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Emory University is a private research university in metropolitan Atlanta, located in the Druid Hills section of unincorporated DeKalb County, Georgia, United States. The university was founded as Emory College in 1836 in Oxford, Georgia by the Methodist Episcopal Church and was named in honor of Methodist bishop John Emory. In 1915 the college relocated to metropolitan Atlanta and was rechartered as Emory University.Emory University has nine academic divisions: Emory College of Arts and science, Oxford College, Goizueta Business School, Laney Graduate School, School of Law, School of Medicine, Nell Hodgson Woodruff School of Nursing, Rollins School of Public Health, and the Candler School of Theology. Emory University and the Georgia Institute of Technology have a strong research partnership and jointly administer the Emory-Georgia Tech Predictive Health Institute and the Wallace H. Coulter Department of Biomedical Engineering Program with Peking University in Beijing, China. Emory University and the Georgia Institute of Technology's combined annual research expenditures exceed $1.25 billion.Emory University is 16th among the list of colleges and universities in the United States by endowment, 5th among universities in the United States regarding licensing revenue per dollars spent on research, and 21st in U.S. News & World Report's 2015 National Universities Rankings. The university also ranks as one of the top universities in the world. In 1995 Emory University was elected to the Association of American Universities, an association of the 62 leading research universities in the United States & Canada.The university has nearly 3,000 faculty members; Emory faculty and alumni include international leaders in the fields of politics, business and academia, and its members have been recognized with numerous national and international awards and honors. Wikipedia.

Fauci A.S.,National Institute of Allergy and Infectious Diseases | Marovich M.A.,National Institute of Allergy and Infectious Diseases | Dieffenbach C.W.,National Institute of Allergy and Infectious Diseases | Hunter E.,Emory University | Buchbinder S.P.,University of California at San Francisco
Science | Year: 2014

Future HIV vaccine research should consider the balance between responses that favor protection and those that lead to susceptibility to infection.

Zughaier S.M.,Emory University
Journal of Leukocyte Biology | Year: 2011

CPS are major virulence factors in infections caused by Neisseria meningitidis and form the basis for meningococcal serogroup designation and protective meningococcal vaccines. CPS polymers are anchored in the meningococcal outer membrane through a 1,2-diacylglycerol moiety, but the innate immunostimulatory activity of CPS is largely unexplored. Well-established human and murine macrophage cell lines and HEK/TLR stably transfected cells were stimulated with CPS, purified from an endotoxin-deficient meningococcal serogroup B NMB-lpxA mutant. CPS induced inflammatory responses via TLR2- and TLR4-MD-2. Meningococcal CPS induced a dose-dependent release of cytokines (TNF-α, IL-6, IL-8, and CXCL10) and NO from human and murine macrophages, respectively. CPS induced IL-8 release from HEK cells stably transfected with TLR2/6, TLR2, TLR2/CD14, and TLR4/MD-2/CD14 but not HEK cells alone. mAb to TLR2 but not an isotype control antibody blocked CPS-induced IL-8 release from HEK-TLR2/6-transfected cells. A significant reduction in TNF-α and IL-8 release was seen when THP-1-and HEK-TLR4/MD-2-CD14- but not HEK-TLR2- or HEK-TLR2/6-transfected cells were stimulated with CPS in the presence of Eritoran (E5564), a lipid A antagonist that binds to MD-2, and a similar reduction in NO and TNF-α release was also seen in RAW 264.7 cells in the presence of Eritoran. CD14 and LBP enhanced CPS bioactivity, and NF-κB was, as anticipated, the major signaling pathway. Thus, these data suggest that innate immune recognition of meningococcal CPS by macrophages can occur via TLR2- and TLR4-MD-2 pathways. © Society for Leukocyte Biology.

Herndon J.G.,Emory University
Gerontology | Year: 2010

Background: Women experience more years of vigorous life after ovulation has ceased than do females of other primate species. Is this an epiphenomenon of the greater life expectancy humans have enjoyed in the past century or so, or is long post-menopausal survival the result of an evolutionary selection process? Recent research implies the latter: Long post-menopausal survival came about through natural selection. One prominent line of thought explaining this selection process is the grandmother hypothesis. Objective: To evaluate the implications of the hypothesis for non-human primate studies of aging and cognition. Method: The author presents a synopsis of the hypothesis, evaluates the uniqueness of the 'grandmother effect' to humans, and discusses its implications for non-human primate models of cognitive aging. Results: The hypothesis contends that, in past epochs, women who remained vigorous beyond their fertile years may have enhanced their reproductive success by providing care for their grandchildren. This care would have enabled their daughters to resume reproduction sooner, endowing them with greater lifetime fertility. Genes of grandmothers possessing such old-age vigor would be more likely to persist in subsequent generations. Is midlife menopause a uniquely human phenomenon, or does the chimpanzee, our closest primate relative, also display this trait? If so, we might expect a grandmother effect in this species as well. However, female chimpanzees continue to cycle until near the end of their maximum life span of about 60 years. Conclusion: Long survival beyond fertility and a long life expectancy are distinctive human adaptations. The robustness of ancestral human grandmothers necessarily included resistance to cognitive decline through preservation of functions present in many primates but also development of processes of social cognition unique to our species. Cognitive traits such as language and social cognitive functions may function in our species in particular as mechanisms to compensate for age-related decline. This has significant implications for research in which non-human primates are considered as models of human cognitive aging; it also means that some processes can be studied only in humans. © 2009 S. Karger AG, Basel.

This article is part of a Special Issue "Hormones & Neurotrauma".Despite decades of laboratory research and clinical trials, a safe and effective treatment for traumatic brain injury (TBI) has yet to be put into successful clinical use. I suggest that much of the problem can be attributed to a reductionist perspective and attendant research strategy directed to finding or designing drugs that target a single receptor mechanism, gene, or brain locus. This approach fails to address the complexity of TBI, which leads to a cascade of systemic toxic events in the brain and throughout the body that may persist over long periods of time. Attention is now turning to pleiotropic drugs: drugs that act on multiple genomic, proteomic and metabolic pathways to enhance morphological and functional outcomes after brain injury.Of the various agents now in clinical trials, the neurosteroid progesterone (PROG) is gaining attention despite the widespread assumption that it is "just a female hormone" with limited, if any, neuroprotective properties. This perspective should change. PROG is also a powerful developmental hormone that plays a critical role in protecting the fetus during gestation. I argue here that development, neuroprotection and cellular repair have a number of properties in common. I discuss evidence that PROG is pleiotropically neuroprotective and may be a useful therapeutic and neuroprotective agent for central nervous system injury and some neurodegenerative diseases. © 2012 Elsevier Inc.

Jacob J.T.,Emory University | DiazGranados C.A.,Sanofi S.A.
International Journal of Infectious Diseases | Year: 2013

Background: Patients with methicillin-resistant Staphylococcus aureus (MRSA) infections caused by isolates with a high but 'susceptible' minimum inhibitory concentration (MIC) to vancomycin may suffer poor outcomes. The aim of this study was to determine the association of high compared to low vancomycin MICs and clinical outcomes (treatment failure and mortality) in patients with MRSA infections. Methods: PubMed, the Cochrane Library, and electronic abstracts from meetings were queried from January 2000 to July 2010. Two reviewers independently screened titles and abstracts of studies evaluating outcomes of patients with MRSA infections, using broth microdilution (BMD) or the Etest to determine MIC, for full-text review. Patients participating in included studies were classified into two mutually exclusive groups: high MIC or low MIC. High MIC was defined as MIC ≥1. mg/l by BMD or ≥1.5. mg/l by Etest. Study-defined failure and mortality were assessed in each group. Results: Fourteen publications and six electronic abstracts met the inclusion criteria, with 2439 patients (1492 high MIC and 947 low MIC). There was no evidence of publication bias or heterogeneity. An increased risk of failure was observed in the high MIC group compared to the low MIC group (summary risk ratio (RR) 1.40, 95% confidence interval (CI) 1.15-1.71). The overall mortality risk was greater in the high MIC group than in the low MIC group (summary RR 1.42, 95% CI 1.08-1.87). Sensitivity analyses showed similar findings for failure (summary RR 1.37, 95% CI 1.09-1.73) and mortality (summary RR 1.46, 95% CI 1.06-2.01) for patients with bacteremia. The study quality was poor-to-moderate, and study-defined endpoints were variable. Conclusions: A susceptible but high MIC to vancomycin is associated with increased mortality and treatment failure among patients with MRSA infections. © 2012 International Society for Infectious Diseases.

Singhal S.,University of Pennsylvania | Nie S.,Emory University | Wang M.D.,Georgia Institute of Technology
Annual Review of Medicine | Year: 2010

Surgery is currently the most effective and widely used procedure in treating human cancers, and the single most important predictor of patient survival is a complete surgical resection. Major opportunities exist to develop new and innovative technologies that could help the surgeon to delineate tumor margins, to identify residual tumor cells and micrometastases, and to determine if the tumor has been completely removed. Here we discuss recent advances in nanotechnology and optical instrumentation, and how these advances can be integrated for applications in surgical oncology. A fundamental rationale is that nanometer-sized particles such as quantum dots and colloidal gold have functional and structural properties that are not available from either discrete molecules or bulk materials. When conjugated with targeting ligands such as monoclonal antibodies, peptides, or small molecules, these nanoparticles can be used to target malignant tumor cells and tumor microenvironments with high specificity and affinity. In the mesoscopic-size range of 10-100 nm, nanoparticles also have large surface areas for conjugating to multiple diagnostic and therapeutic agents, opening new possibilities in integrated cancer imaging and therapy. © 2010 by Annual Reviews All rights reserved.

Rochat P.,Emory University
Developmental Review | Year: 2015

Distinct layers of awareness about objects, people, and the self grow from an implicit biologically given core at birth. Each added layer of subjective experience would correspond to major qualitative shifts: the emergence of a contemplative stance by 2 months, self-consciousness from around 21 months and the manifestation of an ethical stance by 3-5 years. This new "onion" way of looking at psychological experience is meant to capture the fact that a new emerging layer of awareness does not block, re-construct, or fundamentally re-structure "à la Piaget" the expression of those ontogenetically anterior via bounding up equilibration and other reflective abstraction "bootstrapping" mechanisms. In contrast to Piaget's overall representational re-organization, what is proposed here with the onion metaphor model is a multilayer view on consciousness in development, each layer offering a particular zone of awareness through which we constantly navigate depending on the mind state of our being in the world: dozing and dreaming, implicitly or explicitly aware, co-aware, conscious, or co-conscious. The model is illustrated using facts on the early development of pictorial understanding, mirror self-experience, self-consciousness, interpersonal awareness, and sharing awareness in development. The main purpose of the theory is to show that what develop in children between birth and 5 years are ultimately additional ranges of subjective experience, new possibilities of being aware in the world. © 2015 Elsevier Inc.

Objective: Poor quality of healthcare contributes to impaired health and excess mortality in individuals with severe mental disorders. The authors tested a population-based medical care management intervention designed to improve primary medical care in community mental health settings. Method: A total of 407 subjects with severe mental illness at an urban community mental health center were randomly assigned to either the medical care management intervention or usual care. For individuals in the intervention group, care managers provided communication and advocacy with medical providers, health education, and support in overcoming system-level fragmentation and barriers to primary medical care. Results: At a 12-month follow-up evaluation, the intervention group received an average of 58.7% of recommended preventive services compared with a rate of 21.8% in the usual care group. They also received a significantly higher proportion of evidence-based services for cardiometabolic conditions (34.9% versus 27.7%) and were more likely to have a primary care provider (71.2% versus 51.9%). The intervention group showed significant improvement on the SF-36 mental component summary (8.0% [versus a 1.1% decline in the usual care group]) and a nonsignificant improvement on the SF-36 physical component summary. Among subjects with available laboratory data, scores on the Framingham Cardiovascular Risk Index were significantly better in the intervention group (6.9%) than the usual care group (9.8%). Conclusions: Medical care management was associated with significant improvements in the quality and outcomes of primary care. These findings suggest that care management is a promising approach for improving medical care for patients treated in community mental health settings.

Faught E.,Emory University
Epilepsy Currents | Year: 2011

Ezogabine is a new drug for adjunctive therapy of partial-onset seizures with a novel mechanism of action. As a potassium-channel facilitator, it promotes membrane repolarization and thus opposes rapid repetitive discharges. Side effects are typical for antiepileptic drugs and the safety profile is good. Occasional instances of urinary difficulty may require surveillance. © American Epilepsy Society.

Friedel D.N.,Urbana University | Widicus Weaver S.L.,Emory University
Astrophysical Journal, Supplement Series | Year: 2012

It has recently been suggested that chemical processing can shape the spatial distributions of complex molecules in the Orion-KL region and leads to the nitrogen-oxygen "chemical differentiation" seen in previous observations of this source. Orion-KL is a very dynamic region, and it is therefore also possible that physical conditions can shape the molecular distributions in this source. Only high spatial resolution observations can provide the information needed to disentangle these effects. Here, we present millimeter imaging studies of Orion-KL at various beam sizes using the Combined Array for Research in Millimeter-wave Astronomy. We compare molecular images with high spatial resolution images that trace the temperature, density, and kinematics of the source in order to investigate the effects of physical conditions on molecular distributions. These observations were conducted at λ= 3mm and included transitions of ethyl cyanide [C 2H 5CN], methyl formate [HCOOCH 3], formic acid [HCOOH], acetone [(CH 3) 2CO], SiO, and methanol [CH 3OH]. We find differences in the molecular distributions as a function of each of the aforementioned physical factors. These results indicate that acetone may be produced by chemical processing and is robust to large changes in physical conditions, while formic acid is readily destroyed by gas-phase processing in warm and dense regions. We also find that while the spatial distributions of ethyl cyanide and methyl formate are not distinct as is suggested by the concept of "chemical differentiation," local physical conditions shape the small-scale emission structure for these species. © 2012. The American Astronomical Society. All rights reserved.

OBJECTIVES: We previously reported combined analysis of 6-week and 6-month endpoints of three randomized controlled trials [Six Week Extended Dose Nevirapine (SWEN) trials] that compared extended-dose nevirapine through 6 weeks of age to single-dose nevirapine to prevent HIV transmission via breastfeeding and mortality. We now present endpoints through 12 months of age. DESIGN: Infants in Ethiopia, India, and Uganda born to HIV-infected women who chose to breastfeed were randomized to receive single-dose or extended-dose nevirapine. MAIN OUTCOMES: HIV transmission, mortality, HIV transmission or death. RESULTS: Primary analysis included 987 and 903 infants in the single-dose and the extended-dose arms, respectively. HIV transmission was 8.9% in the extended-dose group compared to 10.4% in the single-dose group, but the difference was not significant [risk ratio: 0.87, 95% confidence interval (CI): 0.65-1.15]. Cumulative mortality at 12 months was half in the extended-dose group compared to the single-dose group (risk ratio: 0.53, 95% CI: 0.32-0.85). The impact of extended-dose nevirapine was highest in infants of mothers with CD4 cell count more than 350 cells/μl. Risk ratios for death (risk ratio: 0.38, 95% CI: 0.17-0.84) and HIV transmission or death (risk ratio: 0.54, 95% CI: 0.35-0.85) were statistically significant for the CD4 cell counts more than 350 cells/μl category, whereas none of the risk ratios were significant for the CD4 cell counts 200 cells/μl or less and CD4 cell counts 201-350 cells/μl categories. CONCLUSION: For populations with limited access to HAART, our results provide evidence for the use of extended-dose regimens to prevent infant deaths and increase HIV-free survival in infants of HIV-infected breastfeeding women, particularly for infants of women with CD4 cell counts more than 350 cells/μl. © 2011 Lippincott Williams & Wilkins, Inc.

Wang Y.,Emory University | Hill J.A.,University of Texas Southwestern Medical Center
Journal of Molecular and Cellular Cardiology | Year: 2010

Heart failure affects nearly 6 million Americans, with a half-million new cases emerging each year. Whereas up to 50% of heart failure patients die of arrhythmia, the diverse mechanisms underlying heart failure-associated arrhythmia are poorly understood. As a consequence, effectiveness of antiarrhythmic pharmacotherapy remains elusive. Here, we review recent advances in our understanding of heart failure-associated molecular events impacting the electrical function of the myocardium. We approach this from an anatomical standpoint, summarizing recent insights gleaned from pre-clinical models and discussing their relevance to human heart failure. © 2010 Elsevier Ltd. All rights reserved.

Olfson M.,Columbia University | Druss B.G.,Emory University | Marcus S.C.,University of Pennsylvania
New England Journal of Medicine | Year: 2015

BACKGROUND: Increasing mental health treatment of young people and broadening conceptualizations of psychopathology have triggered concerns about a disproportionate increase in the treatment of youths with low levels of mental health impairment. METHODS: We analyzed the 1996-1998, 2003-2005, and 2010-2012 Medical Expenditure Panel Surveys, which were nationally representative surveys of U.S. households, for trends in outpatient use of mental health services by persons 6 to 17 years of age; 53,622 persons were included in the analysis. Mental health impairment was measured with the use of the Columbia Impairment Scale (range, 0 to 52, with higher scores indicating more severe impairment); we classified youths with scores of 16 or higher as having more severe impairment and those with scores of less than 16 as having less severe impairment. RESULTS: The percentage of youths receiving any outpatient mental health service increased from 9.2% in 1996-1998 to 13.3% in 2010-2012 (odds ratio, 1.52; 95% confidence interval, 1.35 to 1.72). The proportionate increase in the use of mental health services among youths with more severe impairment (from 26.2% to 43.9%) was larger than that among youths with less severe or no impairment (from 6.7% to 9.6%). However, the absolute increase in annual service use was larger among youths with less severe or no impairment (from 2.74 million to 4.19 million) than among those with more severe impairment (from 1.56 million to 2.28 million). Significant overall increases occurred in the use of psychotherapy (from 4.2% to 6.0%) and psychotropic medications (from 5.5% to 8.9%), including stimulants and related medications (from 4.0% to 6.6%), antidepressants (from 1.5% to 2.6%), and antipsychotic drugs (from 0.2% to 1.2%). CONCLUSIONS: Outpatient mental health treatment and psychotropic-medication use in children and adolescents increased in the United States between 1996-1998 and 2010-2012. Although youths with less severe or no impairment accounted for most of the absolute increase in service use, youths with more severe impairment had the greatest relative increase in use, yet fewer than half accessed services in 2010-2012. Copyright © 2015 Massachusetts Medical Society.

Hunter G.L.,Emory University
Reports on progress in physics. Physical Society (Great Britain) | Year: 2012

As one increases the concentration of a colloidal suspension, the system exhibits a dramatic increase in viscosity. Beyond a certain concentration, the system is said to be a colloidal glass; structurally, the system resembles a liquid, yet motions within the suspension are slow enough that it can be considered essentially frozen. For several decades, colloids have served as a valuable model system for understanding the glass transition in molecular systems. The spatial and temporal scales involved allow these systems to be studied by a wide variety of experimental techniques. The focus of this review is the current state of understanding of the colloidal glass transition, with an emphasis on experimental observations. A brief introduction is given to important experimental techniques used to study the glass transition in colloids. We describe features of colloidal systems near and in glassy states, including increases in viscosity and relaxation times, dynamical heterogeneity and ageing, among others. We also compare and contrast the glass transition in colloids to that in molecular liquids. Other glassy systems are briefly discussed, as well as recently developed synthesis techniques that will keep these systems rich with interesting physics for years to come.

Background: Modular structures are ubiquitous across various types of biological networks. The study of network modularity can help reveal regulatory mechanisms in systems biology, evolutionary biology and developmental biology. Identifying putative modular latent structures from high-throughput data using exploratory analysis can help better interpret the data and generate new hypotheses. Unsupervised learning methods designed for global dimension reduction or clustering fall short of identifying modules with factors acting in linear combinations.Results: We present an exploratory data analysis method named MLSA (Modular Latent Structure Analysis) to estimate modular latent structures, which can find co-regulative modules that involve non-coexpressive genes.Conclusions: Through simulations and real-data analyses, we show that the method can recover modular latent structures effectively. In addition, the method also performed very well on data generated from sparse global latent factor models. The R code is available at http://userwww.service.emory.edu/~tyu8/MLSA/. © 2010 Yu; licensee BioMed Central Ltd.

Kogon B.,Emory University | Oster M.,Childrens Healthcare Of Atlanta
Journal of Thoracic and Cardiovascular Surgery | Year: 2014

Background Patients with congenital heart disease are frequently surviving into adulthood, and many of them will require surgery. Currently, there is no validated risk scoring system for adult congenital heart surgery, and predicting outcomes in these patients is challenging. Our objective was to determine if commonly used pediatric congenital heart disease surgery risk scores are also applicable to adults. Methods Four hundred fifty-eight adult (age ≥18 years) operations involving cardiac surgery for congenital heart disease between 2000 and 2010 at a single institution were studied retrospectively. The pediatric scores evaluated were the Risk Adjustment for Congenital Heart Surgery (RACHS-1) score, the Aristotle Basic Score, and the Society of Thoracic Surgery-European Association for Cardio-Thoracic Surgery (STAT) Congenital Heart Surgery Mortality score. Receiver operating characteristic (ROC) curves were generated to assess the ability of the scoring systems to predict mortality, major adverse events (stroke, renal failure, prolonged ventilation, prolonged coma, deep sternal infection, reoperation, and operative mortality), and prolonged length of stay (>7 days). Results Of 458 operations, there were 16 (3%) deaths, 94 (21%) major adverse events, and 90 (20%) prolonged lengths of stay. Four hundred thirty (94%) of the operations were included in all 3 scoring systems and the ROC analysis. For mortality, areas under the ROC curve were 0.91, 0.91, and 0.65 for the Aristotle, STAT, and RACHS-1 scores, respectively. For major adverse event, areas under the ROC curves were 0.81, 0.76, and 0.61 for the Aristotle, STAT, and RACHS-1 scores, respectively. For prolonged length of stay, areas under the ROC curve were 0.82, 0.76, and 0.61 for the Aristotle, STAT, and RACHS-1 scores, respectively. Conclusions Pediatric risk scoring systems such as Aristotle, STAT, and RACHS-1 offer prognostic value in adults undergoing congenital heart surgery. The scores are predictive of mortality, major adverse events, and prolonged lengths of stay. The STAT and Aristotle systems fared best. Copyright © 2014 by The American Association for Thoracic Surgery.

Xu C.,Emory University
Journal of Molecular and Cellular Cardiology | Year: 2012

Human cardiomyocytes derived from pluripotent stem cells hold great promise for cardiac cell therapy, disease modeling, drug discovery, and the study of developmental biology. Reaching these potentials fully requires the development of methods that enable efficient and robust generation of cardiomyocytes with expected characteristics. This review summarizes and discusses up-to-date methods that have been used to derive and enrich human cardiomyocytes from pluripotent stem cells, provides a brief overview of in vitro and in vivo characterization of these cardiomyocytes, and considers future advancement needed to further harness the power of these cells. © 2012 Elsevier Ltd.

Bluemke D.A.,U.S. National Institutes of Health | Meltzer C.C.,Emory University
Radiology | Year: 2015

At present, there is a major emphasis on Ebola virus disease (EVD) preparedness training at medical facilities throughout the United States. Failure to have proper EVD procedures in place was cited as a major reason for infection of medical personnel in the United States. Medical imaging does not provide diagnosis of EVD, but patient assessment in the emergency department and treatment isolation care unit is likely to require imaging services. The purpose of this article is to present an overview of relevant aspects of EVD disease and preparedness relevant to the radiologic community. © 2014 RSNA.

The growing interest of modeling human diseases using genetically modified (transgenic) nonhuman primates (NHPs) is a direct result of NHPs (rhesus macaque, etc.) close relation to humans. NHPs share similar developmental paths with humans in their anatomy, physiology, genetics, and neural functions; and in their cognition, emotion, and social behavior. The NHP model within biomedical research has played an important role in the development of vaccines, assisted reproductive technologies, and new therapies for many diseases. Biomedical research has not been the primary role of NHPs. They have mainly been used for safety evaluation and pharmacokinetics studies, rather than determining therapeutic efficacy. The development of the first transgenic rhesus macaque (2001) revolutionized the role of NHP models in biomedicine. Development of the transgenic NHP model of Huntington's disease (2008), with distinctive clinicalfeatures, further suggested the uniqueness of the model system; and the potential role of the NHP model for human genetic disorders. Modeling human genetic diseases using NHPs will continue to thrive because of the latest advances in molecular, genetic, and embryo technologies. NHPs rising role in biomedical research, specifically pre-clinical studies, is foreseeable. The path toward the development of transgenic NHPs and the prospect of transgenic NHPs in their new role in future biomedicine needs to be reviewed. This article will focus on the advancement of transgenic NHPs in the past decade, including transgenic technologies and disease modeling. It will outline new technologies that may have significant impact in future NHP modeling and will conclude with a discussion of the future prospects of the transgenic NHP model. © The Author 2013. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved.

Pranski E.,Emory University
Neuroscience letters | Year: 2013

RING finger protein 11 (RNF11), a negative regulator of NF-κB signaling pathway, colocalizes with α-synuclein and is sequestered in Lewy bodies in Parkinson's disease (PD). Since persistent NF-κB activation is reported in PD, in this report we investigated if RNF11 expression level is correlated to activated NF-κB in PD. We examined RNF11 expression levels in correlation to phospho-p65, a marker for activated NF-κB, in control and PD brain tissue from cerebral cortex. In addition we performed double immunofluorescence labeling experiments to confirm this correlation. Our investigations demonstrated that the neuronal RNF11 expression was down-regulated in PD and was usually associated with increased expression of phospho-p65. Double labeling confirmed that loss of neuronal RNF11 was linked to increased phospho-p65 expression, suggesting that persistent presence of NF-κB activation could be due to decreased levels of its negative regulator. Our data exemplifies the relevance of RNF11 and persistent NF-κB activation in PD. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Sherman A.C.,Emory University | Sherman K.E.,University of Cincinnati
Current HIV/AIDS Reports | Year: 2015

This article describes the importance of extrahepatic systemic manifestations of chronic hepatitis C virus (HCV) infection. While most HCV literature focuses on liver injury and fibrosis progression, a spectrum of systemic disease processes, collectively called C hepatitis-associated systemic manifestations (CHASMs), are present in a high proportion of infected persons. These include thyroid disease (Hashimoto’s thyroiditis, Graves disease, and thyroid cancer), cardiovascular disease (atherosclerosis, carotid artery disease, and coronary artery disease), renal disease (MPGN and glomerulosclerosis), eye disease (Mooren’s ulcers and sicca syndrome), skin disease (PCT, vasculitis, and lichen planus), lymphomas (NHL and splenic T-cell), and diabetes. Mechanistic understanding of how HCV leads to CHASM processes could lead to development of new interventions. The role of early HCV treatment and cure may result in preventive strategies for a variety of complex disease states. Key Points • Systemic extrahepatic complications of HCV comprise a spectrum of disease states in many organs and systems. • Effective treatment of HCV may reduce or eliminate some but not all of these systemic complications. • Further research into early treatment intervention as a prevention strategy for systemic disease is warranted. © 2015, Springer Science+Business Media New York.

Grossniklaus D.A.,Emory University
European journal of cardiovascular nursing : journal of the Working Group on Cardiovascular Nursing of the European Society of Cardiology | Year: 2012

In the U.S., Europe, and throughout the world, abdominal obesity prevalence is increasing. Depressive symptoms may contribute to abdominal obesity through the consumption of diets high in energy density. To test dietary energy density ([DED]; kilocalories/gram of food and beverages consumed) for an independent relationship with abdominal obesity or as a mediator between depressive symptoms and abdominal obesity. This cross-sectional study included 87 mid-life, overweight adults; 73.6% women; 50.6% African-American. Variables and measures: Beck depression inventory-II (BDI-II) to measure depressive symptoms; 3-day weighed food records to calculate DED; and waist circumference, an indicator of abdominal obesity. Hierarchical regression tested if DED explained waist circumference variance while controlling for depressive symptoms and consumed food and beverage weight. Three approaches tested DED as a mediator. Nearly three-quarters of participants had abdominal obesity, and the mean waist circumference was 103.2 (SD 14.3) cm. Mean values: BDI-II was 8.67 (SD 8.34) which indicates that most participants experienced minimal depressive symptoms, and 21.8% reported mild to severe depressive symptoms (BDI-II ≥ 14); DED was 0.75 (SD 0.22) kilocalories/gram. Hierarchical regression showed an independent association between DED and waist circumference with DED explaining 7.0% of variance above that accounted for by BDI-II and food and beverage weight. DED did not mediate between depressive symptoms and abdominal obesity. Depressive symptoms and DED were associated with elevated waist circumference, thus a comprehensive intervention aimed at improving depressive symptoms and decreasing DED to reduce waist circumference is warranted.

Kindt J.T.,Emory University
Journal of Chemical Theory and Computation | Year: 2013

An approach is given to analyze aggregate size distributions obtained from simulations of a fixed number N of monomers undergoing reversible self-assembly. Equilibrium distributions are derived from size-dependent equilibrium association constants by appropriately weighted sums over all partitions of N monomers into aggregates. Conversely, equilibrium association constants can be obtained from an iterative fit to a finite-N equilibrium distribution. Model data for a micelle-forming system are used to show how results from simulations containing few micelles can yield infinite-N limiting distributions. A strategy is also suggested to exploit small-N effects on aggregate size distributions to enhance sampling of critical clusters in determination of nucleation free energy functions. © 2012 American Chemical Society.

Go Y.M.,Emory University
Methods in enzymology | Year: 2010

Extracellular thiol/disulfide redox environments are highly regulated in healthy individuals and become oxidized in disease. This oxidation affects the function of cell surface receptors, ion channels, and structural proteins. Downstream signaling due to changes in extracellular redox potential can be studied using a redox clamp in which thiol and disulfide concentrations are varied to obtain a series of controlled redox potentials. Previous applications of this approach show that cell proliferation, apoptosis, and proinflammatory signaling respond to extracellular redox potential. Furthermore, gene expression and proteomic studies reveal the global nature of redox effects, and different cell types, for example, endothelial cells, fibroblasts, monocytes, and epithelial cells, show cell-specific redox responses. Application of the redox clamp to studies of different signaling pathways could enhance the understanding of redox transitions in many aspects of normal physiology and disease. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Most leading crime theories and crime-control policies are based on the assumption that people are self-interested. But recent work in a variety of fields has challenged this assumption, suggesting that people are both self-interested and socially concerned. Social concern involves biologically based inclinations that sometimes lead people to give more consideration to others than to their own interests. These inclinations include caring about others, forming close ties to and cooperating with others, following certain moral intuitions, and conforming. This article describes the nature of and evidence for social concern, as well as the ways in which social factors shape social concern. The article then presents a theory of social concern and crime. Social concern has direct, indirect, mediating, and conditioning effects on crime. Although social concern generally reduces the likelihood of crime, it has little effect on or increases crime under certain conditions. © 2013 American Society of Criminology.

Kane G.C.,Chestnut Hill College | Alavi M.,Emory University | Labianca G.,University of Kentucky | Borgatti S.P.,University of Kentucky
MIS Quarterly: Management Information Systems | Year: 2014

In recent years, we have witnessed the rapid proliferation and widespread adoption of a new class of information technologies, commonly known as social media. Researchers often rely on social network analysis (SNA) when attempting to understand these technologies, often without considering how the novel capabilities of social media platforms might affect the underlying theories of SNA, which were developed primarily through studies of offline social networks. This article outlines several key differences between traditional offline social networks and online social media networks by juxtaposing an established typology of social network research with a well-regarded definition of social media platforms that articulates four key features. The results show that at four major points of intersection, social media has considerable theoretical implications for SNA. In exploring these points of intersection, this study outlines a series of theoretically distinct research questions for SNA in social media contexts. These points of intersection offer considerable opportunities for researchers to investigate the theoretical implications introduced by social media and lay the groundwork for a robust social media agenda potentially spanning multiple disciplines.

Chellappa R.K.,Emory University | Saraf N.,Simon Fraser University
Information Systems Research | Year: 2010

Enterprise systems software (ESS) is a multibillion dollar industry that produces systems components to support a variety of business functions for a widerange of vertical industry segments. Even if it forms the core of an organization's information systems (IS) infrastructure, there is little prior IS research on the competitive dynamics in this industry. Whereas economic modeling has generally provided the methodological framework for studying standards-driven industries, our research employs social network methods to empirically examine ESS firm competition. Although component compatibility is critical to organizational end users, there is an absence of industry-wide ESS standards and compatibility is ensured through interfirm alliances. First, our research observes that this alliance network does not conform to the equilibrium structures predicted by economics of network evolution supporting the view that it is difficult to identify dominant standards and leaders in this industry. This state of flux combined with the multifirm multicomponent nature of the industry limits the direct applicability of extant analytical models. Instead, we propose that the relative structural position acquired by a firm in its alliance network is a reasonable proxy for its standards dominance and is an indicator of its performance. In lieu of structural measures developed mainly for interpersonal networks, we develop a measure of relative firm prominence specifically for the business software network where benefits of alliances may accrue through indirect connections even if attenuated. Panel data analyses of ESS firms that account for over 95% of the industry revenues, show that our measure provides a superior model fit to extant social network measures. Two interesting counterintuitive findings emerge from our research. First, unlike other software industries compatibility considerations can trump rivalry concerns. We employ quadratic assignment procedure to show that firms freely form alliances even with their rivals. Second, we find that smaller firms enjoy a greater value from acquiring a higher structural position as compared to larger firms. © 2010 INFORMS.

Sechopoulos I.,Emory University
Medical Physics | Year: 2012

Purpose: To improve image quality and accuracy in dedicated breast computed tomography (BCT) by removing the x-ray scatter signal included in the BCT projections. Methods: The previously characterized magnitude and distribution of x-ray scatter in BCT results in both cupping artifacts and reduction of contrast and accuracy in the reconstructions. In this study, an image processing method is proposed that estimates and subtracts the low-frequency x-ray scatter signal included in each BCT projection postacquisition and prereconstruction. The estimation of this signal is performed using simple additional hardware, one additional BCT projection acquisition with negligible radiation dose, and simple image processing software algorithms. The high frequency quantum noise due to the scatter signal is reduced using a noise filter postreconstruction. The dosimetric consequences and validity of the assumptions of this algorithm were determined using Monte Carlo simulations. The feasibility of this method was determined by imaging a breast phantom on a BCT clinical prototype and comparing the corrected reconstructions to the unprocessed reconstructions and to reconstructions obtained from fan-beam acquisitions as a reference standard. One-dimensional profiles of the reconstructions and objective image quality metrics were used to determine the impact of the algorithm. Results: The proposed additional acquisition results in negligible additional radiation dose to the imaged breast (∼0.4% of the standard BCT acquisition). The processed phantom reconstruction showed substantially reduced cupping artifacts, increased contrast between adipose and glandular tissue equivalents, higher voxel value accuracy, and no discernible blurring of high frequency features. Conclusions: The proposed scatter correction method for dedicated breast CT is feasible and can result in highly improved image quality. Further optimization and testing, especially with patient images, is necessary to characterize its impact on clinical performance. © 2012 American Association of Physicists in Medicine.

Israili Z.H.,Emory University
American Journal of Therapeutics | Year: 2011

There is a rising worldwide prevalence of diabetes, especially type 2 diabetes mellitus (T2DM), which is one of the most challenging health problems in the 21st century. The associated complications of diabetes, such as cardiovascular disease, peripheral vascular disease, stroke, diabetic neuropathy, amputations, renal failure, and blindness result in increasing disability, reduced life expectancy, and enormous health costs. T2DM is a polygenic disease characterized by multiple defects in insulin action in tissues and defects in pancreatic insulin secretion, which eventually leads to loss of pancreatic insulin-secreting cells. The treatment goals for T 2DM patients are effective control of blood glucose, blood pressure, and lipids (if elevated) and, ultimately, to avert the serious complications associated with sustained tissue exposure to excessively high glucose concentrations. Prevention and control of diabetes with diet, weight control, and physical activity has been difficult. Treatment of T2DM has centered on increasing insulin levels, either by direct insulin administration or oral agents that promote insulin secretion, improving sensitivity to insulin in tissues, or reducing the rate of carbohydrate absorption from the gastrointestinal tract. This review presents comprehensive and up-to-date information on the mechanism(s) of action, efficacy, pharmacokinetics, pleiotropic effects, drug interactions, and adverse effects of the newer antidiabetic drugs, including (1) peroxisome proliferator-activated-receptor- γ agonists (thiazolidinediones, pioglitazone, and rosiglitazone); (2) the incretin, glucagon-like peptide-) receptor agonists (incretin-mimetics, exenatide. and liraglutide), (3) inhibitors of dipeptidyl-peptidase-4 (incretin enhancers, sitagliptin, and vildagliptin), (4) short-acting, nonsulfonylurea secretagogue, meglitinides (repaglinide and nateglinide), (5) amylin anlog-pramlintide, (6) α-glucosidase inhibitors (miglitol and voglibose), and (7) colesevelam (a bile acid sequestrant). In addition, information is presented on drug candidates in clinical trials, experimental compounds, and some plants used in the traditional treatment of diabetes based on experimental evidence. In the opinion of this reviewer, therapy based on orally active incretins and incretin mimetics with long duration of action that will be efficacious, preserve the β-cell number/function, and block the progression of diabetes will be highly desirable. However, major changes in lifestyle factors such as diet and, especially, exercise will also be needed if the growing burden of diabetes is to be contained. © 2011 Lippincott Williams &Wilkins.

Tiwana A.,University of Georgia | Konsynski B.,Emory University
Information Systems Research | Year: 2010

This study addresses the theoretically neglected interplay between organizational information technology (IT) architecture and IT governance structure in shaping IT alignment. We theoretically develop the idea that IT architecture modularity helps sustain IT alignment by increasing IT agility, and that decentralization of IT governance strengthens this relationship. IT architecture therefore complements IT governance structure. Tests of the proposed mediated-moderation model using data from 223 organizations support these ideas. Implications for theory and practice are also discussed. © 2010 INFORMS.

Shaw L.J.,Emory University
Canadian Journal of Cardiology | Year: 2013

This review highlights the current economic climate for health care and the evidentiary standards that are increasingly applied to appropriate use of cardiovascular imaging. Additionally, the evidence on cost efficiency and effectiveness is explored in this review. Ongoing multicentre registries and clinical trials will further enrich this evidence base with regard to value-based imaging strategies that provide enhanced effectiveness and efficiency resulting in improved patient outcomes. © 2013 Canadian Cardiovascular Society.

Williams C.R.,Emory University
Expert reviews in molecular medicine | Year: 2012

Organ transplantation is the state of the art for treating end-stage organ failure. Over 25000 organ transplants are performed in the USA each year. Survival rates following transplantation are now approaching 90% for 1 year and 75% for 5 years. Central to this success was the introduction of drugs that suppress the immune system and prevent rejection. The most commonly used class of immunosuppressing drugs are calcineurin inhibitors (CNIs). Calcineurin is a ubiquitous enzyme that is important for T-cell function. With more people taking CNIs for longer and longer periods of time the consequences of calcineurin inhibition on other organ systems - particularly the kidney - have become a growing concern. Virtually all people who take a CNI will develop some degree of kidney toxicity and up to 10% will progress to kidney failure. In the past 15 years, research into calcineurin action has identified distinct actions of the two main isoforms of the catalytic subunit of the enzyme. The α-isoform is required for kidney function whereas the β-isoform has a predominant role in the immune system. This review will discuss the current state of knowledge about calcineurin isoforms and how these new insights may reshape post-transplant immunosuppression.

Herdman S.J.,Emory University
Current Opinion in Neurology | Year: 2013

PURPOSE OF REVIEW: This review examines the research from 2011 through 2012 on treatment efficacy in two common vestibular disorders-vestibular hypofunction and benign paroxysmal positional vertigo (BPPV). RECENT FINDINGS: Significant numbers of randomized controlled trials now support the use of specific exercises for the treatment of patients with unilateral peripheral vestibular hypofunction. We do not know if some treatment approaches are more effective than others. There is preliminary evidence that head movement may be the component critical to recovered function and decreased symptoms. Some patient characteristics and initial assessment results appear to predict treatment outcome but the evidence is incomplete. Treatment of posterior canal BPPV canalithiasis is well established. New evidence supports certain treatments for horizontal canal BPPV. SUMMARY: Treatments for unilateral vestibular hypofunction and for posterior canal BPPV are effective; however, there are many as yet unanswered questions such as why some patients with vestibular hypofunction do not improve with a course of vestibular exercises. We also do not know what would be the best treatment for anterior canal BPPV or for multiple-canal involvement BPPV. © 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.

Friedman A.,Ben - Gurion University of the Negev | Dingledine R.,Emory University
Epilepsia | Year: 2011

Experimental evidence strongly indicates a significant role for inflammatory and immune mediators in initiation of seizures and epileptogenesis. Here we will summarize data supporting the involvement of IL-1β, TNF-α and toll-like receptor 4 in seizure generation and the process of epileptogenesis. The physiological homeostasis and control over brain immune response depends on the integrity of the blood-brain barrier, transforming growth factor (TGF)-β signaling and leukocyte migration. To what extent targeting the immune system is successful in preventing epileptogenesis, and which signaling pathway should be beleaguered is still under intensive research. © 2011 International League Against Epilepsy.

Depression is associated with alterations in corticostriatal reward circuitry. One pathophysiological pathway that may drive these changes is inflammation. Biomarkers of inflammation (for example, cytokines and C-reactive protein (CRP)) are reliably elevated in depressed patients. Moreover, administration of inflammatory stimuli reduces neural activity and dopamine release in reward-related brain regions in association with reduced motivation and anhedonia. Accordingly, we examined whether increased inflammation in depression affects corticostriatal reward circuitry to lead to deficits in motivation and goal-directed motor behavior. Resting-state functional magnetic resonance imaging was conducted on 48 medically stable, unmedicated outpatients with major depression. Whole-brain, voxel-wise functional connectivity was examined as a function of CRP using seeds for subdivisions of the ventral and dorsal striatum associated with motivation and motor control. Increased CRP was associated with decreased connectivity between ventral striatum and ventromedial prefrontal cortex (vmPFC) (corrected P<0.05), which in turn correlated with increased anhedonia (R=−0.47, P=0.001). Increased CRP similarly predicted decreased dorsal striatal to vmPFC and presupplementary motor area connectivity, which correlated with decreased motor speed (R=0.31 to 0.45, P<0.05) and increased psychomotor slowing (R=−0.35, P=0.015). Of note, mediation analyses revealed that these effects of CRP on connectivity mediated significant relationships between CRP and anhedonia and motor slowing. Finally, connectivity between striatum and vmPFC was associated with increased plasma interleukin (IL)-6, IL-1beta and IL-1 receptor antagonist (R=−0.33 to −0.36, P<0.05). These findings suggest that decreased corticostriatal connectivity may serve as a target for anti-inflammatory or pro-dopaminergic treatment strategies to improve motivational and motor deficits in patients with increased inflammation, including depression.Molecular Psychiatry advance online publication, 10 November 2015; doi:10.1038/mp.2015.168. © 2015 Macmillan Publishers Limited

Orskov and colleagues demonstrate the impact of birth weight on the mean age of end-stage renal disease (ESRD) in a large Danish ADPKD cohort. Each kilogram of birth weight extended the mean age of ESRD onset by 1.7 years. Placental insufficiency, activation of the renin-angiotensin-aldosterone system, increased fetal vasopressin levels, compensatory increases in insulin like growth factor-I, and a reduction in total nephron number may all contribute to this observation. Collectively, these changes result in an accelerated pace of cyst formation and expansion, and an inability to maintain glomerular hyperfiltration during kidney expansion which results in a more rapid progression to ESRD. Therefore the intrauterine environment may play a critical role in disease severity in ADPKD. © 2012 International Society of Nephrology.

Lonial S.,Emory University
Cancer Treatment Reviews | Year: 2010

Major improvement milestones in the treatment of patients with multiple myeloma (MM) include the introduction of the melphalan/prednisone combination in the 1960s; high-dose chemotherapy supported by autologous stem cell transplant in the 1980s; and the more recent introduction of the novel agents, thalidomide, lenalidomide, bortezomib, and pegylated liposomal doxorubicin. While, historically, age and eligibility for autologous stem cell transplantation were the primary basis for treatment selection, cytogenetics and other risk stratification methods are increasingly being used to guide treatment, especially with the newer agents. This trend reflects our improved understanding of the numerous genetic and biological abnormalities that mark this complex disease. In the absence of prospective, randomised studies assessing the value of risk stratification in guiding treatment decisions, and the use of the newest therapies, results of a number of studies provide a rationale for this approach. Currently available data indicate that the use of novel therapies in both the induction and maintenance settings, accompanied by risk stratification, may improve prognosis for patients with MM. Large, prospective randomised studies are needed to confirm these early pilot studies. © 2010 Elsevier Ltd.

De Cock K.M.,Centers for Disease Control and Prevention | Jaffe H.W.,Centers for Disease Control and Prevention | Curran J.W.,Emory University
AIDS | Year: 2012

Following its recognition in 1981, the HIV/AIDS epidemic has evolved to become the greatest challenge in global health, with some 34 million persons living with HIV worldwide. Early epidemiologic studies identified the major transmission routes of the virus before it was discovered, and enabled the implementation of prevention strategies. Although the first identified cases were in MSM in the United States and western Europe, the greatest impact of the epidemic has been in sub-Saharan Africa, where most of the transmission occurs between heterosexuals. Nine countries in southern Africa account for less than 2% of the world's population but now they represent about one third of global HIV infections. Where broadly implemented, HIV screening of donated blood and antiretroviral treatment (ART) of pregnant women have been highly effective in preventing transfusion-associated and perinatally acquired HIV, respectively. Access to sterile equipment has also been a successful intervention for injection drug users. Prevention of sexual transmission has been more difficult. Perhaps the greatest challenge in terms of prevention has been in the global community of MSM in which HIV remains endemic at high prevalence. The most promising interventions are male circumcision for prevention of female-to-male transmission and use of ART to reduce infectiousness, but the extent to which these interventions can be brought to scale will determine their population-level impact. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Jin H.T.,Emory University
Current topics in microbiology and immunology | Year: 2011

Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers negative signals upon interaction with its two ligands, PD-L1 or PD-L2. PD-1 and its ligands are broadly expressed and exert a wider range of immunoregulatory roles in T cells activation and tolerance compared with other CD28 members. Subsequent studies show that PD-1-PD-L interaction regulates the induction and maintenance of peripheral tolerance and protect tissues from autoimmune attack. PD-1 and its ligands are also involved in attenuating infectious immunity and tumor immunity, and facilitating chronic infection and tumor progression. The biological significance of PD-1 and its ligand suggests the therapeutic potential of manipulation of PD-1 pathway against various human diseases. In this review, we summarize our current understanding of PD-1 and its ligands ranging from discovery to clinical significance.

Sarrett J.C.,Emory University
Journal of Medical Humanities | Year: 2011

The lay public inherits much of its information about disability and mental illness through the media, which often relies on information from popular scientific works. Autism, as it was defined during the dominance of psychogenic paradigms of mental illness, generated certain tropes surrounding it, many of which have been popularized through media representations. Often inaccurate, these tropes have persisted into contemporary times despite a paradigmatic shift from psychogenic to biological explanations and treatments for mental illness. The current article examines images and articles of children with autism from the 1960s and the early 2000s in major news media and scientific literature to highlight the persistence of themes of fragmentation and the imprisonment of children with autism. While these themes have persisted in psychological and media literature, narratives of people with autism and their families often present a different perspective. This results in two divergent 'realities' of autism being disseminated into the general public. © Springer Science+Business Media, LLC 2011.

Brawley O.W.,Emory University
World Journal of Urology | Year: 2012

Background: Prostate cancer is a significant public health issue in the United States. It is the most commonly diagnosed non-skin cancer and the second leading cause of cancer death. The American Cancer Society estimates that in 2011, 240,890 men were diagnosed with prostate cancer and 33,720 men died of it. Methods: A review of the peer-reviewed literature was conducted: American Cancer Society, National Cancer Institute Surveillance, Epidemiology and End Results. Program data were assessed to describe trends in incidence, mortality, and survival rates and look at other predictors of risk of prostate cancer diagnosis and death. Results: Since 1985, there have been significant changing trends in prostate cancer incidence, mortality, and survival rates, as well as changes in the age distribution of the population diagnosed and even in the distribution of pathologies at diagnosis. Major risk factors for diagnosis include age, family history, race, and screening behavior. Conclusion: While prostate cancer remains largely a disease diagnosed in older men (over age 65), screening has increased risk of diagnosis among men in their 40s and 50s. The incidence rates and 5-year survival rates are heavily influenced by the introduction of serum prostate-specific antigen (PSA) and widespread screening. The effects of PSA usage and screening on mortality rates are less certain. Outcome studies among men treated with radical prostatectomy show that greater than 30% relapse rates are common. This suggests that many men who are diagnosed with "localized early stage disease" actually have "apparently localized early stage disease," which is really low volume metastatic disease. © 2012 Springer-Verlag.

Meiklejohn C.D.,University of Rochester | Tao Y.,Emory University
Trends in Ecology and Evolution | Year: 2010

Chromosomal sex determination systems create the opportunity for the evolution of selfish genetic elements that increase the transmission of one sex chromosome at the expense of its homolog. Because such selfish elements on sex chromosomes can reduce fertility and distort the sex ratio of progeny, unlinked suppressors are expected to evolve, bringing different regions of the genome into conflict over the meiotic transmission of the sex chromosomes. Here we argue that recurrent genetic conflict over sex chromosome transmission is an important evolutionary force that has shaped a wide range of seemingly disparate phenomena including the epigenetic regulation of genes expressed in the germline, the distribution of genes in the genome, and the evolution of hybrid sterility between species. © 2009 Elsevier Ltd. All rights reserved.

Meador K.J.,Stanford University | Loring D.W.,Emory University
Neurology | Year: 2016

Antiepileptic drugs (AEDs) are among the most common teratogenic drugs prescribed to women of childbearing age. AEDs can induce both anatomical (malformations) and behavioral (cognitive/ behavioral deficits) teratogenicity. Only in the last decade have we begun to truly discriminate differential AED developmental effects. Fetal valproate exposure carries a special risk for both anatomical and behavioral teratogenic abnormalities, but the mechanisms and reasons for individual variability are unknown. Intermediate anatomical risks exist for phenobarbital and topiramate. Several AEDs (e.g., lamotrigine and levetiracetam) appear to possess low risks for both anatomical and behavioral teratogenesis. Despite advances in the past decade, our knowledge of the teratogenic risks for most AEDs and the underlying mechanisms remain inadequate. Further, the long-term effects of AEDs in neonates and older children remain uncertain. The pace of progress is slow given the lifelong consequences of diminished developmental outcomes, exposing children unnecessarily to potential adverse effects. It is imperative that new approaches be employed to determine risks more expediently. Our recommendations include a national reporting system for congenital malformations, federal funding of the North American AED Pregnancy Registry, routine meta-analyses of cohort studies to detect teratogenic signals, monitoring of AED prescription practices for women, routine preclinical testing of all new AEDs for neurodevelopmental effects, more specific Food and Drug Administration requirements to establish differential AED cognitive effects in children, and improved funding of basic and clinical research to fully delineate risks and underlying mechanisms for AED-induced anatomical and behavioral teratogenesis. © 2015 American Academy of Neurology.

Kitchens W.H.,Emory University
Transplantation Reviews | Year: 2011

The long-term shortage of livers available for transplantation has spurred the development of many strategies to bolster the donor organ supply. One particularly innovative strategy is domino liver transplantation in which a select group of liver transplant recipients can donate their explanted native livers for use as liver grafts in other patients. Several hereditary metabolic diseases (such as familial amyloid polyneuropathy, maple syrup urine disease, and familial hypercholesterolemia) are caused by aberrant or deficient protein production in the liver, and these conditions can be cured with an orthotopic liver transplant. Although their native livers eventually caused severe systemic disease in these patients, these livers are otherwise structurally and functionally normal, and they have been used successfully in domino liver transplants for the past 15 years. This article will review the indications for donating or receiving a domino liver transplant, the surgical techniques necessary to perform these transplants, as well as the recently revealed long-term outcomes and risks of domino transplantation. © 2011 Elsevier Inc.

Michael Lane J.,Emory University
Emerging Infectious Diseases | Year: 2011

After the recent summary of World Health Organization-authorized research on smallpox, several clinical issues remain. This policy review addresses whether early hemorrhagic smallpox is disseminated intravascular coagulation and speculates about the cause of the high mortality rate among pregnant women and whether ocular smallpox is partly the result of trachoma or vitamin A defi -ciency. The joint destruction common in children with smallpox might be prevented by antiviral drugs, but intraarticular infusion of antiviral drugs is unprecedented. Development of highly effective antiviral drugs against smallpox raises the issue of whether postexposure vaccination can be performed without interference by an antiviral drug. Clinicians should consider whether patients with smallpox should be admitted to general hospitals. Although an adequate supply of secondgeneration smallpox vaccine exists in the United States, its use is unclear. Finally, political and ethical forces suggest that destruction of the remaining stocks of live smallpox virus is now appropriate.

Mcgowan J.E.,Emory University
Infection Control and Hospital Epidemiology | Year: 2012

Antimicrobial stewardship programs attempt to optimize prescribing of these drugs to benefit both current and future patients. Recent regulatory and other incentives have led to widespread adoption of such programs. Measurements of the success of these programs have focused primarily on process measures. However, evaluation of outcome measures will be needed to ensure sustainability of these efforts. Outcome efforts to date provide some evidence for improved care of individual patients, some evidence for minimizing emergence of resistance, and ample evidence for cost reduction. Attention to evaluation methods must be increased to provide convincing evidence for the continuation of such programs. © 2012 by The Society for Healthcare Epidemiology of America. All rights reserved.

Aiken A.H.,Emory University
Seminars in Ultrasound, CT and MRI | Year: 2012

Thyroid cancer is a heterogeneous group of malignancies, including differentiated thyroid carcinomas, medullary and anaplastic carcinomas, and non-Hodgkin lymphoma. The incidence, presentation, natural history, prognosis, and treatment vary greatly among this diverse group of malignancies. The primary role of imaging in thyroid cancer is to evaluate for extension of tumor beyond the thyroid capsule and to assess for nodal metastases. Ultrasound is the standard imaging option for uncomplicated thyroid cancer, but patients with symptoms suggesting extrathyroidal extension or palpable lateral lymphadenopathy should be considered for cross-sectional imaging with computed tomography or magnetic resonance imaging. © 2012 Elsevier Inc.

Guy Jr. G.P.,Emory University
Health Services Research | Year: 2010

Objectives. To analyze the impact of public health insurance expansions and the use of enrollee cost sharing on insurance status and receipt of clinically indicated preventive screenings and physician services. Data Source. This study uses Behavioral Risk Factor Surveillance System (BRFSS) data from 1997 to 2007. Study Design. This study uses multivariate difference-in-difference logistic regression modeling of pooled cross-sectional time series data. The effect of the expansions on insurance status and access to care is identified by cross-state variation in program implementation, as well as cross-state and within-state variation in program eligibility criteria over time. Principal Findings. Childless adult expansions, regardless of cost-sharing levels, reduced uninsurance rates and decreased the likelihood that childless adults needed to see a physician but did not because of cost. Expansions with traditional public insurance cost-sharing requirements increased the use of preventive screenings, while expansions with increased cost-sharing requirements did not. Conclusions. Cost-sharing requirements did not have an impact on the ability to see a physician when needed, but they played an important role in the utilization of preventive services. Expanding public health insurance to low-income, childless adults presents a promising policy opportunity, but there are trade-offs between the efficiencies obtained through increased cost sharing and the potential inefficiencies due to the lower use of preventive services. © Health Research and Educational Trust.

Yamaguchi M.,Emory University
Molecular and Cellular Biochemistry | Year: 2010

Regucalcin transgenic (TG) rat has been generated to determine the role in metabolic disorders. Regucalcin homozygote male and female rats induce a prominent increase in regucalcin protein in the various tissues. Bone loss has been found to induce in regucalcin TG rats with growing (5 weeks old) and aging (50 weeks old). Osteoclastogenesis has been shown to stimulate in culture with the bone marrow cells obtained from regucalcin TG rats. Exogenous regucalcin stimulates osteoclastogenesis in mouse marrow culture in vitro. Regucalcin has a suppressive effect on the differentiation and mineralization in osteoblastic MC3T3-E1 cells in vitro. The mechanism by which regucalcin TG rat induces bone loss may result from the enhancement of osteoclastic bone resorption and the suppression of osteoblastic bone formation. Moreover, regucalcin TG rat has been found to induce hyperlipidemia with increasing age (14-50 weeks); serum triglyceride, high-density lipoprotein (HDL)-cholesterol, free fatty acid, albumin and calcium concentrations are markedly increased in regucalcin TG male and female rats with increasing age. The decrease in lipid and glycogen contents in liver tissues is induced in regucalcin TG rats. The gene expression of leptin and adiponectin is suppressed in the TG rats. Overexpression of regucalcin has been shown to enhance glucose utilization and lipid production in the cloned rat hepatoma H4-II-E cells in vitro, and insulin resistance is seen in the cells. The expression of glucose transporter 2 mRNA is increased in the transfectants, while it has been shown to suppress insulin receptor and phosphatidylinositol 3-kinase mRNA expressions that are involved in insulin signaling. This review proposes that regucalcin relates in osteoporosis and hyperlipidemia, and that the regucalcin TG rat model may be useful in determining the pathophysiologic state and the development of therapeutic tool for osteoporosis and hyperlipidemia. © 2010 Springer Science+Business Media, LLC.

Among the accolades most valued by a clinical cardiologist is to be selected to deliver the annual James B. Herrick Lecture. This lecture honors the legacy of James Herrick as an icon for the cardiac clinician/scientist. I am enormously grateful to the Council on Clinical Cardiology for this singular recognition. © 2012 American Heart Association, Inc.

Bauer P.J.,Emory University
Developmental Review | Year: 2015

Some memories of the events of our lives have a long shelf-life - they remain accessible to recollection even after long delays. Yet many other of our experiences are forgotten, sometimes very soon after they take place. In spite of the prevalence of forgetting, theories of the development of episodic and autobiographical memory largely ignore it as a potential source of variance in explanation of age-related variability in long-term recall. They focus instead on what may be viewed as positive developmental changes, that is, changes that result in improvements in the quality of memory representations that are formed. The purpose of this review is to highlight the role of forgetting as an important variable in understanding the development of episodic and autobiographical memory. Forgetting processes are implicated as a source of variability in long-term recall due to the protracted course of development of the neural substrate responsible for transformation of fleeting experiences into memory traces that can be integrated into long-term stores and retrieved at later points in time. It is logical to assume that while the substrate is developing, neural processing is relatively inefficient and ineffective, resulting in loss of information from memory (i.e., forgetting). For this reason, focus on developmental increases in the quality of representations of past events and experiences will tell only a part of the story of how memory develops. A more complete account is afforded when we also consider changes in forgetting. © 2015 Elsevier Inc.

Yokoyama S.,Emory University
Molecular Biology and Evolution | Year: 2013

For over the last 2 decades, positively selected amino acid sites have been inferred almost exclusively by showing that the number of nonsynonymous substitutions per nonsynonymous site (dn) is greater than that of synonymous substitutions per synonymous site (ds). However, virtually none of these statistical results have been experimentally tested and remain as hypotheses. To perform such experimental tests, we must connect genotype and phenotype and relate the phenotypic changes to the environmental and behavioral changes of the organism. The genotype-phenotype relationship can be established only by synthesizing and manipulating "proper" ancestral phenotypes, whereas the actual functions of adaptive mutations can be learned by studying their chemical roles in phenotypic changes. © 2013 The Author.

Brawley O.W.,American Cancer Society | Brawley O.W.,Emory University
Journal of the National Cancer Institute - Monographs | Year: 2012

In the United States, prostate cancer is the most commonly diagnosed non-skin cancer and the second leading cause of cancer death. The American Cancer Society estimates that 241 740 American men will be diagnosed with the disease and 28 170 men will die of it in 2012. Prostate cancer demographics have changed dramatically over the past 30 years. The prostate cancer age-adjusted incidence rate increased through the 1980s and peaked in the early to mid-1990s. The incidence rate has declined since. American mortality rates rose through the 1980s and peaked in 1991. Today, the American incidence rates are below 1975 levels. Both the incidence rate and the 5-year survival rates are heavily influenced by the introduction of serum prostate-specific antigen test and the widespread use of it in cancer screening. The effect of screening on prostate cancer mortality is less certain. Screening has caused a dramatic increase in the number and proportion of men diagnosed with localized disease. Outcomes studies among men treated with radical prostatectomy show that greater than 30% serum prostate-specific antigen relapse rates are common. This suggests that many men who are diagnosed with "localized early stage disease" actually have "apparently localized early stage disease," which is really low-volume metastatic disease. © The Author 2012. Published by Oxford University Press. All rights reserved.

Israili Z.H.,Emory University
American Journal of Therapeutics | Year: 2014

Honey has been widely accepted as food and medicine by all generations, traditions, and civilizations, both ancient and modern. For at least 2700 years, honey has been used by humans to treat a variety of ailments through topical application, but only recently have the antiseptic and antimicrobial properties of honey been discovered. Honey has been reported to be effective in a number of human pathologies. Clinical studies have demonstrated that application of honey to severely infected cutaneous wounds rapidly clears infection from the wound and improves tissue healing. A large number of in vitro and limited clinical studies have confirmed the broad-spectrum antimicrobial (antibacterial, antifungal, antiviral, and antimycobacterial) properties of honey, which may be attributed to the acidity (low pH), osmotic effect, high sugar concentration, presence of bacteriostatic and bactericidal factors (hydrogen peroxide, antioxidants, lysozyme, polyphenols, phenolic acids, flavonoids, methylglyoxal, and bee peptides), and increase in cytokine release, and to immune modulating and anti-inflammatory properties of honey; the antimicrobial action involves several mechanisms. Despite a large amount of data confirming the antimicrobial activity of honey, there are no studies that support the systemic use of honey as an antibacterial agent. © 2013 Lippincott Williams & Wilkins.

Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) represent the cornerstone of drug therapy to reduce lowdensity lipoprotein (LDL) cholesterol and cardiovascular risk. However, even optimal statin management of LDL cholesterol leaves many patients with residual cardiovascular risk, in part because statins are more effective in reducing LDL cholesterol than apolipoprotein B (Apo B). Apo B may be a better marker of atherogenic risk than LDL cholesterol because Apo B measures the total number of all atherogenic particles (total atherosclerotic burden), including LDL, very low-density lipoprotein, intermediate-density lipoprotein, remnant lipoproteins, and lipoprotein(a). To determine whether Apo B is a better indicator of baseline cardiovascular risk and residual risk after lipid therapy compared with LDL cholesterol, a MEDLINE search of the literature published in English from January 1, 1975, through December 1, 2010, was conducted. On the basis of data from most population studies, elevated Apo B was more strongly associated with incident coronary heart disease than similarly elevated LDL cholesterol. Apo B was also a superior benchmark (vs LDL cholesterol) of statins' cardioprotective efficacy in both primary-prevention and secondary-prevention trials. To minimize cardiovascular risk among persons with hypercholesterolemia or dyslipidemia, the best available evidence suggests that intensive therapy with statins should be initiated to achieve the lowest possible Apo B level (with adequate drug toleration) and then other therapies (eg, niacin, bile acid resins, ezetimibe) added to potentiate these Apo B - lowering effects. In future consensus lipid-lowering treatment guidelines, Apo B should be considered as an index of residual risk, a potential parameter of treatment efficacy, and a treatment target to minimize risk of coronary heart disease. © 2011 Mayo Foundation for Medical Education and Research.

Nemenman I.,Emory University
Physical Biology | Year: 2012

Statistical properties of environments experienced by biological signaling systems in the real world change, which necessitates adaptive responses to achieve high fidelity information transmission. One form of such adaptive response is gain control. Here, we argue that a certain simple mechanism of gain control, understood well in the context of systems neuroscience, also works for molecular signaling. The mechanism allows us to transmit more than 1 bit (on or off) of information about the signal independent of the signal variance. It does not require additional molecular circuitry beyond that already present in many molecular systems, and in particular, it does not depend on existence of feedback loops. The mechanism provides a potential explanation for abundance of ultrasensitive response curves in biological regulatory networks. © 2012 IOP Publishing Ltd.

Thomas D.M.,Emory University | Bostrom R.P.,University of Georgia
MIS Quarterly: Management Information Systems | Year: 2010

This study explores how team leaders sense the need for technology adaptation intervention in distributed, computermediated ("virtual") teams. Analysis and coding of critical incident data collected in interviews of practicing leaders produce a five-trigger model including (1) external constraint, (2) internal constraint, (3) information and communication technology (ICT) inadequacy, (4) ICT knowledge, skills, and abilities inadequacy, and (5) trust and relationship inadequacies. The resulting five-trigger model provides several key contributions including (1) a diagnostic tool for examining real, multi-trigger team technology adaptation contexts, enabling better leader training and evaluation as well as improved research on team technology adaptation and interventions and (2) a better understanding of the relationship between the technology structure strength indicators in adaptive structuration theory and the need for team technology adaptation intervention.

Minor K.,Emory University
The American journal of emergency medicine | Year: 2013

Leptospirosis is a common zoonotic infection worldwide and is recognized as an emerging public health problem. Although commonly thought of as a tropical disease, incidence in temperate climates is increasing, with recent outbreaks in the United States and Germany, among other countries. The disease presents with symptoms ranging from fever, headache, nausea, and vomiting to life-threatening multiorgan failure characterized by acute liver failure, nephritis, pulmonary hemorrhage, meningitis, and cardiac arrhythmia. We describe a case of an otherwise healthy 28-year-old man who had just returned from a 2-month trip to Southeast Asia. He presented to our emergency department twice after his return with the complaint of fever and malaise. Initially, he was treated with symptomatic measures and discharged home with malaria smears and blood cultures pending. On his final presentation before admission, he presented with severe fatigue, myalgia, acute renal failure, and marked thrombocytopenia. After several days, inpatient testing revealed the patient's leptospira antibody titer was markedly positive. Given the nonspecificity of patient symptoms, early diagnosis of leptospirosis can be challenging. Diagnostic uncertainty may lead to delay in recommended intravenous antibiotic treatment. We present a case of severe leptospirosis treated exclusively with supportive measures and intravenous corticosteroids. Copyright © 2013 Elsevier Inc. All rights reserved.

The use of cryopreserved unmatched allogeneic mesenchymal stromal cells (MSCs) for treatment of steroid-resistant graftversus- host disease has become medical practice in many European jurisdictions. The enthusiasm for use of MSCs in transplantation medicine builds on compelling phase II clinical trial data published by European collaborative groups in the past few years. Notwithstanding, it was reported in 2009 that a large multicenter phase III clinical trial (NCT00366145) conducted in the USA examining the use of an industrial MSC product (Prochymal; Osiris Therapeutics, Inc., Columbia, MD, USA) failed to meet its primary clinical endpoint of achieving a significant increase of complete response of steroidresistant graft-versus-host disease lasting at least 28 days compared with placebo. Although peer-reviewed publication of the trial and its results are not in public domain at the time of this writing, it is worthwhile to reflect on the apparent discrepancy between the European experience and this industry-sponsored phase III study. This review presents a heuristic failure analysis focusing on the potential variables affecting MSCs and their utility as a cellular pharmaceutical. © 2013, International Society for Cellular Therapy.

Paulozzi L.J.,National Center for Injury Prevention and Control | Mack K.A.,Research and Practice Integration | Hockenberry J.M.,Emory University
Morbidity and Mortality Weekly Report | Year: 2014

Background: Overprescribing of opioid pain relievers (OPR) can result in multiple adverse health outcomes, including fatal overdoses. Interstate variation in rates of prescribing OPR and other prescription drugs prone to abuse, such as benzodiazepines, might indicate areas where prescribing patterns need further evaluation.Methods: CDC analyzed a commercial database (IMS Health) to assess the potential for improved prescribing of OPR and other drugs. CDC calculated state rates and measures of variation for OPR, long-acting/extended-release (LA/ER) OPR, high-dose OPR, and benzodiazepines.Results: In 2012, prescribers wrote 82.5 OPR and 37.6 benzodiazepine prescriptions per 100 persons in the United States. State rates varied 2.7-fold for OPR and 3.7-fold for benzodiazepines. For both OPR and benzodiazepines, rates were higher in the South census region, and three Southern states were two or more standard deviations above the mean. Rates for LA/ER and high-dose OPR were highest in the Northeast. Rates varied 22-fold for one type of OPR, oxymorphone.Conclusions: Factors accounting for the regional variation are unknown. Such wide variations are unlikely to be attributable to underlying differences in the health status of the population. High rates indicate the need to identify prescribing practices that might not appropriately balance pain relief and patient safety.Implications for Public Health: State policy makers might reduce the harms associated with abuse of prescription drugs by implementing changes that will make the prescribing of these drugs more cautious and more consistent with clinical recommendations. © 2014, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. All rights reserved.

Doughty D.,Emory University
Journal of Wound, Ostomy and Continence Nursing | Year: 2013

The damaging effects of moisture, pressure, friction, and shear on human tissue are well-known among wound care experts. Nevertheless, accurate classifi cation of these lesions is frequently challenging, even for experienced wound clinicians. The authors gathered clinical illustrations of gluteal cleft wounds and conducted a literature search as a basis for presentation to conference attendees, with the goal of gaining consensus regarding guidelines for accurate classifi cation of these wounds. The aim of this article was to summarize results of the consensus sessions that occurred at the Wound Ostomy Continence Nurses' Society National conferences in 2011 and 2012, and to highlight areas where consensus has been achieved as well as areas in which consensus has not yet been reached. Copyright © 2013 by the Wound, Ostomy and Continence Nurses Society™.

Linzer D.A.,Emory University | Lewis J.B.,University of California at Los Angeles
Journal of Statistical Software | Year: 2011

poLCA is a software package for the estimation of latent class and latent class regression models for polytomous outcome variables, implemented in the R statistical computing environment. Both models can be called using a single simple command line. The basic latent class model is a finite mixture model in which the component distributions are assumed to be multi-way cross-classification tables with all variables mutually independent. The latent class regression model further enables the researcher to estimate the effects of covariates on predicting latent class membership. poLCA uses expectation-maximization and Newton-Raphson algorithms to find maximum likelihood estimates of the model parameters.

Miller A.H.,Emory University | Raison C.L.,University of Wisconsin - Madison
Nature Reviews Immunology | Year: 2016

Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression. © 2015 Macmillan Publishers Limited.

Berkelman R.,Emory University
Journal of Public Health Policy | Year: 2012

Three decades into the HIV/AIDS epidemic, HIV prevention programs have been only partially effective. New prevention tools are providing new reasons for optimism. Effective use of these new tools, including the test-and-treat strategy, will require considerable effort to assure that their potential for prevention is fully realized. Challenges with the test-and-treat strategy are global ones, and include retention in care and adherence to treatment. Worldwide, those with HIV infection become less adherent to antiretroviral therapy over time. Many factors contributing to retention in care and adherence to therapy differ among countries and regions of the world. HIV-infected persons receiving treatment in sub-Saharan Africa have been reported to have higher adherence rates than those receiving treatment on the North American continent; higher health literacy and perception of treatment as a social obligation may enhance adherence to treatment and retention in care. The HIV test-and-treat strategy offers a major step forward when combined with other prevention efforts; we need to consider what additional steps are needed to deliver on the promise of prevention through treatment. © 2012 Macmillan Publishers Ltd.

The 2011 Update to the Unstable Angina/Non-ST-Elevation Myocardial Infarction (UA/NSTEMI) Guideline is based in evolving data or expert opinion and incorporates information from late-breaking clinical trials presented at the 2008-2009 Scientific Sessions of the American College of Cardiology, the American Heart Association, and the European Society of Cardiology, among others, as well as selected data through April 2010. The 5 key issues highlighted in this summary are: (1) the timing of acute interventional therapy in non-ST-elevation myocardial infarction; (2) emphasis on the timing, duration, and application of dual and triple antiplatelet therapy; (3) specific recommendations for patients with diabetes mellitus; (4) the role and potential benefit of invasive therapy in patients with advanced renal dysfunction; and (5) issues of quality improvement for acute coronary syndromes. © 2011 Wiley Periodicals, Inc.

Gosmanov A.R.,University of Tennessee Health Science Center | Umpierrez G.E.,Emory University
Current Diabetes Reports | Year: 2013

Hyperglycemia is a frequent complication of enteral and parenteral nutrition in hospitalized patients. Extensive evidence from observational studies indicates that the development of hyperglycemia during parenteral and enteral nutrition is associated with an increased risk of death and infectious complications. There are no specific guidelines recommending glycemic targets and effective strategies for the management of hyperglycemia during specialized nutritional support. Managing hyperglycemia in these patients should include optimization of carbohydrate content and administration of intravenous or subcutaneous insulin therapy. The administration of continuous insulin infusion and insulin addition to nutrition bag are efficient approaches to control hyperglycemia during parenteral nutrition. Subcutaneous administration of long-acting insulin with scheduled or corrective doses of short-acting insulin is superior to the sliding scale insulin strategy in patients receiving enteral feedings. Randomized controlled studies are needed to evaluate safe and effective therapeutic strategies for the management of hyperglycemia in patients receiving nutritional support. © 2012 Springer Science+Business Media New York.

Niyyar V.D.,Emory University
Seminars in Dialysis | Year: 2012

Vascular access dysfunction is a major cause of morbidity in hemodialysis (HD) patients. An upper extremity autogenous arteriovenous fistula (AVF) that preferentially involves the cephalic vein is the access of choice for HD patients, followed by autogenous AVF utilizing the basilic vein and the use of prosthetic arteriovenous grafts (AVGs). Despite these recommendations, central venous catheter (CVC) use is widespread among both incident and prevalent HD patients. Long-term use of CVCs for HD is complicated by a high rate of infection and thrombus-related dysfunction. Catheter locking solutions have been used both prophylactically and therapeutically for catheter thrombosis as well as catheter-related infections, with varying degrees of success. This review aims to address the different catheter locking solutions, their advantages and disadvantages, and new directions in this field. © 2011 Wiley Periodicals, Inc.

Gilman S.L.,Emory University
Journal of Nervous and Mental Disease | Year: 2012

"Self-harm" is now proposed as a full-fledged diagnostic category for DSM-5. The existing literature of the topic posits that it is a transhistorical psychiatric category and that examples of self-harm can be found from the earliest written records, which is part of the underlying argument for its inclusion in DSM-5. However, how old is self-harm and, indeed, what defines self-harm historically and culturally? Copyright © 2012 by Lippincott Williams & Wilkins.

Yang Z.,Emory University | Zhang N.,University of Massachusetts Amherst
Medical Care | Year: 2014

BACKGROUND: The obesity rate among the elderly long-term care (LTC) residents in the United States is increasing rapidly. However, there is a paucity of research investigating the burden of obesity on LTC and Medicaid financing. The purpose of this study is to fill the knowledge gap by estimating the burden of overweight and obesity on LTC and Medicaid financing. METHODS: Using nationally representative Cost and Use Files of Medicare Current Beneficiary Survey from 1997 to 2005, we used 2-part model and cohort-based simulation to evaluate the effect of overweight and obesity on LTC days and Medicaid expenditures across the lifespan among the current elderly population. Combining the per capita estimates with 2010 census, we project future aggregate burden of obesity on LTC demand and Medicaid cost among baby boomers. RESULTS: Obesity and related chronic diseases lead to higher probability to enter LTC facility in a younger age, more LTC days before death, and higher lifetime LTC cost reimbursed by Medicaid. However, such effect is only statistically significant among women, not significant among men. At the population level, we project that overweight and obesity will induce 1.3 billion or more LTC patient days and $68 billion or more Medicaid costs (in 2012 value) among baby boomers. CONCLUSIONS: Overweight and obesity among the elderly will bring tremendous burden to LTC providers and Medicaid. Policy makers should keep the burden of obesity on LTC in mind when planning LTC and Medicaid policy reform. Copyright © 2014 by Lippincott Williams & Wilkins.

Lutz S.,Emory University
Science | Year: 2010

First-principles design and directed evolution expand the role of enzymes in chemical synthesis.

Padilla-Parra S.,Emory University | Tramier M.,French National Center for Scientific Research | Tramier M.,University of Rennes 1
BioEssays | Year: 2012

New imaging methodologies in quantitative fluorescence microscopy, such as Förster resonance energy transfer (FRET), have been developed in the last few years and are beginning to be extensively applied to biological problems. FRET is employed for the detection and quantification of protein interactions, and of biochemical activities. Herein, we review the different methods to measure FRET in microscopy, and more importantly, their strengths and weaknesses. In our opinion, fluorescence lifetime imaging microscopy (FLIM) is advantageous for detecting inter-molecular interactions quantitatively, the intensity ratio approach representing a valid and straightforward option for detecting intra-molecular FRET. Promising approaches in single molecule techniques and data analysis for quantitative and fast spatio-temporal protein-protein interaction studies open new avenues for FRET in biological research. © 2012 WILEY Periodicals, Inc.

Parr L.A.,Emory University
Frontiers in Behavioral Neuroscience | Year: 2014

There are currently no drugs approved for the treatment of social deficits associated with autism spectrum disorders (ASD). One hypothesis for these deficits is that individuals with ASD lack the motivation to attend to social cues because those cues are not implicitly rewarding. Therefore, any drug that could enhance the rewarding quality of social stimuli could have a profound impact on the treatment of ASD, and other social disorders. Oxytocin (OT) is a neuropeptide that has been effective in enhancing social cognition and social reward in humans. The present study examined the ability of OT to selectively enhance learning after social compared to nonsocial reward in rhesus monkeys, an important species for modeling the neurobiology of social behavior in humans. Monkeys were required to learn an implicit visual matching task after receiving either intranasal (IN) OT or Placebo (saline). Correct trials were rewarded with the presentation of positive and negative social (play faces/threat faces) or nonsocial (banana/cage locks) stimuli, plus food. Incorrect trials were not rewarded. Results demonstrated a strong effect of socially reinforced learning, monkeys’ performed significantly better when reinforced with social vs. nonsocial stimuli. Additionally, socially-reinforced learning was significantly better and occurred faster after IN-OT compared to placebo treatment. Performance in the IN-OT, but not Placebo, condition was also significantly better when the reinforcement stimuli were emotionally positive compared to negative facial expressions. These data support the hypothesis that OT may function to enhance prosocial behavior in primates by increasing the rewarding quality of emotionally positive, social compared to emotionally negative or nonsocial images. These data also support the use of the rhesus monkey as a model for exploring the neurobiological basis of social behavior and its impairment. © 2014 Parr.

Green V.L.,Emory University
Obstetrics and Gynecology Clinics of North America | Year: 2013

Today breast cancer remains a major public health problem, although reducing its risk is now an achievable medical objective. Risk-assessment models may be used in estimating a woman's risk for developing breast cancer and to direct suitable candidates for preventive therapy. Researchers are attempting to enhance individualized risk assessment through incorporation of phenotypic biomarkers. Individual selective estrogen receptor modulators have been approved for breast cancer risk reduction, and other drug categories are being studied. It is critical that obstetrician-gynecologists be familiar with the evolving science of the risk assessment of breast cancer as well as interventional and surveillance strategies. © 2013 Elsevier Inc.

Hanna-Pladdy B.,Emory University | Gajewski B.,University of Kansas Medical Center
Frontiers in Human Neuroscience | Year: 2012

Studies evaluating the impact of modifiable lifestyle factors on cognition offer potential insights into sources of cognitive aging variability. Recently, we reported an association between extent of musical instrumental practice throughout the life span (greater than 10 years) on preserved cognitive functioning in advanced age. These findings raise the question of whether there are training-induced brain changes in musicians that can transfer to non-musical cognitive abilities to allow for compensation of age-related cognitive declines. However, because of the relationship between engagement in general lifestyle activities and preserved cognition, it remains unclear whether these findings are specifically driven by musical training or the types of individuals likely to engage in greater activities in general. The current study controlled for general activity level in evaluating cognition between musicians and nomusicians. Also, the timing of engagement (age of acquisition, past versus recent) was assessed in predictive models of successful cognitive aging. Seventy age and education matched older musicians (>10 years) and non-musicians (ages 59-80) were evaluated on neuropsychological tests and general lifestyle activities. Musicians scored higher on tests of phonemic fluency, verbal working memory, verbal immediate recall, visuospatial judgment, and motor dexterity, but did not differ in other general leisure activities. Partition analyses were conducted on significant cognitive measures to determine aspects of musical training predictive of enhanced cognition. The first partition analysis revealed education best predicted visuospatial functions in musicians, followed by recent musical engagement which offset low education. In the second partition analysis, early age of musical acquisition (<9 years) predicted enhanced verbal working memory in musicians, while analyses for other measures were not predictive. Recent and past musical activity, but not general lifestyle activities, predicted variability across both verbal and visuospatial domains in aging. These findings are suggestive of different use-dependent adaptation periods depending on cognitive domain. Furthermore, they imply that early age of musical acquisition, sustained and maintained during advanced age, may enhance cognitive functions and buffer age and education influences. © 2012 Hanna-Pladdy and Gajewski.

Stein D.G.,Emory University
Dialogues in Clinical Neuroscience | Year: 2011

Although progesterone is critical to a healthy pregnancy, it is now known to have other important functions as well. Recent research demonstrates that this hormone is also a potent neurosteroid that can protect damaged cells in the central and peripheral nervous systems and has rapid actions that go well beyond its effects on the classical intranuclear progesterone receptor. Based on years of preclinical research demonstrating its safety and effectiveness in animal models of central nervous system injury the hormone was recently tested in two Phase II clinical trials for traumatic brain injury (TBI). A US National Institutes of Health-sponsored, nationwide Phase III clinical trial is now evaluating progesterone for moderate-to-severe TBI in 1200 patients. An industry-sponsored Phase III international trial is also under way, and planning for a trial using progesterone to treat pediatric brain injury has begun. Preclinical data suggest that progesterone may also be effective in stroke and some neurodegenerative disorders.

Davis M.,Emory University
Dialogues in Clinical Neuroscience | Year: 2011

Based primarily on studies that employ Pavlovian fear conditioning, extinction of conditioned fear has been found to be mediated by N-methyl-D-aspartate (NMDA) receptors in the amygdala and medial prefrontal cortex. This led to the discovery that an NMDA partial agonist, D-cycloserine, could facilitate fear extinction when given systemically or locally into the amygdala. Because many forms of cognitive behavioral therapy depend on fear extinction, this led to the successful use of D-cycloserine as an adjunct to psychotherapy in patients with so-called simple phobias (fear of heights), social phobia, obsessive-compulsive behavior, and panic disorder. Data in support of these conclusions are reviewed, along with some of the possible limitations of D-cycloserine as an adjunct to psychotherapy. © 2011, LLS SAS.

Katsikis P.D.,Drexel University | Mueller Y.M.,Drexel University | Villinger F.,Emory University
PLoS Pathogens | Year: 2011

Cytokines play a central role in the pathogenesis of many diseases, including HIV infection. However, the role of the cytokine network in early HIV infection is only now starting to be elucidated. A number of studies conducted in recent years have indicated that cytokines of the acute/early stages of HIV and SIV infection can impact viral set-point months later, and this is of critical importance since viral set-point during chronic HIV infection affects virus transmission and disease progression. This raises the question whether modulating the cytokine environment during acute/early HIV infection can be a target for novel approaches to develop a vaccine and therapeutics. In this review we focus on the kinetics and function of cytokines during acute HIV and SIV infection and how these may impact viral set-point. We also discuss unresolved questions that are essential for our understanding of the role of acute infection cytokines in HIV infection and that, if answered, may suggest novel therapeutic and vaccine strategies to control the worldwide HIV pandemic. © 2011 Katsikis et al.

Brenchley J.M.,U.S. National Institutes of Health | Paiardini M.,Emory University
Blood | Year: 2011

The host immune system is profoundly affected during the acute phase of progressive immunodeficiency lentiviral infections. Studies of these alterations have been quite restricted in humans because of the limited availability of samples from acutely HIV-infected persons. Therefore, numerous studies have turned attention to nonhuman primate models. Specifically, SIV-infected rhesus macaques (RMs) have been informative for understanding the pathogenesis of HIV infection in humans. Indeed, advantages of the nonhuman primate model include the ability to study the very early events after infection and the ability to retrieve copious amounts of tissues. In addition, nonhuman primates allow for comparative studies between non-natural and natural hosts for SIV, in which SIV infection results in progression, or not, to AIDS, respectively. Although SIV infection of RM is the best model for HIV infection, the immunologic and/or virologic phenomena in SIV-infected RM do not always reflect those seen in HIV-infected humans. Here virologic and immunologic aspects of acute HIV infection of humans and SIV infection of Asian and African nonhuman primates are discussed and compared in relation to how these aspects relate to disease progression. © 2011 by The American Society of Hematology.

Bianchi E.C.,Emory University
Psychological Science | Year: 2014

Despite widespread interest in narcissism, relatively little is known about the conditions that encourage or dampen it. Drawing on research showing that macroenvironmental conditions in emerging adulthood can leave a lasting imprint on attitudes and behaviors, I argue that people who enter adulthood during recessions are less likely to be narcissistic later in life than those who come of age in more prosperous times. Using large samples of American adults, Studies 1 and 2 showed that people who entered adulthood during worse economic times endorsed fewer narcissistic items as older adults. Study 3 extended these findings to a behavioral manifestation of narcissism: the relative pay of CEOs. CEOs who came of age in worse economic times paid themselves less relative to other top executives in their firms. These findings suggest that macroenvironmental experiences at a critical life stage can have lasting implications for how unique, special, and deserving people believe themselves to be. © The Author(s) 2014.

Cahn Z.,Emory University
Journal of Public Health Policy | Year: 2013

France is deciding how to regulate electronic cigarettes. I first consider the French approach and how it contrasts with other attempts at electronic cigarette regulation globally. Next, I critique the individual elements of the French proposal. The overall approach taken by France is a positive development, but banning indoor use appears unnecessary and banning advertising may be counterproductive. © 2013 Macmillan Publishers Ltd.

Gerardo N.M.,Emory University
PLoS Biology | Year: 2015

Many organisms harbor microbial associates that have profound impacts on host traits. The phenotypic effect of symbionts on their hosts may include changes in development, reproduction, longevity, and defense against natural enemies. Determining the consequences of associating with a microbial symbiont requires experimental comparison of hosts with and without symbionts. Then, determining the mechanism by which symbionts alter these phenotypes can involve genomic, genetic, and evolutionary approaches; however, many host-associated symbionts are not amenable to genetic approaches that require cultivation of the microbe outside the host. In the current issue of PLOS Biology, Chrostek and Teixeira highlight an elegant approach to studying functional mechanisms of symbiont-conferred traits. They used directed experimental evolution to select for strains of Wolbachia wMelPop (a bacterial symbiont of fruit flies) that differed in copy number of a region of the genome suspected to underlie virulence. Copy number evolved rapidly when under selection, and wMelPop strains with more copies of the region shortened the lives of their Drosophila hosts more than symbionts with fewer copies. Interestingly, the wMelPop strains with more copies also increase host resistance to viruses compared to symbionts with fewer copies. Their study highlights the power of exploiting alternative approaches when elucidating the functional impacts of symbiotic associations. © 2015 Nicole M. Gerardo.

Differential assessment of trunk wounds is a critical element of their effective management. In reviewing the pathology and typical presentation for pressure necrosis, IAD, and ITD, four factors provide guidance in differential assessment: location, depth, characteristics, and exposure. Pressure ulcers are full-thickness lesions located over bony prominences or under medical devices. IAD and ITD are superficial lesions that occur in areas exposed to urine and/or stool (IAD) or trapped perspiration (ITD). Undermining and tunneling are common features of pressure ulcers, but never occur with IAD or ITD. Similarly, pressure ulcers frequently present with tissue necrosis, whereas ITD and IAD are commonly associated with maceration of the surrounding skin.

Jacobson T.A.,Emory University
Mayo Clinic Proceedings | Year: 2013

Elevated lipoprotein(a) (Lp[a]) is a causal genetic risk factor for cardiovascular disease. To determine if current evidence supports both screening and treatment for elevated Lp(a) in high-risk patients, an Englishlanguage search of PubMed and MEDLINE was conducted. In population studies, there is a continuous association between Lp(a) concentrations and cardiovascular risk, with synergistic effects when low-density lipoprotein (LDL) is also elevated. Candidates for Lp(a) screening include patients with a personal or family history of premature cardiovascular disease, familial hypercholesterolemia, recurrent cardiovascular events, or inadequate LDL cholesterol (LDL-C) responses to statins. Given the comparative strength of clinical evidence, reducing LDL-C to the lowest attainable value with a high-potency statin should be the primary focus of lipid-modifying therapies. If the Lp(a) level is 30 mg/dL or higher in a patient who has the aforementioned characteristics plus residual LDL-C elevations (≥70-100 mg/dL) despite maximum-potency statins or combination statin therapy, the clinician may consider adding niacin (up to 2 g/d). If, after these interventions, the patient has progressive coronary heart disease (CHD) or LDL-C levels of 160-200 mg/dL or higher, LDL apheresis should be contemplated. Although Lp(a) is a major causal risk factor for CHD, no currently available controlled studies have suggested that lowering it through either pharmacotherapy or LDL apheresis specifically and significantly reduces coronary risk. Further research is needed to (1) optimize management in order to reduce CHD risk associated with elevated Lp(a) and (2) determine what other intermediate- or high-risk groups might benefit from Lp(a) screening. © 2013 Mayo Foundation for Medical Education and Research.

Wang X.H.,Emory University
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2013

PURPOSE OF REVIEW: To understand the impact of microRNA on myogenesis and muscle wasting in order to provide valuable information for clinical investigation. RECENT FINDINGS: Muscle wasting increases the risk of morbidity/mortality in primary muscle diseases, secondary muscle disorders and elderly population. Muscle mass is controlled by several different signalling pathways. Insulin-like growth factor/PI3K/Akt is a positive signalling pathway, as it increases muscle mass by increasing protein synthesis and decreasing protein degradation. This pathway is directly and/or indirectly downregulated by miR-1, miR-133, miR-206 or miR-125b, and upregulated by miR-23a or miR-486. Myostatin and the transforming growth factor-β signalling pathway are negative regulators that cause muscle wasting. An increase of miR-27 reduces myostatin and increases muscle cell proliferation. Muscle regeneration capacity also plays a significant role in the regulation of muscle mass. This review comprehensively describes the effect of microRNA on myoblasts proliferation and differentiation, and summarizes the varied influences of microRNA on different muscle atrophy. SUMMARY: Growing evidence indicates that microRNAs significantly impact muscle growth, regeneration and metabolism. MicroRNAs have a great potential to become diagnostic and/or prognostic markers, therapeutic agents and therapeutic targets. © 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.

Plantinga L.C.,Emory University
Nephrologie et Therapeutique | Year: 2013

Background: Socio-economic status (SES) may be conceptualized as an individual's position in society, as determined by their income, occupation, education, wealth, and housing situation. This review summarizes the current literature regarding associations of these markers of SES with both chronic kidney disease (CKD) and associated poor outcomes. Methods: Literature searches were conducted in the US National Library of Medicine, National Institutes of Health, PubMed database using the search terms "chronic kidney disease" and "chronic renal insufficiency," combined with "socio-economic status," "income," "occupation," "employment," "education," "social class," "wealth," and "housing." Articles not in the English language, using nonhuman subjects, or primarily concerning subjects with ESRD or acute kidney injury were excluded. Results: Income is the most-studied aspect of SES in relation to CKD, but there is increasing literature involving occupation and education as well. Additionally, the associations of CKD and its outcomes with area-level and life course SES are both burgeoning areas of research. There are several research areas that remain mostly unexplored, including the roles of wealth and housing in defining SES-related risk in CKD. Additionally, none have explored the relative utility of composite versus individual indicators of SES in predicting risk of CKD and outcomes. Conclusion: Given the overwhelming evidence that SES plays an important role in the development and progression of disease, the development and testing of more targeted interventions should be a top priority in CKD research. Continuing examination of these factors, with increased rigor and focus on potentially modifiable intermediate pathways, is needed. © 2013 Publié par Elsevier Masson SAS pour I'Association Société de néphrologie.

Jones D.P.,Emory University
Journal of Internal Medicine | Year: 2010

Living systems have three major types of cell signalling systems that are dependent upon high-energy chemicals, redox environment and transmembranal ion-gating mechanisms. Development of integrated systems biology descriptions of cell signalling require conceptual models incorporating all three. Recent advances in redox biology show that thiol-disulphide redox systems are regulated under dynamic, nonequilibrium conditions, progressively oxidized with the life cycle of cells and distinct in terms of redox potentials amongst subcellular compartments. This article uses these observations as a basis to distinguish 'redox-sensing' mechanisms, which are more global biologic redox control mechanisms, from 'redox signalling', which involves conveyance of discrete activating or inactivating signals. Both redox sensing and redox signalling use sulphur switches, especially cysteine (Cys) residues in proteins which are sensitive to reversible oxidation, nitrosylation, glutathionylation, acylation, sulfhydration or metal binding. Unlike specific signalling mechanisms, the redox-sensing mechanisms provide means to globally affect the rates and activities of the high-energy, ion-gating and redox-signalling systems by controlling sensitivity, distribution, macromolecular interactions and mobility of signalling proteins. Effects mediated through Cys residues not directly involved in signalling means redox-sensing control can be orthogonal to the signalling mechanisms. This provides a capability to integrate signals according to cell cycle and physiologic state without fundamentally altering the signalling mechanisms. Recent findings that thiol-disulphide pools in humans are oxidized with age, environmental exposures and disease risk suggest that redox-sensing thiols could provide a central mechanistic link in disease development and progression. © 2010 The Association for the Publication of the Journal of Internal Medicine.

Clustered, Regularly Interspaced Short Palindromic Repeats (CRISPR) abound in the genomes of almost all archaebacteria and nearly half the eubacteria sequenced. Through a genetic interference mechanism, bacteria with CRISPR regions carrying copies of the DNA of previously encountered phage and plasmids abort the replication of phage and plasmids with these sequences. Thus it would seem that protection against infecting phage and plasmids is the selection pressure responsible for establishing and maintaining CRISPR in bacterial populations. But is it? To address this question and provide a framework and hypotheses for the experimental study of the ecology and evolution of CRISPR, I use mathematical models of the population dynamics of CRISPR-encoding bacteria with lytic phage and conjugative plasmids. The results of the numerical (computer simulation) analysis of the properties of these models with parameters in the ranges estimated for Escherichia coli and its phage and conjugative plasmids indicate: (1) In the presence of lytic phage there are broad conditions where bacteria with CRISPR-mediated immunity will have an advantage in competition with non-CRISPR bacteria with otherwise higher Malthusian fitness. (2) These conditions for the existence of CRISPR are narrower when there is envelope resistance to the phage. (3) While there are situations where CRISPR-mediated immunity can provide bacteria an advantage in competition with higher Malthusian fitness bacteria bearing deleterious conjugative plasmids, the conditions for this to obtain are relatively narrow and the intensity of selection favoring CRISPR weak. The parameters of these models can be independently estimated, the assumption behind their construction validated, and the hypotheses generated from the analysis of their properties tested in experimental populations of bacteria with lytic phage and conjugative plasmids. I suggest protocols for estimating these parameters and outline the design of experiments to evaluate the validity of these models and test these hypotheses.

Dhabaan A.,Emory University
Journal of applied clinical medical physics / American College of Medical Physics | Year: 2012

Frameless radiosurgery is an attractive alternative to the framed procedure if it can be performed with comparable precision in a reasonable time frame. Here, we present a positioning approach for frameless radiosurgery based on in-room volumetric imaging coupled with an advanced six-degrees-of-freedom (6 DOF) image registration technique which avoids use of a bite block. Patient motion is restricted with a custom thermoplastic mask. Accurate positioning is achieved by registering a cone-beam CT to the planning CT scan and applying all translational and rotational shifts using a custom couch mount. System accuracy was initially verified on an anthropomorphic phantom. Isocenters of delineated targets in the phantom were computed and aligned by our system with an average accuracy of 0.2 mm, 0.3 mm, and 0.4 mm in the lateral, vertical, and longitudinal directions, respectively. The accuracy in the rotational directions was 0.1°, 0.2°, and 0.1° in the pitch, roll, and yaw, respectively. An additional test was performed using the phantom in which known shifts were introduced. Misalignments up to 10 mm and 3° in all directions/rotations were introduced in our phantom and recovered to an ideal alignment within 0.2 mm, 0.3 mm, and 0.4 mm in the lateral, vertical, and longitudinal directions, respectively, and within 0.3° in any rotational axis. These values are less than couch motion precision. Our first 28 patients with 38 targets treated over 63 fractions are analyzed in the patient positioning phase of the study. Mean error in the shifts predicted by the system were less than 0.5 mm in any translational direction and less than 0.3° in any rotation, as assessed by a confirmation CBCT scan. We conclude that accurate and efficient frameless radiosurgery positioning is achievable without the need for a bite block by using our 6DOF registration method. This system is inexpensive compared to a couch-based 6 DOF system, improves patient comfort compared to systems that utilize a bite block, and is ideal for the treatment of pediatric patients with or without general anesthesia, as well as of patients with dental issues. From this study, it is clear that only adjusting for 4 DOF may, in some cases, lead to significant compromise in PTV coverage. Since performing the additional match with 6 DOF in our registration system only adds a relatively short amount of time to the overall process, we advocate making the precise match in all cases.

Lumey L.H.,Columbia University | Stein A.D.,Emory University | Susser E.,Columbia University | Susser E.,New York State Psychiatric Institute
Annual Review of Public Health | Year: 2011

We review human studies on the relation between acute exposures to prenatal famine and adult physical and mental health. These studies are observational and include exposures to a famine environment by natural or man-made causes or, more commonly, from the interplay between natural and human factors. These natural experiments provide an opportunity to examine long-term outcomes after famine exposures by comparing exposed and nonexposed individuals. The studies show consistent associations between prenatal famine and adult body size, diabetes, and schizophrenia. For other measures of adult health, findings are less robust. A relation between prenatal famine and some reported epigenetic changes may provide a potential mechanism to explain specific associations. Much progress can be made if current separate studies are further analyzed with comparable definitions of exposures and outcomes and using common analytic strategies. © 2011 by Annual Reviews. rights reserved.

Schelbert E.B.,University of Pittsburgh | Fonarow G.C.,University of California at Los Angeles | Bonow R.O.,Northwestern University | Butler J.,Emory University | Gheorghiade M.,Northwestern University
Journal of the American College of Cardiology | Year: 2014

New therapeutic targets, agents, and strategies are needed to prevent and treat heart failure (HF) after a decade of failed research efforts to improve long-term patient outcomes, especially in patients after hospitalization for HF. Conceptually, an accurate assessment of left ventricular structure is an essential step in the development of novel therapies because heterogeneous pathophysiologies underlie chronic HF and hospitalization for HF. Improved left ventricular characterization permits the identification and targeting of the intrinsic fundamental disease-modifying pathways that culminate in HF. Interstitial heart disease is one such pathway, characterized by extracellular matrix (ECM) expansion that is associated with mechanical, electrical, and vasomotor dysfunction and adverse outcomes. Previous landmark trials that appear to treat interstitial heart disease were effective in improving outcomes. Advances in cardiovascular magnetic resonance now enable clinicians and researchers to assess the interstitium and quantify ECM expansion using extracellular volume fraction measures and other derangements in cardiovascular structure. These capabilities may provide a mechanistic platform to advance understanding of the role of the ECM, foster the development of novel therapeutics, and target specific disease-modifying pathways intrinsic to the ventricle. Refocusing on the interstitium may potentially improve care through the identification and targeted treatment of key patient subgroups. © 2014 by the American College of Cardiology Foundation.

Proper control of confounding due to population stratification is crucial for valid analysis of case-control association studies. Fine matching of cases and controls based on genetic ancestry is an increasingly popular strategy to correct for such confounding, both in genome-wide association studies (GWASs) as well as studies that employ next-generation sequencing, where matching can be used when selecting a subset of participants from a GWAS for rare-variant analysis. Existing matching methods match on measures of genetic ancestry that combine multiple components of ancestry into a scalar quantity. However, we show that including nonconfounding ancestry components in a matching criterion can lead to inaccurate matches, and hence to an improper control of confounding. To resolve this issue, we propose a novel method that assigns cases and controls to matched strata based on the stratification score (Epstein et al. [2007] Am J Hum Genet 80:921-930), which is the probability of disease given genomic variables. Matching on the stratification score leads to more accurate matches because case participants are matched to control participants who have a similar risk of disease given ancestry information. We illustrate our matching method using the African-American arm of the GAIN GWAS of schizophrenia. In this study, we observe that confounding due to stratification can be resolved by our matching approach but not by other existing matching procedures. We also use simulated data to show our novel matching approach can provide a more appropriate correction for population stratification than existing matching approaches. © 2012 Wiley Periodicals, Inc.

Kobrynski L.,Emory University
Current Opinion in Allergy and Clinical Immunology | Year: 2015

Purpose of review: Newborn screening for severe combined immune deficiency (SCID) has been implemented in more than half of the states in the United States. Despite the success of these programs, numerous challenges remain for implementing newborn screening. The present review will focus on technical, programmatic, and political aspects pertinent to newborn screening for SCID. Recent findings: Recent data from newborn screening in 11 U.S. programs suggest that the birth prevalence of SCID is higher than previous estimates. In addition, a large number of other conditions causing T-cell lymphopenia have been detected. Several European countries have initiated pilot screening for SCID. Significant cost savings for treatment of infants with SCID detected at birth, compared with later in life, has been demonstrated. Published evidence of the favorable cost-benefit ratio for screening supports implementation of universal SCID newborn screening. Summary: SCID fulfills criteria for a condition that should be included in routine newborn screening. Data presented from multiple newborn screening programs in the United States and Europe have shown that high throughput screening of all newborns is cost-effective. Screening improves early detection of this lifethreatening condition and follow-up studies have shown a clear improvement in survival for early treatment. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Schinazi R.,Emory University | Halfon P.,Hopital Europeen and Laboratoire Alphabio Marseille | Marcellin P.,University Paris Diderot | Asselah T.,University Paris Diderot
Liver International | Year: 2014

For HCV infection, there have been major advancements during last several years with large numbers of ongoing trials with various direct-acting antivirals (DAA) showing high potency, favourable tolerability profile, higher barrier to resistance, shortened treatment duration, all oral regimen, pan-genotypic, fewer drug interactions and reduced pill burden. By 2014, several DAAs are anticipated to complete successful phase III trials and will be commercially available. Initially, a wave of IFN-based regimen (sofosbuvir, faldaprevir and simeprevir) will be available for treatment of HCV genotype 1. In the near future, combination of antiviral agents with additive potency that lack cross-resistance with good safety profile will likely be the new recommended regimens, making HCV, the first chronic viral infection to be eradicated worldwide with a finite duration of combination DAA therapy without IFN or ribavirin. The aim of this review was to summarize the results obtained from recent DAA combination studies without IFN. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

De Waal F.B.M.,Emory University
Behaviour | Year: 2014

The evolution of behavior is sometimes considered irrelevant to the issue of human morality, since it lacks the normative character of morality ('ought'), and consist entirely of descriptions of how things are or came about ('is'). Evolved behavior, including that of other animals, is not entirely devoid of normativity, however. Defining normativity as adherence to an ideal or standard, there is ample evidence that animals treat their social relationships in this manner. In other words, they pursue social values. Here I review evidence that nonhuman primates actively try to preserve harmony within their social network by, e.g., reconciling after conflict, protesting against unequal divisions, and breaking up fights amongst others. In doing so, they correct deviations from an ideal state. They further show emotional self-control and anticipatory conflict resolution in order to prevent such deviations. Recognition of the goal-orientation and normative character of animal social behavior permits us to partially bridge the is/ought divide erected in relation to human moral behavior. © 2014 Koninklijke Brill NV, Leiden, The Netherlands.

Budnitz D.S.,Centers for Disease Control and Prevention | Lovegrove M.C.,Centers for Disease Control and Prevention | Shehab N.,Centers for Disease Control and Prevention | Richards C.L.,Centers for Disease Control and Prevention | Richards C.L.,Emory University
New England Journal of Medicine | Year: 2011

Background: Adverse drug events are important preventable causes of hospitalization in older adults. However, nationally representative data on adverse drug events that result in hospitalization in this population have been limited. Methods: We used adverse-event data from the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project (2007 through 2009) to estimate the frequency and rates of hospitalization after emergency department visits for adverse drug events in older adults and to assess the contribution of specific medications, including those identified as high-risk or potentially inappropriate by national quality measures. Results: On the basis of 5077 cases identified in our sample, there were an estimated 99,628 emergency hospitalizations (95% confidence interval [CI], 55,531 to 143,724) for adverse drug events in U.S. adults 65 years of age or older each year from 2007 through 2009. Nearly half of these hospitalizations were among adults 80 years of age or older (48.1%; 95% CI, 44.6 to 51.6). Nearly two thirds of hospitalizations were due to unintentional overdoses (65.7%; 95% CI, 60.1 to 71.3). Four medications or medication classes were implicated alone or in combination in 67.0% (95% CI, 60.0 to 74.1) of hospitalizations: warfarin (33.3%), insulins (13.9%), oral antiplatelet agents (13.3%), and oral hypoglycemic agents (10.7%). High-risk medications were implicated in only 1.2% (95% CI, 0.7 to 1.7) of hospitalizations. Conclusions: Most emergency hospitalizations for recognized adverse drug events in older adults resulted from a few commonly used medications, and relatively few resulted from medications typically designated as high-risk or inappropriate. Improved management of antithrombotic and antidiabetic drugs has the potential to reduce hospitalizations for adverse drug events in older adults. Copyright © 2011 Massachusetts Medical Society.

Kingston D.G.I.,Virginia Polytechnic Institute and State University | Snyder J.P.,Emory University
Accounts of Chemical Research | Year: 2014

ConspectusPaclitaxel (PTX), introduced into the clinic in 1991, has revealed itself as an effective antimicrotubule drug for treatment of a range of otherwise intractable cancers. Along with docetaxel (DTX) and in combination with other agents such as cisplatin, it has proven to be a first-line therapy. Unfortunately, PTX and DTX carry severe liabilities such as debilitating side effects, rapid onset of resistance, and rather complex molecular structures offering substantial challenges to ease of synthetic manipulation. Consequently, the past 15 years has witnessed many efforts to synthesize and test highly modified analogs based on intuitive structural similarity relationships with the PTX molecular skeleton, as well as efforts to mimic the conformational profile of the ligand observed in the macromolecular tubulin-PTX complex.Highly successful improvements in potency, up to 50-fold increases in IC50, have been achieved by constructing bridges between distal centers in PTX that imitate the conformer of the electron crystallographic binding pose. Much less successful have been numerous attempts to truncate PTX by replacing the baccatin core with simpler moieties to achieve PTX-like potencies and applying a wide range of flexible synthesis-based chemistries. Reported efforts, characterized by a fascinating array of baccatin substitutes, have failed to surpass the bioactivities of PTX in both microtubule disassembly assays and cytotoxicity measurements against a range of cell types. Most of the structures retain the main elements of the PTX C13 side chain, while seeking a smaller rigid bicycle as a baccatin replacement adorned with substituents to mimic the C2 benzoyl moiety and the oxetane ring.We surmise that past studies have been handicapped by solubility and membrane permeability issues, but primarily by the existence of an expansive taxane binding pocket and the discrepancy in molecular size between PTX and the pruned analogs. A number of these molecules offer molecular volumes 50-60% that of PTX, fewer contacts with the tubulin protein, severe mismatches with the PTX pharmacophore, lessened capacity to dispel binding site waters contributing to δGbind, and unanticipated binding poses. The latter is a critical drawback if molecular designs of simpler PTX structures are based on a perceived or known PTX binding conformation. We conclude that design and synthesis of a highly cytotoxic tubulin-Assembly agent based on the paclitaxel pharmacophore remains an unsolved challenge, but one that can be overcome by focus on the architecture of the taxane binding site independent of the effective, but not unique, hand-in-glove match represented by the PTX-tubulin complex. © 2014 American Chemical Society.

Fleischer C.C.,Georgia Institute of Technology | Fleischer C.C.,Emory University | Payne C.K.,Georgia Institute of Technology
Accounts of Chemical Research | Year: 2014

ConspectusThe use of nanoparticles (NPs) in biology and medicine requires a molecular-level understanding of how NPs interact with cells in a physiological environment. A critical difference between well-controlled in vitro experiments and in vivo applications is the presence of a complex mixture of extracellular proteins. It has been established that extracellular serum proteins present in blood will adsorb onto the surface of NPs, forming a "protein corona". Our goal was to understand how this protein layer affected cellular-level events, including NP binding, internalization, and transport. A combination of microscopy, which provides spatial resolution, and spectroscopy, which provides molecular information, is necessary to probe protein-NP-cell interactions. Initial experiments used a model system composed of polystyrene NPs functionalized with either amine or carboxylate groups to provide a cationic or anionic surface, respectively. Serum proteins adsorb onto the surface of both cationic and anionic NPs, forming a net anionic protein-NP complex. Although these protein-NP complexes have similar diameters and effective surface charges, they show the exact opposite behavior in terms of cellular binding. In the presence of bovine serum albumin (BSA), the cellular binding of BSA-NP complexes formed from cationic NPs is enhanced, whereas the cellular binding of BSA-NP complexes formed from anionic NPs is inhibited. These trends are independent of NP diameter or cell type. Similar results were obtained for anionic quantum dots and colloidal gold nanospheres. Using competition assays, we determined that BSA-NP complexes formed from anionic NPs bind to albumin receptors on the cell surface. BSA-NP complexes formed from cationic NPs are redirected to scavenger receptors. The observation that similar NPs with identical protein corona compositions bind to different cellular receptors suggested that a difference in the structure of the adsorbed protein may be responsible for the differences in cellular binding of the protein-NP complexes. Circular dichroism spectroscopy, isothermal titration calorimetry, and fluorescence spectroscopy show that the structure of BSA is altered following incubation with cationic NPs, but not anionic NPs. Single-particle-tracking fluorescence microscopy was used to follow the cellular internalization and transport of protein-NP complexes. The single particle-tracking experiments show that the protein corona remains bound to the NP throughout endocytic uptake and transport. The interaction of protein-NP complexes with cells is a challenging question, as the adsorbed protein corona controls the interaction of the NP with the cell; however, the NP itself alters the structure of the adsorbed protein. A combination of microscopy and spectroscopy is necessary to understand this complex interaction, enabling the rational design of NPs for biological and medical applications. © 2014 American Chemical Society.

Barlett P.F.,Emory University
American Anthropologist | Year: 2011

Campus sustainable food projects recently have expanded rapidly. A review of four components-purchasing goals, academic programs, direct marketing, and experiential learning-shows both intent and capacity to contribute to transformational change toward an alternative food system. The published rationales for campus projects and specific purchasing guidelines join curricular and cocurricular activities to evaluate, disseminate, and legitimize environmental, economic, social justice, and health concerns about conventional food. Emerging new metrics of food service practices mark a potential shift from rhetoric to market clout, and experiential learning builds new coalitions and can reshape relations with food and place. Campus projects are relatively new and their resilience is not assured, but leading projects have had regional, state, and national impact. The emergence of sustainability rankings in higher education and contract-based compliance around purchasing goals suggests that if support continues, higher education's leadership can extend to the broader agrifood system. © 2011 by the American Anthropological Association.

Estrada E.,University of Strathclyde | Hatano N.,University of Tokyo | Benzi M.,Emory University
Physics Reports | Year: 2012

A fundamental problem in the study of complex networks is to provide quantitative measures of correlation and information flow between different parts of a system. To this end, several notions of communicability have been introduced and applied to a wide variety of real-world networks in recent years. Several such communicability functions are reviewed in this paper. It is emphasized that communication and correlation in networks can take place through many more routes than the shortest paths, a fact that may not have been sufficiently appreciated in previously proposed correlation measures. In contrast to these, the communicability measures reviewed in this paper are defined by taking into account all possible routes between two nodes, assigning smaller weights to longer ones. This point of view naturally leads to the definition of communicability in terms of matrix functions, such as the exponential, resolvent, and hyperbolic functions, in which the matrix argument is either the adjacency matrix or the graph Laplacian associated with the network.Considerable insight on communicability can be gained by modeling a network as a system of oscillators and deriving physical interpretations, both classical and quantum-mechanical, of various communicability functions. Applications of communicability measures to the analysis of complex systems are illustrated on a variety of biological, physical and social networks. The last part of the paper is devoted to a review of the notion of locality in complex networks and to computational aspects that by exploiting sparsity can greatly reduce the computational efforts for the calculation of communicability functions for large networks. © 2012 Elsevier B.V.

Stefanovic S.,Duquesne University | Bassell G.J.,Emory University | Mihailescu M.R.,Duquesne University
RNA | Year: 2015

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability caused by the CGG trinucleotide expansion in the 3' -untranslated region of the FMR1 gene on the X chromosome, that silences the expression of the Fragile X mental retardation protein (FMRP). FMRP has been shown to bind to a G-rich region within the PSD-95 mRNA which encodes for the postsynaptic density protein 95 (PSD-95), and together with the microRNA miR-125a, to play an important role in the reversible inhibition of the PSD-95 mRNA translation in neurons. The loss of FMRP in Fmr1 KO mice disables this translation control in the production of the PSD-95 protein. Interestingly, the miR-125a binding site on PSD-95 mRNA is embedded in the G-rich region bound by FMRP and postulated to adopt one or more G quadruplex structures. In this study, we have used different biophysical techniques to validate and characterize the formation of parallel G quadruplex structures and binding of miR-125a to its complementary sequence located within the 3? UTR of PSD-95 mRNA. Our results indicate that the PSD-95 mRNA G-rich region folds into alternate G quadruplex conformations that coexist in equilibrium. miR-125a forms a stable complex with PSD-95 mRNA, as evident by characteristic Watson-Crick base-pairing that coexists with one of the G quadruplex forms, suggesting a novel mechanism for G quadruplex structures to regulate the access of miR-125a to its binding site. © 2014 Stefanovic et al.

Brenchley J.M.,U.S. National Institutes of Health | Silvestri G.,Emory University | Douek D.C.,U.S. National Institutes of Health
Immunity | Year: 2010

Natural hosts for simian immunodeficiency virus (SIV) can be, and are often naturally, infected with species-specific SIVs, but do not develop acquired immunodeficiency syndrome (AIDS). These natural hosts maintain high SIV viral loads, but avoid immunodeficiency. Elucidating the mechanisms that allow natural hosts to coexist with SIV without overt disease may provide crucial information for understanding AIDS pathogenesis. Over the past few years, several key features of natural SIV infections have been described in studies conducted predominantly in sooty mangabeys (SMs), African green monkeys (AGMs), and mandrills. Natural SIV hosts are able to avoid the chronic, generalized immune system activation that is associated with disease progression in HIV-infected individuals and are known to downmodulate the expression of the receptors for SIV. In this perspective we propose that a critical factor that differentiates nonprogressive from progressive HIV or SIV infection is the maintenance of T cell immune competence in the face of a virus that infects and kills CD4+ T cells. Elucidation of the mechanisms underlying the preservation of immune function during and after the acute phase of natural SIV infection may lead to the design of novel preventive and therapeutic interventions for treatment of chronic HIV infection. © 2010 Elsevier Inc.

Levi M.,University of Amsterdam | Levy J.H.,Emory University | Andersen H.F.,Novo Nordisk AS | Truloff D.,Novo Nordisk AS
New England Journal of Medicine | Year: 2010

BACKGROUND: The use of recombinant activated factor VII (rFVIIa) on an off-label basis to treat life-threatening bleeding has been associated with a perceived increased risk of thromboembolic complications. However, data from placebo-controlled trials are needed to properly assess the thromboembolic risk. To address this issue, we evaluated the rate of thromboembolic events in all published randomized, placebo-controlled trials of rFVIIa used on an off-label basis. METHODS: We analyzed data from 35 randomized clinical trials (26 studies involving patients and 9 studies involving healthy volunteers) to determine the frequency of thromboembolic events. The data were pooled with the use of random-effects models to calculate the odds ratios and 95% confidence intervals. RESULTS: Among 4468 subjects (4119 patients and 349 healthy volunteers), 498 had thromboembolic events (11.1%). Rates of arterial thromboembolic events among all 4468 subjects were higher among those who received rFVIIa than among those who received placebo (5.5% vs. 3.2%, P = 0.003). Rates of venous thromboembolic events were similar among subjects who received rFVIIa and those who received placebo (5.3% vs. 5.7%). Among subjects who received rFVIIa, 2.9% had coronary arterial thromboembolic events, as compared with 1.1% of those who received placebo (P = 0.002). Rates of arterial thromboembolic events were higher among subjects who received rFVIIa than among subjects who received placebo, particularly among those who were 65 years of age or older (9.0% vs. 3.8%, P = 0.003); the rates were especially high among subjects 75 years of age or older (10.8% vs. 4.1%, P = 0.02). CONCLUSIONS: In a large and comprehensive cohort of persons in placebo-controlled trials of rFVIIa, treatment with high doses of rFVIIa on an off-label basis significantly increased the risk of arterial but not venous thromboembolic events, especially among the elderly. (Funded by Novo Nordisk.) Copyright © 2010 Massachusetts Medical Society.

Blue S.N.,Emory University
Journal of the International Neuropsychological Society : JINS | Year: 2013

This study traces the development of spatial memory abilities in monkeys and reports the effects of selective neonatal hippocampal lesions on performance across development. Two different versions of the visual paired-comparison (VPC) task were used. The VPC-Spatial-Location task tested memory for object-locations that could be solved using an egocentric spatial frame of reference and the VPC-Object-In-Place task taxed memory for spatial relations using an allocentric reference frame. Eleven rhesus macaques (6 neonatal sham-operated controls and 5 with neonatal neurotoxic hippocampal lesions) were tested on both tasks as infants (8 months), juveniles (18 months), and adults (5-6 years). Memory for spatial locations was present by 18 months of age, whereas memory for object-place relations was present only in adulthood. Also, neonatal hippocampal lesions delayed the emergence of memory for spatial locations and abolished memory for object-place associations, particularly in animals that had sustained extensive and bilateral hippocampal lesions. The differential developmental time course of spatial memory functions and of the effects of neonatal hippocampal lesions on these functions are discussed in relation to morphological maturation of the medial temporal lobe structures in monkeys. Implications of the findings for the neural basis of spatial memory development in humans are also considered.

Diazgranados C.A.,Emory University
American Journal of Infection Control | Year: 2012

Background: The impact of antimicrobial audit and feedback on outcomes of critically ill adults is unclear. Methods: A prospective study was performed in the intensive care units (ICU) of a public hospital in Atlanta, GA. Critically ill adults receiving empiric imipenem or piperacillin-tazobactam were eligible. Outcomes for 3 periods were compared: baseline (B, February to May 2006), model 1 (M1, October 2006 to July 2008), and model 2 (M2, September 2008 to February 2009). No audit was performed during B. During M1, an infectious diseases physician evaluated patients, and a critical care pharmacist communicated recommendations to the treating team. During M2, an infectious diseases physician directly participated in interdisciplinary rounds with the medical ICU team. Results: One hundred ninety-four patients were included during B, 415 during M1, and 83 during M2. M1 and M2 were associated with appropriate antimicrobial selection (B, 70%; M1, 78%; M2, 82%; P =.042) and with lower rates of resistance (B, 31%; M1, 25%; M2, 17%; P =.033). Logistic regression analysis confirmed that audit and feedback were independently associated with appropriate antimicrobial selection and prevention of resistance. The association remained strongest for M2. Conclusion: Audit and feedback had an influence on antimicrobial prescription patterns in the ICU with a favorable impact on the emergence of resistance. Copyright © 2012 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

Rommelfanger K.S.,Emory University
Nature Reviews Neurology | Year: 2013

Psychogenic movement disorders (PMDs) mimic known movement disorders but are not attributed to an underlying neurological pathology and are generally thought to have a psychological origin. Owing to the lack of a clear pathology, patients often experience multiple referrals, frequent office visits, and numerous - often fruitless - technically sophisticated tests and interventions. No standard of care exists for PMDs, and affected patients can experience debilitating symptoms for a lifetime. Some physicians advocate the use of placebo treatment for patients with PMDs, and placebo therapy can have beneficial neurophysiological effects. Innovative research will be necessary to develop effective therapeutics for psychogenic disorders and to make recommendations for future clinician training and health care policy. This Perspectives article aims to trigger international dialogue focusing on the diagnosis and treatment of patients with PMDs, and to reframe and deepen discussion of placebo prescribing for PMDs and beyond. © 2013 Macmillan Publishers Limited. All rights reserved.

Lahey B.B.,University of Chicago | Waldman I.D.,Emory University
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2012

Background: A better understanding of the nature and etiology of conduct disorder (CD) can inform nosology and vice versa. We posit that any prevalent form of psychopathology, including CD, can be best understood if it is studied in the context of other correlated forms of child and adolescent psychopathology using formal models to guide inquiry. Methods: Review of both cross-sectional and longitudinal studies of the place of CD in the phenotypic and causal structure of prevalent psychopathology, with an emphasis on similarities and differences between CD and oppositional defiant disorder (ODD). Papers were located using Web of Science by topic searches with no restriction on year of publication. Results: Although some important nosologic questions remain unanswered, the dimensional phenotype of CD is well defined. CD differs from other disorders in its correlates, associated impairment, and course. Nonetheless, it is robustly correlated with many other prevalent dimensions of psychopathology both concurrently and predictively, including both other 'externalizing' disorders and some 'internalizing' disorders. Based on emerging evidence, we hypothesize that these concurrent and predictive correlations result primarily from widespread genetic pleiotropy, with some genetic factors nonspecifically influencing risk for multiple correlated dimensions of psychopathology. In contrast, environmental influences mostly act to differentiate dimensions of psychopathology from one another both concurrently and over time. CD and ODD share half of their genetic influences, but their genetic etiologies are distinct in other ways. Unlike most other dimensions of psychopathology, half of the genetic influences on CD appear to be unique to CD. In contrast, ODD broadly shares nearly all of its genetic influences with other disorders and has little unique genetic variance. Conclusions: Conduct disorder is a relatively distinct syndrome at both phenotypic and etiologic levels, but much is revealed by studying CD in the context of its causal and phenotypic associations with other disorders over time. Advancing and refining formal causal models that specify the common and unique causes and biological mechanisms underlying each correlated dimension of psychopathology should facilitate research on the fundamental nature and nosology of CD. © 2011 The Authors. Journal of Child Psychology and Psychiatry © 2011 Association for Child and Adolescent Mental Health.

Grossniklaus U.,University of Zurich | Kelly B.,Emory University | Ferguson-Smith A.C.,University of Cambridge | Pembrey M.,University College London | And 2 more authors.
Nature Reviews Genetics | Year: 2013

Much attention has been given to the idea of transgenerational epigenetic inheritance, but fundamental questions remain regarding how much takes place and the impact that this might have on organisms. We asked five leading researchers in this area-working on a range of model organisms and in human disease-for their views on these topics. Their responses highlight the mixture of excitement and caution that surrounds transgenerational epigenetic inheritance and the wide gulf between species in terms of our knowledge of the mechanisms that may be involved. © 2013 Macmillan Publishers Limited. All rights reserved.

Duralde X.A.,Peachtree Orthopaedic Clinic | McClelland Jr. W.B.,Emory University
Arthroscopy - Journal of Arthroscopic and Related Surgery | Year: 2012

Purpose: The purpose of this study was to evaluate the clinical results of arthroscopic transtendinous repair of deep partial articular-sided rotator cuff tears. Methods: We retrospectively evaluated the results of 53 patients who underwent arthroscopic transtendinous repair for Ellman grade III articular-sided rotator cuff tears (>50% of the thickness of the rotator cuff). The intact bursal side of the cuff was not detached, and all associated pathology was treated. Fifty patients available for follow-up were evaluated with the American Shoulder and Elbow Surgeons (ASES) questionnaire. Results: American Shoulder and Elbow Surgeons scores improved from a mean of 48.0 to 89.4 (+41.4) (P <.0001). Pain scores on a visual analog scale improved from 5.7 to 1.0 (P <.0001). Ninety-eight percent of patients were satisfied with the results of surgery. Results for the 50 patients available for follow-up were excellent in 32 (64%), good in 6 (12%), fair in 6 (12%), and poor in 6 (12%). Articular-sided rotator cuff tears rarely occurred in isolation but were typically found in association with coexisting pathology suggestive of the tears' etiology. Most common were impingement lesions, seen in 94% of patients, and instability lesions such as labral tears, seen in 30% of patients. Associated procedures included acromioplasty in 47, distal clavicle resection in 29, treatment of biceps pathology in 7, and instability repair in 15. One patient sustained a postoperative pulmonary embolism, which represented the only complication. Tears varied in size from 50% to 90% of the thickness of the cuff insertion. Significant differences were identified in the results of Workers' Compensation patients. Preoperative magnetic resonance imaging and magnetic resonance arthrography were accurate in identifying a partial-thickness rotator cuff tear in less than 40% of cases. Conclusions: Arthroscopic transtendinous repair of partial articular-sided rotator cuff tears is a safe and effective treatment that allows identification of commonly associated pathology and reliable improvement in pain and function. Level of Evidence: Level IV, therapeutic case series. © 2012 Arthroscopy Association of North America.

Martorell R.,Emory University | Zongrone A.,Cornell University
Paediatric and Perinatal Epidemiology | Year: 2012

Intergenerational effects on linear growth are well documented. Several generations are necessary in animal models to 'wash out' effects of undernutrition, consistent with the unfolding of the secular trend in height in Europe and North America. Birthweight is correlated across generations and short maternal stature, which reflects intrauterine and infant growth failure, is associated with low birthweight, child stunting, delivery complications and increased child mortality, even after adjusting for socio-economic status. A nutrition intervention in Guatemala reduced childhood stunting; it also improved growth of the next generation, but only in the offspring of girls. Possible mechanisms explaining intergenerational effects on linear growth are not mutually exclusive and include, among others, shared genetic characteristics, epigenetic effects, programming of metabolic changes, and the mechanics of a reduced space for the fetus to grow. There are also socio-cultural factors at play that are important such as the intergenerational transmission of poverty and the fear of birthing a large baby, which leads to 'eating down' during pregnancy. It is not clear whether there is an upper limit for impact on intrauterine and infant linear growth that programmes in developing countries could achieve that is set by early childhood malnutrition in the mother. Substantial improvements in linear growth can be achieved through adoption and migration, and in a few selected countries, following rapid economic and social development. It would seem, despite clear documentation of intergenerational effects, that nearly normal lengths can be achieved in children born to mothers who were malnourished in childhood when profound improvements in health, nutrition and the environment take place before conception. To achieve similar levels of impact through public health programmes alone in poor countries is highly unlikely. The reality in poor countries limits the scope, quality and coverage of programmes that can be implemented and modest impact should be expected instead. The Lancet series on Maternal and Child Undernutrition estimated that implementation to scale of proven interventions in high burden countries would reduce stunting by one-third; this is perhaps a realistic upper bound for impact for high quality programmes, unless accompanied by sweeping improvements in social services and marked reductions in poverty. Finally, because so much can be achieved in a single generation, intergenerational influences are unlikely to be an important explanation for lack of programme impact aimed at the window of the first 1000 days. Failure to prevent linear growth failure in developing countries has serious consequences for short- and long-term health as well as for the formation of human capital. The nutrition transition has created a double burden by adding obesity and related chronic diseases to the public health agenda of countries still struggling with the 'old' problems of maternal and child undernutrition. The challenge ahead is to increase efforts to prevent linear growth failure while keeping child overweight at bay. © 2012 Blackwell Publishing Ltd.

Bendoly E.,Emory University
Production and Operations Management | Year: 2014

Systems thinking has proven useful in project management planning activities and has been suggested as a critical driver of a range of beneficial organizational behaviors. Yet, empirical evidence on the myriad of ways in which systems thinking can impact internal project dynamics and performance remains limited. This study focuses on one aspect of systems thinking in particular: the ability to recognize and understand the dynamics of systems and their features (e.g., feedback and delay). It makes use of a unique, large-scale interview data set along with objective and structured survey data drawn from multiple sources associated with supply chain system implementation projects. Analysis suggests that an individual's understanding of system dynamics as well as the similarity of such understanding to that typical of their team is, in fact, a strong predictor of both perceptions of psychological safety and information sharing quality in project work. These outcomes appear to mediate the relationship between system dynamics understanding and performance. © 2013 Production and Operations Management Society.

Bonomi L.,Emory University
Proceedings of the VLDB Endowment | Year: 2013

The mining of frequent patterns is a fundamental component in many data mining tasks. A considerable amount of research on this problem has led to a wide series of efficient and scalable algorithms for mining frequent patterns. However, releasing these patterns is posing concerns on the privacy of the users participating in the data. Indeed the information from the patterns can be linked with a large amount of data available from other sources creating opportunities for adversaries to break the individual privacy of the users and disclose sensitive information. In this proposal, we study the mining of frequent patterns in a privacy preserving setting. We first investigate the difference between sequential and itemset patterns, and second we extend the definition of patterns by considering the absence and presence of noise in the data. This leads us in distinguishing the patterns between exact and noisy. For exact patterns, we describe two novel mining techniques that we previously developed. The first approach has been applied in a privacy preserving record linkage setting, where our solution is used to mine frequent patterns which are employed in a secure transformation procedure to link records that are similar. The second approach improves the mining utility results using a two-phase strategy which allows to effectively mine frequent substrings as well as prefixes patterns. For noisy patterns, first we formally define the patterns according to the type of noise and second we provide a set of potential applications that require the mining of these patterns. We conclude the paper by stating the challenges in this new setting and possible future research directions. © 2013 VLDB Endowment.

Peic G.,Emory University
Studies in Conflict and Terrorism | Year: 2014

Given the onset of a violent rebellion by an armed non-state group, how do states reestablish intra-state peace and hence fulfill their basic function as providers of internal security? In this article I argue that one way governments perform this core function is by recruiting non-combatants into local self-defense units called civilian defense forces (CDFs). By providing for local security, leveraging their superior local knowledge, and provoking insurgent reprisals against civilians, CDF units facilitate the influx of tactical intelligence as well as isolate insurgents from non-combatant populations physically as well as politically. Consistent with the argument, statistical analyses of two different cross-national data sets of insurgencies from 1944 to 2006 reveal that a state is 53 percent more likely to vanquish a guerrilla threat if the incumbent deploys CDFs. The analyses also cast doubt on a recent claim in the literature that incumbent force mechanization adversely affects the states' ability to counter insurgent threats. Given that CDF deployment is a more easily manipulable variable than most other elements of state power, CDFs appear to be an effective instrument of counterinsurgency deserving of further academic and policy attention. © Taylor & Francis Group, LLC.

We sought to determine whether a combination of angiotensin-converting enzyme inhibitors (ACEIs) and the nutraceutical α-lipoic acid (ALA) regulates blood pressure, endothelial function, and proteinuria in diabetic patients with Stage I hypertension. A total of 40 diabetic patients with Stage I hypertension were treated in a crossover double-blinded manner. Patients were administered quinapril ([QUI] 40 mg/d) for 8 weeks or QUI + ALA (600 mg/d) for 8 weeks. Measurements included blood pressure, 24-hour collection of urinary albumin, and endothelial-dependent flow-mediated dilation (FMD). There was a change of metabolic parameters in both study groups after 8 weeks of therapy. In comparison to baseline, the 24-hour urinary albumin significantly decreased by 30% in the QUI group (P = .018, time comparison) and 53% in QUI + ALA group (P < .005, time and group comparison). Also, when compared with baseline, FMD significantly increased by 58% in QUI group (P < .005, time comparison) and by 116% in QUI + ALA group (P < .005, time and group comparison). Systolic and diastolic blood pressure reduced significantly by 10% with QUI treatment. There was no further blood pressure reduction when patients were administered both QUI and ALA. In diabetic patients with hypertension, QUI reduces blood pressure, proteinuria, and improves endothelial function. Moreover, this effect is strongly potentiated with a combination of QUI and ALA. These results may attenuate the progression of vascular pathophysiology seen in patients with a combination of diabetes and hypertension.

Dunkle K.L.,Emory University | Decker M.R.,Family and Reproductive Health
American Journal of Reproductive Immunology | Year: 2013

A growing body of international research documents strong associations between gender-based violence and HIV, both in the general population and among high-risk subpopulations such as female sex workers. The causal pathways responsible are multiple and complex, thus conceptual clarity is needed to best inform population-based, clinical, and individually oriented interventions. Our brief overview is intended to provide an introduction to the research on the various mechanisms that link GBV to HIV risk. We review the evidence, describe the causal pathways, provide a conceptual framework, and outline prevention and intervention priorities at both the individual and population levels. © 2012 John Wiley & Sons A/S.

Nanes M.S.,Emory University
Current Opinion in Endocrinology, Diabetes and Obesity | Year: 2013

Derangements in FGF-23 production, half-life or downstream response are responsible for several disorders of phosphate wasting, rickets and oncogenic osteomalacia. Very high levels of FGF-23 in renal failure are an independent risk for cardiovascular disease. ©2013 Wolters Kluwer Health Lippincott Williams & Wilkins.

Barton E.,Purdue University | Mandal P.,Purdue University | Speck S.H.,Emory University
Annual Review of Immunology | Year: 2011

Gammaherpesviruses are lymphotropic viruses that are associated with the development of lymphoproliferative diseases, lymphomas, as well as other nonlymphoid cancers. Most known gammaherpesviruses establish latency in B lymphocytes. Research on Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68/γHV68/MHV4) has revealed a complex relationship between virus latency and the stage of B cell differentiation. Available data support a model in which gammaherpesvirus infection drives B cell proliferation and differentiation. In general, the characterized gammaherpesviruses exhibit a very narrow host tropism, which has severely limited studies on the human gammaherpesviruses EBV and Kaposi's sarcomaâ€"associated herpesvirus. As such, there has been significant interest in developing animal models in which the pathogenesis of gammaherpesviruses can be characterized. MHV68 represents a unique model to define the effects of chronic viral infection on the antiviral immune response. © 2011 by Annual Reviews. All rights reserved.

Shen Y.,Georgia Institute of Technology | Koh K.D.,Georgia Institute of Technology | Weiss B.,Emory University | Storici F.,Georgia Institute of Technology
Nature Structural and Molecular Biology | Year: 2012

Numerous studies have shown that ribonucleoside monophosphates (rNMPs) are probably abundant among all nonstandard nucleotides occurring in genomic DNA. Therefore, it is important to understand to what extent rNMPs may alter genome integrity and what factors affect their stability. We developed oligonucleotide-driven gene correction assays in Escherichia coli and Saccharomyces cerevisiae to show that mispaired rNMPs embedded into genomic DNA, if not removed, serve as templates for DNA synthesis and produce a genetic change. We discovered that isolated mispaired rNMPs in chromosomal DNA are removed by the mismatch repair system in competition with RNase H type 2. However, a mismatch within an RNA-DNA heteroduplex region requires RNase H type 1 for removal. In the absence of mismatch repair and RNases H, ribonucleotide-driven gene modification increased by a factor of 47 in yeast and 77,000 in E. coli. © 2012 Nature America, Inc. All rights reserved.

Martin G.S.,Emory University
Expert Review of Anti-Infective Therapy | Year: 2012

Sepsis has been around since the dawn of time, having been described for more than 2000 years, although clinical definitions are recent. The consensus sepsis definitions have permitted worldwide epidemiological studies of sepsis to be conducted. We now recognize the common nature of sepsis and the consistency of its disease - particularly severe sepsis and septic shock. The incidence of sepsis, severe sepsis and septic shock continues to increase, and although Gram-positive bacterial pathogens remain the most common cause of sepsis, fungal organisms are increasing rapidly. We have made progress over the past half-century in identifying and treating patients with sepsis, and decreasing fatality rates reflect this progress. However, owing to the increasing incidence of sepsis, the number of people who die each year continues to increase. The mortality with sepsis, particularly related to treating organ dysfunction, remains a priority to clinicians worldwide and is deserving of greater public health attention. © 2012 Expert Reviews Ltd.

Sun S.-Y.,Emory University
Autophagy | Year: 2010

Our long-term research goal is to develop efficacious regimens for cancer therapy through our understanding of cancer biology and drug mechanisms. Perifosine is an alkylphospholipid exhibiting antitumor activity and is currently being tested in clinical trials. Its activity is partly associated with its ability to inhibit Akt activity. In an effort to understand the mechanism by which perifosine exerts its anticancer activity, our recent work shows that perifosine, in addition to inhibition of Akt, inhibits mTOR signaling through a different mechanism than classical mTOR inhibitors such as rapamycin via facilitating the degradation of major components in the mTOR axis including mTOR, raptor and rictor. Accordingly, perifosine substantially induces autophagy in addition to apoptosis. The combination of perifosine with a lysosomal inhibitor enhances apoptosis and inhibition of the growth of xenografts in nude mice, suggesting that perifosine-induced autophagy protects cells from undergoing apoptosis. Thus, our findings highlight a novel mechanism accounting for perifosine's anticancer activity involving degradation-mediated mTOR inhibition and also suggest a potential strategy to enhance perifosine's anticancer efficacy by preventing autophagy. © 2010 Landes Bioscience.

Paplomata E.,Emory University
Breast cancer research and treatment | Year: 2013

Everolimus is an orally available inhibitor of the mammalian target of rapamycin (mTOR), which has been approved in combination with exemestane for hormone receptor-positive (HR) breast cancer after failure of treatment with non-steroidal aromatase inhibitors. Everolimus is generally very well tolerated with most common side effects including stomatitis, rash, fatigue, hyperglycemia, hyperlipidemia, and myelosuppression. Most of these side effects are mild and resolve with dose interruptions or dose reductions. Symptomatic non-infectious pneumonitis is a relatively uncommon class effect of mTOR inhibitors, which can be life threatening. Given the efficacy of everolimus in HR-positive metastatic breast cancer, it is crucial for physicians to recognize toxicities related to everolimus and start timely interventions. This review will focus on the adverse events reported with everolimus in breast cancer trials and will provide practical guidelines for the management of these adverse events.

Venkat Narayan K.M.,Emory University
Diabetes Care | Year: 2016

Diabetes is among the biggest of the 21st-century global health challenges. In the U.S. and other high-income countries, thanks to investments in science, dedication to implementing these findings, and measurement of quality of care, there have been improvements in diabetes management and declines in rate of diabetes complications and mortality. This good news, however, is overshadowed by the ever-increasing absolute numbers of people with diabetes and its complications and the unprecedented growth of diabetes in low- and middle-income countries of the world. To comprehensively win the war against diabetes requires 1) concerted attention to prevention and 2) expansion of global research to better inform population-level policies to curb diabetes but also to better understand individualand population-level variations inpathophysiology and phenotypes globallysothat prevention and treatment can be tailored. For example, preliminary data show that thin people in low- and middle-income countries such as India commonly experience type 2 diabetes. Global studies comparing these thin Asian Indians with other high-risk groups such as Pima Indians, a population with a high mean BMI, suggest that type 2 diabetes may not be a single pathophysiological entity. Pima Indians may represent the well-studied phenotype of poor insulin action (type 2A), whereas Asian Indians represent the grossly understudied phenotype of poor insulin secretion (type 2B). This has major implications for diagnosis, prevention, and treatment and highlights the mismatch between where diabetes burdens occur (i.e., low- and middle-income countries) and where research happens (i.e., high-income countries). Correcting this imbalance will advance our knowledge and arsenal to win the global war against diabetes. © 2016 by the American Diabetes Association.

Schwab D.J.,Princeton University | Nemenman I.,Emory University | Mehta P.,Boston University
Physical Review Letters | Year: 2014

The joint probability distribution of states of many degrees of freedom in biological systems, such as firing patterns in neural networks or antibody sequence compositions, often follows Zipf's law, where a power law is observed on a rank-frequency plot. This behavior has been shown to imply that these systems reside near a unique critical point where the extensive parts of the entropy and energy are exactly equal. Here, we show analytically, and via numerical simulations, that Zipf-like probability distributions arise naturally if there is a fluctuating unobserved variable (or variables) that affects the system, such as a common input stimulus that causes individual neurons to fire at time-varying rates. In statistics and machine learning, these are called latent-variable or mixture models. We show that Zipf's law arises generically for large systems, without fine-tuning parameters to a point. Our work gives insight into the ubiquity of Zipf's law in a wide range of systems. © 2014 American Physical Society.

Klatt N.R.,National Institute of Allergy and Infectious Diseases | Silvestri G.,Emory University
Science Translational Medicine | Year: 2012

When it comes to HIV infection, CD4 + T cells are usually thought of as the cells that are preferentially infected and killed by the virus. In a new study, Soghoian et al. now show that during the early stages of HIV infection, CD4 + T cells suppress virus replication and delay disease onset. Thus, the robustness of the CD4 + T cell response during early HIV infection could be used as a marker to determine the speed of disease progression. The new findings also have implications for the design of preventive and therapeutic AIDS vaccines.

Yamaguchi M.,Emory University
Cell and Tissue Research | Year: 2013

Regucalcin (RGN/SMP30) was discovered in 1978 as a calcium (Ca 2+)-binding protein that contains no EF-hand motif of the Ca 2+-binding domain. The name of regucalcin was proposed for this Ca2+-binding protein, which can regulate various Ca 2+-dependent enzyme activations in liver cells. The regucalcin gene is localized on the X chromosome. Regucalcin plays a multifunctional role in cell regulation through maintaining intracellular Ca2+ homeostasis and suppressing signal transduction in various cell types. The cytoplasmic regucalcin is translocated into the nucleus and inhibits nuclear Ca 2+-dependent and -independent protein kinases and protein phosphatases, Ca2+-activated deoxyribonucleic acid (DNA) fragmentation and DNA and ribonucleic acid (RNA) synthesis. Moreover, overexpression of endogenous regucalcin regulates the gene expression of various proteins that are related to cell proliferation and apoptosis. This review will discuss the role of regucalcin in the regulation of cell nuclear function and an involvement in gene expression as a novel transcription factor. © 2013 Springer-Verlag Berlin Heidelberg.

Chan M.,Emory University | Johansson M.A.,Centers for Disease Control and Prevention
PLoS ONE | Year: 2012

Dengue viruses are major contributors to illness and death globally. Here we analyze the extrinsic and intrinsic incubation periods (EIP and IIP), in the mosquito and human, respectively. We identified 146 EIP observations from 8 studies and 204 IIP observations from 35 studies. These data were fitted with censored Bayesian time-to-event models. The best-fitting temperature-dependent EIP model estimated that 95% of EIPs are between 5 and 33 days at 25°C, and 2 and 15 days at 30°C, with means of 15 and 6.5 days, respectively. The mean IIP estimate was 5.9 days, with 95% expected between days 3 and 10. Differences between serotypes were not identified for either incubation period. These incubation period models should be useful in clinical diagnosis, outbreak investigation, prevention and control efforts, and mathematical modeling of dengue virus transmission.

Lerakis S.,Emory University
Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance | Year: 2014

BACKGROUND: Significant paravalvular leak (PVL) after transcatheter aortic valve replacement (TAVR) confers a worse prognosis. Symptoms related to significant PVL may be difficult to differentiate from those related to other causes of heart failure. Cardiovascular magnetic resonance (CMR) directly quantifies valvular regurgitation, but has not been extensively studied in symptomatic post-TAVR patients.METHODS: CMR was compared to qualitative (QE) and semi-quantitative echocardiography (SQE) for classifying PVL and prognostic value at one year post-imaging in 23 symptomatic post-TAVR patients. The primary outcome was a composite of all-cause death, heart failure hospitalization, and intractable symptoms necessitating repeat invasive therapy; the secondary outcome was a composite of all-cause death and heart failure hospitalization. The difference in event-free survival according to greater than mild PVL versus mild or less PVL by QE, SQE, and CMR were evaluated by Kaplan-Meier survival analysis.RESULTS: Compared to QE, CMR reclassified PVL severity in 48% of patients, with most patients (31%) reclassified to at least one grade higher. Compared to SQE, CMR reclassified PVL severity in 57% of patients, all being reclassified to at least one grade lower; SQE overestimated PVL severity (mean grade 2.5 versus 1.7, p=0.001). The primary and secondary outcomes occurred in 48% and 35% of patients, respectively. Greater than mild PVL by CMR was associated with reduced event-free survival for the primary outcome (p<0.0001), however greater than mild PVL by QE and SQE were not (p=0.83 and p=0.068). Greater than mild PVL by CMR was associated with reduced event-free survival for the secondary outcome, as well (p=0.012).CONCLUSION: In symptomatic post-TAVR patients, CMR commonly reclassifies PVL grade compared with QE and SQE. CMR provides superior prognostic value compared to QE and SQE, as patients with greater than mild PVL by CMR (RF>20%) had a higher incidence of adverse events.

Banja J.,Emory University
American Journal of Bioethics | Year: 2014

Various kinds of alcohol and drug testing, such as preemployment, routine, and for-cause testing, are commonly performed by employers. While healthcare organizations usually require preemployment drug testing, they vary on whether personnel will be subjected to further testing. Recently, a call has gone out for postincident testing among physicians who are involved in serious, preventable events, especially ones leading to a patient's death. This article will offer a number of counterarguments to that proposal and discuss an alternate approach: that health institutions can better improve patient safety and employees’ well-being by implementing an organizational policy of “speaking up” when system operators notice work behaviors or environmental factors that threaten harm or peril. The article will conclude with a description of various strategies that facilitate speaking up, and why the practice constitutes a superior alternative to mandatory alcohol and drug testing in the wake of serious, harm-causing medical error. © 2014, Copyright © Taylor & Francis Group, LLC.

Current efforts to reduce maternal mortality and morbidity in low-resource settings often depend on global standards and indicators to assess obstetric care, particularly skilled birth attendants and emergency obstetric care. This paper describes challenges in using these standards to assess obstetric services in the Kilombero Valley of Tanzania. A health facility survey and extensive participant observation showed existing services to be complicated and fluid, involving a wide array of skills, resources, and improvisations. Attempts to measure these services against established standards and indicators were not successful. Some aspects of care were over-valued while others were under-valued, with significant neglect of context and quality. This paper discusses the implications of these findings for ongoing maternal health care efforts in unique and complex settings, questioning the current reliance on generic (and often obscure) archetypes of obstetric care in policy and programming. It suggests that current indicators may be insufficient to assess services in low-resource settings, but not that these settings should settle for lower standards of care. In addition to global benchmarks, assessment approaches that emphasize quality of care and recognize available resources might better account for local realities, leading to more effective, more sustainable service delivery. © 2012 Reproductive Health Matters.

Honeycutt S.,Emory University
Preventing chronic disease | Year: 2010

Researchers believe that nutrition environments contribute to obesity and may explain some health disparities. The Nutrition Environment Measures Surveys (NEMS) are valid and reliable observational measures of the nutrition environment. This article describes the dissemination of the measures, including the development, implementation, and evaluation of training workshops, and a follow-up survey of training participants. To disseminate the NEMS measures, we developed a 2-day intensive, participatory workshop. We used an immediate postcourse evaluation and a structured telephone follow-up interview to evaluate the workshops and the dissemination strategy. Topics included use of the NEMS measures, reactions to the workshops, and participants' training others on the measures. During the study period, 173 people participated in 14 workshops. Participants indicated a high level of satisfaction with the training workshops. Almost two-thirds of respondents reported using the measures to train an additional 292 people and to rate more than 3,000 food outlets. The measures have been used in diverse locations across the United States for various purposes. Respondents have reported NEMS results in peer-reviewed journals, master's theses, newspaper articles, and presentations. The NEMS measures are the only nutrition environment measures that have been packaged for distribution and widely disseminated. The measures fill a need in the worlds of research and community action, and dissemination was successful in accelerating diffusion and promoting adoption of the measures. The use of an ongoing, continual process to improve workshops and measures contributes to the usefulness of the surveys and accelerates their adoption and continued use.

Fournier B.,Emory University
Frontiers in cellular and infection microbiology | Year: 2012

Staphylococcus aureus is a versatile pathogen causing a wide range of infections. It has been a major threat both in hospitals and in the community for decades. S. aureus is a pyogenic bacterium that elicits recruitment of polymorphonuclear leukocytes (neutrophils) to the site of infection. Neutrophils are among the first immune cells to migrate to an infection site attracted by chemoattractant gradients, usually initiated in response to inflammation. Neutrophil recruitment to an inflammation and/or infection site is a sophisticated process involving their interaction with endothelial and epithelial cells through adhesion molecules. Phagocytes have various receptors to detect pathogens, and they include Toll-like receptors (TLRs). TLRs have been extensively studied over the last 10 years and it is now established that they are critical during bacterial infections. However, the function of TLRs, and more particularly TLR2, during staphylococcal infections is still debated. In this review we will consider recent findings concerning the staphylococcal ligands sensed by TLR2 and more specifically the role of staphylococcal lipoproteins in TLR2 recognition. A new concept to emerge in recent years is that staphylococcal components must be phagocytosed and digested in the phagosome to be efficiently detected by the TLR2 of professional phagocytes. Neutrophils are an essential part of the immune response to staphylococcal infections, and in the second part of this review we will therefore describe the role of TLR2 in PMN recruitment in response to staphylococcal infections.

Klein J.D.,Emory University
Pflügers Archiv : European journal of physiology | Year: 2012

In the late 1980s, urea permeability measurements produced values that could not be explained by paracellular transport or lipid phase diffusion. The existence of urea transport proteins were thus proposed and less than a decade later, the first urea transporter was cloned. The family of urea transporters has two major subgroups, designated SLC14A1 (or UT-B) and Slc14A2 (or UT-A). UT-B and UT-A gene products are glycoproteins located in various extra-renal tissues however, a majority of the resulting isoforms are found in the kidney. The UT-B (Slc14A1) urea transporter was originally isolated from erythrocytes and two isoforms have been reported. In kidney, UT-B is located primarily in the descending vasa recta. The UT-A (Slc14A2) urea transporter yields six distinct isoforms, of which three are found chiefly in the kidney medulla. UT-A1 and UT-A3 are found in the inner medullary collecting duct (IMCD), while UT-A2 is located in the thin descending limb. These transporters are crucial to the kidney's ability to concentrate urine. The regulation of urea transporter activity in the IMCD involves acute modification through phosphorylation and subsequent movement to the plasma membrane. UT-A1 and UT-A3 accumulate in the plasma membrane in response to stimulation by vasopressin or hypertonicity. Long-term regulation of the urea transporters in the IMCD involves altering protein abundance in response to changes in hydration status, low protein diets, or adrenal steroids. Urea transporters have been studied using animal models of disease including diabetes mellitus, lithium intoxication, hypertension, and nephrotoxic drug responses. Exciting new genetically engineered mouse models are being developed to study these transporters.

Taylor A.T.,Emory University
Journal of Nuclear Medicine | Year: 2014

Radionuclide renal scintigraphy provides important functional data to assist in the diagnosis and management of patients with a variety of suspected genitourinary tract problems, but the procedures are underutilized. Maximizing the utility of the available studies (as well as the perception of utility by referring physicians) requires a clear understanding of the clinical question, attention to quality control, acquisition of the essential elements necessary to produce an informed interpretation, and production of a report that presents a coherent impression based on data contained in the report and that specifically addresses the clinical question. To help achieve these goals, part 1 of this review addressed the available radiopharmaceuticals, quality control, and quantitative indices, including the measurement of absolute and relative renal function. Part 2 assumes familiarity with part 1 and focuses on the common clinical indications of suspected obstruction and renovascular hypertension; part 2 also summarizes the status of radionuclide renal imaging in the evaluation of the transplanted kidney and the detection of infection, discusses potential pitfalls, and concludes with suggestions for future research. The series of SAM questions accompanying parts 1 and 2 has been designed to reinforce and extend points made in the review. Although the primary focus is the adult patient, aspects of the review also apply to the pediatric population. © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Sechopoulos I.,Emory University
Medical Physics | Year: 2013

Mammography is a very well-established imaging modality for the early detection and diagnosis of breast cancer. However, since the introduction of digital imaging to the realm of radiology, more advanced, and especially tomographic imaging methods have been made possible. One of these methods, breast tomosynthesis, has finally been introduced to the clinic for routine everyday use, with potential to in the future replace mammography for screening for breast cancer. In this two part paper, the extensive research performed during the development of breast tomosynthesis is reviewed, with a focus on the research addressing the medical physics aspects of this imaging modality. This first paper will review the research performed on the issues relevant to the image acquisition process, including system design, optimization of geometry and technique, x-ray scatter, and radiation dose. The companion to this paper will review all other aspects of breast tomosynthesis imaging, including the reconstruction process. © 2013 American Association of Physicists in Medicine.

Combination therapy with ezetimibe/simvastatin (E/S) and extended-release niacin (N) has been reported to be safe and efficacious in concomitantly reducing low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol in hyperlipidemic patients at high risk for atherosclerotic cardiovascular events. This analysis evaluated the effect of E/S coadministered with N on low-density lipoprotein particle number (LDL-P) and high-density lipoprotein particle number (HDL-P) as assessed by nuclear magnetic resonance (NMR) spectroscopy in patients with type IIa or IIb hyperlipidemia. This was an analysis of a previously reported 24-week randomized, double-blind study in type IIa/IIb hyperlipidemic patients randomized to treatment with E/S (10/20 mg/day)+N (titrated to 2 g/day) or N (titrated to 2 g/day) or E/S (10/20 mg/day). Samples from a subset of patients (577 of 1220) were available for post hoc analysis of LDL-P and HDL-P by NMR spectroscopy. Increases in HDL-P (+16.2%) and decreases in LDL-P (-47.7%) were significantly greater with E/S+N compared with N (+9.8% for HDL-P and -21.5% for LDL-P) and E/S (+12.8% for HDL-P and -36.8% for LDL-P). In tertile analyses, those with the lowest baseline HDL-P had the greatest percent increase in HDL-P (N, 18.4/7.9/2.1; E/S, 19.3/12.2/5.3; and E/S+N, 26.9/13.8/6.9; all P<0.001). Individuals in the highest tertile of LDL-P had the greatest percent reduction in LDL-P (N, 18.3/23.1/24.6; E/S, 29.7/38.3/41.8; and E/S+N, 44.3/49.0/50.5; all P<0.001). These results suggest that E/S+N improves lipoprotein particle number, consistent with its lipid-modifying benefits in type IIa or IIb hyperlipidemia patients and may exert the greatest effect in those with high LDL-P and low HDL-P at baseline.

Many important post-acquisition aspects of breast tomosynthesis imaging can impact its clinical performance. Chief among them is the reconstruction algorithm that generates the representation of the three-dimensional breast volume from the acquired projections. But even after reconstruction, additional processes, such as artifact reduction algorithms, computer aided detection and diagnosis, among others, can also impact the performance of breast tomosynthesis in the clinical realm. In this two part paper, a review of breast tomosynthesis research is performed, with an emphasis on its medical physics aspects. In the companion paper, the first part of this review, the research performed relevant to the image acquisition process is examined. This second part will review the research on the post-acquisition aspects, including reconstruction, image processing, and analysis, as well as the advanced applications being investigated for breast tomosynthesis. © 2013 American Association of Physicists in Medicine.

Puetz T.W.,Emory University | Herring M.P.,University of Alabama at Birmingham
American Journal of Preventive Medicine | Year: 2012

Context: Exercise-induced improvements in cancer-related fatigue may be moderated differentially in patients during and following treatment. These effects have not been reviewed systematically. In accordance with PRISMA guidelines, the population effect size for exercise training on cancer-related fatigue during and following treatment was estimated and the extent to which the effect is differentiated across the time course of treatment and recovery was determined. Evidence acquisition: Articles published before August 2011 were retrieved using Google Scholar, MEDLINE, PsycINFO, PubMed, and Web of Science databases. Seventy studies involving 4881 cancer patients during or following treatment were selected. Articles included a cancer-related fatigue outcome measured at baseline and post-intervention and randomized allocation to exercise or non-exercise comparison. From August to October 2011, Hedges' d effect sizes were computed, study quality was evaluated, and random effects models were used to estimate sampling error and population variance. Evidence synthesis: Exercise significantly reduced cancer-related fatigue by a mean effect Δ (95% CI) of 0.32 (0.21, 0.43) and 0.38 (0.21, 0.54) during and following cancer treatment, respectively. During treatment, patients with lower baseline fatigue scores and higher exercise adherence realized the largest improvements. Following treatment, improvements were largest for trials with longer durations between treatment completion and exercise initiation, trials with shorter exercise program lengths, and trials using wait-list comparisons. Conclusions: Exercise reduces cancer-related fatigue among patients during and following cancer treatment. These effects are moderated differentially over the time course of treatment and recovery. Exercise has a palliative effect in patients during treatment and a recuperative effect post-treatment. © 2012 American Journal of Preventive Medicine.

Lilienfeld S.O.,Emory University
American Psychologist | Year: 2012

Data indicate that large percentages of the general public regard psychology's scientific status with considerable skepticism. I examine 6 criticisms commonly directed at the scientific basis of psychology (e.g., psychology is merely common sense, psychology does not use scientific methods, psychology is not useful to society) and offer 6 rebuttals. I then address 8 potential sources of public skepticism toward psychology and argue that although some of these sources reflect cognitive errors (e.g., hindsight bias) or misunderstandings of psychological science (e.g., failure to distinguish basic from applied research), others (e.g., psychology's failure to police itself, psychology's problematic public face) reflect the failure of professional psychology to get its own house in order. I offer several individual and institutional recommendations for enhancing psychology's image and contend that public skepticism toward psychology may, paradoxically, be one of our field's strongest allies. © 2011 American Psychological Association.

Morris C.R.,Emory University
Hematology/Oncology Clinics of North America | Year: 2014

Low global arginine bioavailability (GAB) is associated with numerous complications of SCD including early mortality. Mechanisms of arginine dysregulation involve a complex paradigm of excess activity of the arginine-consuming enzyme arginase, elevated levels of asymmetric dimethylarginine, altered intracellular arginine transport, and nitric oxide synthase dysfunction. Restoration of GAB through exogenous supplementation is therefore, a promising therapeutic target. Studies of arginine therapy demonstrate efficacy in treating patients with leg ulcers, pulmonary hypertension risk, and pain. Co-administration with hydroxyurea increases levels of nitrite and fetal hemoglobin. Addressing the alterations in the arginine metabolome may result in new strategies for treatment of SCD. © 2014 Elsevier Inc.

Lilienfeld S.O.,Emory University
Behaviour Research and Therapy | Year: 2014

In a bold effort to address the longstanding shortcomings of the Diagnostic and Statistical Manual (DSM) framework for the classification and diagnosis of psychopathology, the National Institute of Mental Health recently launched a research program - the Research Domain Criteria (RDoC) - in the hopes of developing an alternative taxonomic system rooted in dysfunctional brain circuitry. Although the RDoC endeavor has considerable promise, it faces several methodological and conceptual challenges, four of which I address here: (a) an overemphasis on biological units and measures, (b) neglect of measurement error, (c) biological and psychometric limitations of endophenotypes, and (d) the distinction between biological predispositions and their behavioral manifestations. Because none of these challenges is in principle insurmountable, I encourage investigators to consider potential remedies for them. RDoC is a calculated gamble that appears to be worth the risk, but its chances of success will be maximized by a thoughtful consideration of hard-won lessons learned - but frequently forgotten - over the past several decades of psychological and psychiatric research. © 2014 Elsevier Ltd. All rights reserved.

Ellis C.L.,Emory University | Epstein J.I.,Johns Hopkins Hospital
American Journal of Surgical Pathology | Year: 2015

Twenty-nine men with metastatic prostate adenocarcinoma to the penis were identified at our institution between 1993 and 2013. Of the 29 patients, 19 had a prior history of adenocarcinoma of the prostate, and 8 of those had ductal features in the primary lesion. Sixteen of 29 revealed ductal features in the metastasis. Seven of the 8 cases with ductal features in the primary had ductal features in the penile metastasis. Seven penile metastases were proven to be of prostatic origin solely by immunohistochemistry. Three cases were originally misdiagnosed as urothelial carcinoma upon review of the penile lesion. Other variant morphologies in the metastases included sarcomatoid carcinoma, small cell carcinoma, and adenosquamous carcinoma. In summary, prostate carcinoma involving the penis displays ductal features considerably more often than prostate cancer in general. Features that can cause difficulty in recognizing metastatic prostate adenocarcinoma to the penis include the unusual anatomic site for prostate cancer, poor differentiation, an increased prevalence of variant morphology, a long interval from the primary lesion, and, in some cases, no documented history of a primary prostatic lesion. Immunohistochemical analysis should be performed to rule out prostate carcinoma in penile/penile urethral tumors with morphology that differs from typical squamous or urothelial carcinoma. Even in the setting of metastatic disease, there is a critical need for an accurate diagnosis so that the appropriate therapy can be initiated, symptomatic relief can be provided, and longterm survival achieved in some cases, while at the same time avoiding penectomy for a misdiagnosis of a primary penile cancer. Copyright © 2014 by Lippincott Williams & Wilkins.

Coutu D.L.,Helmholtz Center Munich | Galipeau J.,Emory University
Aging | Year: 2011

The aging process decreases tissue function and regenerative capacity, which has been associated with cellular senescence and a decline in adult or somatic stem cell numbers and self-renewal within multiple tissues. The potential therapeutic application of stem cells to reduce the burden of aging and stimulate tissue regeneration after trauma is very promising. Much research is currently ongoing to identify the factors and molecular mediators of stem cell self-renewal to reach these goals. Over the last two decades, fibroblast growth factors (FGFs) and their receptors (FGFRs) have stood up as major players in both embryonic development and tissue repair. Moreover, many studies point to somatic stem cells as major targets of FGF signaling in both tissue homeostasis and repair. FGFs appear to promote self-renewing proliferation and inhibit cellular senescence in nearly all tissues tested to date. Here we review the role of FGFs and FGFRs in stem cell self-renewal, cellular senescence, and aging. © Galipeau et al.

Ioachimescu O.C.,Emory University | Teodorescu M.,University of Wisconsin - Madison
Respirology | Year: 2013

Obstructive lung diseases (OLD) such as asthma and chronic obstructive pulmonary disease (COPD) are very prevalent conditions. Disease phenotypes (e.g. chronic bronchitis, emphysema, etc.) often overlap, and significant confusion exists about their optimal nosologic characterization. Obstructive sleep apnoea (OSA) is also a common condition that features bidirectional interactions with OLD. OSA appears to be more commonly seen in patients with OLD, perhaps as a result of shared risk factors, for example obesity, smoking, increased airway resistance, local and systemic inflammation, anti-inflammatory therapy. Conversely, OSA is associated with worse clinical outcomes in patients with OLD, and continuous positive airway pressure therapy has potential beneficial effects on this vicious pathophysiological interaction. Possible shared mechanistic links include increased parasympathetic tone, hypoxaemia-related reflex bronchoconstriction/vasoconstriction, irritation of upper airway neural receptors, altered nocturnal neurohormonal secretion, pro-inflammatory mediators, within and inter-breath interactions between upper and lower airways, lung volume-Airway dependence, etc. While the term overlap syndrome has been defined as the comorbid association of COPD and OSA, the interaction between asthma and OSA has not been integrated yet nosologically; in this review, the latter will be called alternative overlap syndrome. In an effort to bolster further investigations in this area, an integrated, lumping nomenclature for OSA in the setting of OLD is proposed here - OLDOSA (obstructive lung disease and obstructive sleep apnoea) syndrome. © 2013 The Authors. Respirology © 2013 Asian Pacific Society of Respirology.

Li R.,Emory University | Emsley J.,University of Nottingham
Journal of Thrombosis and Haemostasis | Year: 2013

The glycoprotein (GP)Ib-IX-V complex is the platelet receptor for von Willebrand factor and many other molecules that are critically involved in hemostasis and thrombosis. The lack of functional GPIb-IX-V complexes on the platelet surface is the cause of Bernard-Soulier syndrome, a rare hereditary bleeding disorder that is also associated with macrothrombocytopenia. GPIb-IX-V contains GPIbα, GPIbβ, GPIX and GPV subunits, all of which are type I transmembrane proteins containing leucine-rich repeat domains. Although all of the subunits were identified decades ago, not until recently did the mechanism of complex assembly begin to emerge from a systematic characterization of inter-subunit interactions. This review summarizes the forces driving the assembly of GPIb-IX-V, discusses their implications for the pathogenesis of Bernard-Soulier syndrome, and identifies questions that remain about the structure and organization of GPIb-IX-V. © 2013 International Society on Thrombosis and Haemostasis.

Hawkins C.M.,Emory University
Journal of the American College of Radiology | Year: 2014

The planning phases of quality improvement projects are commonly overlooked. Disorganized planning and implementation can escalate chaos, intensify resistance to change, and increase the likelihood of failure. Two important steps in the planning phase are (1) assessing local resources available to aid in the quality improvement project and (2) evaluating the culture in which the desired change is to be implemented. Assessing local resources includes identifying and engaging key stakeholders and evaluating if appropriate expertise is available for the scope of the project. This process also involves engaging informaticists and gathering available IT tools to plan and automate (to the extent possible) the data-gathering, analysis, and feedback steps. Culture in a department is influenced by the ability and willingness to manage resistance to change, build consensus, span boundaries between stakeholders, and become a learning organization. Allotting appropriate time to perform these preparatory steps will increase the odds of successfully performing a quality improvement project and implementing change. © 2014 American College of Radiology.

Gregg E.W.,Centers for Disease Control and Prevention | Li Y.,Centers for Disease Control and Prevention | Wang J.,Centers for Disease Control and Prevention | Burrows N.R.,Centers for Disease Control and Prevention | And 5 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Preventive care for adults with diabetes has improved substantially in recent decades. We examined trends in the incidence of diabetes-related complications in the United States from 1990 through 2010. METHODS: We used data from the National Health Interview Survey, the National Hospital Discharge Survey, the U.S. Renal Data System, and the U.S. National Vital Statistics System to compare the incidences of lower-extremity amputation, end-stage renal disease, acute myocardial infarction, stroke, and death from hyperglycemic crisis between 1990 and 2010, with age standardized to the U.S. population in the year 2000. RESULTS: Rates of all five complications declined between 1990 and 2010, with the largest relative declines in acute myocardial infarction (-67.8%; 95% confidence interval [CI], -76.2 to -59.3) and death from hyperglycemic crisis (-64.4%; 95% CI, -68.0 to -60.9), followed by stroke and amputations, which each declined by approximately half (-52.7% and -51.4%, respectively); the smallest decline was in endstage renal disease (-28.3%; 95% CI, -34.6 to -21.6). The greatest absolute decline was in the number of cases of acute myocardial infarction (95.6 fewer cases per 10,000 persons; 95% CI, 76.6 to 114.6), and the smallest absolute decline was in the number of deaths from hyperglycemic crisis (-2.7; 95% CI, -2.4 to -3.0). Rate reductions were larger among adults with diabetes than among adults without diabetes, leading to a reduction in the relative risk of complications associated with diabetes. When expressed as rates for the overall population, in which a change in prevalence also affects complication rates, there was a decline in rates of acute myocardial infarction and death from hyperglycemic crisis (2.7 and 0.1 fewer cases per 10,000, respectively) but not in rates of amputation, stroke, or end-stage renal disease. CONCLUSIONS: Rates of diabetes-related complications have declined substantially in the past two decades, but a large burden of disease persists because of the continued increase in the prevalence of diabetes. Copyright © 2014 Massachusetts Medical Society.

Achenbach S.,Friedrich - Alexander - University, Erlangen - Nuremberg | Raggi P.,Emory University
European Heart Journal | Year: 2010

Modern computed tomography (CT) systems afford sufficient spatial and temporal resolution for imaging of the heart and coronary arteries. The detection of coronary artery calcium (CAC) is relatively straightforward and it is applied to detect and quantify subclinical coronary atherosclerosis even in asymptomatic individuals. A large body of evidence has accumulated that uniformly attests to a high predictive value of CAC for future cardiac events. More complex data acquisition protocols, which require higher spatial and temporal resolution, specific patient preparation, and the intravenous injection of contrast agent, allow to perform coronary CT angiography (CTA). With CTA, the presence of luminal stenoses and, given sufficient image quality, calcified as well as non-calcified atherosclerotic plaque can be visualized. Initial studies have shown that certain plaque characteristics, such as positive remodelling or very low CT attenuation, are associated with plaque vulnerability. So far, the available clinical data are not sufficient to draw specific conclusions as to the risk-benefit ratio of contrast-enhanced coronary CTA for risk prediction, especially for asymptomatic individuals. Hence, CTA is currently not recommended for risk stratification purposes. However, the technology of coronary CTA continues to evolve at a rapid pace and clinical applications for plaque imaging and characterization may become possible in the future. © 2010 The Author.

Min J.K.,Cornell University | Shaw L.J.,Emory University | Berman D.S.,Cedars Sinai Medical Center
Journal of the American College of Cardiology | Year: 2010

In the past 5 years since the introduction of 64-detector row cardiac computed tomography angiography (CCTA), there has been an exponential growth in the quantity of scientific evidence to support the feasibility of its use in the clinical evaluation of individuals with suspected coronary artery disease (CAD). Since then, there has been considerable debate as to where CCTA precisely fits in the algorithm of evaluation of individuals with suspected CAD. Proponents of CCTA contend that the quality and scope of the available evidence to date support the replacement of conventional methods of CAD evaluation by CCTA, whereas critics assert that clinical use of CCTA is not yet adequately proven and should be restricted, if used at all. Coincident with the scientific debate underlying the clinical utility of CCTA, there has developed a perception by many that the rate of growth in cardiac imaging is disproportionately high and unsustainable. In this respect, all noninvasive imaging modalities and, in particular, more newly introduced ones, have undergone a higher level of scrutiny for demonstration of clinical and economic effectiveness. We herein describe the latest available published evidence supporting the potential clinical and cost efficiency of CCTA, drawing attention not only to the significance but also the limitations of such studies. These points may trigger discussion as to what future studies will be both necessary and feasible for determining the exact role of CCTA in the workup of patients with suspected CAD. © 2010 American College of Cardiology Foundation.

Workowski K.A.,Emory University
Topics in Antiviral Medicine | Year: 2012

Accurate assessment, diagnosis, and treatment of sexually transmitted infections (STIs) in HIV-infected persons can identify sexual risk behaviors and specific STIs that may increase transmission of STIs and HIV. HIV-infected men and women should be screened annually for syphilis and urogenital gonorrhea and chlamydia. Serologic testing for hepatitis A, B, and C viruses should also be performed. Women should be tested for trichomoniasis and undergo a cervical Papanicolaou test annually. Men who report receptive anal intercourse with men during the preceding year should be screened for rectal gonorrhea and chlamydia. Men who report receptive oral intercourse with men during the preceding year should be screened for oropharyngeal gonorrhea. More frequent screening at 3- to 6-month intervals may be indicated for men who have sex with men who have numerous or anonymous partners. STIs may have unusual presentations in HIV-infected patients. Aspects of diagnosis and management of common STIs will be discussed in this article. © 2011, IAS-USA.

Sadikot R.T.,Emory University
Advanced Drug Delivery Reviews | Year: 2014

In recent years nanomedicine has become an attractive concept for the targeted delivery of therapeutic and diagnostic compounds to injured or inflamed organs. Nanoscale drug delivery systems have the ability to improve the pharmacokinetics and increase the biodistribution of therapeutic agents to target organs, thereby resulting in improved efficacy and reduced drug toxicity. These systems are exploited for therapeutic purposes to carry the drug in the body in a controlled manner from the site of administration to the therapeutic target. The mortality in many of the critical illnesses such as sepsis and acute respiratory distress syndrome continues to remain high despite of an increased understanding of the molecular pathogenesis of these diseases. Several promising targets that have been identified as potential therapies for these devastating diseases have been limited because of difficulty with delivery systems. In particular, delivery of peptides, proteins, and miRNAs to the lung is an ongoing challenge. Hence, it is an attractive strategy to test potential targets by employing nanotechnology. Here some of the novel nanomedicine approaches that have been proposed and studied in recent years to facilitate the delivery of therapeutic agents in the setting of critical illnesses such as acute respiratory distress syndrome, sepsis and ventilator associated pneumonia are reviewed. © 2014.

Ariely D.,Duke University | Berns G.S.,Emory University
Nature Reviews Neuroscience | Year: 2010

The application of neuroimaging methods to product marketing neuromarketing has recently gained considerable popularity. We propose that there are two main reasons for this trend. First, the possibility that neuroimaging will become cheaper and faster than other marketing methods; and second, the hope that neuroimaging will provide marketers with information that is not obtainable through conventional marketing methods. Although neuroimaging is unlikely to be cheaper than other tools in the near future, there is growing evidence that it may provide hidden information about the consumer experience. The most promising application of neuroimaging methods to marketing may come before a product is even released when it is just an idea being developed. © 2010 Macmillan Publishers Limited. All rights reserved.

Ramakrishnan U.,Emory University
Food and nutrition bulletin | Year: 2012

Inadequate nutrient intake, early and multiple pregnancies, poverty, caste discrimination, and gender inequality contribute to poor maternal nutrition in India. While malnutrition is seen throughout the life cycle, it is most acute during childhood, adolescence, pregnancy, and lactation. Although nutrition policies are on the books and interventions are in place, child malnutrition and maternal undernutrition persist as severe public health problems. To evaluate the implementation of maternal nutrition programs in India. The research was conducted in two phases. Phase 1 consisted of a desk review of national and state policies pertinent to maternal nutrition and national-level key informant interviews with respondents who have a working knowledge of relevant organizations and interventions. Phase 2 utilized in-depth interviews and focus group discussions at the state, district, and community levels in eight districts of two states: Tamil Nadu and Uttar Pradesh. All data were analyzed thematically. India has a rich portfolio of programs and policies that address maternal health and nutrition; however, systematic weaknesses, logistical gaps, resource scarcity, and poor utilization continue to hamper progress. Elevating the priority given to maternal nutrition in government health programs and implementing strategies to improve women's status will help to address many of the challenges facing India's nutrition programs. Programs can be strengthened by promoting integration of services, ensuring effective procurement mechanisms for micronutrient and food supplements, establishing regional training facilities for improved program implementation, and strengthening program monitoring and evaluation.

Efficacious strategies to improve maternal nutrition and subsequent maternal, neonatal, and child health exist, but their utilization and application at scale is limited. This study explored the gaps, barriers, and opportunities for maternal nutrition policy and programming in Nigeria, a country with a disproportionate share of the global burden of maternal and child mortality Research was conducted in three phases in four Local Government Authorities in Taraba State. Phase 1 consisted of a desk review of policies, programs, and sociodemographic and health indicators pertinent to maternal nutrition. In-depth interviews were conducted with key informants in state and local ministries of health as well as international nongovernmental organizations and community- and faith-based organizations. Phase 2 utilized in-depth interviews and focus group discussions with community leaders, health promoters, and mothers. Phase 3 consisted of key informant interviews with federal policy and program leaders in government ministries and nongovernmental organizations. Nutrition, especially maternal nutrition, is not prioritized and is poorly funded in both the governmental and the nongovernmental systems. Perceived weak advocacy for nutrition and its role in economic development and the lack of coordination among governmental and nongovernmental actors were said to contribute to low prioritization. Dependence on health facilities as the primary platform for delivering maternal nutrition is problematic, given severe resource constraints and perceived community barriers, including cost, distance, and poor quality of care. Advocacy for maternal nutrition that improves understanding of its consequences for health and economic development could hasten prioritization, coordination, and investment in maternal nutrition at the national, state, and local levels. Innovative, multisectoral strategies that move beyond facility-based platforms are needed to reduce the burden of maternal undernutrition in Northeast Nigeria.

Martin L.G.,Emory University
American Journal of Roentgenology | Year: 2012

OBJECTIVE. Many patients with cirrhotic effusions in the peritoneal and pleural spaces lead a difficult existence. In addition to their decreased mobility and physical discomfort, they spend hours in the hospital or an outpatient facility undergoing peritoneal and pleural drainage. Liver transplantation is the ultimate solution for those with cirrhotic effusions refractory to medical management; however, most are on a long waiting list, forcing them to undergo a year or more of percutaneous centesis. Transjugular intrahepatic portosystemic shunts offer relief to those with cirrhotic ascites but at the cost of accelerated hepatic failure and hepatic encephalopathy. This article will review the development of the peritoneovenous and pleurovenous shunt, discuss reasons for its loss of favor, and suggest its current role in the armamentarium of the interventional radiologist. CONCLUSION. Peritoneovenous and pleurovenous shunt creation is a procedure that has the potential to significantly improve the quality of life of the patient by controlling the fluid collections, reducing dependence on frequent drainage procedures, improving renal function, and reducing protein loss. © American Roentgen Ray Society.

Cates C.U.,Emory University | Gallagher A.G.,University College Cork
European Heart Journal | Year: 2012

Changing work practices and the evolution of more complex interventions in cardiovascular medicine are forcing a paradigm shift in the way doctors are trained. Implantable cardioverter defibrillator (ICD), trasncatheter aortic valve implantation (TAVI), carotid artery stenting (CAS), and acute stroke intervention procedures are forcing these changes at a faster pace than in other disciplines. As a consequence, cardiovascular medicine has had to develop a sophisticated understanding of precisely what is meant by 'training' and 'skill'. An evolving conclusion is that procedure training on a virtual reality (VR) simulator presents a viable current solution. These simulations should characterize the important performance characteristics of procedural skill that have metrics derived and defined from, and then benchmarked to experienced operators (i.e. level of proficiency). Simulation training is optimal with metric-based feedback, particularly formative trainee error assessments, proximate to their performance. In prospective, randomized studies, learners who trained to a benchmarked proficiency level on the simulator performed significantly better than learners who were traditionally trained. In addition, cardiovascular medicine now has available the most sophisticated virtual reality simulators in medicine and these have been used for the roll-out of interventions such as CAS in the USA and globally with cardiovascular society and industry partnered training programmes. The Food and Drug Administration has advocated the use of VR simulation as part of the approval of new devices and the American Board of Internal Medicine has adopted simulation as part of its maintenance of certification. Simulation is rapidly becoming a mainstay of cardiovascular education, training, certification, and the safe adoption of new technology. If cardiovascular medicine is to continue to lead in the adoption and integration of simulation, then, it must take a proactive position in the development of metric-based simulation curriculum, adoption of proficiency benchmarking definitions, and then resolve to commit resources so as to continue to lead this revolution in physician training. © 2012 The Author.

Independent component analysis (ICA) has become an important tool for analyzing data from functional magnetic resonance imaging (fMRI) studies. ICA has been successfully applied to single-subject fMRI data. The extension of ICA to group inferences in neuroimaging studies, however, is challenging due to the unavailability of a prespecified group design matrix and the uncertainty in between-subjects variability in fMRI data. We present a general probabilistic ICA (PICA) model that can accommodate varying group structures of multisubject spatiotemporal processes. An advantage of the proposed model is that it can flexibly model various types of group structures in different underlying neural source signals and under different experimental conditions in fMRI studies. A maximum likelihood (ML) method is used for estimating this general group ICA model. We propose two expectation-maximization (EM) algorithms to obtain the ML estimates. The first method is an exact EM algorithm, which provides an exact E-step and an explicit noniterative M-step. The second method is a variational approximation EM algorithm, which is computationally more efficient than the exact EM. In simulation studies, we first compare the performance of the proposed general group PICA model and the existing probabilistic group ICA approach. We then compare the two proposed EM algorithms and show the variational approximation EM achieves comparable accuracy to the exact EM with significantly less computation time. An fMRI data example is used to illustrate application of the proposed methods. © 2011, The International Biometric Society.

Lutgring J.D.,Emory University | Limbago B.M.,Centers for Disease Control and Prevention
Journal of Clinical Microbiology | Year: 2016

The emergence and spread of carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CP-CRE) are a significant clinical and public health concern. Reliable detection of CP-CRE is the first step in combating this problem. There are both phenotypic and molecular methods available for CP-CRE detection. There is no single detection method that is ideal for all situations. © 2016, American Society for Microbiology. All Rights Reserved.

Raison C.L.,Emory University | Lowry C.A.,University of Colorado at Boulder | Rook G.A.W.,University College London
Archives of General Psychiatry | Year: 2010

Context: Inflammation is increasingly recognized as contributing to the pathogenesis of major depressive disorder (MDD), even in individuals who are otherwise medically healthy. Most studies in search of sources for this increased inflammation have focused on factors such as psychosocial stress and obesity that are known to activate inflammatory processes and increase the risk for depression. However, MDD may be so prevalent in the modern world not just because proinflammatory factors are widespread, but also because we have lost contact with previously available sources of anti-inflammatory, immunoregulatory signaling. Objective: To examine evidence that disruptions in coevolved relationships with a variety of tolerogenic microorganisms that were previously ubiquitous in soil, food, and the gut, but that are largely missing from industrialized societies, may contribute to increasing rates of MDD in the modern world. Data Sources: Relevant studies were identified using PubMed and Ovid MEDLINE. Study Selection: Included were laboratory animal and human studies relevant to immune functioning, the hygiene hypothesis, and major depressive disorder identified via PubMed and Ovid MEDLINE searches. Data Extraction: Studies were reviewed by all authors, and data considered to be potentially relevant to the contribution of hygiene-related immune variables to major depressive disorder were extracted. Data Synthesis: Significant data suggest that a variety of microorganisms (frequently referred to as the "old friends") were tasked by coevolutionary processes with training the human immune system to tolerate a wide array of non-threatening but potentially proinflammatory stimuli. Lacking such immune training, vulnerable individuals in the modern world are at significantly increased risk of mounting inappropriate inflammatory attacks on harmless environmental antigens (leading to asthma), benign food contents and commensals in the gut (leading to inflammatory bowel disease), or self-antigens (leading to any of a host of autoimmune diseases). Loss of exposure to the old friends may promote MDD by increasing background levels of depressogenic cytokines and may predispose vulnerable individuals in industrialized societies to mount inappropriately aggressive inflammatory responses to psychosocial stressors, again leading to increased rates of depression. Conclusion: Measured exposure to the old friends or their antigens may offer promise for the prevention and treatment of MDD in modern industrialized societies. ©2010 American Medical Association. All rights reserved.

Moreno-de-Luca A.,Genomic Health | Ledbetter D.H.,Genomic Health | Martin C.L.,Emory University
The Lancet Neurology | Year: 2012

Cerebral palsy-the most common physical disability of childhood-is a clinical diagnosis encompassing a heterogeneous group of neurodevelopmental disorders that cause impairments of movement and posture that persist throughout life. Despite being commonly attributed to a range of environmental factors, particularly birth asphyxia, the specific cause of cerebral palsy remains unknown in most individuals. A growing body of evidence suggests that cerebral palsy is probably caused by multiple genetic factors, similar to other neurodevelopmental disorders such as autism and intellectual disability. Recent advances in next-generation sequencing technologies have made possible rapid and cost-effective sequencing of the entire human genome. Novel cerebral palsy genes will probably be identified as more researchers and clinicians use this approach to study individuals with undiagnosed neurological disorders. As our knowledge of the underlying pathophysiological mechanisms of cerebral palsy increases, so will the possibility of developing genomically guided therapeutic interventions. © 2012 Elsevier Ltd.

Background: Despite positive preclinical studies and two positive Phase II clinical trials, two large Phase III clinical trials of progesterone treatment of acute traumatic brain injury (TBI) recently ended with negative results, so a 100% failure rate continues to plague the field of TBI trials.Methods: This paper reviews and analyses the trial structures and outcomes and discusses the implications of these failures for future drug and clinical trial development. Persistently negative trial outcomes have led to disinvestment in new drug research by companies and policy-makers and disappointment for patients and their families, failures which represent a major public health concern. The problem is not limited to TBI. Failure rates are high for trials in stroke, sepsis, cardiology, cancer and orthopaedics, among others.Results: This paper discusses some of the reasons why the Phase III trials have failed. These reasons may include faulty extrapolation from pre-clinical data in designing clinical trials and the use of subjective outcome measures that accurately reflect neither the nature of the deficits nor long-term quantitative recovery.Conclusions: Better definitions of injury and healing and better outcome measures are essential to change the embrace of failure that has dominated the field for over 30 years. This review offers suggestions to improve the situation. © 2015 © Donald G. Stein.

Ampullary (AMP) carcinomas comprise a heterogeneous group of cancers lacking adequate subcategorization. In the present study, 249 strictly defined primary AMP carcinomas (ACs) identified in 1469 malignant pancreatoduodenectomy specimens were analyzed for defining features. Gross and microscopic findings were used to determine tumor epicenter and extent of preinvasive component. ACs were classified into 4 distinct subtypes based on location: (1) Intra-AMP (25%): Invasive carcinomas arising in intra-ampullary papillary-tubular neoplasms with zero to minimal, duodenal surface involvement (<25% of the tumor). These tumors were more commonly found in men, they had a relatively large overall size (mean, 2.9 cm) but had smaller invasive component (mean, 1.5 cm), and were predominantly of a lower TNM stage (85%, T1/2; and 72% N0). They carried the best prognosis among the 4 groups (3-y survival, 73%). (2) AMP-ductal (15%): These were tumors forming constrictive, sclerotic, plaque-like thickening of the walls of the common bile duct and/or pancreatic duct resulting in mucosa-covered, button-like elevations of the papilla into the duodenal lumen. There was no significant exophytic (preinvasive) growth. These were the smallest tumors (mean overall size, 1.9 cm; mean invasion size 1.7 cm), but carried the worst prognosis (3-y survival, 41%), presumably due to the pancreatobiliary histology/origin (in 86%); however, even this group had significantly better prognosis when compared with 113 ordinary pancreatic ductal adenocarcinomas (3 y, 11%; P<0.0001). (3) Peri-AMP-duodenal (5%): Massive exophytic, ulcero-fungating tumors growing into the duodenal lumen and eccentrically encasing the ampullary orifice with only minimal intra-ampullary luminal involvement. These were mostly of intestinal phenotype (75%) and some had mucinous features. Although these tumors were the largest (mean overall size 4.7 cm; and mean invasion size 3.4 cm), and had the highest incidence of lymph node metastasis (50%), they carried an intermediate prognosis (3-y survival, 69%) to that seen among a group of 55 nonampullary duodenal carcinoma controls. (4) AC-not otherwise specified ("papilla of Vater"; 55%): Ulcero-nodular tumors located at the papilla of Vater, which do not show the specific characteristics identified among the other 3 subtypes. In conclusion, ACs comprise 4 clinicopathologic subtypes that are prognostically distinct.

Revenue management (RM) systems now have an established role in the hospitality industry. Nevertheless, use of the systems varies. The price points that these systems generate through the analysis of demand forecasts are, by their very nature, imperfect prescriptions. Given the risk of forecast error in certain reservation contexts, hotel agents are often given the latitude to accept rate bids below the pricing prescriptions of these systems. The frequency and extent of such deviation is dependent in large part on the judgment of reservation agents, who in turn are influenced by their perceptions of how their actions will be viewed by higher levels of management. In this study, we use a laboratory experiment to investigate how different forms of continuous performance feedback influence agent decisions. More specifically, we consider both a revenue-focused metric as well as a metric framed around pricing-curve adherence as the basis of two feedback mechanisms of interest. In an attempt to provide additional insight, we also monitored physiological markers of stress and arousal to determine the emotional state of subjects. The purpose is to use such observations in support of theory regarding the impact of performance measure orientation on decision making. The results suggest implications for the practical use of continuous feedback in these settings. © 2012 Elsevier B.V. All rights reserved.

African American adolescent females are disproportionately affected by the HIV epidemic. Recent findings suggest that gender- and culturally appropriate HIV prevention interventions can significantly reduce HIV-associated sexual risk behaviors among this vulnerable population. Currently, there are no evidence-based interventions (EBIs) for this vulnerable subgroup. Thus, interventions specifically tailored for this subgroup are urgently needed. Effective interventions that reduce HIV risk behaviors remain one of the most powerful tools in curbing the HIV epidemic. The selected intervention (Horizons) was adapted using a coordinated and systematically guided adaptation process based on the ADAPT-ITT framework. This article serves as a starting point to support using the ADAPT-ITT model, which was beneficial when using an EBI in an alternative setting than originally created. Using this prescriptive method for adapting Horizons for incarcerated young girls proved to be a time- and cost-effective method.

Wang X.H.,Emory University | Mitch W.E.,Baylor College of Medicine
International Journal of Biochemistry and Cell Biology | Year: 2013

Purpose: Muscle atrophy is a frequent complication of chronic kidney disease (CKD) and is associated with increased morbidity and mortality. The processes causing loss of muscle mass are also present in several catabolic conditions. Understanding the pathogenesis of CKD-induced muscle loss could lead to therapeutic interventions that prevent muscle wasting in CKD and potentially, other catabolic conditions. Major findings: Insulin or IGF-1 resistance caused by CKD, acidosis, inflammation, glucocorticoids or cancer causes defects in insulin-stimulated intracellular signaling that suppresses IRS-1 activity leading to decreased phosphorylation of Akt (p-Akt). A low p-Akt activates caspase-3 which provides muscle proteins substrates of the ubiquitin-proteasome system (UPS). A low p-Akt also leads to decreased phosphorylation of forkhead transcription factors which enter the nucleus to stimulate the expression of atrogin-1/MAFbx and MuRF1,E3 ubiquitin ligases that can be associated with proteolysis of muscle cells by the UPS. Caspase-3 also stimulates proteasome-dependent proteolysis in muscle. Summary: In CKD, diabetes, inflammatory conditions or in response to acidosis or excess glucocorticoids, insulin resistance develops, initiating reduced IRS-1/PI3K/Akt signaling. In CKD, this reduces p-Akt which stimulates muscle proteolysis by activating caspase-3 and the UPS. Second, caspase-3 cleaves actomyosin yielding substrates for the UPS and increased proteasome-mediated proteolysis. Third, p-Akt down-regulation suppresses myogenesis in CKD. Fourth, exercise in CKD stimulates insulin/IGF-1 signaling to reduce muscle atrophy. Lastly, there is evidence that microRNAs influence insulin signaling providing a potential opportunity to design therapeutic interventions. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. © 2013 Elsevier Ltd. All rights reserved.

O'Reilly Zwald F.,Emory University | Brown M.,University of Rochester
Journal of the American Academy of Dermatology | Year: 2011

Skin cancer is the most frequent malignancy in organ transplant recipients, 95% of which are nonmelanoma skin cancer, especially squamous cell and basal cell carcinomas. This paper also discusses the incidence of other tumors (eg, melanoma, Merkel cell carcinoma, and Kaposi sarcoma) that are also increased in organ transplant patients compared to the general population. Part I of this two-part series describes the latest data concerning the epidemiologic and pathogenic aspects of nonmelanoma skin cancer development in solid organ transplant recipients. This review also highlights the concept of "field cancerization," represented by extensive areas of actinic damage and epidermal dysplasia, which accounts for increased risk of aggressive skin cancer development in susceptible patients. © 2010 by the American Academy of Dermatology, Inc.

O'Reilly Zwald F.,Emory University | Brown M.,University of Rochester
Journal of the American Academy of Dermatology | Year: 2011

The management of skin cancer in solid organ transplant recipients is a challenge to both the dermatologist and transplant physician. Part II of this continuing medical education review offers an approach to the management of this increasing problem. The importance of specialty dermatology clinics providing access to transplant patients, frequent skin cancer screening, patient education, and multidisciplinary care is discussed. The management of low risk squamous cell carcinoma with topical therapies, photodynamic therapy, systemic retinoids, and capecitabine is reviewed. Revision of immunosuppression in the management of high-risk patients is discussed in association with the potential role of sentinel lymph node biopsy for aggressive disease. Finally, management of in-transit and metastatic squamous cell carcinoma is reviewed, with a discussion of the role of more recent innovative therapies, including epidermal growth factor receptor inhibitors in advanced squamous cell carcinoma in solid organ transplant recipients. © 2010 by the American Academy of Dermatology, Inc.

Provencal N.,Max Planck Institute of Psychiatry | Binder E.B.,Max Planck Institute of Psychiatry | Binder E.B.,Emory University
Current Opinion in Neurobiology | Year: 2015

A large body of evidence describes the long term impact of stress on a number of biological systems and with it associated adverse health outcomes. This article will discuss the epigenetic mechanisms of the embedding of these long term changes, the differences in these mechanisms depending on the type and timing of stress exposure, including transgenerational effects as well as differences in the mechanisms for tissue specific versus more global epigenetic changes. A mechanistic understanding of the long term epigenetic consequences of stress may allow novel, targeted intervention and prevention strategies for psychiatric and other stress-associated disorders. © 2014 Elsevier B.V.

Levy K.,Aurora University | Levy K.,Emory University
American Journal of Epidemiology | Year: 2014

The impact of heavy rainfall events on waterborne diarrheal diseases is uncertain. We conducted weekly, active surveillance for diarrhea in 19 villages in Ecuador from February 2004 to April 2007 in order to evaluate whether biophysical and social factors modify vulnerability to heavy rainfall events. A heavy rainfall event was defined as 24-hour rainfall exceeding the 90th percentile value (56 mm) in a given 7-day period within the study period. Mixed-effects Poisson regression was used to test the hypothesis that rainfall in the prior 8 weeks, water and sanitation conditions, and social cohesion modified the relationship between heavy rainfall events and diarrhea incidence. Heavy rainfall events were associated with increased diarrhea incidence following dry periods (incidence rate ratio = 1.39, 95% confidence interval: 1.03, 1.87) and decreased diarrhea incidence following wet periods (incidence rate ratio = 0.74, 95% confidence interval: 0.59, 0.92). Drinking water treatment reduced the deleterious impacts of heavy rainfall events following dry periods. Sanitation, hygiene, and social cohesion did not modify the relationship between heavy rainfall events and diarrhea. Heavy rainfall events appear to affect diarrhea incidence through contamination of drinking water, and they present the greatest health risks following periods of low rainfall. Interventions designed to increase drinking water treatment may reduce climate vulnerability. © 2013 The Author.

The oxidative pentose phosphate pathway (PPP) is crucial for cancer cell metabolism and tumor growth. We recently reported that targeting a key oxidative PPP enzyme, 6-phosphogluconate dehydrogenase (6PGD), using our novel small-molecule 6PGD inhibitors Physcion and its derivative S3, shows anticancer effects. Notably, humans with genetic deficiency of either 6PGD or another oxidative PPP enzyme, glucose-6-phosphate dehydrogenase, exhibit non-immune hemolytic anemia upon exposure to aspirin and various antimalarial drugs. Inspired by these clinical observations, we examined the anticancer potential of combined treatment with 6PGD inhibitors and antimalarial drugs. We found that stable knockdown of 6PGD sensitizes leukemia cells to antimalarial agent dihydroartemisinin (DHA). Combined treatment with DHA and Physcion activates AMP-activated protein kinase, leading to synergistic inhibition of human leukemia cell viability. Moreover, our combined therapy synergistically attenuates tumor growth in xenograft nude mice injected with human K562 leukemia cells and cell viability of primary leukemia cells from human patients, but shows minimal toxicity to normal hematopoietic cells in mice as well as red blood cells and mononucleocytes from healthy human donors. Our findings reveal the potential for combined therapy using optimized doses of Physcion and DHA as a novel antileukemia treatment without inducing hemolysis.Oncogene advance online publication, 6 June 2016; doi:10.1038/onc.2016.196. © 2016 Macmillan Publishers Limited

Lennox J.L.,Emory University
Current Opinion in HIV and AIDS | Year: 2012

PURPOSE OF REVIEW: In this review we will discuss recent findings on the use of inhibitors of the HIV-1 integrase enzyme for the treatment of antiretroviral naive patients. We will also discuss differences between integrase inhibitors, and comment on the use of this class of drugs in the future. RECENT FINDINGS: Raltegravir when taken twice daily is as effective and well tolerated as efavirenz. Once daily dosing of raltegravir is virologically inferior to raltegravir taken twice daily. A novel nucleoside-free regimen of raltegravir in combination with a once daily ritonavir-boosted protease inhibitor did not produce adequate viral suppression, although raltegravir with a twice daily protease inhibitor yielded better results. Subset analyses have demonstrated a favorable impact of raltegravir on lipid levels and body fat composition. Two once daily integrase inhibitors not yet Food and Drug Administration-approved, elvitegravir and dolutegravir, have completed phase-2 testing and are also virologically noninferior to efavirenz. SUMMARY: Integrase inhibitors provide potent antiretroviral activity, little short-term toxicity and excellent tolerability. For patients with preexisting atherosclerosis or cardiac risk factors this class of therapy is a logical preferred treatment choice. Raltegravir is a preferred option for those in whom therapy for hepatitis C virus infection is anticipated. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Dikalov S.,Emory University
Free Radical Biology and Medicine | Year: 2011

Reactive oxygen species (ROS) play an important role in physiological and pathological processes. In recent years, a feed-forward regulation of the ROS sources has been reported. The interactions between the main cellular sources of ROS, such as mitochondria and NADPH oxidases, however, remain obscure. This work summarizes the latest findings on the role of cross talk between mitochondria and NADPH oxidases in pathophysiological processes. Mitochondria have the highest levels of antioxidants in the cell and play an important role in the maintenance of cellular redox status, thereby acting as an ROS and redox sink and limiting NADPH oxidase activity. Mitochondria, however, are not only a target for ROS produced by NADPH oxidase but also a significant source of ROS, which under certain conditions may stimulate NADPH oxidases. This cross talk between mitochondria and NADPH oxidases, therefore, may represent a feed-forward vicious cycle of ROS production, which can be pharmacologically targeted under conditions of oxidative stress. It has been demonstrated that mitochondria-targeted antioxidants break this vicious cycle, inhibiting ROS production by mitochondria and reducing NADPH oxidase activity. This may provide a novel strategy for treatment of many pathological conditions including aging, atherosclerosis, diabetes, hypertension, and degenerative neurological disorders in which mitochondrial oxidative stress seems to play a role. It is conceivable that the use of mitochondria-targeted treatments would be effective in these conditions. © 2011 Elsevier Inc. All rights reserved.

Lobb C.J.,Emory University
Basal Ganglia | Year: 2014

Despite remarkable advances in Parkinson's disease (PD) research, the pathophysiological mechanisms causing motor dysfunction remain unclear, possibly delaying the advent of new and improved therapies. Several such mechanisms have been proposed including changes in neuronal firing rates, the emergence of pathological oscillatory activity, increased neural synchronization, and abnormal bursting. This review focuses specifically on the role of abnormal bursting of basal ganglia neurons in PD, where a burst is a physiologically relevant, transient increase in neuronal firing over some reference period or activity. After reviewing current methods for how bursts are detected and what the functional role of bursts may be under normal conditions, existing studies are reviewed that suggest that bursting is abnormally increased in PD and that this increases with worsening disease. Finally, the influence of therapeutic approaches for PD such as dopamine-replacement therapy with levodopa or dopamine agonists, lesions, or deep brain stimulation on bursting is discussed. Although there is insufficient evidence to conclude that increased bursting causes motor dysfunction in PD, current evidence suggests that targeted investigations into the role of bursting in PD may be warranted. © 2013 Elsevier GmbH.

Pulendran B.,Emory University
Annual Review of Immunology | Year: 2015

In the 40 years since their discovery, dendritic cells (DCs) have been recognized as central players in immune regulation. DCs sense microbial stimuli through pathogen-recognition receptors (PRRs) and decode, integrate, and present information derived from such stimuli to T cells, thus stimulating immune responses. DCs can also regulate the quality of immune responses. Several functionally specialized subsets of DCs exist, but DCs also display functional plasticity in response to diverse stimuli. In addition to sensing pathogens via PRRs, emerging evidence suggests that DCs can also sense stress signals, such as amino acid starvation, through ancient stress and nutrient sensing pathways, to stimulate adaptive immunity. Here, I discuss these exciting advances in the context of a historic perspective on the discovery of DCs and their role in immune regulation. I conclude with a discussion of emerging areas in DC biology in the systems immunology era and suggest that the impact of DCs on immunity can be usefully contextualized in a hierarchy-of-organization model in which DCs, their receptors and signaling networks, cell-cell interactions, tissue microenvironment, and the host macroenvironment represent different levels of the hierarchy. Immunity or tolerance can then be represented as a complex function of each of these hierarchies. © 2015 by Annual Reviews. All rights reserved.

Feng S.S.J.,Emory University | Sechopoulos I.,Georgia Institute of Technology
Radiology | Year: 2012

Purpose: To comprehensively characterize the dosimetric properties of a clinical digital breast tomosynthesis (DBT) system for the acquisition of mammographic and tomosynthesis images. Materials and Methods: Compressible water-oil mixture phantoms were created and imaged by using the automatic exposure control (AEC) of the Selenia Dimensions system (Hologic, Bedford, Mass) in both DBT and full-field digital mammography (FFDM) mode. Empirical measurements of the x-ray tube output were performed with a dosimeter to measure the air kerma for the range of tube current-exposure time product settings and to develop models of the automatically selected x-ray spectra. A Monte Carlo simulation of the system was developed and used in conjunction with the AEC-chosen settings and spectra models to compute and compare the mean glandular dose (MGD) resulting from both imaging modalities for breasts of varying sizes and glandular compositions. Results: Acquisition of a single craniocaudal view resulted in an MGD ranging from 0.309 to 5.26 mGy in FFDM mode and from 0.657 to 3.52 mGy in DBT mode. For a breast with a compressed thickness of 5.0 cm and a 50% glandular fraction, a DBT acquisition resulted in an only 8% higher MGD than an FFDM acquisition (1.30 and 1.20 mGy, respectively). For a breast with a compressed thickness of 6.0 cm and a 14.3% glandular fraction, a DBT acquisition resulted in an 83% higher MGD than an FFDM acquisition (2.12 and 1.16 mGy, respectively). Conclusion: For two-dimensional-three-dimensional fusion imaging with the Selenia Dimensions system, the MGD for a 5-cmthick 50% glandular breast is 2.50 mGy, which is less than the Mammography Quality Standards Act limit for a two-view screening mammography study. © RSNA, 2012.

Bharadwaj A.,Emory University | El Sawy O.A.,University of Southern California | Pavlou P.A.,Temple University | Venkatraman N.,Boston University
MIS Quarterly: Management Information Systems | Year: 2013

Over the last three decades, the prevailing view of information technology strategy has been that it is a functional-level strategy that must be aligned with the firm's chosen business strategy. Even within this socalled alignment view, business strategy directed IT strategy. During the last decade, the business infrastructure has become digital with increased interconnections among products, processes, and services. Across many firms spanning different industries and sectors, digital technologies (viewed as combinations of information, computing, communication, and connectivity technologies) are fundamentally transforming business strategies, business processes, firm capabilities, products and services, and key interfirm relationships in extended business networks. Accordingly, we argue that the time is right to rethink the role of IT strategy, from that of a functional-level strategy-aligned but essentially always subordinate to business strategy-to one that reflects a fusion between IT strategy and business strategy. This fusion is herein termed digital business strategy. We identify four key themes to guide our thinking on digital business strategy and help provide a framework to define the next generation of insights. The four themes are (1) the scope of digital business strategy, (2) the scale of digital business strategy, (3) the speed of digital business strategy, and (4) the sources of business value creation and capture in digital business strategy. After elaborating on each of these four themes, we discuss the success metrics and potential performance implications from pursuing a digital business strategy. We also show how the papers in the special issue shed light on digital strategies and offer directions to advance insights and shape future research.

All surviving jawed vertebrate representatives achieve diversity in immunoglobulin-based B and T cell receptors for antigen recognition through recombinatorial rearrangement of V(D)J segments. However, the extant jawless vertebrates, lampreys and hagfish, instead generate three types of variable lymphocyte receptors (VLRs) through a template-mediated combinatorial assembly of different leucine-rich repeat (LRR) sequences. The clonally diverse VLRB receptors are expressed by B-like lymphocytes, while the VLRA and VLRC receptors are expressed by lymphocyte lineages that resemble αβ and γδ T lymphocytes, respectively. These findings suggest that three basic types of lymphocytes, one B-like and two T-like, are an essential feature of vertebrate adaptive immunity. Around 500 million years ago, a common ancestor of jawed and jawless vertebrates evolved a genetic program for the development of prototypic lymphoid cells as a foundation for an adaptive immune system. This acquisition preceded the convergent evolution of alternative types of clonally diverse receptors for antigens in all vertebrates, as reviewed in this article. © 2015 WILEY Periodicals, Inc.

Garcia E.V.,Emory University
Journal of Nuclear Cardiology | Year: 2012

Advances in SPECT and PET imaging hardware, software, and radiotracers are vastly improving the non-invasive evaluation of myocardial perfusion and function. In contrast to traditional dual-headed, sodium iodide crystal and photomultiplier cameras with mechanical collimators, new SPECT camera designs utilize novel, collimators, and solid-state detectors that convert photons directly to electrical signals. These cameras simultaneously collect data from as many as 76 small detectors narrowly focused on the heart. New noise regularization and resolution recovery/noise reduction reconstruction software interprets emitted counts more efficiently and thus more effectively discriminates between useful signals and noise. As a result, shorter acquisition times and/or lower tracer doses produce higher quality SPECT images than were possible before. PET perfusion imaging has benefitted from the introduction of novel detectors that now allow true 3D imaging, new radiopharmaceuticals, and precise attenuation correction (AC). These developments have resulted in perfusion images with higher spatial and contrast resolution that may be acquired in shorter protocols and/or with less patient radiation exposure than traditional SPECT. Hybrid SPECT/CT and PET/CT cameras utilize transmission computed tomographic (CT) scans for AC, and offer the additional clinical advantages of evaluating coronary calcium, myocardial anatomy (including non-invasive CT angiography), myocardial function, and myocardial perfusion in a single imaging procedure. Copyright © 2012 American Society of Nuclear Cardiology.

Mullins M.E.,Emory University
Radiologic Clinics of North America | Year: 2011

Infectious and inflammatory processes of the intracranial compartment often result in acute clinical presentations. The possible causes are legion. Clues to the diagnosis involve clinical presentation, laboratory analysis, and neuroimaging. This article reviews some of the salient factors in understanding intracranial infection/ inflammation, including pathophysiology and neuroimaging protocols/findings, and provides some examples and a few "pearls and pitfalls." © 2011 Elsevier Inc.

Mrug S.,University of Alabama at Birmingham | Windle M.,Emory University
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2010

Background: Violence exposure within each setting of community, school, or home has been linked with internalizing and externalizing problems. Although many children experience violence in multiple contexts, the effects of such cross-contextual exposure have not been studied. This study addresses this gap by examining independent and interactive effects of witnessing violence and victimization in the community, home, and school on subsequent internalizing and externalizing problems in early adolescence. Methods: A community sample of 603 boys and girls (78% African American, 20% Caucasian) participated in a longitudinal study of youth violence. During two assessments 16 months apart, adolescents reported on witnessing violence and victimization in the community, school, and home, and their internalizing and externalizing problems. Results: Multiple regressions tested the independent and interactive effects of witnessing violence or victimization across contexts on subsequent adjustment, after controlling for initial levels of internalizing and externalizing problems and demographic covariates. Witnessing violence at school predicted anxiety and depression; witnessing at home was related to anxiety and aggression; and witnessing community violence predicted delinquency. Victimization at home was related to subsequent anxiety, depression, and aggression; victimization at school predicted anxiety; and victimization in the community was not independently related to any outcomes. Finally, witnessing violence at home was associated with more anxiety, delinquency, and aggression only if adolescents reported no exposure to community violence. Conclusions: Violence exposure at home and school had the strongest independent effects on internalizing and externalizing outcomes. Witnessing community violence attenuated the effects of witnessing home violence on anxiety and externalizing problems, perhaps due to desensitization or different norms or expectations regarding violence. However, no comparable attenuation effects were observed for victimization across contexts. © 2010 Association for Child and Adolescent Mental Health.

Many hepatic functions including lipid metabolism, drug metabolism, and inflammatory responses are regulated in a sex-specific manner due to distinct patterns of hepatic gene expression between males and females. Regulation for the majority of these genes is under control of Nuclear Receptors (NRs). Retinoid X Receptor alpha (RXRα) is an obligate partner for multiple NRs and considered a master regulator of hepatic gene expression, yet the full extent of RXRα chromatin binding in male and female livers is unclear. ChIP-Seq analysis of RXRα and RNA Polymerase2 (Pol2) binding was performed livers of both genders and combined with microarray analysis. Mice were gavage-fed with the RXR ligand LG268 for 5 days (30 mg/kg/day) and RXRα-binding and RNA levels were determined by ChIP-qPCR and qPCR, respectively. ChIP-Seq revealed 47,845 (male) and 46,877 (female) RXRα binding sites (BS), associated with ∼12,700 unique genes in livers of both genders, with 91% shared between sexes. RXRα-binding showed significant enrichment for 2227 and 1498 unique genes in male and female livers, respectively. Correlating RXRα binding strength with Pol2-binding revealed 44 genes being male-dominant and 43 female-dominant, many previously unknown to be sexually-dimorphic. Surprisingly, genes fundamental to lipid metabolism, including Scd1, Fasn, Elovl6, and Pnpla3-implicated in Fatty Liver Disease pathogenesis, were predominant in females. RXRα activation using LG268 confirmed RXRα-binding was 2-3 fold increased in female livers at multiple newly identified RXRα BS including for Pnpla3 and Elovl6, with corresponding ∼10-fold and ∼2-fold increases in Pnpla3 and Elovl6 RNA respectively in LG268-treated female livers, supporting a role for RXRα regulation of sexually-dimorphic responses for these genes. RXRα appears to be one of the most widely distributed transcriptional regulators in mouse liver and is engaged in determining sexually-dimorphic expression of key lipid-processing genes, suggesting novel gender- and gene-specific responses to NR-based treatments for lipid-related liver diseases.

Lonial S.,Emory University
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2010

Advances in treatment options for patients with multiple myeloma have made a significant impact on the overall survival of patients and have helped achieve levels of response and duration of remission previously not achievable with standard chemotherapy-based approaches. These improvements are due, in large part, to the development of the novel agents thalidomide, bortezomib, and lenalidomide, each of which has substantial single-agent activity. In addition, a large number of second-generation agents are also in clinical development, such that the repertoire of available treatment options continues to expand. To better interpret clinical trials performed in the relapsed setting, it is important that definitions of relapse categories are used to help better pinpoint the specific benefit for a given therapy, especially in the combination therapy setting as it aids in determining if ongoing work should be continued or abandoned for a given new agent. Insights from preclinical modeling and in vitro work have identified several new combinations, new targets and second- or third-generation versions of existing targets that hold great promise in the setting of relapsed myeloma. Combinations of thalidomide, bortezomib, and lenalidomide with conventional agents or among each other have resulted in enhanced response rates and efficacy. Clinical trials of agents such as carfilzomib, pomalidomide, vorinostat, panobinostat, and elotuzomab are just a few of the many exciting new compounds that are being tested in phase 1 and phase 2 clinical trials for relapsed patients. Further clinical and translational testing are critical to better understanding how best to combine these new agents, as well as identifying patient populations that may best benefit from treatment with these developing new agents.

Newman N.J.,Emory University
Nature Reviews Neurology | Year: 2012

The hereditary optic neuropathies are inherited disorders in which optic nerve dysfunction is a prominent feature in the phenotypic expression of disease. Optic neuropathy may be primarily an isolated finding, such as in Leber hereditary optic neuropathy and dominant optic atrophy, or part of a multisystem disorder. The pathophysiological mechanisms underlying the hereditary optic neuropathies involve mitochondrial dysfunction owing to mutations in mitochondrial or nuclear DNA that encodes proteins essential to mitochondrial function. Effective treatments are limited, and current management includes therapies directed at enhancing mitochondrial function and preventing oxidative damage, as well as genetic counselling, and supportive and symptomatic measures. New therapies, including gene therapy, are emerging via animal models and human clinical trials. Leber hereditary optic neuropathy, in particular, provides a unique model for testing promising treatments owing to its characteristic sequential bilateral involvement and the accessibility of target tissue within the eye. Lessons learned from treatment of the hereditary optic neuropathies may have therapeutic implications for other disorders of presumed mitochondrial dysfunction. In this Review, the natural history of the common inherited optic neuropathies, the presumed pathogenesis of several of these disorders, and the literature to date regarding potential therapies are summarized. © 2012 Macmillan Publishers Limited. All rights reserved.

Coca A.,University of Rochester | Sanz I.,Emory University
Current Opinion in Rheumatology | Year: 2012

PURPOSE OF REVIEW: Last year was marked by important clinical and mechanistic studies that improved our understanding of B-cell immunotherapy for systemic lupus erythematosus (SLE) and Sjogren's syndrome. Here, we will highlight the most relevant studies published in the last 18 months. RECENT FINDINGS: The highlight of the year was the approval of belimumab on the basis of two major trials. On the flip side, the disappointing results of rituximab in lupus nephritis provided a clinical and mechanistic counterpoint in SLE. Still, major limitations in the LUpus Nephritis Assessment with Rituximab (LUNAR) trial, positive subset analysis and new open studies and registries continue to provide hope for and major insights into the use of B-cell depletion. In Sjogren's syndrome, the role of B-cell depletion has been further investigated, both for glandular and extraglandular manifestations of the disease with mixed results in a disease in which outcomes are notoriously hard to measure. SUMMARY: The approval of anti-B cell activating factor therapy and an increasing body of open studies with rituximab as well as subset studies and secondary analysis of the Efficacy and Safety of Rituximab in Moderately-to-Severely Active Systemic Lupus Erythematosus (EXPLORER) and LUNAR trials provide hope for B-cell immunotherapy and significant insight into its mechanisms of action and utilization in a selected subset of patients. Ongoing clinical trials of other B-cell targeting agents are eagerly anticipated. © Lippincott Williams & Wilkins.

O'Neill W.C.,Emory University
Kidney International | Year: 2016

Hypocalcemia is common in advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD), and it is standard practice to correct this back to the normal range, presumably to prevent symptomatic hypocalcemia and help control hyperparathyroidism. However, there are few studies to support this approach, and recent data suggest that this promotes vascular calcification and adynamic bone disease. Whether setting a lower target will improve outcomes has not been tested, but existing data suggest that this may have minimal risks and substantial potential benefits and should be explored. © 2016 International Society of Nephrology.

Hogue C.J.,Emory University
American Journal of Epidemiology | Year: 2016

Pregnancy loss is common and can lead to long-standing parental depression and related problems. In this issue, a study of Danish registries by Bruckner et al. (Am J Epidemiol. 2016;183(8):701-708) correlates monthly trends in unemployment with monthly trends in reported spontaneous abortion, lagged by 1 month. The observed association might be caused by a general population phenomenon, as suggested by the authors, or might represent an increased miscarriage risk only within the subset of the population that is directly affected by lost income. Preventive interventions will vary depending on which interpretation is more likely. Research into the preventability of miscarriages and stillbirths is hampered in the United States by poor-quality vital registration of these events. Investment in improved surveillance systems is needed and would be worthwhile, as illustrated by the knowledge gained about the black/white gap in infant mortality when national birth and infant death records began to be linked. In addition, institution of the Pregnancy Risk Assessment Monitoring System in 1987 shed light on the association of stressful life events with poor birth outcomes. That system can be improved by sampling women who have experienced stillbirths. Better data would facilitate not only surveillance but also hypothesis-generating epidemiologic studies for identifying preventable pregnancy loss. © 2016 The Author. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved.

Kegler M.C.,Emory University
Prevention science : the official journal of the Society for Prevention Research | Year: 2014

Despite the recognition that environments play a role in shaping physical activity and healthy eating behaviors, relatively little research has focused on rural homes and neighborhoods as important settings for obesity prevention. This study, conducted through community-based participatory research, used a social ecological model to examine how home and neighborhood food and physical activity environments were associated with weight status among rural-dwelling adults. Data were from a cross-sectional survey of White and African American adults (n = 513) aged 40-70 years living in rural southwest Georgia. Data were analyzed using measured variable path analysis, a form of structural equation modeling. The results support a social ecological approach to obesity prevention. Physical activity had a direct effect on BMI; self-efficacy, family support for physical activity, and household inventory of physical activity equipment also had direct effects on physical activity. Neighborhood walkability had an indirect effect on physical activity through self-efficacy and family social support. Although neither fruit and vegetable intake nor fat intake had direct effects on BMI, self-efficacy and household food inventories had direct effects on dietary behavior. Perceived access to healthy foods in the neighborhood had an indirect effect on healthy eating and a direct effect on weight; neighborhood cohesion had an indirect effect on healthy eating through self-efficacy. Overall, individual factors and home environments tended to exhibit direct effects on behavior, and neighborhood variables more often exhibited an indirect effect.

Stout D.,Emory University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

Although many species display behavioural traditions, human culture is unique in the complexity of its technological, symbolic and social contents. Is this extraordinary complexity a product of cognitive evolution, cultural evolution or some interaction of the two? Answering this question will require a much better understanding of patterns of increasing cultural diversity, complexity and rates of change in human evolution. Palaeolithic stone tools provide a relatively abundant and continuous record of such change, but a systematic method for describing the complexity and diversity of these early technologies has yet to be developed. Here, an initial attempt at such a system is presented. Results suggest that rates of Palaeolithic culture change may have been underestimated and that there is a direct relationship between increasing technological complexity and diversity. Cognitive evolution and the greater latitude for cultural variation afforded by increasingly complex technologies may play complementary roles in explaining this pattern. © 2011 The Royal Society.

Hinkle S.N.,Emory University
International journal of obesity (2005) | Year: 2012

Both underweight and obese mothers have an increased risk for adverse offspring outcomes. Few studies have examined the association between prepregnancy body mass index (BMI) and children's neurodevelopment. We used data from the nationally representative Early Childhood Longitudinal Study-Birth Cohort (ECLS-B; n=6850). Children were classified according to their mother's prepregnancy BMI (kg m(-2)) status: underweight (BMI <18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9), obese class I (BMI 30.0-34.9), and obese class II and III (BMI ≥35.0). Children's age-adjusted mental development index (MDI) and psychomotor development index (PDI) T-scores (mean 50, s.d. 10) were obtained using a validated shortened version of the Bayley Scales of Infant Development-II at approximately 2 years of age. While adjusting for sociodemographics, we estimated the average MDI and PDI scores or the risk of delayed (<-1 s.d. vs >1 s.d.) mental or motor development, relative to children of normal weight mothers. Compared with children of normal weight mothers, MDI scores were lower among children of mothers of all other prepregnancy BMI categories, with the greatest adjusted difference among children of class II and III obese mothers (-2.13 (95% CI -3.32, -0.93)). The adjusted risk of delayed mental development was increased among children of underweight (risk ratio (RR) 1.36 (95% CI 1.04, 1.78)) and class II and III obese (RR 1.38 (95% CI 1.03, 1.84)) mothers. Children's PDI scores or motor delay did not differ by maternal prepregnancy BMI. In this nationally representative sample of 2-year-old US children, low and very-high maternal prepregnancy BMI were associated with increased risk of delayed mental development but not motor development.

Asante A.,Emory University
Obstetrics and Gynecology | Year: 2010

Objectives: To examine trends in rates of elective bilateral salpingo-oophorectomy in the United States and to assess the association of perioperative complications with elective bilateral salpingo-oophorectomy. Methods: This cross-sectional study uses 1998-2006 data from the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project, a nationally representative sample of inpatient hospitalizations. Analyses were limited to women aged 15 years or older at average risk for ovarian cancer who underwent hysterectomy for a benign gynecologic condition. Tests for trends in elective bilateral salpingo-oophorectomy rates were performed using weighted least squares regression for two time periods, 1998 to 2001 and 2002 to 2006. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for risks of complications associated with elective bilateral salpingo-oophorectomy were estimated using logistic regression. Results: During the period from 1998 to 2006, 39% of the 2,250,041 women who underwent hysterectomy for benign gynecologic indications had elective bilateral salpingo-oophorectomy (rate, 8.3 per 10,000). The elective bilateral salpingo-oophorectomy rate increased from 7.8 per 10,000 in 1998 to 9.0 per 10,000 in 2001 (P trend <.05) and decreased from 9.0 per 10,000 in 2002 to 7.4 per 10,000 in 2006 (P trend <.05). The largest decline from 2002 to 2006 (20.3%) occurred among those aged 45 to 49 years. Compared with hysterectomy only, elective bilateral salpingo-oophorectomy was associated with an increased risk of complications when performed vaginally (OR 1.12; 95% CI 1.08-1.17) and a decreased risk of complications when performed abdominally (OR 0.91; 95% CI 0.89-0.94) or laparoscopically (OR 0.89; 95% CI 0.83-0.94). Conclusion: Elective bilateral salpingo-oophorectomy rates declined since 2002. However, the risks compared with the benefits of the procedure have not been clearly established. Prospective studies examining elective bilateral salpingo-oophorectomy with and without estrogen therapy are needed to guide practice patterns. © 2010 by The American College of Obstetricians and Gynecologists.

Barsalou L.W.,Emory University
Topics in Cognitive Science | Year: 2010

Thirty years ago, grounded cognition had roots in philosophy, perception, cognitive linguistics, psycholinguistics, cognitive psychology, and cognitive neuropsychology. During the next 20years, grounded cognition continued developing in these areas, and it also took new forms in robotics, cognitive ecology, cognitive neuroscience, and developmental psychology. In the past 10years, research on grounded cognition has grown rapidly, especially in cognitive neuroscience, social neuroscience, cognitive psychology, social psychology, and developmental psychology. Currently, grounded cognition appears to be achieving increased acceptance throughout cognitive science, shifting from relatively minor status to increasing importance. Nevertheless, researchers wonder whether grounded mechanisms lie at the heart of the cognitive system or are peripheral to classic symbolic mechanisms. Although grounded cognition is currently dominated by demonstration experiments in the absence of well-developed theories, the area is likely to become increasingly theory driven over the next 30years. Another likely development is the increased incorporation of grounding mechanisms into cognitive architectures and into accounts of classic cognitive phenomena. As this incorporation occurs, much functionality of these architectures and phenomena is likely to remain, along with many original mechanisms. Future theories of grounded cognition are likely to be heavily influenced by both cognitive neuroscience and social neuroscience, and also by developmental science and robotics. Aspects from the three major perspectives in cognitive science-classic symbolic architectures, statistical/dynamical systems, and grounded cognition-will probably be integrated increasingly in future theories, each capturing indispensable aspects of intelligence. © 2010 Cognitive Science Society, Inc.

Stout D.,Emory University
Topics in Cognitive Science | Year: 2010

One of the key challenges confronting cognitive science is to discover natural categories of cognitive function. Of special interest is the unity or diversity of cognitive control mechanisms. Evolutionary history is an underutilized resource that, together with neuropsychological and neuroscientific evidence, can help to provide a biological ground for the fractionation of cognitive control. Comparative evidence indicates that primate brain evolution has produced dissociable mechanisms for external action control and internal self-regulation, but that most real-world behaviors rely on a combination of these. The archeological record further indicates the timing and context of distinctively human elaborations to these cognitive control functions, including the gradual emergence of increasingly complex hierarchical action control. © 2010 Cognitive Science Society, Inc.

The benefits of renal transplantation have been demonstrated to extend to the elderly. As a result, more seniors have been placed on the kidney transplant wait list and have received renal allografts in recent years. In June 2013 significant amendments to deceased donor kidney allocation policy were approved to be instituted in 2014 with the goal of increasing overall life years and graft years achieved compared to the current system. Going forward, it is conceivable that transplant centers may perceive a need to adjust practice patterns and modify evaluation and listing criteria for the elderly as the proportion of kidneys distributed to this segment of the wait list would potentially decrease under the new system, further increasing wait times. This review examines contemporary perspectives on access to transplantation for seniors and pertinent issues for this subgroup such as wait time, comorbidity, and evaluation and listing practices. Potential approaches to improve the evaluation of elderly patients being considered for transplant and to increase availability of expanded criteria donor (or higher kidney donor profile index) and living donor organ transplant opportunities while maintaining acceptable outcomes for seniors are explored. © 2014 Elsevier Inc.

O'Neill W.C.,Emory University
Clinical Journal of the American Society of Nephrology | Year: 2014

Ultrasound is commonly used in nephrology for diagnostic studies of the kidneys and lower urinary tract and to guide percutaneous procedures, such as insertion of hemodialysis catheters and kidney biopsy. Nephrologists must, therefore, have a thorough understanding of renal anatomy and the sonographic appearance of normal kidneys and lower urinary tract, and they must be able to recognize common abnormalities. Proper interpretation requires correlation with the clinical scenario. With the advent of affordable, portable scanners, sonography has become a procedure that can be performed by nephrologists, and both training and certification in renal ultrasonography are available. © 2014 by the American Society of Nephrology.

Dietze E.C.,Duke University | Sistrunk C.,Duke University | Miranda-Carboni G.,University of Tennessee Health Science Center | O'Regan R.,Emory University | Seewaldt V.L.,Duke University
Nature Reviews Cancer | Year: 2015

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects BRCA1 mutation carriers and young women of African origin. There is evidence that African-American women with TNBC have worse clinical outcomes than women of European descent. However, it is unclear whether survival differences persist after adjusting for disparities in access to health-care treatment, co-morbid disease and income. It remains controversial whether TNBC in African-American women is a molecularly distinct disease or whether African-American women have a higher incidence of aggressive biology driven by disparities: there is evidence in support of both. Understanding the relative contributions of biology and disparities is essential for improving the poor survival rate of African-American women with TNBC. © 2015 Macmillan Publishers Limited. All rights reserved.

Yamaguchi M.,Emory University
Journal of Cancer Research and Clinical Oncology | Year: 2015

Regucalcin, which its gene is located on the X chromosome, plays a multifunctional role as a suppressor protein in cell signal transduction in various types of cells and tissues. The suppression of regucalcin gene expression has been shown to involve in carcinogenesis. Regucalcin gene expression was uniquely downregulated in carcinogenesis of rat liver in vivo, although the expression of other many genes was upregulated, indicating that endogenous regucalcin plays a suppressive role in the development of hepatocarcinogenesis. Overexpression of endogenous regucalcin was found to suppress proliferation of rat cloned hepatoma cells in vitro. Moreover, the regucalcin gene and its protein levels were demonstrated specifically to downregulate in human hepatocellular carcinoma by analysis with multiple gene expression profiles and proteomics. Regucalcin gene expression was also found to suppress in human tumor tissues including kidney, lung, brain, breast and prostate, suggesting that repressed regucalcin gene expression leads to the development of carcinogenesis in various tissues. Regucalcin may play a role as a suppressor protein in carcinogenesis. Overexpression of endogenous regucalcin is suggested to reveal preventive and therapeutic effects on carcinogenesis. Delivery of the regucalcin gene may be a novel useful tool in the gene therapy of carcinogenesis. This review will discuss regarding to an involvement of regucalcin as a suppressor protein in human carcinogenesis in insight into the gene therapy. © 2014, Springer-Verlag Berlin Heidelberg.

Collins R.,Yale University | Cheng X.,Emory University
Nucleic Acids Research | Year: 2010

The histone code hypothesis predicts that the post-translational modification of histones can bring about distinct chromatin states, and it therefore serves a key regulatory role in chromatin biology. The impact of one mark on another has been termed cross-talk. Some marks are mutually exclusive, while others act in concert. As multiple marks contributing to one outcome are generally brought about by complexes containing multiple catalytic and binding domains, it appears regulation of chromatin involves a web of writers and readers of histone modifications, chromatin remodeling activities and DNA methylation. Here, we focus on the protein lysine methyltransferases G9a and GLP as examples of this extended cross-talk. G9a and GLP can catalyze the formation of and bind to the same methyl mark via distinct domains. We consider the impact of other histone modifications on G9a/GLP activity and the coordination of activities within G9a/GLP containing complexes. We evaluate the potential impact of product binding on product specificity and on maintenance and propagation of the methyl mark. Lastly, we examine the recruitment of other silencing factors by G9a/GLP. Regulated assembly of specific complexes around key marks may reinforce or alter the biological outcome associated with given histone modifications. © The Author(s) 2010. Published by Oxford University Press.

Hardison R.C.,Pennsylvania State University | Taylor J.,Emory University
Nature Reviews Genetics | Year: 2012

Differential gene expression is the fundamental mechanism underlying animal development and cell differentiation. However, it is a challenge to identify comprehensively and accurately the DNA sequences that are required to regulate gene expression: namely, cis-regulatory modules (CRMs). Three major features, either singly or in combination, are used to predict CRMs: clusters of transcription factor binding site motifs, non-coding DNA that is under evolutionary constraint and biochemical marks associated with CRMs, such as histone modifications and protein occupancy. The validation rates for predictions indicate that identifying diagnostic biochemical marks is the most reliable method, and understanding is enhanced by the analysis of motifs and conservation patterns within those predicted CRMs. © 2012 Macmillan Publishers Limited. All rights reserved.

Agnew R.,Emory University
Criminology | Year: 2016

The "causes of crime" research has up to this point focused on those events and conditions that push or pressure individuals into crime (strains), that pull or attract individuals to crime (social learning for crime), and that restrain individuals from responding to pressures and attractions with crime (controls). Work in several areas, however, has suggested that the response to the pressures for and attractions to crime is not simply a function of controls. It is also a function of the individual's resistance or susceptibility to the events and conditions described by strain and social learning theories. Those high in resistance are less likely to experience these criminogenic events and conditions as pressures for or attractions to crime, whereas those high in susceptibility are more likely. Resistance and susceptibility are a function of factors that influence the perception and interpretation of criminogenic events and conditions, the emotional reaction to them, and the behavioral inclinations prompted by them. These factors include negativity, pleasure and sensation seeking, conventional efficacy and perceived social support, and general sensitivity to the environment. With certain notable exceptions, these factors have been neglected in mainstream crime research, but they have the potential to improve the explanation and prediction of crime substantially. © 2016 by the American Society of Criminology.

Perreault M..-C.,Emory University | Glover J.C.,University of Oslo
Annals of the New York Academy of Sciences | Year: 2013

Subcortical descending glutamatergic neurons, such as reticulospinal (RS) neurons, play decisive roles in the initiation and control of many motor behaviors in mammals. However, little is known about the mechanisms used by RS neurons to control spinal motor networks because most of the neuronal elements involved have not been identified and characterized. In this review, we compare, in the embryonic mouse, the timing of developmental events that lead to the formation of synaptic connections between RS and spinal cord neurons. We then summarize our recent research in the postnatal mouse on the organization of synaptic connections between RS neurons and lumbar axial motoneurons (MNs), hindlimb MNs, and commissural interneurons. Finally, we give a brief account of some of the most recent studies on the intrinsic capabilities for plasticity of the mammalian RS system. The present review should give an updated insight into how functional specificity in RS motor networks emerges. © 2013 New York Academy of Sciences.

Wenner P.,Emory University
Annals of the New York Academy of Sciences | Year: 2013

Endocannabinoid signaling typically mediates a form of synaptic plasticity in which a postsynaptic cell acts retrogradely to reduce vesicle release from presynaptic terminals impinging on that cell. In the embryonic spinal cord, endocannabinoids inhibit spontaneously released glutamatergic vesicles in both a brief and ongoing tonic manner. Together these endocannabinoid-mediated forms of synaptic regulation appear to play an important role in regulating the frequency of a form of spontaneous network activity (SNA) that is expressed in the embryonic spinal cord. Because of the importance of SNA to the maturation of the developing network, fetal exposure to drugs that influence endocannabinoid signaling may have profound effects on spinal maturation. In this review, endocannabinoid signaling in the embryonic spinal cord is described and compared to signaling in the mature lamprey spinal cord as well as in the developing hippocampal network, which expresses a form of SNA. © 2013 New York Academy of Sciences..

Hall R.A.,Emory University
Science Signaling | Year: 2011

The olfactory epithelium is extensively innervated by sympathetic nerve endings, which release norepinephrine, and parasympathetic nerve endings, which release acetylcholine. Because olfactory sensory neurons have adrenergic and muscarinic receptors in addition to odorant receptors, autonomic stimulation can modulate the responses of olfactory sensory neurons to odorants. Recent studies have shed light on the molecular mechanisms that underlie crosstalk between muscarinic and odorant receptor signaling. The emerging view is that the stimulation of odorant receptor signaling by odorants, which is the earliest step in olfaction, can be substantially regulated by the autonomic nervous system.

Gerardo N.M.,Emory University | Parker B.J.,University of Oxford
Current Opinion in Insect Science | Year: 2014

Many vertically-transmitted microbial symbionts protect their insect hosts from natural enemies, including host-targeted pathogens and parasites, and those vectored by insects to other hosts. Protection is often achieved through production of inhibiting toxins, which is not surprising given that toxin production mediates competition in many environments. Classical models of macroecological interactions, however, demonstrate that interspecific competition can be less direct, and recent research indicates that symbiont-protection can be mediated through exploitation of limiting resources, and through activation of host immune mechanisms that then suppress natural enemies. Available data, though limited, suggest that effects of symbionts on vectored pathogens and parasites, as compared to those that are host-targeted, are more likely to result from symbiont activation of the host immune system. We discuss these different mechanisms in light of their potential impact on the evolution of host physiological processes. © 2014 Elsevier Inc. All rights reserved.

Yamaguchi M.,Emory University
Molecular and Cellular Biochemistry | Year: 2011

Regucalcin was discovered in 1978 as a calcium-binding protein that does not contain EF-hand motif of calcium-binding domain (Yamaguchi and Yamamoto Chem Pharm Bull 26:1915-1918, 1978). The name regucalcin was proposed for this calcium-binding protein, which can regulate various Ca2+-dependent enzyme activations in liver cells. The regucalcin gene is localized on the chromosome X, and the organization of the regucalcin gene consists of seven exons and six introns. AP-1, NF1-A1, and RGPR-p117 bind to the promoter region of the rat regucalcin gene and enhance transcription activity of regucalcin gene expression that is mediated through calcium signaling. Regucalcin plays a pivotal role in the keep of intracellular calcium ion (Ca2+) homeostasis due to activating Ca2+ pump enzymes in the plasma membrane (basolateral membrane), microsomes (endoplasmic reticulum), mitochondria, and nuclei of many cell types. Regucalcin has a suppressive effect on calcium signaling from the cytoplasm to the nucleus in the proliferative cells. Regucalcin has also been demonstrated to transport to the nucleus, and it can inhibit Ca2+-dependent protein kinase and protein phosphatase activities, Ca2+-activated deoxyribonucleic acid (DNA) fragmentation, and DNA and ribonucleic acid (RNA) synthesis in the nucleus. Overexpression of regucalcin suppresses cell death and apoptosis in the cloned rat hepatoma cells induced by various signaling factors. Regucalcin can inhibit the enhancement of cell proliferation due to hormonal stimulation. Regucalcin plays an important role as a regulatory protein in cell signaling system, and it is proposed to play a pivotal role in keep of cell homeostasis and function. © 2011 Springer Science+Business Media, LLC.

Brrgeon D.,University Paris - Sud | Doetsch P.W.,Emory University
Nature Reviews Cancer | Year: 2011

The majority of human cells do not multiply continuously but are quiescent or slow-replicating and devote a large part of their energy to transcription. When DNA damage in the transcribed strand of an active gene is bypassed by a RNA polymerase, they can miscode at the damaged site and produce mutant transcripts. This process is known as transcriptional mutagenesis and, as discussed in this Perspective, could lead to the production of mutant proteins and might therefore be important in tumour development. © 2011 Macmillan Publishers Limited. All rights reserved.

Menger F.M.,Emory University
Langmuir | Year: 2011

Research on four types of self-assemblies (micelles, coacervates, gels, and vesicles) is discussed via a particular investigative methodology (in order of appearance): kinetics, dynamic NMR, PGSE-NMR, double-13C labeling, molecular dynamics computations, phase diagrams, cryo-HRSEM, rheology, light/electron microscopy, electrophoretic mobility, electroformation, confocal microscopy, and calorimetry. The emphasis here is on how a given method, each in its own special way, illuminates a complex system. © 2010 American Chemical Society.

Saltman R.B.,Emory University
Health Economics, Policy and Law | Year: 2015

This perspective reviews key institutional and organizational patterns in Swedish health care over the last 30 years, probing the roots of several complicated policy questions that concern present-day Swedish decision-makers. It explores in particular the ongoing structural tension between stability, on the one hand, and the necessary levels of innovation and dynamism demanded by the current period of major clinical, technological, economic, social and supranational (EU) change. Where useful, the article compares Swedish developments with those in the other three European Nordic countries as well as other northern European health systems. Sweden's health sector evolution can provide valuable insight for other countries into the complexity involved in re-thinking tradeoffs between policies that emphasize stability as against those that encourage innovation in health sector governance and provision. © 2014 Cambridge University Press.

Calvert J.W.,Emory University
Cardiovascular Research | Year: 2011

Exercise training has been shown to reduce many risk factors related to cardiovascular disease, including high blood pressure, high cholesterol, obesity, and insulin resistance. More importantly, exercise training has been consistently shown to confer sustainable protection against myocardial infarction in animal models and has been associated with improved survival following a heart attack in humans. It is still unclear how exercise training is able to protect the heart, but some studies have suggested that it increases a number of classical signalling molecules. For instance, exercise can increase components of the endogenous antioxidant defences (i.e. superoxide dismutase and catalase), increase the expression of heat shock proteins, activate ATP-sensitive potassium (KATP) channels, and increase the expression and activity of endothelial nitric oxide (NO) synthase resulting in an increase in NO levels. This review article will provide a brief summary of the role that these signalling molecules play in mediating the cardioprotective effects of exercise. In particular, it will highlight the role that NO plays and introduce the idea that the stable NO metabolite, nitrite, may play a major role in mediating these cardioprotective effects. © 2010 The Author.

Faught E.,Emory University
Expert Opinion on Investigational Drugs | Year: 2014

Introduction: AMPA-type glutamate receptor (AMPAR) antagonism is under development as a novel mechanism of action for antiepileptic drugs. Selurampanel (BGG492) is an experimental competitive AMPA antagonist currently in clinical trials. Areas covered: This article provides a review of the roles of glutamate receptors, especially of the AMPA type, in normal and epileptic synaptic transmission. It also provides a discussion of the mechanisms of action of AMPAR antagonist compounds. The article includes a summary of the preclinical and clinical data on the efficacy and safety of BGG492 and provides a discussion of the future role of these compounds in clinical therapy. Expert opinion: Since many persons with epilepsy remain inadequately treated, compounds exploiting new mechanisms for seizure control are welcome. Based on available clinical trial data as adjunctive therapy, the AMPAR antagonists will likely be highly useful in a small subset of persons and moderately helpful in a larger subset, similar to other new drugs for epilepsy developed since 1993. It remains impossible to predict which patients will respond to which class of drugs. © 2014 Informa UK, Ltd.

Saindane A.M.,Emory University
Neuroimaging Clinics of North America | Year: 2013

Lymph nodes status is an important predictor of prognosis in head and neck squamous cell carcinoma, making accurate staging critical. The physical examination of the neck is highly inaccurate. CT, MR imaging, ultrasound (US), and positron emission tomography-CT (PET-CT) improve accuracy but have limitations. Size criteria, nodal shape and clustering, central necrosis, and findings of extracapsular spread and vascular encasement suggest metastatic involvement on CT and MR imaging. US features help differentiate benign from malignant nodes, aided by US-guided fine-needle aspiration for indeterminate cases. PET-CT is useful for staging the lymph nodes and detection of distant metastasis. © 2013 Elsevier Inc.

Third-hand smoke (THS) is the residual tobacco smoke contaminant that remains after a cigarette is extinguished. It can react with the indoor air pollutant nitrous acid to produce a carcinogen. Understanding perceptions of THS is critical, as it may inform the development of messages for promoting smoke-free homes. Six focus groups, of smokers and non-smokers, with 39 participants were conducted. Participants were asked whether they knew about THS and its harmful effects and whether it would motivate people to make their homes smoke free. They also answered questions about THS beliefs. Participants were mostly African-American, female and high-school graduate or General Educational Development (GED) recipients. Most of the participants had not heard about it and did not know what THS was. When asked about the dangers of THS, some participants made references to children indicating that they can easily inhale or ingest the residue leading to harmful effects. Almost all of the participants stated that they thought being educated about THS would motivate people to make their homes smoke free. There is a need for more scientific understanding of the potential dangers of THS and subsequent education about its exposure and harm to children and possibly adults.

Mashburn J.,Emory University
Journal of Midwifery and Women's Health | Year: 2012

Vaginal symptoms are one of the leading reasons that women visit their health care providers. Women often self-diagnose and may treat themselves inappropriately. This article describes the etiology, risk factors, symptoms, diagnosis, and treatment of the 3 most common vaginal infections: bacterial vaginosis, trichomoniasis, and vulvovaginal candidiasis. © 2012 by the American College of Nurse-Midwives.

Howards P.P.,Emory University
American journal of epidemiology | Year: 2012

In a 1993 paper (Am J Epidemiol. 1993;137(1):1-8), Weinberg considered whether a variable that is associated with the outcome and is affected by exposure but is not an intermediate variable between exposure and outcome should be considered a confounder in etiologic studies. As an example, she examined the common practice of adjusting for history of spontaneous abortion when estimating the effect of an exposure on the risk of spontaneous abortion. She showed algebraically that such an adjustment could substantially bias the results even though history of spontaneous abortion would meet some definitions of a confounder. Directed acyclic graphs (DAGs) were introduced into epidemiology several years later as a tool with which to identify confounders. The authors now revisit Weinberg's paper using DAGs to represent scenarios that arise from her original assumptions. DAG theory is consistent with Weinberg's finding that adjusting for history of spontaneous abortion introduces bias in her original scenario. In the authors' examples, treating history of spontaneous abortion as a confounder introduces bias if it is a descendant of the exposure and is associated with the outcome conditional on exposure or is a child of a collider on a relevant undirected path. Thoughtful DAG analyses require clear research questions but are easily modified for examining different causal assumptions that may affect confounder assessment.

Rapid eye movement (REM) sleep behaviour disorder (RBD) is a sleep disorder in which patients appear to be enacting their dreams while in REM sleep. The behaviours are typically violent, in association with violent dream content, so serious harm can be done to the patient or the bed partner. The disorder predominantly affects older adults, and has an estimated prevalence in adults of 0.4-0.5%. However, the frequency is much higher in certain neurodegenerative diseases, especially Parkinsons disease, dementia with Lewy bodies and multiple systems atrophy. RBD can occur in the absence of diagnosed neurological diseases (the 'idiopathic' form), although patients with this form of RBD may have subtle neurological abnormalities and often ultimately develop a neurodegenerative disorder. Data from animal models and cases of RBD developing after brainstem (pontine tegmentum, medulla) lesions have led to the understanding that RBD is caused by a lack of normal REM muscle atonia and a lack of normal suppression of locomotor generators during REM sleep. Clonazepam is used as first-line therapy for RBD and melatonin as second-line therapy, although evidence for both of these interventions comes from uncontrolled case series. Because the risk of injury to the patient or the bed partner is high, interventions to improve the safety of the sleep environment are also often necessary. This review describes the epidemiology, pathophysiology and treatment of RBD. © 2010 Adis Data Information BV.

BACKGROUND:: Stereotactic radiosurgery (SRS) is an increasingly common modality used with surgery for resectable brain metastases (BM). OBJECTIVE:: To present a multi-institutional retrospective comparison of outcomes and toxicities of preoperative SRS (Pre-SRS) and postoperative SRS (Post-SRS). METHODS:: We reviewed the records of patients who underwent resection of BM and either Pre-SRS or Post-SRS alone between 2005 and 2013 at 2 institutions. Pre-SRS used a dose-reduction strategy based on tumor size, with planned resection within 48 hours. Cumulative incidence with competing risks was used to determine estimated rates. RESULTS:: A total of 180 patients underwent surgical resection for 189 BM: 66 (36.7%) underwent Pre-SRS and 114 (63.3%) underwent Post-SRS. Baseline patient characteristics were balanced except for higher rates of performance status 0 (62.1% vs 28.9%, P < .001) and primary breast cancer (27.2% vs 10.5%, P = .010) for Pre-SRS. Pre-SRS had lower median planning target volume margin (0 mm vs 2 mm) and peripheral dose (14.5 Gy vs 18 Gy), but similar gross tumor volume (8.3 mL vs 9.2 mL, P = .85). The median imaging follow-up period was 24.6 months for alive patients. Multivariable analyses revealed no difference between groups for overall survival (P = .1), local recurrence (P = .24), and distant brain recurrence (P = .75). Post-SRS was associated with significantly higher rates of leptomeningeal disease (2 years: 16.6% vs 3.2%, P = .010) and symptomatic radiation necrosis (2 years: 16.4% vs 4.9%, P = .010). CONCLUSION:: Pre-SRS and Post-SRS for resected BM provide similarly favorable rates of local recurrence, distant brain recurrence, and overall survival, but with significantly lower rates of symptomatic radiation necrosis and leptomeningeal disease in the Pre-SRS cohort. A prospective clinical trial comparing these treatment approaches is warranted. ABBREVIATIONS:: BM, brain metastasesCI, confidence intervalCTV, clinical target volumeDBR, distant brain recurrenceGTV, gross tumor volumeLC, local controlLMD, leptomeningeal diseaseLR, local recurrenceMVA, multivariable analysisOS, overall survivalPost-SRS, postoperative stereotactic radiosurgeryPre-SRS, preoperative stereotactic radiosurgeryPTV, planning target volumeRN, radiation necrosisSRN, symptomatic radiation necrosisSRS, stereotactic radiosurgeryWBRT, whole-brain radiation therapy Copyright © by the Congress of Neurological Surgeons

Metastasis is responsible for >90% of cancer-related deaths. Complex signaling in cancer cells orchestrates the progression from a primary to a metastatic cancer. However, the mechanisms of these cellular changes remain elusive. We previously demonstrated that p90 ribosomal S6 kinase 2 (RSK2) promotes tumor metastasis. Here we investigated the role of RSK2 in the regulation of microtubule dynamics and its potential implication in cancer cell invasion and tumor metastasis. Stable knockdown of RSK2 disrupted microtubule stability and decreased phosphorylation of stathmin, a microtubule-destabilizing protein, at serine 16 in metastatic human cancer cells. We found that RSK2 directly binds and phosphorylates stathmin at the leading edge of cancer cells. Phosphorylation of stathmin by RSK2 reduced stathmin-mediated microtubule depolymerization. Moreover, overexpression of phospho-mimetic mutant stathmin S16D significantly rescued the decreased invasive and metastatic potential mediated by RSK2 knockdown in vitro and in vivo. Furthermore, stathmin phosphorylation positively correlated with RSK2 expression and metastatic cancer progression in primary patient tumor samples. Our finding demonstrates that RSK2 directly phosphorylates stathmin and regulates microtubule polymerization to provide a pro-invasive and pro-metastatic advantage to cancer cells. Therefore, the RSK2–stathmin pathway represents a promising therapeutic target and a prognostic marker for metastatic human cancers.Oncogene advance online publication, 4 April 2016; doi:10.1038/onc.2016.79. © 2016 Macmillan Publishers Limited

BACKGROUND:: Surgery is indicated for cerebral cavernous malformations (CCMs) that cause medically refractory epilepsy. Real-time magnetic resonance thermography (MRT)-guided stereotactic laser ablation (SLA) is a minimally invasive approach to treating focal brain lesions. SLA of CCM has not previously been described. OBJECTIVE:: To describe MRT-guided SLA, a novel approach to treating CCM-related epilepsy, with respect to feasibility, safety, imaging, and seizure control in 5 consecutive patients. METHODS:: Five patients with medically refractory epilepsy undergoing standard presurgical evaluation were found to have corresponding lesions fulfilling imaging characteristics of CCM and were prospectively enrolled. Each underwent stereotactic placement of a saline-cooled cannula containing an optical fiber to deliver 980-nm diode laser energy via twist drill craniostomy. MR anatomic imaging was used to evaluate targeting before ablation. MR imaging provided evaluation of targeting and near real-time feedback regarding the extent of tissue thermocoagulation. Patients maintained seizure diaries, and remote imaging (6-21 months postablation) was obtained in all patients. RESULTS:: Imaging revealed no evidence of acute hemorrhage following fiber placement within presumed CCM. MRT during treatment and immediate postprocedure imaging confirmed the desired extent of ablation. We identified no adverse events or neurological deficits. Four of 5 (80%) patients achieved freedom from disabling seizures after SLA alone (Engel class 1 outcome), with follow-up ranging 12 to 28 months. Reimaging of all subjects (6-21 months) indicated lesion diminution with surrounding liquefactive necrosis, consistent with the surgical goal of extended lesionotomy. CONCLUSION:: Minimally invasive MRT-guided SLA of epileptogenic CCM is a potentially safe and effective alternative to open resection. Additional experience and longer follow-up are needed. ABBREVIATIONS:: CCM, cerebral cavernous malformationsGRE, gradient recalled echoMRT, magnetic resonance thermographySLA, stereotactic laser ablation © by the Congress of Neurological Surgeons.

Osunkoya A.O.,Emory University
Pathology | Year: 2012

This update on prostate pathology is very timely, as we celebrate the 20th anniversary of our great society, the International Society of Urological Pathologists (ISUP). Most of the key advances in this field over the past two decades have been made by several distinguished members of our society, as will be demonstrated herein. I am therefore indeed honored and privileged to be given the opportunity to present this paper. I will start with a brief historical perspective prior to delving into the update on prostate pathology over the past two decades and beyond. The topics discussed in this update will be somewhat limited, but will include The Gleason grading system; handling and staging of radical prostatectomy specimens; variants of prostatic adenocarcinoma; treatment effect on the prostate; other primary and secondary tumours involving the prostate, and biomarkers of prostate cancer. © 2012 Royal College of Pathologists of Australasia.

Markovitz R.C.,Emory University
Blood | Year: 2013

Approximately 30% of patients with severe hemophilia A develop inhibitory anti-factor VIII (fVIII) antibodies (Abs). We characterized 29 anti-human A2 monoclonal Abs (mAbs) produced in a murine hemophilia A model. A basis set of nonoverlapping mAbs was defined by competition enzyme-linked immunosorbent assay, producing 5 major groups. The overlapping epitopes covered nearly the entire A2 surface when mapped by homolog-scanning mutagenesis. Most group A mAbs recognized a previously described epitope bounded by Arg484-Ile508 in the N-terminal A2 subdomain, resulting in binding to activated fVIII and noncompetitive inhibition of the intrinsic fXase complex. Group B and C mAbs displayed little or no inhibitory activity. Group D and E mAbs recognized epitopes in the C-terminal A2 subdomain. A subset of group D mAbs inhibited the activation of fVIII by interfering with thrombin-catalyzed cleavage at Arg372 at the A1-A2 domain junction. Other group D mAbs displayed indeterminate or no inhibitory activity despite inhibiting cleavage at Arg740 at the A2-B domain junction. Group E mAbs inhibited fVIII light-chain cleavage at Arg1689. Inhibition of cleavages at Arg372 and Arg1689 represent novel mechanisms of inhibitor function and, along with the extensive epitope spectrum identified in this study, reveal hitherto unrecognized complexity in the immune response to fVIII.

Gass K.,Emory University
Environmental health : a global access science source | Year: 2014

Identifying and characterizing how mixtures of exposures are associated with health endpoints is challenging. We demonstrate how classification and regression trees can be used to generate hypotheses regarding joint effects from exposure mixtures. We illustrate the approach by investigating the joint effects of CO, NO2, O3, and PM2.5 on emergency department visits for pediatric asthma in Atlanta, Georgia. Pollutant concentrations were categorized as quartiles. Days when all pollutants were in the lowest quartile were held out as the referent group (n = 131) and the remaining 3,879 days were used to estimate the regression tree. Pollutants were parameterized as dichotomous variables representing each ordinal split of the quartiles (e.g. comparing CO quartile 1 vs. CO quartiles 2-4) and considered one at a time in a Poisson case-crossover model with control for confounding. The pollutant-split resulting in the smallest P-value was selected as the first split and the dataset was partitioned accordingly. This process repeated for each subset of the data until the P-values for the remaining splits were not below a given alpha, resulting in the formation of a "terminal node". We used the case-crossover model to estimate the adjusted risk ratio for each terminal node compared to the referent group, as well as the likelihood ratio test for the inclusion of the terminal nodes in the final model. The largest risk ratio corresponded to days when PM2.5 was in the highest quartile and NO2 was in the lowest two quartiles (RR: 1.10, 95% CI: 1.05, 1.16). A simultaneous Wald test for the inclusion of all terminal nodes in the model was significant, with a chi-square statistic of 34.3 (p = 0.001, with 13 degrees of freedom). Regression trees can be used to hypothesize about joint effects of exposure mixtures and may be particularly useful in the field of air pollution epidemiology for gaining a better understanding of complex multipollutant exposures.

Massachusetts health care reform, designed to expand coverage and access to care for vulnerable populations, serves as the model for national health reform in the United States that will be implemented in 2014. Yet, little is known about how the reform may have affected the demand for and the financial performance of safety net hospitals (SNH), the primary source of care for such populations before the reform. Using a quasi-experimental design that included all acute care hospitals in the state, we calculated changes in mean inpatient and outpatient volumes, revenue, and operating margins at SNH from the pre-reform (Fiscal Year 2006) to the post-reform (Fiscal Year 2009) period. We contrasted these changes with contemporaneous changes occurring among non-safety net hospitals (NSNH) using a difference-in-differences approach. We found that SNH in Massachusetts continue to play a disproportionately large role in caring for disadvantaged patients after reform, but that their financial performance has declined considerably compared with NSNH. Ongoing reform efforts in the United States should account for continued SNH demand among the most vulnerable patients and should be designed so as not to undermine the financial stability of SNH that meet this demand. © 2013, Baywood Publishing Co., Inc.

Analysis of data from the National Medical Expenditure Survey and the Medical Expenditure Panel Surveys from 1987-2009 reinforces previous observations that increased prevalence of treated disease has become the main driver of increased spending on health care in the United States. Higher treated disease prevalence and higher spending per treated case were associated with 50.8 percent and 39.0 percent, respectively, of the spending increase seen in the population ages eighteen and older, while their joint effect accounts for the remaining 10.2 percent. The proportion of increased spending attributable to increased treated prevalence alone is particularly high in the Medicare population: 77.7 percent, compared to 33.5 percent among the privately insured. Moreover, the current findings reveal a substantial contribution to the increase in total spending (10.4 percent) from a doubling of the share of the population considered to be obese and from increases in treatment intensity, a component of spending per treated case (11.9 percent), in 1987-2009. Constraining the cost of health care will require policy options focused on reducing the incidence of disease, as well as improved understanding of the extent to which more aggressive treatments for chronic conditions do, or do not, result in lower morbidity and mortality. © 2013 Project HOPE-The People-to-People Health Foundation, Inc.

Choisy M.,IRD Montpellier | De Roode J.C.,Emory University
American Naturalist | Year: 2010

Mixed-genotype parasite infections are common in nature. Theoretical studies analyze the effects of such infections over evolutionary time and predict an increase in virulence due to the competitive advantage of virulent parasites. In contrast, experimental studies compare the overall virulence of mixed and single infections within one generation. Although these within-generation comparisons have limited relevance to existing theory, they demonstrate that within-host parasite interactions are not restricted to competition for resources, as envisaged by theory. Instead, mixed infections may result in phenotypic changes in growth rate or impaired immune clearance. Developing and using a two-parasite epidemiological model with recovery, we confirm that within-host competition for resources selects for higher virulence. However, parasite phenotypic plasticity and impaired host immunity can select for lower virulence. Because these latter two mechanisms would be detected by experimentalists as an increase in pathology, our results warn against the temptation to draw inferences on virulence evolution on the basis of single-generation experiments. © 2010 by The University of Chicago.

D'Orsi C.J.,Emory University
Journal of the National Cancer Institute - Monographs | Year: 2010

Diagnosis of ductal carcinoma in situ (DCIS) has increased dramatically in parallel with the increased use of screening mammography. There are specific mammographic findings, most associated with shapes (amorphous, fine and coarse pleomorphic, and fine linear) and distributions (linear and segmental) of calcifications that permit a reasonable sensitivity for detection of DCIS without an unreasonable decrease in specificity, especially in view of the dramatic decrease in breast cancer mortality associated with early detection. While some DCIS may never progress to invasive disease, at this time, we cannot make that separation. This should be an active area for research. © The Author 2010. Published by Oxford University Press. All rights reserved.

Fivush R.,Emory University
New directions for child and adolescent development | Year: 2011

Narratives of the self are embedded within families in which narrative interaction is a common practice. Especially in adolescence, when issues of identity and emotional regulation become key, narratives provide frameworks for understating self and emotion. The authors' research on family narratives suggests that adolescents' personal narratives are at least partly shaped by intergenerational narratives about their parents' childhoods. Both personal and intergenerational narratives emerge frequently in typical family dinner conversations, and these narratives reflect gendered ways of being in the world. Adolescents who tell intergenerational narratives that are rich in intergenerational connections and perspective-taking show higher levels of well-being. These findings suggest that individual narrative selves are created within families and across generations. Copyright © 2011 Wiley Periodicals, Inc., A Wiley Company.

Gunderson L.,Emory University
Ecology and Society | Year: 2010

Ecological resilience, adaptive cycles, and panarchy are all concepts that have been developed to explain abrupt and often surprising changes in complex socio-ecological systems that are prone to disturbances. These types of changes involve qualitative and quantitative alterations in systems' structures and processes. This paper uses the concepts of ecological resilience, adaptive cycles, and panarchies to compare ecological and human community systems. At least five important findings emerge from this comparison. 1) Both systems demonstrate the multiple meanings of resilience-both in terms of recovery time from disturbances and the capacity to absorb them. 2) Both systems recognize the role of diversity in contributing to resilience. 3) The comparison highlights the role of different forms of capital and 4) the importance of cross-scale interactions. 5) The comparison reveals the need for experimentation and learning to build adaptive capacities. All of these ideas have broad implications for attempting to manage complex systems with human and ecological components in the face of recurring natural disasters. © 2010 by the author(s).

Estrogen deficiency expands hemopoietic stem and progenitor cells (HSPCs) and mature blood lineages, but the involved mechanism and the affected HSPC populations are mostly unknown. Here we show that ovariectomy (ovx) expands short-term HSPCs (ST-HSPCs) and improves blood cell engraftment and host survival after bone marrow (BM) transplantation through a dual role of the T-cell costimulatory molecule CD40 ligand (CD40L). This surface receptor is required for ovx to stimulate T-cell production of Wnt10b, a Wnt ligand that activates Wnt signaling in HSPCs and stromal cells (SCs). Moreover, CD40L is required for ovx to increase SC production of the hemopoietic cytokines interleukin (IL)-6, IL-7, and granulocyte macrophage-colony-stimulating factor. Attesting to the relevance of CD40L and Wnt10b, ovx fails to expand ST-HSPCs in CD40L-null mice and in animals lacking global or T-cell expression of Wnt10b. In summary, T cells expressed CD40L, and the resulting increased production of Wnt10b and hemopoietic cytokines by T cells and SCs, respectively, plays a pivotal role in the mechanism by which ovx regulates hemopoiesis. The data suggest that antiestrogens may represent pharmacological targets to improve ST-HSPC function through activation of the microenvironment.

The cerebellar nuclei (CN) process inhibition from Purkinje cells (PC) and excitation from mossy and climbing fiber collaterals. CN neurons in slices show intrinsic pace-making activity, which is easily modulated by synaptic inputs. Our work using dynamic clamping and computer modeling shows that synchronicity between PC inputs is an important factor in determining spike rate and spike timing of CN neurons and that brief pauses in PC inputs provide a potent stimulus to trigger CN spikes. Excitatory input can equally control spike rate, but, due to a large slow, NMDA component also amplifies responses to inhibitory inputs. Intrinsic properties of CN neurons are well suited to provide prolonged responses to strong input transients and could be involved in motor pattern generation. One such specific mechanism is given by fast and slow rebound bursting. Nevertheless, we are just beginning to unravel synaptic integration in the CN, and the outcome of the work to date is best characterized by the generation of new specific questions that lend themselves to a combined experimental and computer modeling approach in future studies. © Springer Science+Business Media, LLC 2011.

Postnatal proliferation of cerebellar granule neuron precursors (CGNPs), proposed cells of origin for the SHH-associated subgroup of medulloblastoma, is driven by Sonic hedgehog (Shh) and insulin-like growth factor (IGF) in the developing cerebellum. Shh induces the oncogene Yes-associated protein (YAP), which drives IGF2 expression in CGNPs and mouse Shh-associated medulloblastomas. To determine how IGF2 expression is regulated downstream of YAP, we carried out an unbiased screen for transcriptional regulators bound to IGF2 promoters. We report that Y-box binding protein-1 (YB-1), an onco-protein regulating transcription and translation, binds to IGF2 promoter P3. We observed that YB-1 is upregulated across human medulloblastoma subclasses as well as in other varieties of pediatric brain tumors. Utilizing the cerebellar progenitor model for the Shh subgroup of medulloblastoma in mice, we show for the first time that YB-1 is induced by Shh in CGNPs. Its expression is YAP-dependent and it is required for IGF2 expression in CGNPs. Finally, both gain-of function and loss-of-function experiments reveal that YB-1 activity is required for sustaining CGNP and medulloblastoma cell (MBC) proliferation. Collectively, our findings describe a novel role for YB-1 in driving proliferation in the developing cerebellum and MBCs and they identify the SHH:YAP:YB1:IGF2 axis as a powerful target for therapeutic intervention in medulloblastomas.Oncogene advance online publication, 4 January 2016; doi:10.1038/onc.2015.491. © 2016 Macmillan Publishers Limited

Prenatal exposures to polyfluoroalkyl compounds (PFCs) may be associated with adverse changes in fetal and postnatal growth. We explored associations of prenatal serum concentrations of perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexane sulfonate (PFHxS) with fetal and postnatal growth in girls. We studied a sample of 447 singleton girls and their mothers participating in the Avon Longitudinal Study of Parents and Children (ALSPAC). Data on weight and length were obtained at birth and at 2, 9, and 20 months. Serum samples were obtained in 1991-1992, from mothers during pregnancy. We explored associations between prenatal PFC concentrations and weight at birth as well as longitudinal changes in weight-for-age SD scores between birth and 20 months. PFOS (median, 19.6 ng/mL), PFOA (median, 3.7 ng/mL), and PFHxS (median, 1.6 ng/mL) were detected in 100% of samples. On average, girls born to mothers with prenatal concentrations of PFOS in the upper tertile weighed 140 g less [95% confidence interval (CI): -238, -42] at birth than girls born to mothers with concentrations in the lower tertile in adjusted models. Similar patterns were seen for PFOA (-133 g; 95% CI: -237, -30) and PFHxS (-108 g; 95% CI: -206, -10). At 20 months, however, girls born to mothers with prenatal concentrations of PFOS in the upper tertile weighed 580 g more (95% CI: 301, 858) when compared with those in the lower tertile. No differences in weight were found for PFOA and PFHxS. Girls with higher prenatal exposure to each of the PFCs examined were smaller at birth than those with lower exposure. In addition, those with higher exposure to PFOS were larger at 20 months.

Krammer F.,Mount Sinai School of Medicine | Palese P.,Mount Sinai School of Medicine | Steel J.,Emory University
Current Topics in Microbiology and Immunology | Year: 2015

The threat of novel influenza viruses emerging into the human population from animal reservoirs, as well as the short duration of protection conferred by licensed vaccines against human seasonal strains has spurred research efforts to improve upon current vaccines and develop novel therapeutics against influenza viruses. In recent years these efforts have resulted in the identification of novel, highly conserved epitopes for neutralizing antibodies on the influenza virus hemagglutinin protein, which are present in both the stalk and globular head domains of the molecule. The existence of such epitopes may allow for generation of novel therapeutic antibodies, in addition to serving as attractive targets of novel vaccine design. The aims of developing improved vaccines include eliciting broader protection from drifted strains, inducing long-lived immunity against seasonal strains, and allowing for the rational design of vaccines that can be stockpiled for use as pre-pandemic vaccines. In addition, an increased focus on influenza virus vaccine research has prompted an improved understanding of how the immune system responds to influenza virus infection. © Springer International Publishing Switzerland 2014.

Lee L.B.,Emory University
Ophthalmic surgery, lasers & imaging : the official journal of the International Society for Imaging in the Eye | Year: 2011

Spectral-domain optical coherence tomography (SD-OCT) is a non-invasive imaging modality that generates detailed images of retinal microstructure. In this study, this technology was employed to investigate changes that occur intraoperatively during repair of complex rhegmatogenous retinal detachment using perfluorocarbon liquids. Intraoperative SD-OCT images were obtained for two patients who underwent pars plana vitrectomy, perfluoro-n-octane instillation, and silicone oil fill for rhegmatogenous retinal detachment. The results demonstrate the ability to obtain high-resolution images of retinal architecture intraoperatively through perfluoro-n-octane and silicone oil. Residual subretinal fluid may be identified intraoperatively despite tamponade with perfluoro-n-octane. Copyright 2011, SLACK Incorporated.

Kasahara M.,Hokkaido University | Sutoh Y.,Emory University
Immunological Reviews | Year: 2015

Summary: NKG2D ligands (NKG2DLs) are a group of stress-inducible major histocompatibility complex (MHC) class I-like molecules that act as a danger signal alerting the immune system to the presence of abnormal cells. In mammals, two families of NKG2DL genes have been identified: the MIC gene family encoded in the MHC region and the ULBP gene family encoded outside the MHC region in most species. Some mammals have a third family of NKG2DL-like class I genes which we named MILL (MHC class I-like located near the leukocyte receptor complex). Despite the fact that MILL genes are more closely related to MIC genes than ULBP genes are to MIC genes, MILL molecules do not function as NKG2DLs, and their function remains unknown. With the progress of mammalian genome projects, information on the MIC, ULBP, and MILL gene families became available in many mammalian species. Here, we summarize such information and discuss the origin and evolution of the NKG2DL gene family from the viewpoint of host-pathogen coevolution. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Jacobson T.A.,Emory University
International Journal of Clinical Practice | Year: 2011

Targeting elevations in low-density lipoprotein cholesterol (LDL-C) remains the cornerstone of cardiovascular prevention. However, this fraction does not adequately capture elevated triglyceride-rich lipoproteins (TRLs; e.g. intermediate-density lipoprotein, very low density lipoprotein) in certain patients with metabolic syndrome or diabetic dyslipidaemia. Many such individuals have residual cardiovascular risk that might be lipid/lipoprotein related despite therapy with first-line agents (statins). Epidemiological evidence encompassing > 100,000 persons supports the contention that non-high-density lipoprotein cholesterol (non-HDL-C) is a superior risk factor vs. LDL-C for incident coronary heart disease (CHD) in certain patient populations. In studies with clinical end-points evaluated in the current article, a 1: 1 to 1: 3 relationship was observed between reductions in non-HDL-C and in the relative risk of CHD after long-term treatment with statins, niacin (nicotinic acid) and fibric-acid derivatives (fibrates); this relationship increased to 1: 5 to 1: 10 in smaller subgroups of patients with elevated triglycerides and low HDL-C levels. Treatment with statin-, niacin-, fibrate-, ezetimibe-, and omega 3 fatty acid-containing regimens reduced non-HDL-C by approximately 9-65%. In a range of clinical trials, long-term treatment with these agents also significantly decreased the incidence of clinical/angiographic/imaging efficacy outcome variables. For patients with dyslipidaemia, consensus guidelines have established non-HDL-C treatment targets 30 mg/dl higher than LDL-C goals. Ongoing prospective randomised controlled trials should help to resolve controversies concerning (i) the clinical utility of targeting non-HDL-C in patients with dyslipidaemia; (ii) the most efficacious and well-tolerated therapies to reduce non-HDL-C (e.g. combination regimens); and (iii) associations between such reductions and clinical, angiographic, and/or imaging end-points. © 2010 Blackwell Publishing Ltd.