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Phillips W.A.,University of Stirling | Clark A.,University of Edinburgh | Silverstein S.M.,Rutgers Biomedical and Health science
Neuroscience and Biobehavioral Reviews | Year: 2015

A broad neuron-centric conception of contextual modulation is reviewed and re-assessed in the light of recent neurobiological studies of amplification, suppression, and synchronization. Behavioural and computational studies of perceptual and higher cognitive functions that depend on these processes are outlined, and evidence that those functions and their neuronal mechanisms are impaired in schizophrenia is summarized. Finally, we compare and assess the long-term biological functions of contextual modulation at the level of computational theory as formalized by the theories of coherent infomax and free energy reduction. We conclude that those theories, together with the many empirical findings reviewed, show how contextual modulation at the neuronal level enables the cortex to flexibly adapt the use of its knowledge to current circumstances by amplifying and grouping relevant activities and by suppressing irrelevant activities. © 2015 Elsevier Ltd.


Lewis J.D.,University of Pennsylvania | Habel L.A.,Kaiser Permanente | Quesenberry C.P.,Kaiser Permanente | Strom B.L.,University of Pennsylvania | And 9 more authors.
JAMA - Journal of the American Medical Association | Year: 2015

Importance Studies suggest pioglitazone use may increase risk of cancers. Objective To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers. Design, Setting, and Participants Cohort and nested case-control analyses among persons with diabetes. A bladder cancer cohort followed 193 099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders. A cohort analysis of 10 additional cancers included 236 507 persons aged 40 years or older in 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California. EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent. Main Outcomes and Measures Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. RESULTS Among 193 099 persons in the bladder cancer cohort, 34 181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100 000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95%CI, 0.89-1.26). Results were similar in case-control analyses (pioglitazone use: 19.6%among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95%CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95%CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95%CI, 1.16-1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100 000 person-years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose. Conclusions and Relevance Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality. © 2015 American Medical Association. All rights reserved.


Horton D.B.,University of Pennsylvania | Horton D.B.,DuPont Company | Scott F.I.,University of Pennsylvania | Haynes K.,University of Pennsylvania | And 5 more authors.
Pediatrics | Year: 2015

BACKGROUND AND OBJECTIVE: Recent evidence has linked childhood antibiotic use and microbiome abstract disturbance to autoimmune conditions. This study tested the hypothesis that antibiotic exposure was associated with newly diagnosed juvenile idiopathic arthritis (JIA). METHODS: We performed a nested case-control study in a population-representative medical records database from the United Kingdom. Children with newly diagnosed JIA were compared with age-and gender-matched control subjects randomly selected from general practices containing at least 1 case, excluding those with inflammatory bowel disease, immunodeficiency, or other systemic rheumatic diseases. Conditional logistic regression was used to examine the association between antibacterial antibiotics (including number of antibiotic courses and timing) and JIA after adjusting for significant confounders. RESULTS: Any antibiotic exposure was associated with an increased rate of developing JIA (adjusted odds ratio: 2.1 [95% confidence interval: 1.2-3.5]). This relationship was dose dependent (adjusted odds ratio over 5 antibiotic courses: 3.0 [95% confidence interval: 1.6-5.6]), strongest for exposures within 1 year of diagnosis, and did not substantively change when adjusting for number or type of infections. In contrast, nonbacterial antimicrobial agents (eg, antifungal, antiviral) were not associated with JIA. In addition, antibiotic-treated upper respiratory tract infections were more strongly associated with JIA than untreated upper respiratory tract infections. CONCLUSIONS: Antibiotics were associated with newly diagnosed JIA in a dose-and timedependent fashion in a large pediatric population. Antibiotic exposure may play a role in JIA pathogenesis, perhaps mediated through alterations in the microbiome. Copyright © 2015 by the American Academy of Pediatrics.


Zhao X.,Public Health Research Institute | Zhao X.,Rutgers Biomedical and Health science | Zhao X.,Xiamen University | Hong Y.,Public Health Research Institute | And 2 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2015

Support for the contribution of reactive oxygen species (ROS) to antimicrobial lethality has been refined and strengthened. Killing by diverse antimicrobials is enhanced by defects in genes that protect against ROS, inhibited by compounds that block hydroxyl radical accumulation, and is associated with surges in intracellular ROS. Moreover, support has emerged for a genetic pathway that controls the level of ROS. Since some antimicrobials kill in the absence of ROS, ROS must add to, rather than replace, known killing mechanisms. New work has addressed many of the questions concerning the specificity of dyes used to detect intracellular ROS and the specificity of perturbations that influence ROS surges. However, complexities associated with killing under anaerobic conditions remain to be resolved. Distinctions among primary lesion formation, resistance, direct lesionmediated killing and a self-destructive stress response are discussed to facilitate efforts to potentiate ROSmediated bacterial killing and improve antimicrobial efficacy. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


Feng D.,Rutgers Biomedical and Health science | Feng D.,Rutgers University | Barnes B.J.,Rutgers Biomedical and Health science | Barnes B.J.,Rutgers University
Frontiers in Immunology | Year: 2013

Patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) display increased levels of type I interferon (IFN)-induced genes. Plasmacytoid dendritic cells (PDCs) are natural interferon producing cells and considered to be a primary source of IFN-α in these two diseases. Differential expression patterns of type I IFN-inducible transcripts can be found in different immune cell subsets and in patients with both active and inactive autoimmune disease. A type I IFN gene signature generally consists of three groups of IFN-induced genes - those regulated in response to virus-induced type I IFN, those regulated by the IFN-induced mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) pathway, and those by the IFN-induced phosphoinositide-3 kinase (PI-3K) pathway. These three groups of type I IFN-regulated genes control important cellular processes such as apoptosis, survival, adhesion, and chemotaxis, that when dysregulated, contribute to autoimmunity. With the recent generation of large datasets in the public domain from next-generation sequencing and DNA microarray experiments, one can perform detailed analyses of cell-type specific gene signatures as well as identify distinct transcription factors (TFs) that differentially regulate these gene signatures. We have performed bioinformatics analysis of data in the public domain and experimental data from our lab to gain insight into the regulation of type I IFN gene expression. We have found that the genetic landscape of the IFNA and IFNB genes are occupied by TFs, such as insulators CTCF and cohesin, that negatively regulate transcription, as well as interferon regulatory factor (IRF)5 and IRF7, that positively and distinctly regulate IFNA subtypes. A detailed understanding of the factors controlling type I IFN gene transcription will significantly aid in the identification and development of new therapeutic strategies targeting the IFN pathway in autoimmune disease. © 2013 Feng and Barnes.


Silverstein S.M.,Rutgers Biomedical and Health science | Rosen R.,New York Eye and Ear Infirmary of Mount Sinai
Schizophrenia Research: Cognition | Year: 2015

Although visual processing impairments are common in schizophrenia, it is not clear to what extent these originate in the eye vs. the brain. This review highlights potential contributions, from the retina and other structures of the eye, to visual processing impairments in schizophrenia and high-risk states. A second goal is to evaluate the status of retinal abnormalities as biomarkers for schizophrenia. The review was motivated by known retinal changes in other disorders (e.g., Parkinson's disease, multiple sclerosis), and their relationships to perceptual and cognitive impairments, and disease progression therein. The evidence reviewed suggests two major conclusions. One is that there are multiple structural and functional disturbances of the eye in schizophrenia, all of which could be factors in the visual disturbances of patients. These include retinal venule widening, retinal nerve fiber layer thinning, dopaminergic abnormalities, abnormal ouput of retinal cells as measured by electroretinography (ERG), maculopathies and retinopathies, cataracts, poor acuity, and strabismus. Some of these are likely to be illness-related, whereas others may be due to medication or comorbid conditions. The second conclusion is that certain retinal findings can serve as biomarkers of neural pathology, and disease progression, in schizophrenia. The strongest evidence for this to date involves findings of widened retinal venules, thinning of the retinal nerve fiber layer, and abnormal ERG amplitudes. These data suggest that a greater understanding of the contribution of retinal and other ocular pathology to the visual and cognitive disturbances of schizophrenia is warranted, and that retinal changes have untapped clinical utility. © 2015 The Authors.


King N.,Rutgers Biomedical and Health science | Kunac A.,Rutgers Biomedical and Health science | Merchant A.M.,Rutgers Biomedical and Health science
Journal of Surgical Education | Year: 2016

Upper and lower endoscopy is an important tool that is being utilized more frequently by general surgeons. Training in therapeutic endoscopic techniques has become a mandatory requirement for general surgery residency programs in the United States. The Fundamentals of Endoscopic Surgery has been developed to train and assess competency in these advanced techniques. Simulation has been shown to increase the skill and learning curve of trainees in other surgical disciplines. Several types of endoscopy simulators are commercially available; mechanical trainers, animal based, and virtual reality or computer-based simulators all have their benefits and limitations. However they have all been shown to improve trainee's endoscopic skills. Endoscopic simulators will play a critical role as part of a comprehensive curriculum designed to train the next generation of surgeons. We reviewed recent literature related to the various types of endoscopic simulators and their use in an educational curriculum, and discuss the relevant findings. © 2015 Association of Program Directors in Surgery.


Caulfield M.D.,Stress and Motivated Behavior Institute | Caulfield M.D.,Rutgers Biomedical and Health science | VanMeenen K.M.,Rutgers Biomedical and Health science | Servatius R.J.,Stress and Motivated Behavior Institute | Servatius R.J.,Rutgers Biomedical and Health science
Behavioural Brain Research | Year: 2015

Adolescence is a key age in the development of anxiety disorders. The present study assessed the relationship between behavioral inhibition, a risk factor for anxiety typified by avoidance, and acquisition of the classically conditioned eyeblink response. 168 healthy high school students (mean age 15.7 years, 54% female) were given a battery of self-report measures including the Adult Measure of Behavioural Inhibition (AMBI). The study compared acquisition of three experimental training conditions. Two groups were given paired CS-US training: standard delay of 500-ms or long delay of 1000-ms with CS overlapping and co-terminating with a 50-ms airpuff US. A third group received unpaired training of 1000-ms CS and 50-ms airpuff US. Inhibited individuals showed greater acquisition of the conditioned eyeblink response in the 500-ms CS condition, but not in the paired 1000-ms condition. No differences in spontaneous blinks or reactivity to the stimulus were evident in the 1000-ms unpaired CS condition. Results support a relationship between associative learning and anxiety vulnerability that may be mediated by cerebellar functioning in inhibited individuals. © 2014 Elsevier B.V.


Pimenta E.M.,Rutgers Biomedical and Health science | Barnes B.J.,Rutgers Biomedical and Health science
Molecular cancer | Year: 2015

BACKGROUND: Migration of breast cancer cells out of a duct or lobule is a prerequisite for invasion and metastasis. However, the factors controlling breast cancer cell migration are not fully elucidated. We previously found that expression of the transcription factor interferon regulatory factor 5 (IRF5) is significantly decreased as a breast lesion progresses from a non-malignant stage to ductal carcinoma in situ and is eventually lost in ~80% of invasive ductal carcinomas examined. Human in vitro and murine in vivo models of invasive breast cancer confirmed an important role for IRF5 in regulating cell motility, invasion and/or metastasis; yet, the mechanism(s) by which this occurs is not known. Since IRF5 is primarily expressed in the cytoplasm of human mammary epithelial cells, we hypothesized that IRF5 may function in a transcription-independent manner to control intrinsic cell migration.RESULTS: A series of IRF5 deletion mutants were tested in cell motility, invasion and migration assays. A novel, conserved 10 amino acid domain was identified that regulates mammary epithelial cell migration. This region (∆115-125) is downstream of IRF5's DNA binding domain and therefore when absent, retains IRF5 transcription activity but loses cell migration control. An IRF5 construct with a mutated nuclear localization signal further confirmed that IRF5 controls migration in a cytoplasmic and transcription-independent manner. Candidate cytoskeletal molecules were identified in MDA-MB-231 cells to interact with IRF5 by immunoprecipitation and mass spectrometry analysis. α6-tubulin was independently confirmed to interact with endogenous IRF5 in MCF-10A cells. Alterations in F-actin bundling after staining EV- and IRF5-231 cells with phalloidin suggests that IRF5 may control cell migration/motility through its interaction with cytoskeletal molecules that contribute to the formation of F-actin networks. Last and most notably, we found that IRF5's control of cell migration is not restricted to mammary epithelial cells but functions in other epithelial cell types suggesting a more global role for this newly identified cell migratory function of IRF5.CONCLUSIONS: These findings are significant as they identify a new regulator of epithelial cell migration and provide specific insight into the mechanism(s) by which loss of IRF5 expression in mammary epithelial cells contributes to breast cancer metastasis.


Brown A.M.,Rutgers Biomedical and Health science | Zifchock R.A.,United States Military Academy | Hillstrom H.J.,The New Motion
Gait and Posture | Year: 2014

Purpose: To establish whether lower extremity limb dominance has an effect on overground running mechanics. Background: In attempts to resolve unilateral pathology, physical therapists often use the restoration of symmetry as a clinical milestone. While lower limb dominance has been shown to affect lower extremity mechanics during dynamic tasks such as jump landing, its effect on running gait is poorly understood. Further, despite the role of fatigue in running mechanics and injury, the interaction between fatigue and limb dominance has yet to be examined. Methods: Three-dimensional kinematic and kinetic data were collected on 20 females during overground running. Data were collected prior-to and following a treadmill run to exertion. Dominant and non-dominant limb data were compared in the fresh-state using a paired t-test. A 2-way repeated-measures ANOVA was used to test for an interaction between fatigue and limb dominance. Results: There were no significant differences between the kinematic or kinetic patterns of the dominant and non-dominant lower extremities during fresh-state overground running. Fatigue was not shown to interact with limb dominance. Conclusion: Limb dominance did not affect kinematic or kinetic side-to-side differences. Therefore, physical therapists can continue to use resolution of lower extremity symmetry as a goal of therapy without having to account for limb dominance. The lack of an interaction between fatigue and limb dominance indicates that the dominant and non-dominant limbs fatigue at a similar rate. © 2013 Elsevier B.V.

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