bluuebunny/crossref_metadata_2025 huggingface dataset:
Accumulation of Multipotent Progenitors with a Basal Differentiation Bias during Aging of Human Mammary Epithelia
Authors: Garbe James C. , Pepin Francois , Pelissier Fanny A. , Sputova Klara , Fridriksdottir Agla J. , Guo Diana E. , Villadsen Rene , Park Morag , Petersen Ole W. , Borowsky Alexander D. , Stampfer Martha R. , LaBarge Mark A.
Published: May 2012

Women older than 50 years account for 75% of new breast cancer diagnoses, and the majority of these tumors are of a luminal subtype. Although age-associated changes, including endocrine profiles and alterations within the breast microenvironment, increase cancer risk, an understanding of the cellular and molecular mechanisms that underlies these observations is lacking. In this study, we generated a large collection of normal human mammary epithelial cell strains from women ages 16 to 91 years, derived from primary tissues, to investigate the molecular changes that occur in aging breast cells. We found that in finite lifespan cultured and uncultured epithelial cells, aging is associated with a reduction of myoepithelial cells and an increase in luminal cells that express keratin 14 and integrin-α6, a phenotype that is usually expressed exclusively in myoepithelial cells in women younger than 30 years. Changes to the luminal lineage resulted from age-dependent expansion of defective multipotent progenitors that gave rise to incompletely differentiated luminal or myoepithelial cells. The aging process therefore results in both a shift in the balance of luminal/myoepithelial lineages and to changes in the functional spectrum of multipotent progenitors, which together increase the potential for malignant transformation. Together, our findings provide a cellular basis to explain the observed vulnerability to breast cancer that increases with age. Cancer Res; 72(14); 3687–701. ©2012 AACR.
CD44s Regulates the TGF-β–Mediated Mesenchymal Phenotype and Is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma
Authors: Mima Kosuke , Okabe Hirohisa , Ishimoto Takatsugu , Hayashi Hiromitsu , Nakagawa Shigeki , Kuroki Hideyuki , Watanabe Masayuki , Beppu Toru , Tamada Mayumi , Nagano Osamu , Saya Hideyuki , Baba Hideo
Published: May 2012

The prognosis for individuals diagnosed with hepatocellular carcinoma (HCC) remains poor because of the high frequency of invasive tumor growth, intrahepatic spread, and extrahepatic metastasis. Here, we investigated the role of the standard isoform of CD44 (CD44s), a major adhesion molecule of the extracellular matrix and a cancer stem cell marker, in the TGF-β–mediated mesenchymal phenotype of HCC. We found that CD44s was the dominant form of CD44 mRNA expressed in HCC cells. Overexpression of CD44s promoted tumor invasiveness and increased the expression of vimentin, a mesenchymal marker, in HCC cells. Loss of CD44s abrogated these changes. Also in the setting of CD44s overexpression, treatment with TGF-β1 induced the mesenchymal phenotype of HCC cells, which was characterized by low E-cadherin and high vimentin expression. Loss of CD44s inhibited TGF-β–mediated vimentin expression, mesenchymal spindle-like morphology, and tumor invasiveness. Clinically, overexpression of CD44s was associated with low expression of E-cadherin, high expression of vimentin, a high percentage of phospho-Smad2–positive nuclei, and poor prognosis in HCC patients, including reduced disease-free and overall survival. Together, our findings suggest that CD44s plays a critical role in the TGF-β–mediated mesenchymal phenotype and therefore represents a potential therapeutic target for HCC. Cancer Res; 72(13); 3414–23. ©2012 AACR.
miRNA-708 Control of CD44+ Prostate Cancer–Initiating Cells
Authors: Saini Sharanjot , Majid Shahana , Shahryari Varahram , Arora Sumit , Yamamura Soichiro , Chang Inik , Zaman Mohd Saif , Deng Guoren , Tanaka Yuichiro , Dahiya Rajvir
Published: May 2012

Tumor recurrence in prostate cancer has been attributed to the presence of CD44-expressing tumor-initiating cells. In this study, we report that miR-708 is a key negative regulator of this CD44+ subpopulation of prostate cancer cells, with important implications for diagnosis and prognosis of this disease. miR-708 was underexpressed in CD44+ cells from prostate cancer xenografts. Reconstitution of miR-708 in prostate cancer cell lines or CD44+ prostate cancer cells led to decreased tumorigenicity in vitro. Intratumoral delivery of synthetic miR-708 oligonucleotides triggered regression of established tumors in a murine xenograft model of human prostate cancer. Conversely, miR-708 silencing in a purified CD44− population of prostate cancer cells promoted tumor growth. Functional studies validated CD44 to be a direct target of miR-708 and also identified the serine/threonine kinase AKT2 as an additional target. Clinically, low miR-708 expression was associated significantly with poor survival outcome, tumor progression, and recurrence in patients with prostate cancer. Together, our findings suggest that reduced miR-708 expression leads to prostate cancer initiation, progression, and development by regulating the expression of CD44 as well as AKT2. miR-708 therefore may represent a novel therapeutic target or diagnostic and prognostic biomarker in prostate cancer. Cancer Res; 72(14); 3618–30. ©2012 AACR.
The Continuum Model of Selection in Human Tumors: General Paradigm or Niche Product?
Authors: Leedham Simon , Tomlinson Ian
Published: May 2012

Berger and colleagues recently proposed a continuum model of how somatic mutations cause tumors to grow, thus supplementing the established binary models, such as oncogene activation and “two hits” at tumor suppressor loci. In the basic continuum model, decreases or increases in gene function, short of full inactivation or activation, impact linearly on cancer development. An extension, called the fail-safe model, envisaged an optimum level of gene derangement for tumor growth, but proposed that the cell gained protection from tumorigenesis because additional mutations caused excessive derangement. Most of the evidence in support of the continuum model came from Pten mutant mice rather than humans. In this article, we assess the validity and applicability of the continuum and fail-safe models. We suggest that the latter is of limited use: In part, it restates the existing “just right” of optimum intermediate gene derangement in tumorigenesis, and in part it is inherently implausible that a cell should avoid becoming cancerous only when it is some way down the road to that state. In contrast, the basic continuum model is a very useful addition to the other genetic models of tumorigenesis, especially in certain scenarios. Fittingly for a quantitative model, we propose that the continuum model is most likely to apply where multiple, cancer-promoting mutations have relatively small, additive effects, either through the well-established case of additive germline predisposition alleles or in a largely hypothetical situation where cancers may have acquired several somatic “mini-driver” mutations, each with weaker effects than classical tumor suppressors or fully activated oncogenes. Cancer Res; 72(13); 3131–4. ©2012 AACR.
Role of Apollon in Human Melanoma Resistance to Antitumor Agents That Activate the Intrinsic or the Extrinsic Apoptosis Pathways
Authors: Tassi Elena , Zanon Marina , Vegetti Claudia , Molla Alessandra , Bersani Ilaria , Perotti Valentina , Pennati Marzia , Zaffaroni Nadia , Milella Michele , Ferrone Soldano , Carlo-Stella Carmelo , Gianni Alessandro M. , Mortarini Roberta , Anichini Andrea
Published: May 2012

Purpose: To assess the role of Apollon in melanoma resistance to intrinsic and extrinsic pathways of apoptosis and to identify strategies to reduce its expression.

Experimental Design: Apollon expression was assessed in melanoma cells in vitro and in vivo. Apollon modulation and melanoma apoptosis were evaluated by Western blot and/or flow cytometry in response to cytotoxic drugs, mitogen-activated protein/extracellular signal–regulated kinase (MEK)-, BRAFV600E-, and mTOR-specific inhibitors, TRAIL and anti-HLA class II monoclonal antibodies (mAb). Mitochondrial depolarization, caspase activation, apoptosis assays, and gene expression profiling were used to test effects of Apollon silencing, by siRNA, on melanoma response to antitumor agents.

Results: Apollon was constitutively expressed by melanoma cells, in vitro and in vivo, and at higher levels than in benign melanocytic lesions. Melanoma apoptosis correlated significantly with Apollon protein downmodulation in response to cytotoxic drugs, MEK, or BRAFV600E-specific inhibitors. Combinatorial treatment with MEK and mTOR inhibitors and HLA class II ligation, by a specific mAb, promoted Apollon downmodulation and enhanced melanoma apoptosis. Apollon downmodulation induced by antitumor agents was caspase independent, but proteasome dependent. Knockdown of Apollon, by siRNA, triggered apoptosis and/or significantly enhanced melanoma cell death in response to cytotoxic drugs, MEK- and BRAFV600E-specific inhibitors, and soluble or membrane-bound TRAIL. Apollon silencing promoted mitochondrial depolarization and caspase-2, caspase-8, caspase-9, and caspase-3 activation in response to different antitumor agents and altered the profile of genes modulated by MEK or BRAFV600E-specific inhibitors.

Conclusions: Targeting of Apollon may significantly improve melanoma cell death in response to antitumor agents that trigger the intrinsic or the extrinsic apoptosis pathways. Clin Cancer Res; 18(12); 3316–27. ©2012 AACR.
A Molecular Taxonomy for Urothelial Carcinoma
Authors: Sjödahl Gottfrid , Lauss Martin , Lövgren Kristina , Chebil Gunilla , Gudjonsson Sigurdur , Veerla Srinivas , Patschan Oliver , Aine Mattias , Fernö Mårten , Ringnér Markus , Månsson Wiking , Liedberg Fredrik , Lindgren David , Höglund Mattias
Published: May 2012

Purpose: Even though urothelial cancer is the fourth most common tumor type among males, progress in treatment has been scarce. A problem in day-to-day clinical practice is that precise assessment of individual tumors is still fairly uncertain; consequently efforts have been undertaken to complement tumor evaluation with molecular biomarkers. An extension of this approach would be to base tumor classification primarily on molecular features. Here, we present a molecular taxonomy for urothelial carcinoma based on integrated genomics.

Experimental Design: We use gene expression profiles from 308 tumor cases to define five major urothelial carcinoma subtypes: urobasal A, genomically unstable, urobasal B, squamous cell carcinoma like, and an infiltrated class of tumors. Tumor subtypes were validated in three independent publically available data sets. The expression of 11 key genes was validated at the protein level by immunohistochemistry.

Results: The subtypes show distinct clinical outcomes and differ with respect to expression of cell-cycle genes, receptor tyrosine kinases particularly FGFR3, ERBB2, and EGFR, cytokeratins, and cell adhesion genes, as well as with respect to FGFR3, PIK3CA, and TP53 mutation frequency. The molecular subtypes cut across pathologic classification, and class-defining gene signatures show coordinated expression irrespective of pathologic stage and grade, suggesting the molecular phenotypes as intrinsic properties of the tumors. Available data indicate that susceptibility to specific drugs is more likely to be associated with the molecular stratification than with pathologic classification.

Conclusions: We anticipate that the molecular taxonomy will be useful in future clinical investigations. Clin Cancer Res; 18(12); 3377–86. ©2012 AACR.
CD20+ Tumor-Infiltrating Lymphocytes Have an Atypical CD27− Memory Phenotype and Together with CD8+ T Cells Promote Favorable Prognosis in Ovarian Cancer
Authors: Nielsen Julie S. , Sahota Rob A. , Milne Katy , Kost Sara E. , Nesslinger Nancy J. , Watson Peter H. , Nelson Brad H.
Published: May 2012

Purpose: Tumor-infiltrating lymphocytes (TIL), in particular CD8+ T cells and CD20+ B cells, are strongly associated with survival in ovarian cancer and other carcinomas. Although CD8+ TIL can mediate direct cytolytic activity against tumors, the role of CD20+ TIL is poorly understood. Here, we investigate the possible contributions of CD20+ TIL to humoral and cellular tumor immunity.

Experimental Design: Tumor and serum specimens were obtained from patients with high-grade serous ovarian cancer. CD8+ and CD20+ TIL were analyzed by immunohistochemistry and flow cytometry. Immunoglobulin molecules were evaluated by DNA sequencing. Serum autoantibody responses to the tumor antigens p53 and NY-ESO-1 were measured by ELISA.

Results: The vast majority of CD20+ TIL were antigen experienced, as evidenced by class-switching, somatic hypermutation, and oligoclonality, yet they failed to express the canonical memory marker CD27. CD20+ TIL showed no correlation with serum autoantibodies to p53 or NY-ESO-1. Instead, they colocalized with activated CD8+ TIL and expressed markers of antigen presentation, including MHC class I, MHC class II, CD40, CD80, and CD86. The presence of both CD20+ and CD8+ TIL correlated with increased patient survival compared with CD8+ TIL alone.

Conclusions: In high-grade serous ovarian tumors, CD20+ TIL have an antigen–experienced but atypical CD27− memory B-cell phenotype. They are uncoupled from serum autoantibodies, express markers of antigen-presenting cells, and colocalize with CD8+ T cells. We propose that the association between CD20+ TIL and patient survival may reflect a supportive role in cytolytic immune responses. Clin Cancer Res; 18(12); 3281–92. ©2012 AACR.
Accuracy of In Vivo Multimodal Optical Imaging for Detection of Oral Neoplasia
Authors: Pierce Mark C. , Schwarz Richard A. , Bhattar Vijayashree S. , Mondrik Sharon , Williams Michelle D. , Lee J. Jack , Richards-Kortum Rebecca , Gillenwater Ann M.
Published: May 2012

If detected early, oral cancer is eminently curable. However, survival rates for oral cancer patients remain low, largely due to late-stage diagnosis and subsequent difficulty of treatment. To improve clinicians' ability to detect early disease and to treat advanced cancers, we developed a multimodal optical imaging system (MMIS) to evaluate tissue in situ, at macroscopic and microscopic scales. The MMIS was used to measure 100 anatomic sites in 30 patients, correctly classifying 98% of pathologically confirmed normal tissue sites, and 95% of sites graded as moderate dysplasia, severe dysplasia, or cancer. When used alone, MMIS classification accuracy was 35% for sites determined by pathology as mild dysplasia. However, MMIS measurements correlated with expression of candidate molecular markers in 87% of sites with mild dysplasia. These findings support the ability of noninvasive multimodal optical imaging to accurately identify neoplastic tissue and premalignant lesions. This in turn may have considerable impact on detection and treatment of patients with oral cancer and other epithelial malignancies. Cancer Prev Res; 5(6); 801–9. ©2012 AACR.
Introducing Solid Foods to Preterm Infants in Developed Countries
Authors: Palmer D.J. , Makrides M.
Published: May 2012

The addition of solid foods to an infant’s diet is required to provide adequate nutrition, as eventually an infant will be unable to consume a sufficient volume of breast milk to meet their nutritional needs. The timing of this important dietary change for infants born preterm (<37 weeks of gestation) should take into consideration their delayed early gross motor developmental progress, increased nutritional requirements, organ immaturity, increased gut permeability and increased risk of hospitalization from infections. Good head control is important for safe eating of solid foods: this developmental milestone may be delayed in preterm infants up to 3 months of corrected age. One randomized controlled trial has demonstrated improved nutritional intakes with the introduction of nutrient-dense solid foods from 13 weeks of uncorrected age, resulting in improved nutritional iron status and greater rate of growth during infancy. There is neither current evidence for an increased infection rate with an early introduction of solid foods in developed countries, nor is there evidence that in preterm infants maturation of renal function is reduced. However, one observational study has determined that preterm infants who had 4 or more solid foods introduced prior to 17 weeks of corrected age, or who had any solid foods introduced prior to 10 weeks of corrected age, had an increased risk of eczema development. A compromise is needed to balance the nutritional benefits of commencing solid foods from 13 weeks of uncorrected age with the risks of increased eczema development, along with ensuring developmental readiness. Based on the current evidence, 3 months (13 weeks) of corrected age seems to be an appropriate age to commence nutrient-dense solid foods for most preterm infants. Further research, with an emphasis on immediate as well as longer-term consequences, would be valuable to provide more specific evidence-based guidelines regarding the introduction of solid food for preterm infants.
Timing of Introduction of Complementary Food: Short- and Long-Term Health Consequences
Authors: Przyrembel Hildegard
Published: May 2012

Complementary food is needed when breast milk (or infant formula) alone is no longer sufficient for both nutritional and developmental reasons. The timing of its introduction, therefore, is an individual decision, although 6 months of exclusive breastfeeding can be recommended for most healthy term infants. The new foods are intended to ‘complement’ ongoing breastfeeding with those dietary items whose intake has become marginal or insufficient. Both breastfeeding and complementary feeding can have direct or later consequences on health. The evaluation of consequences of both early and late introduction of complementary food can neither disregard the effect of breastfeeding compared to formula feeding nor the composition or quality of the complementary food. Possible short-term health effects concern growth velocity and infections, and possible long-term effects may relate to atopic diseases, type 1 and 2 diabetes, obesity and neuromuscular development. On the basis of the currently available evidence, it is impossible to exactly determine the age when risks related to the start of complementary feeding are lowest or highest for most of these effects, with the possible exception of infections and early growth velocity. The present knowledge on undesirable health effects, however, is mainly based on observational studies, and although some mechanisms have been proposed, further prospective studies have to clarify these unsolved issues. Even less evidence on the consequences of the timing of complementary food introduction is available for formula-fed infants.
Maternal Hemodynamics at 11–13 Weeks’ Gestation in Gestational Diabetes Mellitus
Authors: Khalil Asma , Garcia-Mandujano Rosario , Chiriac Roxana , Akolekar Ranjit , Nicolaides Kypros H.
Published: May 2012

Objective: Women who develop gestational diabetes mellitus (GDM) are at increased risk of type 2 diabetes and subsequent cardiovascular mortality and morbidity. Individuals with cardiovascular disorders have increased central aortic systolic blood pressure (SBPAo) and arterial stiffness. The hypothesis of this study is that increased SBPAo and arterial stiffness are apparent before the development of GDM. Methods: In this screening study, SBPAo, pulse wave velocity (PWV) and augmentation index (AIx) were measured in women with singleton pregnancies attending for routine antenatal care at 11–13 weeks’ gestation. We compared SBPAo, PWV and AIx, expressed as multiples of the median (MoM), after adjustment for maternal characteristics affecting these measurements, in women who subsequently developed GDM (n = 105) with the values in non-GDM controls (n = 6,736). Results: In the GDM group, compared to non-GDM controls, there was an increase in PWV [1.04 MoM, interquartile range (IQR) 0.93–1.15 vs. 1.00 MoM, IQR 0.90–1.12; p = 0.013] and SBPAo (1.03 MoM, IQR 0.98–1.14 vs. 1.00 MoM, IQR 0.94–1.08; p < 0.0001) but no significant difference in the AIx (1.02 MoM, IQR 0.89–1.22 vs. 1.00 MoM, IQR 0.87–1.17; p = 0.118). Conclusion: Women who develop GDM have increased SBPAo and arterial stiffness from the first trimester of pregnancy before the clinical onset of GDM.
Oxidation Levels Differentially Impact Melanocytes: Low versus High Concentration of Hydrogen Peroxide Promotes Melanin Synthesis and Melanosome Transfer
Authors: Tang Luyan , Li Jian , Lin Xiao , Wu Wenyu , Kang Kefei , Fu Wenwen
Published: May 2012

Background: UVB light can generate potentially harmful hydrogen peroxide (H2O2) in vivo, but it can also promote the beneficial proliferation and migration of melanocytes. The successful use of UVB monotherapy for treatment of vitiligo suggests that H2O2 may have a biphasic effect on melanin synthesis and melanosome transfer. Objective: To study the beneficial role of H2O2 on melanogenesis and melanosome transport in living melanocytes and keratinocytes. Methods: A co-culture system model was constructed using the primary human melanocytes and keratinocytes. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to determine cell proliferation, NaOH was used to determine the melanin content, and real-time PCR was used to determine tyrosinase expression. Western blot was used to determine Rab-27A and protease-activated receptor 2 (PAR-2) expression. Results: This study demonstrated that tyrosinase was activated by low concentrations of H2O2 (≤0.3 mM); however, this activity was downregulated by high concentrations of H2O2 (>0.3 mM). Activation of high levels of melanin synthesis was induced when cells were treated with low concentrations of H2O2 (0.3 mM). Further observation using an in vitro co-culture system of fluorescein (carboxyfluorescein diacetate succinimidyl ester, CFDA-SE)-labeled melanocytes and keratinocytes indicated that melanosome transfer occurred in normal human epidermal melanocytes. Fluorescence microscopy revealed increased melanosome transfer into keratinocytes treated with 0.3 mM H2O2 in the co-culture compared to the control. Examination of melanosomes in the keratinocytes by flow cytometry confirmed these results. Furthermore, treatment with H2O2 (0.3 mM) upregulated the expression of Rab-27A and PAR-2, significant proteins involved in melanosome transfer, according to Western blot. Conclusion: These results confirmed that low concentration levels of H2O2 play a major role in the regulation of human pigmentation by increasing melanin synthesis and melanosome transfer.
Isolation of a Novel Adenovirus from Rousettus leschenaultii Bats from India
Authors: Raut C.G. , Yadav P.D. , Towner J.S. , Amman B.R. , Erickson B.R. , Cannon D.L. , Sivaram A. , Basu A. , Nichol S.T. , Mishra A.C. , Mourya D.T.
Published: May 2012

Surveillance work was initiated to study the presence of highly infectious diseases like Ebola-Reston, Marburg, Nipah and other possible viruses that are known to be found in the bat species and responsible for causing diseases in humans. A novel adenovirus was isolated from a common species of fruit bat (Rousettus leschenaultii) captured in Maharashtra State, India. Partial sequence analysis of the DNA polymerase gene shows this isolate to be a newly recognized member of the genus Mastadenovirus (family Adenoviridae), approximately 20% divergent at the nucleotide level from Japanese BatAdV, its closest known relative.
Ex situ Liver Resection for Unresectable Tumors
Authors: Lei Peng , Liu XueMing , Liu ShiQi , Lv Yi
Published: May 2012

Primary and secondary liver tumors are among the most common tumors in humans. Two surgical approaches may be used to address these tumors: liver transplantation and liver resection. However, some tumors cannot be treated by conventional techniques or liver transplantation due to poor intraoperative exposure, limitations of indication standards, and/or other complex factors. To overcome these problems, ex situ liver resection has been introduced and used successfully in many cases. This technique is based primarily on liver transplantation and perfusion with preservation solution under hypothermic conditions. The major indications for ex situ liver resection are liver tumors that are unresectable or in which resection using conventional surgical techniques is very dangerous due to the close proximity to or involvement of the venous confluence and/or the main hepatic veins. However, high mortality and morbidity rates limit the use of this technique despite the efforts of many surgeons to improve their skills. Patient selection is of utmost importance to achieve a good outcome. Emphasis on basic research (e.g. on reperfusion injury) and the development of key techniques should improve the safety of the procedure and reduce mortality in the future.
Fetal Fraction in Maternal Plasma Cell-Free DNA at 11–13 Weeks’ Gestation: Effect of Maternal and Fetal Factors
Authors: Ashoor Ghalia , Poon Leona , Syngelaki Argyro , Mosimann Beatrice , Nicolaides Kypros H.
Published: May 2012

Objective: It was the aim of this study to examine the possible effects of maternal and fetal characteristics on the fetal fraction in maternal plasma cell-free DNA (cfDNA) at 11–13 weeks’ gestation. Methods: In a nested case-control study, cfDNA was extracted from maternal plasma obtained before chorionic villous sampling from 300 euploid, 50 trisomy 21 and 50 trisomy 18 pregnancies at 11–13 weeks’ gestation. Chromosome-selective sequencing of maternal cfDNA non-polymorphic and polymorphic loci, where fetal alleles differ from maternal alleles, was used to determine the proportion of DNA which is of fetal origin. Multivariate regression analysis was used to determine which of the factors amongst maternal weight, racial origin, smoking status, plasma storage time, serum pregnancy-associated plasma protein (PAPP)-A and free β-subunit of human chorionic gonadotropin (β-hCG), fetal crown-rump length, nuchal translucency thickness, gender and karyotype were significant predictors of the fetal fraction. Results: Significant independent prediction of fetal fraction was provided by maternal weight, serum PAPP-A and serum free β-hCG multiples of the median, but not by other maternal characteristics, fetal karyotype, crown-rump length or nuchal translucency thickness. Fetal fraction increased with serum metabolite levels and decreased with maternal weight. Conclusions: The fetal fraction in maternal plasma cfDNA increases with serum PAPP-A and free β-hCG and decreases with maternal weight.
Colocalization of Immediate Early Genes in Catecholamine Cells after Song Exposure in Female Zebra Finches (Taeniopygia guttata)
Authors: Lynch Kathleen S. , Diekamp Bettina , Ball Gregory F.
Published: May 2012

The physiological state of animals in many taxonomic groups can be modified via social interactions including simply receiving communication signals from conspecifics. Here, we explore whether the catecholaminergic system of female songbirds responds during social interactions that are limited to song reception. We measured the protein product of an immediate early gene (ZENK) within three catecholaminergic brain regions in song-exposed (n = 11) and silence-exposed (n = 6) female zebra finches (Taeniopygia guttata). ZENK-ir induction was quantified in catecholamine cells as well as within cells of unknown phenotypes in three brain regions that synthesize catecholamines, the ventral tegmental area, the periaqueductal gray and the locus coeruleus (LoC). Our results reveal that there are no significant differences in the overall number of cells expressing ZENK between song- and silence-exposed females. However, when we limited our measurements to catecholamine-containing cells, we noticed a greater number of catecholamine-containing cells expressing ZENK within the LoC in the song-exposed females compared to silence-exposed females. Furthermore, we measured five behaviors during the song- and silence-exposed period, as behavioral differences between these groups may account for differences in the coinduction of ZENK and TH-ir. Our results reveal that there were no statistically significant differences in the five measured behaviors between song- and silence-exposed females. Our study demonstrates that noradrenergic cells within the LoC are involved in the neural architecture underlying sound perception and that cells within the catecholaminergic system are modulated by social interactions, particularly the reception of signals used in animal communication.
Chronic Kidney Disease and Cognitive Impairment: A Systematic Review and Meta-Analysis
Authors: Etgen Thorleif , Chonchol Michel , Förstl Hans , Sander Dirk
Published: May 2012

Background: Chronic kidney disease (CKD) has emerged as a possible new risk factor of cognitive impairment and dementia, but results of studies remain conflicting. Methods: A systematic literature research of electronic databases (MEDLINE, Cochrane Library and Goggle Scholar covering the period from 1980 to January 2012) and meta-analysis of relevant cross-sectional and longitudinal studies were conducted to assess the association of CKD and cognitive decline. Results: Most cross-sectional and longitudinal studies suggest an association between cognitive impairment and CKD. Meta-analysis of cross-sectional and longitudinal studies comprising 54,779 participants yielded an association of cognitive decline in patients with CKD compared with patients without CKD (OR 1.65, 95% CI 1.32–2.05; p < 0.001, and OR 1.39, 95% CI 1.15–1.68; p < 0.001, respectively). Conclusion: This is the first meta-analysis assessing the impact of CKD on cognitive decline. Our results suggest CKD being a significant and independent somatic risk factor in the development of cognitive decline.
Treatment of Toxic Epidermal Necrolysis with the Combination of Infliximab and High-Dose Intravenous Immunoglobulin
Authors: Gaitanis Georgios , Spyridonos Panagiota , Patmanidis Konstantinos , Koulouras Vasilios , Nakos Georgios , Tzaphlidou Margaret , Bassukas Ioannis D.
Published: May 2012

Background: Therapeutic evidence for toxic epidermal necrolysis (TEN) is indicative for high-dose intravenous immunoglobulin yet inconclusive for corticosteroids. Objective: To describe the combination of corticosteroids, infliximab and a high-dose intravenous immunoglobulin course for TEN. Patients and Methods: In three patients (SCORTEN survival probabilities: 41.7%, 64.2%, 41.7%) disease control was evaluated by (a) employing quantitative image analysis to measure progression of skin detachment and (b) patients’ outcome (complete re-epithelization). Published cases of TEN treatments with infliximab were retrieved from PubMed. Results: Within 48 h skin disease progression was arrested in all patients. Two patients were discharged after 3 weeks without any sequels from skin or conjunctivae. One patient passed away on the ninth day, however with noticeably improved skin (mortality rate: 33% observed vs. 50% expected). A PubMed search retrieved five TEN patients treated successfully with infliximab. Conclusion: The described combination presents a feasible therapeutic alternative for TEN that warrants further evaluation.
NRAS Mutations in Noonan Syndrome
Authors: Denayer E. , Peeters H. , Sevenants L. , Derbent M. , Fryns J.P. , Legius E.
Published: May 2012

Noonan syndrome is a genetically heterogeneous disorder caused by mutations in PTPN11, SOS1, RAF1 and less frequently in KRAS, NRAS or SHOC2. Here, we performed mutation analysis of NRAS and SHOC2 in 115 PTPN11, SOS1, RAF1, and KRAS mutation-negative individuals. No SHOC2 mutations were found, but we identified 3 NRAS mutations in 3 probands. One NRAS mutation was novel. The phenotype associated with germline NRAS mutations is variable. Our results confirm that a small proportion of Noonan syndrome patients carry germline NRAS mutations.
Discriminative Ability of LDL-Cholesterol to Identify Patients With Familial Hypercholesterolemia
Authors: Huijgen Roeland , Hutten Barbara A. , Kindt Iris , Vissers Maud N. , Kastelein John J.P.
Published: May 2012

Background—

Screening for familial hypercholesterolemia (FH) within affected families is often based on cutoff values for low-density lipoprotein cholesterol (LDL-C). However, the diagnostic accuracy of LDL-C levels is influenced by the magnitude of the LDL-C overlap between FH patients and unaffected relatives. The purpose of the current study was to assess to what extent this overlap is influenced by the severity of specific FH mutations.

Methods and Results—

Individuals were eligible if they underwent family screening for FH between 2003 and 2010. The entire cohort was then compared with those who were investigated for the presence of the most severe mutations (class 1). The area under the receiver operating characteristics curve and the sensitivity of the 90th percentile of LDL-C were calculated for both cohorts. We included 26 406 individuals, of whom 9169 (35%) carried an FH-causing mutation. In the entire cohort at baseline, mean LDL-C was 4.63±1.44 mmol/L for FH carriers (n=5372) and 2.96±0.96 mmol/L for unaffected relatives (n=15 148);
P
<0.001. The corresponding operating characteristics curve (95% CI) was 86.6% (85.9%–87.2%), and the cutoff level of LDL-C above the 90th percentile showed a sensitivity of 68.5%. The operating characteristics curve and sensitivity significantly improved when the 5933 individuals tested for class 1 mutations were assessed separately; 96.2% (95.3%–97.1%) and 91.3%, respectively.

Conclusions—

In summary, the overlap in terms of LDL-C levels between those with molecularly proven FH and unaffected relatives is to a large extent because of the high prevalence of modestly severe LDL-receptor mutations in the Netherlands.
Relative Contributions of Synoptic and Low-Frequency Eddies to Time-Mean Atmospheric Moisture Transport, Including the Role of Atmospheric Rivers
Authors: Newman Matthew , Kiladis George N. , Weickmann Klaus M. , Ralph F. Martin , Sardeshmukh Prashant D.
Published: May 2012

The relative contributions to mean global atmospheric moisture transport by both the time-mean circulation and by synoptic and low-frequency (periods greater than 10 days) anomalies are evaluated from the vertically integrated atmospheric moisture budget based on 40 yr of “chi corrected” NCEP–NCAR reanalysis data. In the extratropics, while the time-mean circulation primarily moves moisture zonally within ocean basins, low-frequency and synoptic anomalies drive much of the mean moisture transport both from ocean to land and toward the poles. In particular, during the cool-season low-frequency variability is the largest contributor to mean moisture transport into southwestern North America, Europe, and Australia. While some low-frequency transport originates in low latitudes, much is of extratropical origin due to large-scale atmospheric anomalies that extract moisture from the northeast Pacific and Atlantic Oceans. Low-frequency variability is also integral to the Arctic (latitudes > 70°N) mean moisture budget, especially during summer, when it drives mean poleward transport from relatively wet high-latitude continental regions. Synoptic variability drives about half of the mean poleward moisture transport in the midlatitudes of both hemispheres, consistent with simple “lateral mixing” arguments. Extratropical atmospheric transport is also particularly focused within “atmospheric rivers” (ARs), relatively narrow poleward-moving moisture plumes associated with frontal dynamics. AR moisture transport, defined by compositing fluxes over those locations and times where column-integrated water vapor and poleward low-level wind anomalies are both positive, represents most of the total extratropical meridional moisture transport. These results suggest that understanding potential anthropogenic changes in the earth ’s hydrological cycle may require understanding corresponding changes in atmospheric variability, especially on low-frequency time scales.
Impacts of Forecaster Involvement on Convective Storm Initiation and Evolution Nowcasting
Authors: Roberts Rita D. , Anderson Amanda R. S. , Nelson Eric , Brown Barbara G. , Wilson James W. , Pocernich Matthew , Saxen Thomas
Published: May 2012

A forecaster-interactive capability was added to an automated convective storm nowcasting system [Auto-Nowcaster (ANC)] to allow forecasters to enhance the performance of 1-h nowcasts of convective storm initiation and evolution produced every 6 min. This Forecaster-Over-The-Loop (FOTL-ANC) system was tested at the National Weather Service Fort Worth–Dallas, Texas, Weather Forecast Office during daily operations from 2005 to 2010. The forecaster’s role was to enter the locations of surface convergence boundaries into the ANC prior to dissemination of nowcasts to the Center Weather Service Unit. Verification of the FOTL-ANC versus ANC (no human) nowcasts was conducted on the convective scale. Categorical verification scores were computed for 30 subdomains within the forecast domain. Special focus was placed on subdomains that included convergence boundaries for evaluation of forecaster involvement and impact on the FOTL-ANC nowcasts. The probability of detection of convective storms increased by 20%–60% with little to no change observed in the false-alarm ratios. Bias values increased from 0.8–1.0 to 1.0–3.0 with human involvement. The accuracy of storm nowcasts notably improved with forecaster involvement; critical success index (CSI) values increased from 0.15–0.25 (ANC) to 0.2–0.4 (FOTL-ANC). Over short time periods, CSI values as large as 0.6 were also observed. This study demonstrated definitively that forecaster involvement led to positive improvement in the nowcasts in most cases while causing no degradation in other cases; a few exceptions are noted. Results show that forecasters can play an important role in the production of rapidly updated, convective storm nowcasts for end users.
Performance Pressure as a Double-edged Sword
Authors: Gardner Heidi K.
Published: May 2012

In this paper, I develop and empirically test the proposition that performance pressure acts as a double-edged sword for teams, providing positive effects by enhancing the team’s motivation to achieve good results while simultaneously triggering process losses. I conducted a multimethod field study of 78 audit and consulting teams from two global professional firms, revealing an irony of team life: even though motivated to perform well on a high-stakes project, pressured teams are more likely to engage in performance-detracting behaviors. Survey results show that, as performance pressure increases, team members begin to overly rely on general expertise while discounting domain-specific expertise, leading to suboptimal performance. I then use longitudinal qualitative case studies of six project teams across two firms to explore the underlying behavioral mechanisms that generate this outcome. Results reveal four limiting team processes: (1) a drive toward consensus, (2) a focus on common knowledge, (3) a shift from learning to project completion, and (4) increased conformity to the status hierarchy. Results also show that only domain-specific expertise—the kind that teams underuse when facing higher pressure—increases client-rated team performance. I thus find, paradoxically, that when teams need domain-specific expertise the most, they tend to use it the least, despite evidence suggesting they are highly motivated to do well on their task.
Public policy to promote healthy nutrition in schools: Views of policymakers
Authors: Walton Mat , Signal Louise , Thomson George
Published: May 2012

Objectives:

This study aimed to identify policy options to support nutrition promotion in New Zealand primary schools. In achieving this aim, the study sought to identify framing by policymakers regarding child diet and obesity; views on the role of schools in nutrition promotion; policy options and degree of support for these options. Issue framing by policymakers and policy option support are important considerations in policy design.

Setting:

New Zealand policymakers within the health and education policy community.

Method:

A qualitative study involving 16 semi-structured interviews with New Zealand policymakers.

Results:

Informants identified multiple drivers and complex causation of childhood obesity. Informants supported the role of schools in promoting nutrition, but recognized that issues external to schools such as poverty and availability of food placed limits on the effectiveness of actions within schools. Most informants agreed state policy was required across settings to encourage and support school nutrition promotion; however, there were some differences expressed in the degree to which state policy should regulate food options and marketing.

Conclusion:

New Zealand policymakers identify schools as a legitimate focus for policy development and commonly identify environmental contributions to child diet and obesity causation. This suggests a starting point for further policy deliberation and offers the possibility of further cross-sector policy development. The study provides an example for research elsewhere, and for international comparison.
Target Finding With a Spatially Aware Handheld Chart Display
Authors: Ware Colin , Arsenault Roland
Published: May 2012

Objective:

The objective was to evaluate the use of a spatially aware handheld chart display in a comparison with a track-up fixed display configuration and to investigate how cognitive strategies vary when performing the task of matching chart symbols with environmental features under different display geometries and task constraints.

Background:

Small-screen devices containing both accelerometers and magnetometers support the development of spatially aware handheld maps. These can be designed so that symbols representing targets in the external world appear in a perspective view determined by the orientation of the device.

Method:

A panoramic display was used to simulate a marine environment. The task involved matching targets in the scene to symbols on simulated chart displays. In Experiment 1, a spatially aware handheld chart display was compared to a fixed track-up chart display. In Experiment 2, a gaze monitoring system was added and the distance between the chart display and the scene viewpoint was varied.

Results:

All respondents were faster with the handheld device. Novices were much more accurate with the handheld device. People allocated their gaze very differently if they had to move between a map display and a view of the environment.

Conclusion:

There may be important benefits to spatially aware handheld displays in reducing errors relating to common navigation tasks.

Application:

Both the difficulty of spatial transformations and the allocation of attention should be considered in the design of chart displays.
Something of Collaborative Manufacture
Authors: Foldy Erica Gabrielle
Published: May 2012

Using qualitative data, this article documents how organizations contribute to the construction of their members’ race and gender identities. Data collection took place in four organizations, from a small nonprofit to a large financial services firm. Using interactions as the unit of analysis, the author compiled and investigated a database of 114 interactions, creating a process model of how working in an organization can spotlight and change the expression of racial, ethnic, and gender identities. The article makes four contributions: It suggests a broader reach for organizational influence on individual identity, since earlier research has explored work-related identities; it distinguishes among levels of influence by isolating the discrete role of interpersonal encounters, organizational practices, and the combination of the two; it casts light on how identity construction happens even without intentional effort by individuals or organizations; and it illustrates the importance of modest changes in the construction of identity.
Export Performance and Increased Services Content in Manufacturing
Authors: Wolfmayr Yvonne
Published: May 2012

Against the background of the increasing services content of many manufactured goods, the paper attempts to assess the role of (domestically and internationally) purchased service inputs for the relative export performance of countries in a particular manufacturing industry. It estimates an empirical model of export market shares for EU15 countries and twelve disaggregated manufacturing industries over the period 1995 to 2007. Whereas most traditional explanations are based on the influence of relative costs and technology-related variables, this paper emphasises the importance of services as a determinant of both product quality and the sectors’ productivity. The service linkage variables are based on national input–output tables. The analysis finds a positive and highly significant impact of services on export market shares of manufactured goods. Distinguishing between domestically-sourced service inputs and imports results in a robust and highly significant impact of international service linkages, while the analysis finds no impact of domestic service linkages.
Toward a Theory of Civil–Military Punishment
Authors: Bessner Daniel , Lorber Eric
Published: May 2012

This article addresses a significant question in American civil–military relations: under what conditions will civilian principals punish military leaders for shirking? In order to inductively derive a theory of civil–military punishment, the authors examine two cases of military shirking where there is little doubt that insubordination occurred. The first case the authors analyze is Douglas MacArthur’s insubordination under Harry Truman during the Korean War, and the second is Colin Powell’s scuttling of Bill Clinton’s plan to allow homosexuals to serve openly in the military in late 1992 and early 1993. This analysis indicates that two factors are linked to civil–military punishment. First, the salience of the issue at stake determines whether he or she decides to punish shirking. The second factor linked to punishment is whether or not the civilian has the military’s support to pursue punishment.
Don’t Tread on Me
Authors: Barnes Collin D. , Brown Ryan P. , Osterman Lindsey L.
Published: May 2012

Using both college students and a national sample of adults, the authors report evidence linking the ideology of masculine honor in the U.S. with militant responses to terrorism. In Study 1, individuals’ honor ideology endorsement predicted, among other outcomes, open-ended hostile responses to a fictitious attack on the Statue of Liberty and support for the use of extreme counterterrorism measures (e.g., severe interrogations), controlling for right-wing authoritarianism, social dominance orientation, and other covariates. In Study 2, the authors used a regional classification to distinguish honor state respondents from nonhonor state respondents, as has traditionally been done in the literature, and showed that students attending a southwestern university desired the death of the terrorists responsible for 9/11 more than did their northern counterparts. These studies are the first to show that masculine honor ideology in the U.S. has implications for the intergroup phenomenon of people’s responses to terrorism.