bluuebunny/crossref_metadata_2025 huggingface dataset:
Early functional muscle regeneration after myotoxic injury in mice is unaffected by nNOS absence
Authors: Church Jarrod E. , Gehrig Stefan M. , Chee Annabel , Naim Timur , Trieu Jennifer , McConell Glenn K. , Lynch Gordon S.
Published: August 2011

Nitric oxide (NO) is an important signaling molecule produced in skeletal muscle primarily via the neuronal subtype of NO synthase (NOS1, or nNOS). While many studies have reported NO production to be important in muscle regeneration, none have examined the contribution of nNOS-derived NO to functional muscle regeneration (i.e., restoration of the muscle's ability to produce force) after acute myotoxic injury. In the present study, we tested the hypothesis that genetic deletion of nNOS would impair functional muscle regeneration after myotoxic injury in nNOS−/− mice. We found that nNOS−/− mice had lower body mass, lower muscle mass, and smaller myofiber cross-sectional area and that their tibialis anterior (TA) muscles produced lower absolute tetanic forces than those of wild-type littermate controls but that normalized or specific force was identical between the strains. In addition, muscles from nNOS−/− mice were more resistant to fatigue than those of wild-type littermates ( P < 0.05). To determine whether deletion of nNOS affected muscle regeneration, TA muscles from nNOS−/− mice and wild-type littermates were injected with the myotoxin notexin to cause complete fiber degeneration, and muscle structure and function were assessed at 7 and 10 days postinjury. Myofiber cross-sectional area was lower in regenerating nNOS−/− mice than wild-type controls at 7 and 10 days postinjury; however, contrary to our original hypothesis, no difference in force-producing capacity of the TA muscle was evident between the two groups at either time point. Our findings reveal that nNOS is not essential for functional muscle regeneration after acute myotoxic damage.
Impedance control is selectively tuned to multiple directions of movement
Authors: Kadiallah Abdelhamid , Liaw Gary , Kawato Mitsuo , Franklin David W. , Burdet Etienne
Published: August 2011

Humans are able to learn tool-handling tasks, such as carving, demonstrating their competency to make movements in unstable environments with varied directions. When faced with a single direction of instability, humans learn to selectively co-contract their arm muscles tuning the mechanical stiffness of the limb end point to stabilize movements. This study examines, for the first time, subjects simultaneously adapting to two distinct directions of instability, a situation that may typically occur when using tools. Subjects learned to perform reaching movements in two directions, each of which had lateral instability requiring control of impedance. The subjects were able to adapt to these unstable interactions and switch between movements in the two directions; they did so by learning to selectively control the end-point stiffness counteracting the environmental instability without superfluous stiffness in other directions. This finding demonstrates that the central nervous system can simultaneously tune the mechanical impedance of the limbs to multiple movements by learning movement-specific solutions. Furthermore, it suggests that the impedance controller learns as a function of the state of the arm rather than a general strategy.
Spatial tuning to sound-source azimuth in the inferior colliculus of unanesthetized rabbit
Authors: Kuwada Shigeyuki , Bishop Brian , Alex Caitlin , Condit Daniel W. , Kim Duck O.
Published: August 2011

Despite decades of research devoted to the study of inferior colliculus (IC) neurons' tuning to sound-source azimuth, there remain many unanswered questions because no previous study has examined azimuth tuning over a full range of 360° azimuths at a wide range of stimulus levels in an unanesthetized preparation. Furthermore, a comparison of azimuth tuning to binaural and contralateral ear stimulation over ranges of full azimuths and widely varying stimulus levels has not previously been reported. To fill this void, we have conducted a study of azimuth tuning in the IC of the unanesthetized rabbit over a 300° range of azimuths at stimulus levels of 10–50 dB above neural threshold to both binaural and contralateral ear stimulation using virtual auditory space stimuli. This study provides systematic evidence for neural coding of azimuth. We found the following: 1) level-tolerant azimuth tuning was observed in the top 35% regarding vector strength and in the top 15% regarding vector angle of IC neurons; 2) preserved azimuth tuning to binaural stimulation at high stimulus levels was created as a consequence of binaural facilitation in the contralateral sound field and binaural suppression in the ipsilateral sound field; 3) the direction of azimuth tuning to binaural stimulation was primarily in the contralateral sound field, and its center shifted laterally toward −90° with increasing stimulus level; 4) at 10 dB, azimuth tuning to binaural and contralateral stimulation was similar, indicating that it was mediated by monaural mechanisms; and 5) at higher stimulus levels, azimuth tuning to contralateral ear stimulation was severely degraded. These findings form a foundation for understanding neural mechanisms of localizing sound-source azimuth.
Design of Polarization-Independent Coarse Wavelength Splitters Based on Ridge-Waveguide Directional Couplers
Authors: Lee Chee-Wei
Published: August 2011

We present the first unique design of a polarization-independent dual-wavelength splitter for wavelengths around 1.3 μm and 1.55 μm that is potentially of great interest to passive optical network (PON) applications. The filter design is simple compared with the other architectures and is based on ridge-type lateral directional couplers that can be readily integrated with other planar waveguide devices. Two design examples, based on InP/InGaAsP and Si/SiGe waveguides, are given. This polarization-independent wavelength splitting is achieved by exploiting the polarization dependence of the waveguides to produce coupling lengths that are sensitive to polarization and wavelength. We show that, to split the wavelengths without splitting the polarizations, the coupling lengths must be sufficiently different for TE and TM and for the different wavelengths in order to give the correct required ratios between the TE and TM coupling lengths for the two wavelengths of interest. We also show that the same approach can be applied to the design of a polarization splitter. The crosstalk, optical bandwidth, and fabrication sensitivity for the wavelength filter are evaluated.
Structure and Optical Properties of Doped SiO2Mesoporous Glasses
Authors: Hernández-Padrón G. , Hernández-Ortiz M. , Durán-Muñoz H. A. , García-Garduño M. , Castaño V. M.
Published: August 2011

Monolithic mesoporous silica glasses were synthesized. The presence of Cu2+and Fe3+cations during the synthesis of sol-gel precursors leads to different morphologies and pore sizes. The materials are characterized via IR and Raman scattering spectra to detect surface groups and -Si-O-Si- rings (i.e., 3–6 Si atoms) and morphology is examined through electron microscopy. N2sorption isotherms reveal details of the mesoporous structure of the materials, which are endowed with significantly large surface areas and pore volumes. Vapor percolation occurs in these samples because of a void arrangement consisting of pore bulges delimited by narrower necks. The optical characterization shows the luminescence spectrum and thermoluminescent behavior subjected to successive exposures of beta particles.
Mechanisms of GABAergic Homeostatic Plasticity
Authors: Wenner Peter
Published: August 2011

Homeostatic plasticity ensures that appropriate levels of activity are maintained through compensatory adjustments in synaptic strength and cellular excitability. For instance, excitatory glutamatergic synapses are strengthened following activity blockade and weakened following increases in spiking activity. This form of plasticity has been described in a wide array of networks at several different stages of development, but most work and reviews have focussed on the excitatory inputs of excitatory neurons. Here we review homeostatic plasticity of GABAergic neurons and their synaptic connections. We propose a simplistic model for homeostatic plasticity of GABAergic components of the circuitry (GABAergic synapses onto excitatory neurons, excitatory connections onto GABAergic neurons, cellular excitability of GABAergic neurons): following chronic activity blockade there is a weakening of GABAergic inhibition, and following chronic increases in network activity there is a strengthening of GABAergic inhibition. Previous work on GABAergic homeostatic plasticity supports certain aspects of the model, but it is clear that the model cannot fully account for some results which do not appear to fit any simplistic rule. We consider potential reasons for these discrepancies.
The Broader Autism Phenotype and Its Implications on the Etiology and Treatment of Autism Spectrum Disorders
Authors: Gerdts Jennifer , Bernier Raphael
Published: August 2011

The presence of autism-related traits has been well documented in undiagnosed family members of individuals with autism spectrum disorder (ASD). The most common finding is mild impairments in social and communication skills that are similar to those shown by individuals with autism, but exhibited to a lesser degree. Termed thebroader autism phenotype(BAP), these traits suggest a genetic liability for autism-related traits in families. Genetic influence in autism is strong, with identical twins showing high concordance for the diagnosis and related traits and approximately 20% of all ASD cases having an identified genetic mechanism. This paper highlights the studies conducted to date regarding the BAP and considers the implications of these findings for the etiology and treatment of ASD.
Assessing Errors Inherent in OCT-Derived Macular Thickness Maps
Authors: Odell Daniel , Dubis Adam M. , Lever Jackson F. , Stepien Kimberly E. , Carroll Joseph
Published: August 2011

SD-OCT has become an essential tool for evaluating macular pathology; however several aspects of data collection and analysis affect the accuracy of retinal thickness measurements. Here we evaluated sampling density, scan centering, and axial length compensation as factors affecting the accuracy of macular thickness maps. Forty-three patients with various retinal pathologies and 113 normal subjects were imaged using Cirrus HD-OCT. Reduced B-scan density was associated with increased interpolation error in ETDRS macular thickness plots. Correcting for individual differences in axial length revealed modest errors in retinal thickness maps, while more pronounced errors were observed when the ETDRS plot was not positioned at the center of the fovea (which can occur as a result of errant fixation). Cumulative error can exceed hundreds of microns, even under “ideal observer” conditions. This preventable error is particularly relevant when attempting to compare macular thickness maps to normative databases or measuring the area or volume of retinal features.
Decompensated Cirrhosis after Renal Transplantation: A Case Report
Authors: Patel Vinay , Marsano Luis , Eng Mary
Published: August 2011

Patients with end-stage liver disease with renal failure can be considered for simultaneous liver kidney transplantation. There are, however, no clear guidelines as to the management of the well-compensated cirrhotic patient with end-stage renal disease. We present the case of a patient with cirrhosis who decompensated after renal transplantation. With no indication for liver transplantation, can these patients safely undergo renal transplantation?
Revelations from the NematodeCaenorhabditis eleganson the Complex Interplay of Metal Toxicological Mechanisms
Authors: Martinez-Finley Ebany J. , Aschner Michael
Published: August 2011

Metals have been definitively linked to a number of disease states. Due to the widespread existence of metals in our environment from both natural and anthropogenic sources, understanding the mechanisms of their cellular detoxification is of upmost importance. Organisms have evolved cellular detoxification systems including glutathione, metallothioneins, pumps and transporters, and heat shock proteins to regulate intracellular metal levels. The model organism,Caenorhabditis elegans(C. elegans), contains these systems and provides several advantages for deciphering the mechanisms of metal detoxification. This review provides a brief summary of contemporary literature on the various mechanisms involved in the cellular detoxification of metals, specifically, antimony, arsenic, cadmium, copper, manganese, mercury, and depleted uranium using theC. elegansmodel system for investigation and analysis.
Localization and Density of Immune Cells in the Invasive Margin of Human Colorectal Cancer Liver Metastases Are Prognostic for Response to Chemotherapy
Authors: Halama Niels , Michel Sara , Kloor Matthias , Zoernig Inka , Benner Axel , Spille Anna , Pommerencke Thora , von Knebel Doeberitz Magnus , Folprecht Gunnar , Luber Birgit , Feyen Nadine , Martens Uwe M. , Beckhove Philipp , Gnjatic Sacha , Schirmacher Peter , Herpel Esther , Weitz Juergen , Grabe Niels , Jaeger Dirk
Published: August 2011

Analysis of tumor-infiltrating lymphocytes (TIL) in primary human colorectal cancer (CRC) by in situ immunohistochemical staining supports the hypothesis that the adaptive immune response influences the course of human CRC. Specifically, high densities of TILs in the primary tumor are associated with good prognosis independent of other prognostic markers. However, the prognostic role of TILs in metastatic CRC lesions is unknown, as is their role in response or resistance to conventional chemotherapy. We analyzed the association of TIL densities at the invasive margin of CRC liver metastases with response to chemotherapy and progression-free survival in a set of 101 large section samples. High-resolution automated microscopy on complete tissue sections was used to objectively generate cell densities for CD3, CD8, granzyme B, or FOXP3 positive immune cells. A predictive scoring system using TIL densities was developed in a training set and tested successfully in an independent validation set. TIL densities at the invasive margin of liver metastases allowed the prediction of response to chemotherapy with a sensitivity of 79% and specificity of 100%. The association of high density values with longer progression-free survival under chemotherapy was statistically significant. Overall, these findings extend the impact of the local immune response on the clinical course from the primary tumor also to metastatic lesions. Because detailed quantification of TILs in metastatic lesions revealed a strong association with chemotherapy efficacy and prognosis, we suggest that the developed scoring system may be used as a predictive tool for response to chemotherapy in metastatic CRC. Cancer Res; 71(17); 5670–7. ©2011 AACR.
Human Solid Tumors Contain High Endothelial Venules: Association with T- and B-Lymphocyte Infiltration and Favorable Prognosis in Breast Cancer
Authors: Martinet Ludovic , Garrido Ignacio , Filleron Thomas , Le Guellec Sophie , Bellard Elisabeth , Fournie Jean-Jacques , Rochaix Philippe , Girard Jean-Philippe
Published: August 2011

The mechanisms governing infiltration of lymphocytes into tumors remain poorly characterized, in spite of the critical impact of these cells on patient prognosis and therapeutic responses. High endothelial venules (HEV) are blood vessels found in lymphoid tissues, specialized in lymphocyte recruitment, but their implications in human cancer are unknown. In this article, we report the presence of MECA 79+ blood vessels displaying all the phenotypic characteristics of HEVs in most of the 319 human primary solid tumors, including melanomas, breast, ovarian, colon, and lung carcinomas, analyzed. Tumor HEVs were specifically located within lymphocyte-rich areas, and their density within the tumor stroma was a strong predictor of infiltration by CD3+ and CD8+ T cells as well as B cells. Large-scale flow cytometric and quantitative reverse transcriptase-PCR analyses in freshly operated breast tumors revealed that high densities of tumor HEVs correlated with increased naive, central memory and activated effector memory T-cell infiltration and upregulation of genes related to T-helper 1 adaptive immunity and T-cell cytotoxicity. Finally, in a retrospective cohort of 146 invasive breast cancer patients, we found that high densities of tumor HEVs independently conferred a lower risk of relapse and significantly correlated with longer metastasis-free, disease-free, and overall survival rates. Together, our findings suggest that tumor HEVs function as major gateways for lymphocyte infiltration into human tumors, and may represent attractive targets for cancer diagnosis and therapy. Cancer Res; 71(17); 5678–87. ©2011 AACR.
Novel Irreversible Small Molecule Inhibitors of Replication Protein A Display Single-Agent Activity and Synergize with Cisplatin
Authors: Neher Tracy M. , Bodenmiller Diane , Fitch Richard W. , Jalal Shadia I. , Turchi John J.
Published: August 2011

Replication protein A (RPA) is a single-strand DNA-binding protein with essential roles in DNA replication, recombination, and repair. It is necessary for the formation of the preincision complex that is required for proper incision of damaged DNA nucleotides during DNA repair. We have previously identified small molecule inhibitors (SMI) with the ability to disrupt RPA-binding activity to ssDNA. Further characterization of these RPA inhibitors was done using both lung and ovarian cancer cell lines. Lung cancer cell lines showed increased apoptotic cell death following treatment with the SMI MCI13E, with IC50 values of approximately 5 μmol/L. The ovarian cancer cell line A2780 and the p53-null lung cancer cell line H1299 were particularly sensitive to MCI13E treatment, with IC50 values less than 3 μmol/L. Furthermore, a cell-cycle effect was observed in lung cancer cell lines that resulted in a lengthening of either G1 or S-phases of the cell cycle following single-agent treatment. Sequential treatment with MCI13E and cisplatin resulted in synergism. Overall, these data suggest that decreasing DNA-binding activity of RPA via a SMI may disrupt the role of RPA in cell-cycle regulation. Thus, SMIs of RPA hold the potential to be used as single-agent chemotherapeutics or in combination with current chemotherapeutic regimens to increase efficacy. Mol Cancer Ther; 10(10); 1796–806. ©2011 AACR.
Methyl Selenocysteine: Single-Dose Pharmacokinetics in Men
Authors: Marshall James R. , Ip Clement , Romano Karen , Fetterly Gerald , Fakih Marwan , Jovanovic Borko , Perloff Marjorie , Crowell James , Davis Warren , French-Christy Renee , Dew Alexander , Coomes Margerie , Bergan Raymond
Published: August 2011

The recently published report of the SELECT evaluation of selenium and vitamin E provided strong evidence that selenium 200 μg per day in the form of selenomethionine does not protect selenium-replete men against prostate or any other cancer. This seems to refute the result of the much smaller Nutritional Prevention of Cancer (NPC) trial of selenium. Because SELECT did not test the NPC agent, it is possible that the difference between the two trials stems partly from the use of different agents: selenomethionine in SELECT, and selenized yeast in the NPC trial. One of the organic selenium forms suspected of having strong chemopreventive effects, and which may have been present in the NPC agent, is methyl selenocysteine. This study characterizes the single-dose pharmacokinetics of methyl selenocysteine. Cancer Prev Res; 4(11); 1938–44. ©2011 AACR.
Red Wine Consumption is Inversely Associated with 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine–DNA Adduct Levels in Prostate
Authors: Rybicki Benjamin A. , Neslund-Dudas Christine , Bock Cathryn H. , Nock Nora L. , Rundle Andrew , Jankowski Michelle , Levin Albert M. , Beebe-Dimmer Jennifer , Savera Adnan T. , Takahashi Satoru , Shirai Tomoyuki , Tang Deliang
Published: August 2011

In humans, genetic variation and dietary factors may alter the biological effects of exposure to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), one of the major heterocyclic amines generated from cooking meats at high temperatures that has carcinogenic potential through the formation of DNA adducts. Previously, we reported grilled red meat consumption associated with PhIP–DNA adduct levels in human prostate. In this study, we expanded our investigation to estimate the associations between beverage consumption and PhIP–DNA adduct levels in prostate for 391 prostate cancer cases. Of the 15 beverages analyzed, red wine consumption had the strongest association with PhIP–DNA adduct levels showing an inverse correlation in both tumor (P = 0.006) and nontumor (P = 0.002) prostate cells. Red wine consumption was significantly lower in African American compared with white cases, but PhIP–DNA adduct levels in prostate did not vary by race. In African Americans compared with whites, however, associations between red wine consumption and PhIP–DNA adduct levels were not as strong as associations with specific (e.g., SULT1A1 and UGT1A10 genotypes) and nonspecific (e.g., African ancestry) genetic variation. In a multivariable model, the covariate for red wine consumption explained a comparable percentage (13%–16%) of the variation in PhIP–DNA adduct levels in prostate across the two racial groups, but the aforementioned genetic factors explained 33% of the PhIP–DNA adduct variation in African American cases, whereas only 19% of the PhIP–DNA adduct variation in whites. We conclude that red wine consumption may counteract biological effects of PhIP exposure in human prostate, but genetic factors may play an even larger role, particularly in African Americans. Cancer Prev Res; 4(10); 1636–44. ©2011 AACR.
The Representation of Early Onset Depression by ICD-9 and ICD-10 Categories
Authors: Sinzig Judith , Schmidt Martin H. , Plueck Julia
Published: August 2011

Background: Concepts of affective disorders have not received substantial validation in childhood and adolescence even after the theoretical separation between neurotic and endogenous depression was changed. The aim of this study was to assess differences in children and adolescents with neurotic and endogenous depression according to ICD-9 and depression according to ICD-10 with regard to the severity of different symptoms as well as anamnestic and psychosocial risk factors. Sampling and Methods: Data of 33 and 88 patients (classified according to ICD-9 and ICD-10, respectively) with a confirmed diagnosis of depression were included. In a standardized study protocol, sociodemographic data, family history, psychopathological symptoms and psychosocial and environmental factors were analyzed. Results: Patients diagnosed with endogenous depression more frequently had a positive family history of psychiatric disorders and had more comorbid symptoms in comparison to those with neurotic depression. Group comparisons of the ICD-9 and ICD-10 demonstrated fewer abnormal psychosocial and environmental factors and fewer affective symptoms in the ICD-9 sample. Logistic regression revealed predictors for endogenous depression in the ICD-9 sample and severe depression in the ICD-10 sample. Conclusions: Neurotic depression might represent a subthreshold depression diagnosis compared with endogenous depression. The present study was limited by small and different sample sizes and the fact that dysthymia was not classified within the ICD-10 diagnosis.
Factor Analysis of the Scale of Prodromal Symptoms: Differentiating between Negative and Depression Symptoms
Authors: Klaassen Rianne M.C. , Velthorst Eva , Nieman Dorien H. , de Haan Lieuwe , Becker Hiske E. , Dingemans Peter M. , van de Fliert J. Reinaud , van der Gaag Mark , Linszen Don H.
Published: August 2011

Background: This study examines the ability of the Scale of Prodromal Symptoms (SOPS) to differentiate between negative and depression symptoms in a young help-seeking ultrahigh risk (UHR) group. Methods: SOPS data of 77 help-seeking patients at UHR for psychosis were analyzed with an exploratory factor analysis. The extracted Depression factor was validated with the Beck Depression Inventory (BDI). The extracted SOPS Negative symptoms factor was validated with the Negative symptoms subscale of the Positive and Negative Syndrome Scale (PANSS). Results: Four factors were extracted from the SOPS: a negative, depression, disorganized and positive factor. The Negative symptom factor consisted of three items (N1: social anhedonia and withdrawal, N3: decreased expression of emotion; N4: decreased experience of emotions and self), and could be validated with the PANSS Negative symptoms subscale. The Depression factor was also made up of three items (G2: dysphoric mood, G4: impaired tolerance to normal stress, and D4: personal hygiene/social attentiveness), and could be validated with the BDI. Conclusions: Our results suggest that 3 items of the Negative symptoms subscale of the SOPS, 2 items of the General and 1 item of the Disorganization subscale differentiate validly between negative and depression symptoms in an UHR population.
Modifiers and Subtype-Specific Analyses in Whole-Genome Association Studies: A Likelihood Framework
Authors: Lee Phil H. , Bergen Sarah E. , Perlis Roy H. , Sullivan Patrick F. , Sklar Pamela , Smoller Jordan W. , Purcell Shaun M.
Published: August 2011

Objective: We propose new statistical methods for analyzing genetic case/control association data in which cases can be further classified into subtypes, for example, based on clinical features. The primary utility of our work is the ability to distinguish between subtype-specific and modifier effects of genetic variants within a single testing framework. Methods: A range of disease/subtype causal models are defined for genetic variants involving subtype-specific and modifier effects. We present a log-linear modeling framework enabling comparison between these causal models and selection of the best-fit model. Results: We evaluate and compare the analytic power and model selection performance of the proposed work with standard two-group-based association tests. Simulation studies demonstrate that our approach has similar or greater power than the traditional approach over a range of causal models. We also report empirical findings about the impact of misspecification of subtype frequency during model selection, and extend the application of the proposed work to the cross-disorder association studies of multiple diseases. Conclusion: Whether a variant is a disease risk factor, is subtype specific, or modifies disease features has important consequences for the interpretation and follow-up of genetic associations. Our framework provides a simple, systematic way to evaluate and describe associations involving such subtype-specific or modifier effects.
Off-Label Thrombolysis for Acute Ischemic Stroke: Rate, Clinical Outcome and Safety Are Influenced by the Definition of ‘Minor Stroke’
Authors: Breuer L. , Blinzler C. , Huttner H.B. , Kiphuth I.C. , Schwab S. , Köhrmann M.
Published: August 2011

Background: Several contraindications for intravenous thrombolysis are not based on controlled trials. Specialized stroke centers often apply less restrictive criteria. The aim of our study was to analyze how many patients at our institution receive off-label thrombolysis. In addition, clinical outcome and safety data were compared to those from patients treated on-label, and the influence of different definitions of ‘minor stroke’ were examined. Methods: Consecutive thrombolysis patients treated between January 2006 and January 2010 were included. Patients treated off-label were compared to patients given on-label therapy according to the European license. Since no specified definition for ‘minor neurological deficit’ exists in the license, two distinct definitions were considered off-label, i.e. National Institutes of Health Stroke Scale score (NIHSSS) <1 (definition 1) and NIHSSS ≤4 (definition 2). Results: Of a total of 422 patients, 232 (55%) were treated off-label. The most prevalent off-label criteria (OLCs) were the following: age >80 years (n = 113), minor stroke (definition 1, n = 3; definition 2, n = 84), elevated blood pressure necessitating aggressive treatment (n = 75), time window >3 h (n = 71) and major surgery or trauma within the preceding 3 months (n = 20). In group comparisons, off-label patients had an overall worse outcome using definition 1 for minor stroke, while there was no difference when definition 2 was applied. In multivariate analysis, off-label therapy (definition 1) in general and age >80 years were independent predictors of poor outcome. None of the contraindications were associated with an increased bleeding risk. Conclusions: Off-label therapy is frequently applied at our center and is not associated with higher complication rates. Overall outcome of off-label treatment largely depends on the definition used for minor stroke. Besides age >80 years, a known poor prognostic factor, no other specific OLC was associated with poor outcome. Our data suggest that the criteria in the European license may be too restrictive.
Podocytes of AT2 Receptor Knockout Mice Are Protected from Angiotensin II-Mediated RAGE Induction
Authors: Rüster Christiane , Franke Sybille , Wenzel Ulrich , Schmidthaupt Robin , Fraune Christoph , Krebs Christian , Wolf Gunter
Published: August 2011

Background/Aims: The interaction of ‘advanced glycation end products’ (AGEs) and their receptor ‘RAGE’ plays an important role in diabetic nephropathy. We have previously found that in cultured differentiated podocytes, angiotensin II (ANG II) induces RAGE expression via an AT2 receptor-mediated pathway. Methods: To further confirm our results in an in vivo study, AT2 receptor knockout mice (AT2–/–) and wild-type mice were infused with ANG II by osmotic minipumps for 14 days. Results: As shown by immunohistochemistry, ANG II treatment of wild-type animals (C57BL6) allowed a significantly increased RAGE expression in renal podocytes in comparison to sham-operated C57BL6 mice. In contrast, RAGE expression in podocytes of ANG II-treated knockout mice (AT2–/–) was only moderately higher than in control animals, but significantly lower than in ANG II-treated wild-type mice. For the AGE species NΕ-carboxymethyllysine, a similar immunohistochemical staining pattern was found. There was no significant change in glomerular AT1a receptor expression. However, no difference in RAGE mRNA expression could be found between ANG II-infused wild-type and AT2–/– animals by real-time PCR using whole kidney mRNA, presumably due to the low abundance of podocyte mRNA in these preparations. No effects were seen on glomerular apoptosis. Conclusion: These data support the fact that ANG II-mediated RAGE induction in podocytes occurs via AT2 receptors. The present findings may suggest that not all ANG II-mediated changes in diabetic nephropathy can be treated with AT1 receptor blockers.
Clinical, Cytogenetic and Molecular Study in a Case of r(3) with 3p Deletion and Review of the Literature
Authors: Guilherme R. Santos , Bragagnolo S. , Pellegrino R. , Christofolini D.M. , Takeno S.S. , Carvolheira G.M. , Kulikowski L. Domenici , Melaragno M.I.
Published: August 2011

Ring chromosome 3 is a rare abnormality with only 10 patients described in the literature. We report a patient with r(3) and ∼6-Mb distal 3p deletion. Single nucleotide polymorphism array, multiplex ligation-dependent probe amplification and fluorescence in situ hybridization techniques revealed that the ring was formed by a break in 3p26.1 and fusion with the subtelomeric region of 3q. The patient presents delayed psychomotor development, growth failure, minor anomalies and other features similar to patients with 3p monosomy. The analysis of 300 metaphase cells using G-banding and fluorescence in situ hybridization with centromeric probe revealed ring instability resulting in cells with secondary aberrations and with ring loss that could also be related to some phenotypic characteristics such as growth delay. This is the first patient with r(3) studied using molecular techniques that determined the exact breakpoints in order to establish a better karyotype-phenotype correlation.
Chromosomal Distribution of Repetitive DNA Sequences Highlights the Independent Differentiation of Multiple Sex Chromosomes in Two Closely Related Fish Species
Authors: Cioffi M.B. , Molina W.F. , Moreira-Filho O. , Bertollo L.A.C.
Published: August 2011

The arrangement of 6 repetitive DNA sequences in the mitotic and meiotic sex chromosomes of 2 Erythrinidae fish, namely Hoplias malabaricus and Erythrinuserythrinus, both with a multiple X1X1X2X2/X1X2Y sex chromosome system, was analyzed using fluorescence in situ hybridization. The distribution patterns of the repetitive sequences were distinct for each species. While some DNA repeats were species-specific, others were present in the sex chromosomes of both species at different locations. These data, together with the different morphological types of sex chromosomes and the distinct chromosomal rearrangements associated with the formation of the neo-Y chromosomes, support the plasticity of sex chromosome differentiation in the Erythrinidae family. Our present data highlight that the sex chromosomes in fish species may follow diverse differentiation patterns, even in the same type of sex chromosome system present in cofamiliar species.
Identification of Transmembrane Protein in Prostate Cancer by the Escherichia coli Ampicillin Secretion Trap: Expression of CDON Is Involved in Tumor Cell Growth and Invasion
Authors: Hayashi Tetsutaro , Oue Naohide , Sakamoto Naoya , Anami Katsuhiro , Oo Htoo Zarni , Sentani Kazuhiro , Ohara Shinya , Teishima Jun , Matsubara Akio , Yasui Wataru
Published: August 2011

Aims: Prostate cancer (PCa) is one of the most common malignancies worldwide. Genes expressed only in cancer tissue, and especially related to proteins located on the cell membrane, will be useful molecular markers for diagnosis and may also be good therapeutic targets. The aim of this study was to identify genes that encode transmembrane proteins present in PCa. Methods and Results: We generated Escherichia coli ampicillin secretion trap (CAST) libraries from 2 PCa cell lines and normal prostate tissues. By sequencing 3,264 colonies from CAST libraries, we identified 18 candidate genes that encode transmembrane proteins present in PCa. Quantitative RT-PCR analysis of these candidates revealed that STEAP1, ADAM9 and CDON were expressed much more highly in PCa than in 15 kinds of normal tissues. Among the candidates, CDON encodes the CDO protein, which is an orphan cell surface receptor of the immunoglobulin superfamily. Additional quantitative RT-PCR revealed that 83% of PCa tissues showed CDON overexpression. Knockdown of CDON in DU145 cells induced 5-fluorouracil-induced apoptosis and inhibited invasion ability. Conclusion: These results suggest that CDON has a high potential as a therapeutic target for PCa.
Including Additional Controls from Public Databases Improves the Power of a Genome-Wide Association Study
Authors: Mukherjee Semanti , Simon Jennifer , Bayuga Sharon , Ludwig Emmy , Yoo Sarah , Orlow Irene , Viale Agnes , Offit Kenneth , Kurtz Robert C. , Olson Sara H. , Klein Robert J.
Published: August 2011

Though genome-wide association studies (GWAS) have identified numerous susceptibility loci for common diseases, their use is limited due to the expense of genotyping large cohorts of individuals. One potential solution is to use ‘additional controls’, or genotype data from control individuals deposited in public repositories. While this approach has been used by several groups, the genetically heterogeneous nature of the population of the United States makes this approach potentially problematic. We empirically investigated the utility of this approach in a US-based GWAS. In a small GWAS of pancreatic cancer in New York, we observed clear population structure differences relative to controls from the database of Genotypes and Phenotypes (dbGaP). When we conduct the GWAS using these additional controls, we find large inflation of the test statistic that is properly corrected by using eigenvectors from principal components analysis as covariates. To deal with errors introduced due to different sources, we propose simultaneously genotyping a small number of controls along with cases and then comparing this group to the additional controls. We show that removing SNPs that show differences between these control groups reduces false-positive findings. Thus, through an empirical approach, this report provides practical guidance for using additional controls from publicly available datasets.
A Geographic Cline of Skull and Brain Morphology among Individuals of European Ancestry
Authors: Bakken Trygve E. , Dale Anders M. , Schork Nicholas J. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: August 2011

Background: Human skull and brain morphology are strongly influenced by genetic factors, and skull size and shape vary worldwide. However, the relationship between specific brain morphology and genetically-determined ancestry is largely unknown. Methods: We used two independent data sets to characterize variation in skull and brain morphology among individuals of European ancestry. The first data set is a historical sample of 1,170 male skulls with 37 shape measurements drawn from 27 European populations. The second data set includes 626 North American individuals of European ancestry participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with magnetic resonance imaging, height and weight, neurological diagnosis, and genome-wide single nucleotide polymorphism (SNP) data. Results: We found that both skull and brain morphological variation exhibit a population-genetic fingerprint among individuals of European ancestry. This fingerprint shows a Northwest to Southeast gradient, is independent of body size, and involves frontotemporal cortical regions. Conclusion: Our findings are consistent with prior evidence for gene flow in Europe due to historical population movements and indicate that genetic background should be considered in studies seeking to identify genes involved in human cortical development and neuropsychiatric disease.
Evaluation of Perpendicular Reflection Intensity for Assessment of Caries Lesion Activity/Inactivity
Authors: Neuhaus K.W. , Nyvad B. , Lussi A. , Jaruszewski L.
Published: August 2011

The aim of this study was to evaluate, using visual assessment, an experimental optical sensor measuring perpendicular reflection intensity (PRI) as an indicator of enamel caries lesion activity/inactivity. Forty teeth with either an active or an inactive enamel lesion were selected from a pool of extracted teeth. Each tooth was cut into halves, with a clinically sound half and a half with a non-cavitated enamel lesion. After gentle plaque removal, the teeth were kept moistened. The lesions were then photographed and a defined measuring site per lesion was chosen and indicated with an arrow on a printout. Independently, the chosen site was visually assessed for lesion activity, and its glossiness was measured with PRI assessment. Surface roughness (SR) was assessed with optical profilometry using a confocal microscope. Visual assessment and PRI were repeated after several weeks and a reliability analysis was performed. For enamel lesions visually scored as active versus inactive, significantly different values were obtained with both PRI and SR. PRI values of the clinically sound control surfaces were significantly different only from active lesions. Generally, inactive lesions had the same glossiness and the same roughness as the sound control surfaces. The reliabilities for visual assessment (ĸ = 0.89) and for PRI (ICC = 0.86) were high. It is concluded that, within the limits of this study, PRI can be regarded as a promising tool for quantitative enamel lesion activity assessment. There is scope and potential for the PRI device to be considerably improved for in vivo use.
Large-Scale Candidate Gene Analysis in Whites and African Americans Identifies
IL6R
Polymorphism in Relation to Atrial Fibrillation
Authors: Schnabel Renate B. , Kerr Kathleen F. , Lubitz Steven A. , Alkylbekova Ermeg L. , Marcus Gregory M. , Sinner Moritz F. , Magnani Jared W. , Wolf Philip A. , Deo Rajat , Lloyd-Jones Donald M. , Lunetta Kathryn L. , Mehra Reena , Levy Daniel , Fox Ervin R. , Arking Dan E. , Mosley Thomas H. , Müller-Nurasyid Martina , Young Taylor R. , Wichmann H.-Erich , Seshadri Sudha , Farlow Deborah N. , Rotter Jerome I. , Soliman Elsayed Z. , Glazer Nicole L. , Wilson James G. , Breteler Monique M.B. , Sotoodehnia Nona , Newton-Cheh Christopher , Kääb Stefan , Ellinor Patrick T. , Alonso Alvaro , Benjamin Emelia J. , Heckbert Susan R. ,   for the Candidate Gene Association Resource (CARe) Atrial Fibrillation/Electrocardiography Working Group
Published: August 2011

Background—

The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated.

Methods and Results—

We examined a panel of approximately 50 000 common single-nucleotide polymorphisms (SNPs) in 2095 cardiovascular candidate genes and AF in 3 cohorts with participants of European (n=18 524; 2260 cases) or African American descent (n=3662; 263 cases) in the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident ischemic stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology Stroke Consortium (n=19 602 whites, 1544 incident strokes). SNP rs4845625 in the
IL6R
gene was associated with AF (relative risk [RR] C allele, 0.90; 95% confidence interval [CI], 0.85–0.95;
P
=0.0005) in whites but did not reach statistical significance in African Americans (RR, 0.86; 95% CI, 0.72–1.03;
P
=0.09). The results were comparable in the German AF Network replication, (RR, 0.71; 95% CI, 0.57–0.89;
P
=0.003). No association between rs4845625 and stroke was observed in whites. The known chromosome 4 locus near PITX2 in whites also was associated with AF in African Americans (rs4611994; hazard ratio, 1.40; 95% CI, 1.16–1.69;
P
=0.0005).

Conclusions—

In a community-based cohort meta-analysis, we identified genetic association in
IL6R
with AF in whites. Additionally, we demonstrated that the chromosome 4 locus known from recent genome-wide association studies in whites is associated with AF in African Americans.
Pseudepigraphy, Anonymity, and Auteur Theory
Authors: Silverman Jason M.
Published: August 2011

One of the striking features of Second Temple Judaism is the appearance of the phenomenon of pseudepigraphy. Intertwined with this phenomenon are the questions of authorship, fidelity to tradition, and the creative formation of new works. This paper attempts to bring to bear the debates on the “Auteur” in Film Studies to the understanding of authorial persona and voice in the Jewish writings of the Persian and Hellenistic Period. By focusing on a broader set of issues centered on creative production, this paper hopes to find new ways of viewing the old problems inherent in redaction theory.
Beneath the glass ceiling: Explaining gendered role segmentation in call centres
Authors: Scholarios Dora , Taylor Phil
Published: August 2011

Although the call centre is much researched, the literature on gender remains surprisingly undeveloped given the importance of this setting for women’s employment. This study of role segmentation in four call centres demonstrates women’s disproportionate representation in more routinized mass production roles, as opposed to higher status or managerial grades. It also analyses three explanations – human capital, domestic status and supervisor career support. The evidence shows that women face a ‘glass ceiling’, first, on entry to the call centre in terms of human capital disadvantage and levels of domestic constraint and, second, within the call centre in their ability to secure supervisor support for career opportunities. We argue that even for women with similar career aspiration and human capital to men, domestic responsibilities create obstacles before they reach the glass ceiling, especially for managerial roles, and contribute thereafter to reinforcing their concentration in more intensive, lower status work.
Understanding Customer Delight
Authors: Magnini Vincent P. , Crotts John C. , Zehrer Anita
Published: August 2011

Distinct from satisfaction, delight occurs when a customer receives a positive surprise beyond his or her expectations. Because of strong correlations with repurchase intention and positive word of mouth, customer delight is a quintessentially germane topic of inquiry. This study illustrates that determinants of customer delight in tourism venues can be identified through travel blog analysis. Using the hotel sector as the context, this research text-mines and content-analyzes 743 pertinent travel blogs that contain the phrase “pleasant surprise,” “delightful surprise,” excellent surprise,” or “positive surprise” and finds that the most frequent cause of guest delight in the hotel sector appears to be customer service, followed by cleanliness. In addition, this study also finds that triggers of delight are statistically different for domestic versus international travel and for travelers to more-developed versus less-developed countries. Based on the study’s findings, the article concludes with a presentation of managerial and research implications.
Reconciling the Varieties of Pragmatism in Public Administration
Authors: Whetsell Travis A. , Shields Patricia M.
Published: August 2011

Pragmatism has become a topic of growing discussion in public administration, as demonstrated by ongoing debate within the pages of Administration & Society. Karen Evans recently argued that the pervasive influence of logical positivism has produced a public administration, dominated by an ethically vacuous overemphasis on efficiency. Keith Snider recently responded to Evans by pointing toward confusion arising from debates between competing varieties of pragmatism, arguing that calls for pragmatism may produce unintended consequences under the present paradigm. However, this debate has the potential to produce a more intellectually experienced and mature public administration. Moreover, American pragmatism is uniquely appropriate as a philosophy of public administration in its dual academic/practitioner roles.
Cyberbullying in Turkish middle schools: An exploratory study
Authors: Yilmaz Harun
Published: August 2011

This study explored Turkish students' experience of cyberbullying and their use of social networking tools. A total of 756 7th-grade students participated from eight different middle schools in Istanbul, the largest city of Turkey. A 15-item questionnaire was used in a classroom environment to collect data. Results revealed that male students were more involved in cyberbullying than female students. Students used instant messaging programs in cyberbullying, and bullying victims did not communicate with adults when they were exposed to harassment. The majority of students did not know effective safety strategies for use in cyberspace. Those who were themselves cyberbullied tended to engage in cyberbullying. The prevalence of cyberbullying in Turkish middle schools suggests that schools should adopt appropriate prevention strategies.