restored clot deposition and infarct susceptibility. Moreover, mice deficient in KNG showed less severe blood-brain barrier damage and edema formation, and the local inflammatory response was reduced compared with controls. Because KNG appears to be instrumental in pathologic thrombus formation and inflammation but dispensable for hemostasis, KNG inhibition may offer a selective and safe strategy for combating stroke and other thromboembolic diseases.
Aging and neoteny in the B lineage
Authors: Melamed Doron , Scott David W.
Published: August 2012

Aging and the physiologic decline of tissues and cells were once thought to be irreversible. However, recent studies suggest that various tissues, especially parts of the hematopoietic system, can be rejuvenated. Here we review potential mechanisms for this process and how they may be used to reverse age-related disorders and aging in general. We propose the novel hypothesis that altering the homeostatic process during cellular depletion can reverse aging in the hematopoietic system.
Smoking cessation strategies in patients with COPD
Authors: Warnier Miriam J. , van Riet Evelien E.S. , Rutten Frans H. , De Bruin Marie Louise , Sachs Alfred P.E.
Published: August 2012

Smoking cessation is the cornerstone of treatment of chronic obstructive pulmonary disease (COPD) patients. This systematic review evaluates the effectiveness of behavioural and pharmacological smoking cessation strategies in COPD patients.

MEDLINE was searched from January 2002 to October 2011. Randomised controlled trials evaluating the effect of smoking cessation interventions for COPD patients, published in English, were selected. The methodological quality of included trials was assessed using the Delphi list by two reviewers independently. The relative risks of smoking cessation due to the intervention, compared with controls, were calculated.

Eight studies met the inclusion criteria. Heterogeneity was observed for study population, the intervention strategy, the follow-up period and the outcome. According to the Delphi list methodological quality scores, five studies were considered to be of acceptable quality. Pharmacological therapy combined with behavioural counselling was more effective than each strategy separately. In COPD patients, the intensity of counselling did not seem to influence the results, nor did the choice of drug therapy make a difference.

This systematic review makes clear that in COPD patients, pharmacological therapy combined with behavioural counselling is more effective than each strategy separately. Neither the intensity of counselling nor the type of anti-smoking drug made a difference.
The lectin-like domain of thrombomodulin hampers host defence in pneumococcal pneumonia
Authors: Schouten Marcel , de Boer J. Daan , van ’t Veer Cornelis , Roelofs Joris J.T.H. , Meijers Joost C.M. , Levi Marcel , Conway Edward M. , van der Poll Tom
Published: August 2012

The lectin-like domain of thrombomodulin (TM) plays an important regulatory role in sterile inflammatory conditions, but its role in severe Gram-positive infectious disease is unknown.Streptococcus pneumoniaeis the most common cause of community-acquired pneumonia. The aim of this study was to determine the role of the lectin-like domain of TM in murine pneumococcal pneumonia.

Wild-type (WT) mice and mice lacking the lectin-like domain of TM (TMLeD/LeD) were infected intranasally with viableS. pneumoniaeand either observed in a survival study or euthanised 6, 24 or 48 h after infection.

TMLeD/LeDmice had a markedly better survival in pneumococcal pneumonia when compared with WT mice. At 48 h post-infection withS. pneumoniae,TMLeD/LeDmice had lower bacterial loads in blood and liver, and exhibited less pulmonary inflammation, as shown by having less lung histopathology, less neutrophil influx and lower cytokine and chemokine levels. Plasma levels of pro-inflammatory cytokines were also reduced in TMLeD/LeDmice after exposure to the infection.

Deletion of the lectin-like domain of TM improves the host defence in pneumococcal pneumonia. The lectin-like domain of TM may have a differential role in response to Gram-positive or Gram-negative bacteria.
A potential role for insulin resistance in experimental pulmonary hypertension
Authors: West James , Niswender Kevin D. , Johnson Jennifer A. , Pugh Meredith E. , Gleaves Linda , Fessel Joshua P. , Hemnes Anna R.
Published: August 2012

Patients with pulmonary arterial hypertension have increased prevalence of insulin resistance. We aimed to determine whether metabolic defects are associated with bone morphogenic protein receptor type 2 (Bmpr2) mutations in mice, and whether these may contribute to pulmonary vascular disease development.

Metabolic phenotyping was performed on transgenic mice with inducible expression of Bmpr2 mutation, R899X. Phenotypic penetrance in Bmpr2R899Xwas assessed in a high-fat diet model of insulin resistance. Alterations in glucocorticoid responses were assessed in murine pulmonary microvascular endothelial cells and Bmpr2R899Xmice treated with dexamethasone.

Compared to controls, Bmpr2R899Xmice showed increased weight gain and demonstrated insulin resistance as assessed by the homeostatic model assessment insulin resistance (1.0±0.4versus2.2±1.8) and by fat accumulation in skeletal muscle and decreased oxygen consumption. Bmpr2R899Xmice fed a high-fat diet had strong increases in pulmonary hypertension penetrance (seven out of 11versusthree out of 11). In cell culture andin vivoexperiments, Bmpr2 mutation resulted in a combination of constitutive glucocorticoid receptor activation and insensitivity.

Insulin resistance is present as an early feature of Bmpr2 mutation in mice. Exacerbated insulin resistance through high-fat diet worsened pulmonary phenotype, implying a possible causal role in disease. Impaired glucocorticoid responses may contribute to metabolic defects.
Genome-wide association analysis reveals 12q13.3–q14.1 as new risk locus for sarcoidosis
Authors: Hofmann Sylvia , Fischer Annegret , Nothnagel Michael , Jacobs Gunnar , Schmid Benjamin , Wittig Michael , Franke Andre , Gaede Karoline I. , Schürmann Manfred , Petrek Martin , Mrazek Frantisek , Pabst Stefan , Grohé Christian , Grunewald Johan , Ronninger Marcus , Eklund Anders , Rosenstiel Philip , Höhne Kerstin , Zissel Gernot , Müller-Quernheim Joachim , Schreiber Stefan
Published: August 2012

Sarcoidosis is a systemic inflammatory disease of unknown aetiology, influenced by genetic and environmental factors. However, the loci so far identified for sarcoidosis explain only a part of its assumed heritability.

To identify further susceptibility loci, we performed a genome-wide association analysis using the Affymetrix 6.0 Human GeneChip followed by validation and replication stages.

After quality control, 637 cases, 1233 controls and 677 619 single-nucleotide polymorphisms (SNPs) were available for an initial screening. 99 SNPs were selected for validation in an independent study panel (1664 patients, 2932 controls). SNP rs1050045 was significantly associated with sarcoidosis (corrected p=0.0215) in the validation panel and yielded a p-value of 9.22×10−8(OR 1.24) in the meta-analysis of the screening and validation stage. A meta-analysis of three populations from Germany, the Czech Republic and Sweden confirmed this finding (p=0.024; OR 1.14). Fine-mapping and mRNA expression studies pointed toosteosarcoma amplified 9 (OS9) as the most likely candidate for the underlying risk factor.

The OS9 protein plays an important role in endoplasmic reticulum-associated protein degradation and acts during Toll-like receptor induced activation of myeloid cells. Expression analyses ofOS9mRNA provide evidence for a functional mechanism underlying the detected association signal.
Major bleeding with vitamin K antagonist anticoagulants in pulmonary hypertension
Authors: Henkens Ivo R. , Hazenoot Thomas , Boonstra Anco , Huisman Menno V. , Vonk-Noordegraaf Anton
Published: August 2012

Vitamin K antagonists are advised in pulmonary arterial hypertension patients despite a lack of safety data.

We reviewed major bleeding in three classes of pulmonary hypertension patients, all receiving vitamin K antagonists.

Bleeding event rates were 5.4 per 100 patient-years for patients with idiopathic pulmonary arterial hypertension, 19 per 100 patient-years for connective tissue disease related pulmonary arterial hypertension patients and 2.4 per 100 patient-years for chronic thromboembolic pulmonary hypertension patients. Life tables analysis showed that event-free survival was worse in patients with connective tissue disease related pulmonary hypertension than in patients with idiopathic pulmonary arterial hypertension (Wilcoxon=12.8; p<0.001), and patients with chronic thromboembolic pulmonary hypertension (Wilcoxon=23.2; p<0.001). Patients with idiopathic pulmonary arterial hypertension suffered more events than patients with chronic thromboembolic pulmonary hypertension (Wilcoxon=7.2; p<0.01). Major bleeding was independent of age, sex, target international normalised ratio (INR) range, documented INR, vitamin K antagonist type, or right atrial pressure, but was associated with use of prostacyclin analogues.

Major bleeding risk during vitamin K antagonist therapy differs among groups of patients with pulmonary hypertension. Further research regarding optimal anticoagulant therapy is needed, as well as risk–benefit analyses for pulmonary hypertension patients with a higher bleeding propensity.
Inhaled therapies, azithromycin andMycobacterium abscessusin cystic fibrosis patients
Authors: Catherinot Emilie , Roux Anne-Laure , Vibet Marie-Anne , Bellis Gil , Lemonnier Lydie , Le Roux Evelyne , Bernède-Bauduin Claire , Le Bourgeois Muriel , Herrmann Jean-Louis , Guillemot Didier , Gaillard Jean-Louis ,   for the OMA group
Published: August 2012

Cystic fibrosis (CF) patients are at particularly high risk of developing lung disease caused byMycobacterium abscessuscomplex (MABSC). Over the last 10 years, changes in CF treatment, with increasing use of inhaled therapies and low-dose azithromycin, have been accompanied by an increase in the prevalence of MABSC infections in CF patients. There is therefore some concern about the role of new CF treatments in the emergence of MABSC infections.

We addressed this issue by means of a case–control study including 30 MABSC-positive cases and 60 nontuberculous mycobacteria-negative CF controls matched for age, sex and centre. We also compared practices at the CF centres with the highest prevalence of MABSC with those at the other centres.

No positive association was found between MABSC lung disease and the use of inhaled therapies or low-dose azithromycin in the 4 years preceding MABSC isolation. These treatments were not significantly more frequently used at the CF centres with the highest MABSC prevalence rates.

In conclusion, there is no evidence for a link betweenM. abscessuscomplex lung disease and inhaled therapies or low-dose azithromycin in patients with CF.
Contact investigation for tuberculosis: a systematic review and meta-analysis
Authors: Fox Gregory J. , Barry Simone E. , Britton Warwick J. , Marks Guy B.
Published: August 2012

Investigation of contacts of patients with tuberculosis (TB) is a priority for TB control in high-income countries, and is increasingly being considered in resource-limited settings. This review was commissioned for a World Health Organization Expert Panel to develop global contact investigation guidelines.

We performed a systematic review and meta-analysis of all studies reporting the prevalence of TB and latent TB infection, and the annual incidence of TB among contacts of patients with TB.

After screening 9,555 titles, we included 203 published studies. In 95 studies from low- and middle-income settings, the prevalence of active TB in all contacts was 3.1% (95% CI 2.2–4.4%, I2=99.4%), microbiologically proven TB was 1.2% (95% CI 0.9–1.8%, I2=95.9%), and latent TB infection was 51.5% (95% CI 47.1–55.8%, I2=98.9%). The prevalence of TB among household contacts was 3.1% (95% CI 2.1–4.5%, I2=98.8%) and among contacts of patients with multidrug-resistant or extensively drug-resistant TB was 3.4% (95% CI 0.8–12.6%, I2=95.7%). Incidence was greatest in the first year after exposure. In 108 studies from high-income settings, the prevalence of TB among contacts was 1.4% (95% CI 1.1–1.8%, I2=98.7%), and the prevalence of latent infection was 28.1% (95% CI 24.2–32.4%, I2=99.5%). There was substantial heterogeneity among published studies.

Contacts of TB patients are a high-risk group for developing TB, particularly within the first year. Children <5 yrs of age and people living with HIV are particularly at risk. Policy recommendations must consider evidence of the cost-effectiveness of various contact tracing strategies, and also incorporate complementary strategies to enhance case finding.
Proteinase 3 activity in sputum from subjects with alpha-1-antitrypsin deficiency and COPD
Authors: Sinden Nicola J. , Stockley Robert A.
Published: August 2012

Chronic obstructive pulmonary disease (COPD) is associated with tissue damage believed to result from an imbalance between serine proteinases and their inhibitors. Although the role of neutrophil elastase (NE) has been studied, it is likely that other proteinases play a role. The importance of proteinase 3 (PR3) has not been established, as specific substrates have only recently been available.

We studied clinically stable subjects with either alpha-1-antitrypsin (A1AT) deficiency or usual COPD with chronic bronchitis. Sol phase sputum was analysed for PR3 activity and concentration, NE activity and concentration, concentrations of airway inhibitors (A1AT, secretory leukoproteinase inhibitor and elafin) and markers of neutrophilic inflammation. 12 patients were also studied during exacerbations.

PR3 activity was present in most sputum samples and greater than NE activity (which was largely undetectable) in both subject groups (A1AT deficiency median PR3 128 nM, interquartile range (IQR) 33–558 nM; NE 0 nM, IQR 0–0 nM; p=0.0043; COPD PR3 22 nM, IQR 0–103 nM; NE 0 nM, IQR 0–0 nM; p=0.015). PR3 activity was greater during exacerbations than in the stable state (p=0.037) and correlated with markers of neutrophilic inflammation.

The regular identification of PR3 activity in sputum from stable subjects with A1AT deficiency or usual COPD suggests it may play a greater role in the pathophysiology than previously thought.
Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial
Authors: Hoeper Marius M. , Halank Michael , Wilkens Heinrike , Günther Andreas , Weimann Gerrit , Gebert Irmingard , Leuchte Hanno H. , Behr Jürgen
Published: August 2012

We assessed the safety, tolerability and preliminary efficacy of riociguat, a soluble guanylate cyclase stimulator, in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD).

In this open-label, uncontrolled pilot trial, patients received oral riociguat (1.0–2.5 mg three times daily) for 12 weeks (n=22), followed by an ongoing long-term extension (interim analysis at 12 months) in those eligible (n=15). Primary end-points were safety and tolerability. Secondary end-points included haemodynamic changes and 6-min walk distance (6MWD).

Overall, 104 adverse events were reported, of which 25 were serious; eight of the latter were considered drug-related. After 12 weeks of therapy, mean cardiac output increased (4.4±1.5 L·min−1to 5.5±1.8 L·min−1), pulmonary vascular resistance (PVR) decreased (648±207 dyn·s−1·cm−5to 528±181 dyn·s−1·cm−5) and mean pulmonary artery pressure (mPAP) remained unchanged compared with baseline. Arterial oxygen saturation decreased but mixed-venous oxygen saturation slightly increased. The 6MWD increased from 325±96 m at baseline to 351±111 m after 12 weeks.

Riociguat was well tolerated by most patients and improved cardiac output and PVR, but not mPAP. Further studies are necessary to evaluate the safety and efficacy of riociguat in patients with PH-ILD.
On the generalized Hyers-Ulam-Rassias stability problem of radical functional equations
Authors: Kim Seong Sik , Cho Yeol Je , Eshaghi Gordji Madjid
Published: August 2012

In this paper, the generalized Hyers-Ulam-Rassias stability problem of radical quadratic and radical quartic functional equations in quasi-β-Banach spaces and then the stability by using subadditive and subquadratic functions for radical functional equations in

(
β
,
p
)

-Banach spaces are given.

MSC:39B82, 39B52, 46H25.
Responses to pandemic ASO3-adjuvanted A/California/07/09 H1N1 influenza vaccine in human immunodeficiency virus-infected individuals
Authors: Kelly Deborah , Burt Kimberley , Missaghi Bayan , Barrett Lisa , Keynan Yoav , Fowke Keith , Grant Michael
Published: August 2012

Background

Influenza infection may be more serious in human immunodeficiency virus (HIV)-infected individuals, therefore, vaccination against seasonal and pandemic strains is highly advised. Seasonal influenza vaccines have had no significant negative effects in well controlled HIV infection, but the impact of adjuvanted pandemic A/California/07/2009 H1N1 influenza hemaglutinin (HA) vaccine, which was used for the first time in the Canadian population as an authorized vaccine in autumn 2009, has not been extensively studied.

Objective

Assess vaccine-related effects on CD4+ T cell counts and humoral responses to the vaccine in individuals attending the Newfoundland and Labrador Provincial HIV clinic.

Methods

A single dose of ArepanrixTM split vaccine including 3.75 μg A/California/07/2009 H1N1 HA antigen and ASO3 adjuvant was administered to 81 HIV-infected individuals by intramuscular injection. Plasma samples from shortly before, and 1–5 months after vaccination were collected from 80/81 individuals to assess humoral anti-H1N1 HA responses using a sensitive microbead-based array assay. Data on CD4+ T cell counts, plasma viral load, antiretroviral therapy and patient age were collected from clinical records of 81 individuals.

Results

Overall, 36/80 responded to vaccination either by seroconversion to H1N1 HA or with a clear increase in anti-H1N1 HA antibody levels. Approximately 1/3 (28/80) had pre-existing anti-H1N1 HA antibodies and were more likely to respond to vaccination (22/28). Responders had higher baseline CD4+ T cell counts and responders without pre-existing antibodies against H1N1 HA were younger than either non-responders or responders with pre-existing antibodies. Compared to changes in their CD4+ T cell counts observed over a similar time period one year later, vaccine recipients displayed a minor, transient fall in CD4+ T cell numbers, which was greater amongst responders.

Conclusions

We observed low response rates to the 2009 pandemic influenza vaccine among HIV-infected individuals without pre-existing antibodies against H1N1 HA and a minor transient fall in CD4+ T cell numbers, which was accentuated in responders. A single injection of the ArepanrixTM pandemic A/California/07/2009 H1N1 HA split vaccine may be insufficient to induce protective immunity in HIV-infected individuals without pre-existing anti-H1N1 HA responses.
Production of engineered long-life and male sterile Pelargonium plants
Authors: García-Sogo Begoña , Pineda Benito , Roque Edelín , Antón Teresa , Atarés Alejandro , Borja Marisé , Beltrán José Pío , Moreno Vicente , Cañas Luis Antonio
Published: August 2012

Background

Pelargonium is one of the most popular garden plants in the world. Moreover, it has a considerable economic importance in the ornamental plant market. Conventional cross-breeding strategies have generated a range of cultivars with excellent traits. However, gene transfer via Agrobacterium tumefaciens could be a helpful tool to further improve Pelargonium by enabling the introduction of new genes/traits. We report a simple and reliable protocol for the genetic transformation of Pelargonium spp. and the production of engineered long-life and male sterile Pelargonium zonale plants, using the pSAG12::ipt and PsEND1::barnase chimaeric genes respectively.

Results

The pSAG12::ipt transgenic plants showed delayed leaf senescence, increased branching and reduced internodal length, as compared to control plants. Leaves and flowers of the pSAG12::ipt plants were reduced in size and displayed a more intense coloration. In the transgenic lines carrying the PsEND1::barnase construct no pollen grains were observed in the modified anther structures, which developed instead of normal anthers. The locules of sterile anthers collapsed 3–4 days prior to floral anthesis and, in most cases, the undeveloped anther tissues underwent necrosis.

Conclusion

The chimaeric construct pSAG12::ipt can be useful in Pelargonium spp. to delay the senescence process and to modify plant architecture. In addition, the use of engineered male sterile plants would be especially useful to produce environmentally friendly transgenic plants carrying new traits by preventing gene flow between the genetically modified ornamentals and related plant species. These characteristics could be of interest, from a commercial point of view, both for pelargonium producers and consumers.
Predictor of poor coronary collaterals in chronic kidney disease population with significant coronary artery disease
Authors: Hsu Po-Chao , Juo Suh-Hang , Su Ho-Ming , Chen Szu-Chia , Tsai Wei-chung , Lai Wen-Ter , Sheu Sheng-Hsiung , Lin Tsung-Hsien
Published: August 2012

Background

Coronary collateral circulation plays an important role to protect myocardium from ischemia, preserve myocardial contractility and reduce cardiovascular events. Chronic kidney disease (CKD) is associated with poor coronary collateral development and cardiovascular outcome. However, limited research investigates the predictors for collateral development in the CKD population.

Methods

We evaluated 970 consecutive patients undergoing coronary angiography and 202 patients with CKD, defined as a glomerular filtration rate less than 60 ml/min/1.73 m2, were finally analyzed. The collateral scoring system developed by Rentrop was used to classify patients into poor (grades 0 and 1) or good (grades 2 and 3) collateral group.

Results

The patients with poor collateral (n = 122) had a higher incidence of hypertension (82% vs 63.8%, p = 0.005), fewer diseased vessels numbers (2.1 ± 0.9 vs 2.6 ± 0.6, p < 0.001) and a trend to be diabetic (56.6% vs. 43.8%, p = 0.085) or female sex (37.7% vs. 25.0%, p = 0.067). Multivariate analysis showed hypertension (odd ratio (OR) 2.672, p = 0.006), diabetes (OR 1.956, p = 0.039) and diseased vessels numbers (OR 0.402, p < 0.001) were significant predictors of poor coronary collaterals development. Furthermore, hypertension and diabetes have a negative synergistic effect on collateral development (p = 0.004 for interaction).

Conclusions

In the CKD population hypertension and diabetes might negatively influence the coronary collaterals development.
Role of aldo-keto reductases and other doxorubicin pharmacokinetic genes in doxorubicin resistance, DNA binding, and subcellular localization
Authors: Heibein Allan D , Guo Baoqing , Sprowl Jason A , MacLean David A , Parissenti Amadeo M
Published: August 2012

Background

Since proteins involved in chemotherapy drug pharmacokinetics and pharmacodynamics have a strong impact on the uptake, metabolism, and efflux of such drugs, they likely play critical roles in resistance to chemotherapy drugs in cancer patients.

Methods

To investigate this hypothesis, we conducted a whole genome microarray study to identify difference in the expression of genes between isogenic doxorubicin-sensitive and doxorubicin-resistant MCF-7 breast tumour cells. We then assessed the degree of over-representation of doxorubicin pharmacokinetic and pharmacodynamic genes in the dataset of doxorubicin resistance genes.

Results

Of 27,958 Entrez genes on the array, 7.4 per cent or 2,063 genes were differentially expressed by ≥ 2-fold between wildtype and doxorubicin-resistant cells. The false discovery rate was set at 0.01 and the minimum p value for significance for any gene within the “hit list” was 0.01. Seventeen and 43 per cent of doxorubicin pharmacokinetic genes were over-represented in the hit list, depending upon whether the gene name was identical or within the same gene family, respectively. The most over-represented genes were within the 1C and 1B families of aldo-keto reductases (AKRs), which convert doxorubicin to doxorubicinol. Other genes convert doxorubicin to other metabolites or affect the influx, efflux, or cytotoxicity of the drug. In further support of the role of AKRs in doxorubicin resistance, we observed that, in comparison to doxorubicin, doxorubincol exhibited dramatically reduced cytotoxicity, reduced DNA-binding activity, and strong localization to extra nuclear lysosomes. Pharmacologic inhibition of the above AKRs in doxorubicin-resistant cells increased cellular doxorubicin levels, restored doxorubicin cytotoxicity and re-established doxorubicin localization to the nucleus. The properties of doxorubicinol were unaffected.

Conclusions

These findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledge bases to identify highly relevant genes associated with doxorubicin resistance. The induction of one or more of these genes was found to be correlated with changes in the drug’s properties, while inhibiting one specific class of these genes (the AKRs) increased cellular doxorubicin content and restored drug DNA binding, cytotoxicity, and subcellular localization.