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Charlottesville, VA, United States

The University of Virginia , often referred to as simply Virginia, is a public research university in Charlottesville, Virginia. UVA is known for its historic foundations, student-run honor code, and secret societies.Its initial Board of Visitors included U.S. Presidents Thomas Jefferson, James Madison, and James Monroe. President Monroe was the sitting President of the United States at the time of the founding; Jefferson and Madison were the first two rectors. UVA was established in 1819, with its Academical Village and original courses of study conceived and designed entirely by Jefferson. UNESCO designated it a World Heritage Site in 1987, an honor shared with nearby Monticello.The first university of the American South elected to the Association of American Universities in 1904, UVA is classified as Very High Research Activity in the Carnegie Classification. The university is affiliated with 7 Nobel Laureates, and has produced 7 NASA astronauts, 7 Marshall Scholars, 4 Churchill Scholars, 29 Truman Scholars, and 50 Rhodes Scholars, the most of any state-affiliated institution in the U.S. Supported in part by the Commonwealth, it receives far more funding from private sources than public, and its students come from all 50 states and 147 countries. It also operates a small liberal arts branch campus in the far southwestern corner of the state.Since 1953, Virginia's athletic teams have competed in the Atlantic Coast Conference of Division I of the NCAA and are known as the Virginia Cavaliers. Virginia won its 7th men's soccer national title in December 2014, bringing its collective total to 24 National Championships, and 63 ACC Championships since 2002 , the most of any conference member during that time. Wikipedia.

Myers N.L.,University of Virginia
Current Psychiatry Reports | Year: 2011

The incidence of schizophrenia, as well as the symptoms, course, and outcomes for people so diagnosed seem to vary across some cultural contexts. The mechanisms by which cultural variations may protect one from or increase one's risk of developing schizophrenia remain unclear. Recent findings from transdisciplinary cross-cultural research, indicate ways that we may better understand how socioenvironmental and cultural variables interact with physiologic pathways relating psychosocial stress and psychotic symptoms, epigenetic changes, and people's use of culturally available tools to mitigate stress, in ways that may inform relevant, effective interventions for people diagnosed with psychotic disorders worldwide. © 2011 Springer Science+Business Media, LLC.

DeKosky S.T.,University of Virginia
Alzheimer's & dementia : the journal of the Alzheimer's Association | Year: 2011

The current criteria for classification of Alzheimer's disease (AD) have deficiencies that limit drug development, research, and practice. The current standard for the clinical diagnosis of AD, the National Institute of Neurological and Communicative Disorders and Stroke (now known as the National Institute of Neurological Disorders and Stroke), and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) criteria, are nearly 25 years old and have not been revised to incorporate advances in the epidemiology and genetics of AD, studies of clinicopathologic correlations and recent studies of potential diagnostic biomarkers. In a very real sense our ability to diagnose AD with a very high level of certainty has outpaced our current diagnostic criteria. The Alzheimer's Association Research Roundtable convened a meeting in April 2009 to discuss new data and technologies that could, with further development, enable improvements in the clinical diagnosis of AD, especially in its earliest and mildest stages. This meeting reviewed the current standards for detecting and defining the clinical presentation of AD and discussed areas that could contribute to earlier and more accurate definitive clinical diagnosis. These included clinical, neuropsychological, and other performance-based assessments, genetic contributions, and biochemical and neuroimaging biomarkers that could reflect AD pathology and lead to better ascertainment of AD, mild cognitive impairment, and presymptomatic AD.

Simmonds J.G.,University of Virginia
Journal of Elasticity | Year: 2011

By integrating along a thickness-like coordinate, exact two-dimensional equations of motion and a Second Law of Thermodynamics (a Clausius-Duhem Inequality) are derived, without approximation, for a shell-like body. The theory derived is called classical because the only stress measures that appear are resultants and couples. Construction of a Virtual Power Identity automatically produces associated extensional and bending strains that are nonlinear in the deformed position ȳ of a reference surface and a rotation tensor Q. The only approximations come when the Virtual Power Identity is augmented by heating and an internal energy and the resulting expression taken as the First Law of Thermodynamics (Conservation of Energy) for the shell. A Legendre-Fenchel Transformation is introduced to remove possible ill-conditioning when certain approximations are introduced into the strain-energy density. © The Author(s) 2011.

Al-Shawi M.K.,University of Virginia
Essays in Biochemistry | Year: 2011

ABC (ATP-binding cassette) transporters are arguably the most important family of ATP-driven transporters in biology. Despite considerable effort and advances in determining the structures and physiology of these transporters, their fundamental molecular mechanisms remain elusive and highly controversial. How does ATP hydrolysis by ABC transporters drive their transport function? Part of the problem in answering this question appears to be a perceived need to formulate a universal mechanism. Although it has been generally hoped and assumed that the whole superfamily of ABC transporters would exhibit similar conserved mechanisms, this is proving not to be the case. Structural considerations alone suggest that there are three overall types of coupling mechanisms related to ABC exporters, small ABC importers and large ABC importers. Biochemical and biophysical characterization leads us to the conclusion that, even within these three classes, the catalytic and transport mechanisms are not fully conserved, but continue to evolve. ABC transporters also exhibit unusual characteristics not observed in other primary transporters, such as uncoupled basal ATPase activity, that severely complicate mechanistic studies by established methods. In this chapter, I review these issues as related to ABC exporters in particular. A consensus view has emerged that ABC exporters follow alternating-access switch transport mechanisms. However, some biochemical data suggest that alternating catalytic site transport mechanisms are more appropriate for fully symmetrical ABC exporters. Heterodimeric and asymmetrical ABC exporters appear to conform to simple alternating-access-type mechanisms. © 2011 Biochemical Society.

De Mellon Jr. F.,University of Virginia
Journal of Experimental Biology | Year: 2010

The antennular flagella of the crayfish Procambarus clarkii each possess a linear array of near-field receptors, termed standing feathered sensilla, that are extremely sensitive to movement of the surrounding water. Previously it had been shown that, within each flagellum, the axonal conduction velocity of the sensory neuron pair associated with each feathered sensillum was linearly related to the position of the sensillum along the flagellar axis. In the current studies I show that the conduction velocity of axons within the proximal three segments of the antennules, between the flagellum and the brain, is somewhat higher than the corresponding conduction velocity of the same axons in the flagellum, especially for those whose flagellar conduction velocity is between 1 and 3?m?s-1, even though there is no net change in axonal diameter within this part of the afferent pathway. One consequence of this change in axonal conduction properties is an effective compression of the temporal spread - potentially by as much as tenfold - which otherwise would occur in arrival times of initial spikes from each sensillum following a mechanical stimulus to the antennule. Furthermore, the pattern signature of initial spike volleys at the brain following a global hydrodynamic stimulus to the flagellum is remarkably consistent and conceivably could be recognized as such by central processing centers. I conclude that conduction velocity adjustments improve temporal summation and resolution from input volleys that originate in the highly sensitive and, hence, inherently noisy near-field receptors, thereby more effectively triggering startle response circuitry at the approach of potential predators. © 2010. Published by The Company of Biologists Ltd.

Sutherland A.E.,University of Virginia
Seminars in Cell and Developmental Biology | Year: 2016

Generation of the elongated vertebrate body plan from the initially radially symmetrical embryo requires comprehensive changes to tissue form. These shape changes are generated by specific underlying cell behaviors, coordinated in time and space. Major principles and also specifics are emerging, from studies in many model systems, of the cell and physical biology of how region-specific cell behaviors produce regional tissue morphogenesis, and how these, in turn, are integrated at the level of the embryo. New technical approaches have made it possible more recently, to examine the morphogenesis of the mouse embryo in depth, and to elucidate the underlying cellular mechanisms. This review focuses on recent advances in understanding the cellular basis for the early fundamental events that establish the basic form of the embryo. © 2016 Elsevier Ltd.

Pinkerton J.A.V.,University of Virginia | Santoro N.,Aurora University
Menopause | Year: 2015

Objective: Two surveys (Harris and Rose surveys) were conducted to quantify the use of compounded hormone therapy (CHT; or bioidentical hormone therapy) among perimenopausal and postmenopausal women in the United States, to assess women's knowledge of CHT versus Food and Drug Administration (FDA)-approved hormone therapy, and to gather information on menopausal experience. Methods: The Harris survey was administered to 801 women aged 45 to 60 years who had experienced at least one menopausal symptom. The Rose survey was administered to 2,044 women aged 40 years or older who were ever users of hormone therapy. Women were queried about menopausal symptoms, hormone therapy use, and knowledge of CHT. Findings from the Rose survey were extrapolated using US Census Bureau data and prescription claims for FDA-approved hormone therapy to estimate the prevalence of CHT use. Results: According to extrapolations using Rose data, up to 2.5 million US women aged 40 years or older may use CHT annually, accounting for 28% to 68% of hormone therapy prescriptions. Harris data showed that 86% of women surveyed were unaware that CHT products are not FDA-approved. The Rose survey asked a subset of 1,771 women whether their hormone therapy had been personalized based on hormone levels; 21% (378) answered "yes" whereas 27% (476) did not know. In both surveys, most hormone therapy users stated that their physician had recommended the treatment. Conclusions: We estimate that 1 million to 2.5 million US women aged 40 years or older use CHT. The data suggest that many women are unaware that compounded hormones have not been evaluated or approved by the FDA. Providers have an educational opportunity to ensure that women considering hormone therapy understand the risks and benefits of inadequately regulated CHT. © 2015 by The North American Menopause Society.

Under the Affordable Care Act, the new Center for Medicare and Medicaid Innovation will guide a number of experimental programs in health care payment and delivery. Among the most ambitious of the reform models is the accountable care organization (ACO), which will offer providers economic rewards if they can reduce Medicare's cost growth in their communities. However, the dismal history of provider-led attempts to manage costs suggests that this program is unlikely to accomplish its objectives. What's more, if ACOs foster more market concentration among providers, they have the potential to shift costs onto private insurers. This paper proposes a more flexible payment model for providers and private insurers that would divide health care services into three categories: long-term, low-intensity primary care; unscheduled care, including unscheduled emergency services; and major clinical interventions that usually involve hospitalization or organized outpatient care. Each category of care would be paid for differently, with each containing different elements of financial risk for the providers. Health plans would then be encouraged to provide logistical and analytic support to providers in managing health costs in these categories. ©2011 Project HOPE - The People-to-People Health Foundation, Inc.

Norte G.E.,University of Virginia
American journal of physical medicine & rehabilitation / Association of Academic Physiatrists | Year: 2010

To determine the relationship between quadriceps central activation ratios (CARs) derived from a percutaneous electrical stimulation (CAR(SIB)) and a transcranial magnetic stimulation (CAR(TMS)) in healthy participants. Nineteen healthy participants (5 men, 14 women, 23.7 ± 4.8 yrs, 66.8 ± 10.0 kg, and 170.1 ± 7.0 cm) qualified for this descriptive study. Muscle activation, using both methods (CAR(SIB) and CAR(TMS)), was measured at days 1, 14, and 28. All participants performed both methods in a counterbalanced order. Correlation coefficients and Bland-Altman plots were used to assess relationships and agreement between the two methods. For both methods, reliability was assessed at 14 and 28 days using Bland-Altman plots and intraclass correlation coefficients. CAR(TMS) scores were higher than CAR(SIB) scores for all three sessions, with mean differences between CAR scores of -0.06 (95% confidence interval, -0.19-0.07), -0.03 (95% confidence interval, -0.14-0.08), and -0.03 (95% confidence interval, -0.11-0.05). There was a significant moderate positive correlation between CAR(SIB) and CAR(TMS) at 14 days from baseline (ρ = 0.45, P = 0.05). Intersession reliability was strong for CAR(SIB) at 14 and 28 days from baseline (intraclass correlation coefficients = 0.80 [P = 0.001] and 0.85 [P < 0.001], respectively). Intersession reliability for CAR(TMS) was moderate from baseline to 14 days (intraclass correlation coefficients = 0.68 [P = 0.01]). It does not seem that the CAR(TMS) and CAR(SIB) methods are interchangeable measurements for evaluating volitional quadriceps activation; however, both measurements seem to have acceptable agreement at 14 and 28 days compared with day 1.

Olund C.T.,University of Virginia | Zhao E.,George Mason University
Physical Review B - Condensed Matter and Materials Physics | Year: 2012

Josephson junctions fabricated on the surface of three-dimensional topological insulators (TI) show a few unusual properties distinct from conventional Josephson junctions. In these devices, the Josephson coupling and the supercurrent are mediated by helical metal, the two-dimensional surface state of the TI. A line junction of this kind is known to support Andreev bound states at zero energy for phase bias π and, consequently, the so-called fractional ac Josephson effect. Motivated by recent experiments on TI-based Josephson junctions, here we describe a convenient algorithm to compute the bound-state spectrum and the current-phase relation for junctions of finite length and width. We present analytical results for the bound-state spectrum, and discuss the dependence of the current-phase relation on the length and width of the junction, the chemical potential of the helical metal, and temperature. A thorough understanding of the current-phase relation may help in designing topological superconducting qubits and manipulating Majorana fermions. © 2012 American Physical Society.

Saad W.E.A.,University of Virginia
Seminars in Interventional Radiology | Year: 2012

Portal vein interventions in liver transplant recipients represent a group of interventions in the management of several disease entities including portal vein stenosis, portal vein thrombosis, and recurrent liver cirrhosis with portal hypertension with and without gastric varices. The procedures performed in these patient populations include portal vein angioplasty with or without stent placement for portal vein stenosis, portal vein thrombolysis with or without stent placement for portal vein thrombosis, transjugular intrahepatic portosystemic shunts or splenic embolization for cirrhosis, and balloon-occluded retrograde transvenous obliteration for gastric varices. This article discusses these disease entities and the minimal invasive procedures used in their management. © Copyright 2012 by Thieme Medical Publishers, Inc.

Annex B.H.,University of Virginia
Nature Reviews Cardiology | Year: 2013

Peripheral arterial disease (PAD) is caused by occlusive atherosclerosis in a vascular bed other than the heart. The lower extremity is the most-common location for PAD. Critical limb ischaemia (CLI) is the most-severe clinical manifestation of PAD. Despite improvements in medical care and revascularization, patients with CLI continue to have a high risk of major amputation (below the knee or higher) and cardiovascular death. The primary goal of therapy in CLI is to achieve blood flow to the distal limb vessels with angioplasty or bypass surgery. However, many patients with CLI are unsuitable for revascularization, or the procedure is unsuccessful. Angiogenesis is the growth and proliferation of blood vessels from an existing vascular structure. In therapeutic angiogenesis, attempts are made to utilize blood vessel growth to augment perfusion. In this Review, data from phase II and III clinical trials of therapeutic angiogenesis in patients with PAD will be presented and discussed. Potential explanations for the limited success of therapeutic angiogenesis in humans will be viewed in the context of advances in our understanding of the complex mechanisms underlying angiogenesis and vascular remodelling. This Review will also cover how advances in systems biology, genetics, and gene therapy might still allow the development of new approaches to therapeutic angiogenesis and achieve the goal of restoring perfusion. © 2013 Macmillan Publishers Limited.

Platts-Mills T.A.E.,University of Virginia
Chemical Immunology and Allergy | Year: 2012

The 'foreignness' of proteins that we encounter in our homes and outdoors is in large part dependent on their evolutionary distance from man. This is relevant to understanding the differences between mammalian allergens, e.g. cats, and arthropod allergens, e.g. mites and cockroaches, as well as to understanding responses to a wide range of food allergens. On the other hand, allergic disease has gone through a major evolution of its own from a prehygiene state where there is minimal production of allergen-specific IgE, to the production of high-titer IgE, and then to the dramatic increase in asthma. The challenge is to understand how changes in both hygiene and lifestyle have contributed to the changes in allergic disease. © 2012 S. Karger AG, Basel.

Boyd J.C.,University of Virginia
Asian Journal of Andrology | Year: 2010

This article provides a brief overview of various approaches that may be utilized for the analysis of human semen test results. Reference intervals are the most widely used tool for the interpretation of clinical laboratory results. Reference interval development has classically relied on concepts elaborated by the International Federation of Clinical Chemistry Expert Panel on Reference Values during the 1980s. These guidelines involve obtaining and classifying samples from a healthy population of at least 120 individuals and then identifying the outermost 5% of observations to use in defining limits for two-sided or one-sided reference intervals. More recently, decision limits based on epidemiological outcome analysis have also been introduced to aid in test interpretation. The reference population must be carefully defined on the basis of the intended clinical use of the underlying test. To determine appropriate reference intervals for use in male fertility assessment, a reference population of men with documented time to pregnancy of 12 months would be most suitable. However, for epidemiological assessment of semen testing results, a reference population made up of unselected healthy men would be preferred. Although reference and decision limits derived for individual semen analysis test results will undoubtedly be the interpretational tools of choice in the near future, in the long term, multivariate methods for the interpretation of semen analysis alone or in combination with information from the female partner seem to represent better means for assessing the likelihood of achieving a successful pregnancy in a subfertile couple. © 2010 AJA, SIMM & SJTU.

McCaffrey L.M.,McGill University | Montalbano J.,University of Virginia | Mihai C.,McGill University | Macara I.G.,Vanderbilt University
Cancer Cell | Year: 2012

Loss of epithelial organization is a hallmark of carcinomas, but whether polarity regulates tumor growth and metastasis is poorly understood. To address this issue, we depleted the Par3 polarity gene by RNAi in combination with oncogenic Notch or Ras61L expression in the murine mammary gland. Par3 silencing dramatically reduced tumor latency in both models and produced invasive and metastatic tumors that retained epithelial marker expression. Par3 depletion was associated with induction of MMP9, destruction of the extracellular matrix, and invasion, all mediated by atypical PKC-dependant JAK/Stat3 activation. Importantly, Par3 expression is significantly reduced in human breast cancers, which correlates with active aPKC and Stat3. These data identify Par3 as a regulator of signaling pathways relevant to invasive breast cancer. © 2012 Elsevier Inc.

Klibanov A.L.,University of Virginia
Journal of Cardiovascular Translational Research | Year: 2013

Ultrasound imaging is widely used in cardiovascular diagnostics. Contrast agents expand the range of tasks that ultrasound can perform. In the clinic in the USA, endocardial border delineation and left ventricle opacification have been an approved indication for more than a decade. However, myocardial perfusion contrast ultrasound studies are still at the clinical trials stage. Blood pool contrast and perfusion in other tissues might be an easier indication to achieve: general blood pool ultrasound contrast is in wider use in Europe, Canada, Japan, and China. Targeted (molecular) contrast microbubbles will be the next generation of ultrasound imaging probes, capable of specific delineation of the areas of disease by adherence to molecular targets. The shell of targeted microbubbles (currently in the preclinical research and early stage clinical trials) is decorated with the ligands (antibodies, peptides or mimetics, hormones, and carbohydrates) that ensure firm binding to the molecular markers of disease. © 2013 Springer Science+Business Media New York.

Liedtka J.,University of Virginia
Journal of Product Innovation Management | Year: 2014

"Design thinking" has generated significant attention in the business press and has been heralded as a novel problem-solving methodology well suited to the often-cited challenges business organizations face in encouraging innovation and growth. Yet the specific mechanisms through which the use of design, approached as a thought process, might improve innovation outcomes have not received significant attention from business scholars. In particular, its utility has only rarely been linked to the academic literature on individual cognition and decision-making. This perspective piece advocates addressing this omission by examining "design thinking" as a practice potentially valuable for improving innovation outcomes by helping decision-makers reduce their individual level cognitive biases. In this essay, I first review the assumptions, principles, and key process tools associated with design thinking. I then establish its foundation in the decision-making literature, drawing on an extensive body of research on cognitive biases and their impact. The essay concludes by advancing a set of propositions and research implications, aiming to demonstrate one particular path that future research might take in assessing the utility of design thinking as a method for improving organizational outcomes related to innovation. In doing so, it seeks to address the challenge of conducting academic research on a practice that is obviously popular in management circles but appears resistant to rigorous empirical inquiry because of the multifaceted nature of its "basket" of tools and processes and the complexity of measuring the outcomes it produces. © 2014 Product Development & Management Association.

Blair J.,University of Virginia | Iwasaki T.,University of California at Los Angeles
IEEE Transactions on Automatic Control | Year: 2011

The essential mechanism underlying animal locomotion can be viewed as mechanical rectification that converts periodic body movements to thrust force through interactions with the environment. This paper defines a general class of mechanical rectifiers as multi-body systems equipped with such thrust generation mechanisms. A simple model is developed from the EulerLagrange equation by assuming small body oscillations around a given nominal posture. The model reveals that the rectifying dynamics can be captured by a bilinear, but not linear, term of body shape variables. An optimal gait problem is formulated for the bilinear rectifier model as a minimization of a quadratic cost function over the set of periodic functions subject to a constraint on the average locomotion velocity. We prove that a globally optimal solution is given by a harmonic gait that can be found by generalized eigenvalue computation with a line search over cycle frequencies. We provide case studies of a chain of links for which snake-like undulations and jellyfish-like flapping gaits are found to be optimal. © 2010 IEEE.

Saad W.E.A.,University of Virginia
Seminars in Interventional Radiology | Year: 2012

Patients with gastric variceal bleeding require a multidisciplinary team approach including hepatologists, endoscopists, diagnostic radiologists, and interventional radiologists. Upper gastrointestinal endoscopy is the first-line diagnostic and management tool for bleeding gastric varices, as it is in all upper gastrointestinal bleeding scenarios. In the United States when endoscopy fails to control gastric variceal bleeding, a transjugular intrahepatic portosystemic shunt (TIPS) traditionally is performed along the classic teachings of decompressing the portal circulation. However, TIPS has not shown the same effectiveness in controlling gastric variceal bleeding that it has with esophageal variceal bleeding. For the past 2 decades, the balloon-occluded retrograde transvenous obliteration (BRTO) procedure has become common practice in Asia for the management of gastric varices. BRTO is gaining popularity in the United States. It has been shown to be effective in controlling gastric variceal bleeding with low rebleed rates. BRTO has many advantages over TIPS in that it is less invasive and can be performed on patients with poor hepatic reserve and those with encephalopathy (and may even improve both). However, its by-product is occlusion of a spontaneous hepatofugal (TIPS equivalent) shunt, and thus it is contradictory to the traditional American doctrine of portal decompression. Indeed, BRTO causes an increase in portal hypertension, with potential aggravation of esophageal varices and ascites. This article discusses the concept, technique, and outcomes of BRTO within the broader management of gastric varices. © Copyright 2012 by Thieme Medical Publishers, Inc.

Rowlan J.S.,University of Virginia
Journal of the American Heart Association | Year: 2013

C3H/HeJ (C3H) mice are extremely resistant to atherosclerosis, especially males. To understand the underlying genetic basis, we performed quantitative trait locus (QTL) analysis on a male F2 (the second generation from an intercross between 2 inbred strains) cohort derived from an intercross between C3H and C57BL/6 (B6) apolipoprotein E-deficient (Apoe(-/-)) mice. Two hundred forty-six male F2 mice were started on a Western diet at 8 weeks of age and kept on the diet for 5 weeks. Atherosclerotic lesions in the aortic root and fasting plasma lipid levels were measured. One hundred thirty-four microsatellite markers across the entire genome were genotyped. Four significant QTLs on chromosomes (Chr) 2, 4, 9, and 15 and 4 suggestive loci on Chr1, Chr4, and Chr7 were identified for atherosclerotic lesions. Unexpectedly, the C3H allele was associated with increased lesion formation for 2 of the 4 significant QTLs. Six loci for high-density lipoprotein (HDL), 6 for non-HDL cholesterol, and 3 for triglycerides were also identified. The QTL for atherosclerosis on Chr9 replicated Ath29, originally mapped in a female F2 cohort derived from B6 and C3H Apoe(-/-) mice. This locus coincided with a QTL for HDL, and there was a moderate, but statistically significant, correlation between atherosclerotic lesion sizes and plasma HDL cholesterol levels in F2 mice. These data indicate that most atherosclerosis susceptibility loci are distinct from those for plasma lipids except for the Chr9 locus, which exerts effect through interactions with HDL.

Keith D.S.,University of Virginia
Clinics in Geriatric Medicine | Year: 2013

During the last 2 decades, the number of kidney transplants performed in the candidates older than 65 years has grown dramatically. For selected geriatric patients with end-stage kidney failure, kidney transplantation has emerged as a potential option for treatment of their end organ failure. Aging is associated with functional changes to the immune system known as immunosenescence, and this age-related decline in immune function has important implications for immunosuppression in this subgroup of kidney transplant recipients. © 2013 Elsevier Inc.

Angle J.F.,University of Virginia
Techniques in Vascular and Interventional Radiology | Year: 2013

Cone-beam computed tomography (CBCT) provides three-dimensional rendering of opacified vascular structures that are very useful for catheter guidance and anatomical correlation in many arterial and venous procedures. CBCT has been shown to improve the technical success of transarterial chemoembolization (TACE), which may lead to better outcomes. Similarly, it is useful in planning for selective internal radiation therapy of the liver by defining the treatment volume and preventing misembolization. There is emerging application of CBCT fusion with magnetic resonance angiography (MRA) or computed tomographic angiography (CTA) for use in catheterization or needle puncture of otherwise difficult to opacify vascular structures. CBCT also has a role in needle guidance for type II endoleak embolization, translumbar venous catheter placement, and embolization of vascular malformations. © 2013.

Sabol T.J.,Northwestern University | Pianta R.C.,University of Virginia
Attachment and Human Development | Year: 2012

Theoretical and empirical work on relationships between teachers and children relies on developmental systems theory as the foundational conceptual model, drawing heavily from basic work in attachment as well as research on social development. Recently, the focus on relational processes in effort to support children's development in the classroom has proliferated, with multiple disciplines and fields engaging in research on teacher-child relationship quality to understand and improve the experiences and learning of students. This paper updates the conceptual framework and continues the necessary integration between disciplines by exploring three areas of research: (1) concordance between children's relationships with teachers and parents; (2) the moderating role of teacher-child relationships for the development of at-risk children; and (3) training teachers from a relational perspective. Each of the three areas of research on teacher-child relationships is examined in light of recent findings and considers implications for understanding the nature and impact of relationships between teachers and children. © 2012 Copyright Taylor and Francis Group, LLC.

Garson A.,University of Virginia
Academic Medicine | Year: 2013

Improving access to appropriate health care, currently inadequate for many Americans, is more complex than merely increasing the projected number of physicians and nurses. Any attainable increase in their numbers will not solve the problem. To bring supply and demand closer, new systems of care are required, leveraging every member of the health care workforce, permitting professionals to provide their unique contributions.To increase supply: Redefine the roles of physicians and nurse practitioners (NPs), assess how much primary care must be delivered by a physician, and provide support from other team members to let the physician deal with complex patients. NPs can deliver much primary care and some specialty care. Care must be delivered in integrated systems permitting new payment models (e.g., salary with bonus) and team-based care as well as maximum use of electronic health records. Teams must make better use of nonprofessionals, such as Grand-Aides, using telephone protocols and portable telemedicine with home visits and online direct reporting of every encounter. The goals are to improve health and reduce unnecessary clinic and emergency department visits, admissions, and readmissions.To decrease demand: Physician payment must foster quality and appropriate patient volume (if accompanied by high patient satisfaction). Patients must be part of the team, work to remain healthy, and reduce inappropriate demand.The nation may not need as many physicians and nurses if the systems can be changed to promote integration, leveraging every member of the workforce to perform at his or her maximum competency.

Kaun K.R.,University of California at San Francisco | Azanchi R.,University of California at San Francisco | Maung Z.,University of California at San Francisco | Hirsh J.,University of Virginia | Heberlein U.,University of California at San Francisco
Nature Neuroscience | Year: 2011

The rewarding properties of drugs contribute to the development of abuse and addiction. We developed a new assay for investigating the motivational properties of ethanol in the genetically tractable model Drosophila melanogaster. Flies learned to associate cues with ethanol intoxication and, although transiently aversive, the experience led to a long-lasting attraction for the ethanol-paired cue, implying that intoxication is rewarding. Temporally blocking transmission in dopaminergic neurons revealed that flies require activation of these neurons to express, but not develop, conditioned preference for ethanol-associated cues. Moreover, flies acquired, consolidated and retrieved these rewarding memories using distinct sets of neurons in the mushroom body. Finally, mutations in scabrous, encoding a fibrinogen-related peptide that regulates Notch signaling, disrupted the formation of memories for ethanol reward. Our results thus establish that Drosophila can be useful for understanding the molecular, genetic and neural mechanisms underling the rewarding properties of ethanol. © 2011 Nature America, Inc. All rights reserved.

Salerno M.,University of Virginia
Journal of Nuclear Cardiology | Year: 2010

Non-invasive evaluation of diastolic function continues to play a critical role in furthering our understanding of diastole, improving the diagnosis of diastolic dysfunction, evaluating left ventricular filling pressures, and providing important prognostic information for patients with heart failure. Echocardiography, cardiovascular magnetic resonance, and nuclear cardiology each provide important tools for evaluating diastolic performance. This review will focus on the techniques from multiple cardiovascular imaging modalities which have been used for the clinical assessment of diastolic function. Copyright © 2010 by the American Society of Nuclear Cardiology.

Zhou B.,Harbin Institute of Technology | Lin Z.,University of Virginia
Automatica | Year: 2014

We study in this paper the consensus problem for multi-agent systems with agents characterized by high-order linear systems with time delays in both the communication network and inputs. Provided that the open-loop dynamics of the agents is not exponentially unstable, but may be polynomially unstable, and the communication topology contains a directed spanning tree, a truncated predictor feedback approach is established to solve the consensus problem. It is shown that, if the delays are constant and exactly known, the consensus problems can be solved by both full state feedback and observer based output feedback protocols for arbitrarily large yet bounded delays. If it is further assumed that the open-loop dynamics of the agents only contains zero eigenvalues, the delays are allowed to be time-varying and unknown. Numerical examples are worked out to illustrate the effectiveness of the proposed approaches. © 2013 Elsevier Ltd. All rights reserved.

Malhotra N.R.,University of Pennsylvania | Shaffrey C.I.,University of Virginia
Spine | Year: 2010

Study Design: Review of the literature with analysis of pooled data. Objective: To assess common intraoperative neuromonitoring (IOM) changes that occur during the course of spinal surgery, potential causes of change, and determine appropriate responses. Further, there will be discussion of appropriate application of IOM, and medical legal aspects. The structured literature review will answer the following questions: What are the various IOM methods currently available for spinal surgery? What are the sensitivities and specificities of each modality for neural element injury? How are the changes in each modality best interpreted? What is the appropriate response to indicated changes? Recommendations will be made as to the interpretation and appropriate response to IOM changes. Summary of Background Data: Total number of abstracts identified and reviewed was 187. Full review was performed on 18 articles. Methods: The MEDLINE database was queried using the search terms IOM, spinal surgery, SSEP, wake-up test, MEP, spontaneous and triggered electromyography alone and in various combinations. Abstracts were identified and reviewed. Individual case reports were excluded. Detailed information and data from appropriate articles were assessed and compiled. Results: Ability to achieve IOM baseline data varied from 70% to 98% for somatosensory-evoked potentials (SSEP) and 66% to 100% for motor-evoked potentials (MEP) in absence of neural axis abnormality. Multimodality intraoperative neuromonitoring (MIOM) provided false negatives in 0% to 0.79% of cases, whereas isolated SSEP monitoring alone provided false negative in 0.063% to 2.7% of cases. MIOM provided false positive warning in 0.6% to 1.38% of cases. CONCLUSION.: As spine surgery, and patient comorbidity, becomes increasingly complex, IOM permits more aggressive deformity correction and tumor resection. Combination of SSEP and MEP monitoring provides assessment of entire spinal cord functionality in real time. Spontaneous and triggered electromyography add assessment of nerve roots. The wake-up test can continue to serve as a supplement when needed. MIOM may prove useful in preservation of neurologic function where an alteration of approach is possible. IOM is a valuable tool for optimization of outcome in complex spinal surgery. © 2010, Lippincott Williams & Wilkins.

Agnew S.R.,University of Virginia | Nie J.F.,Monash University
Scripta Materialia | Year: 2010

Research papers, which will guide future research aimed in magnesium alloys at improving the properties and broadening the structural applications of the metal, are discussed. Three papers in the viewpoint set are devoted to creep mechanisms and development of creep-resistant alloys. The paper by Saddock and co-researchers demonstrate that there is no significant contribution of grain boundary sliding to creep in alloys based on the Mg-Al-Ca system, at least when tested at 175°C. Spigarelli and El Mehtedi make a comparison of the constitutive response in creep and hot torsion of both cast and wrought magnesium alloys, obtained in the temperature range 100-150°C. The potential to develop high-strength low-cost magnesium wrought alloys through precipitation hardening is discussed in the paper by Hono and co-researchers, with emphasis on microalloying additions to Mg-Zn and Mg-Sn alloys. The paper by Kim and researchers predicts that even twinroll cast material is not free from the concerns associated with strong basal texture that have plagued traditional direct-chill cast and hot-rolled materials.

Glanowska K.M.,University of Virginia | Burger L.L.,University of Michigan | Moenter S.M.,University of Michigan
Journal of Neuroscience | Year: 2014

Acquisition of a mature pattern of gonadotropin-releasing hormone (GnRH) secretion from theCNSis a hallmark of the pubertal process. Little is known about GnRH release during sexual maturation, but it is assumed to be minimal before later stages of puberty. We studied spontaneous GnRH secretion in brain slices from male mice during perinatal and postnatal development using fast-scan cyclic voltammetry (FSCV) to detect directly the oxidation of secreted GnRH. There was good correspondence between the frequency of GnRH release detected by FSCV in the median eminence of slices from adults with previous reports of in vivo luteinizing hormone (LH) pulse frequency. The frequency of GnRH release in the late embryonic stage was surprisingly high, reaching a maximum in newborns and remaining elevated in 1-week-old animals despite low LH levels. Early high-frequency GnRH release was similar in wild-type and kisspeptin knock-out mice indicating that this release is independent of kisspeptin-mediated excitation. In vivo treatment with testosterone or in vitro treatment with gonadotropin-inhibitory hormone (GnIH) reduced GnRH release frequency in slices from 1-week-old mice. RF9, a putative GnIH antagonist, restoredGnRHrelease in slices from testosterone-treated mice, suggesting that testosterone inhibition may be GnIH-dependent. At 2-3 weeks, GnRH release is suppressed before attaining adult patterns. Reduction in early life spontaneous GnRH release frequency coincides with the onset of the ability of exogenous GnRH to induce pituitary LH secretion. These findings suggest that lack of pituitary secretory response, not lack of GnRH release, initially blocks downstream activation of the reproductive system. © 2014 the authors.

Clayton A.H.,University of Virginia
International Journal of Gynecology and Obstetrics | Year: 2010

Hypoactive sexual desire disorder (HSDD) is defined as a deficiency or absence of sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulty. The dysfunction cannot be better accounted for by another psychiatric disorder (except another sexual dysfunction) and must not be due exclusively to the physiological effects of a substance or a general medical condition. HSDD occurs in approximately 1 in 10 adult women in the USA and its prevalence appears to be similar in Europe. A number of potential causative and contributory factors to low sexual desire have been identified, reflecting the interplay among hormonal, neurobiological, and psychosocial factors. One theory is that sexual desire is controlled in the brain by a balance between inhibitory and excitatory factors. In general, dopamine, estrogen, progesterone, and testosterone play an excitatory role in sexual desire, whereas serotonin, prolactin, and opioids play an inhibitory role. It is hypothesized that decreased sexual desire may be due to a reduced level of excitatory activity, an increased level of inhibitory activity, or both. A greater understanding of the complex pathophysiology of HSDD would improve the identification and management of women for whom low sexual desire is a concern. © 2010 International Federation of Gynecology and Obstetrics.

Clines G.A.,University of Virginia
Current Opinion in Organ Transplantation | Year: 2010

Purpose of review: Bone regeneration and fracture repair are the complex processes of mesenchymal stem cell invasion, chondrogenesis, osteogenesis and angiogenesis. The coordinated actions of these principal processes result in the reconstruction of a normal bone and restoration of a structural unit. However, these normal bone regenerative mechanisms breakdown during fracture repair failure and postmenopausal osteoporosis. Recent findings: Recent discoveries of circulating multipotent stem cells with mixed characteristics of endothelial cell and osteogenic capacity have raised interest in new and potentially breakthrough therapies for fracture and pathologic bone loss. The cooperative actions of other mesenchymal stem cell lineage such as adipocytes and processes such as angiogenesis in bone repair could also serve as novel therapeutic targets. Recent data suggest that anabolic parathyroid hormone therapy, already approved for the treatment of osteoporosis, may recruit osteoprogenitor cells and also have a role in fracture repair. Summary: The present review will highlight recent information on stem cells and bone repair and examine potential avenues for future research. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Caldwell S.,University of Virginia
Current Gastroenterology Reports | Year: 2010

Cryptogenic cirrhosis remains a common clinical condition although recent advances have allowed for a better understanding of underlying conditions and associations. The evolving terminology applied to this condition has resulted in some confusion and persistent variation among pathologists and clinicians. Typical patients are middle aged with only minor liver enzyme abnormalities. Presentations range from incidentally discovered cirrhosis to complications of advanced portal hypertension and hepatocellular cancer. Clinicopathologic analysis of these patients indicates that the leading causes include previously unrecognized nonalcoholic steatohepatitis, silent autoimmune hepatitis, non-B, non-C viral hepatitis, and occult past ethanol exposure. In this article, we review these associations as well as a proposed classification system for cryptogenic cirrhosis and other lesser known genetic and syndromic associations that warrant consideration when evaluating these individuals. © 2010 Springer Science+Business Media, LLC.

BACKGROUND AND PURPOSE—: Noncontrasted head computed tomography (NCHCT) has long been the standard of care for acute stroke imaging. New guidelines recommending advanced vascular imaging to identify eligible patients for endovascular therapy have renewed safety concerns on the use of contrast in the emergent setting without laboratory confirmation of renal function. METHODS—: We compared computed tomographic angiography (CTA) versus NCHCT alone during acute stroke evaluation with focus on renal safety and timeliness of therapy delivery. We reviewed data on all emergency department patients for whom the Acute Stroke Intervention Team was activated between December 2013 and September 2014. Primary outcomes included acute kidney injury and change in serum creatinine from presentation to 24 to 48 hours (Δ serum creatinine [Cr]). We assessed therapy delay using door-to-CT and door-to-needle times. RESULTS—: Of 289 patients requiring Acute Stroke Intervention Team activation, 157 received CTA and 132 NCHCT only. There was no difference between groups in mean Cr at 24 to 48 hours (1.06 CTA; 1.40 NCHCT; P=0.059), ΔCr (−0.07 CTA, −0.11 NCHCT, P=0.489), or rates of acute kidney injury (5 CTA, 7 NCHCT, P=0.422). There was no significant difference in mean intravenous tissue plasminogen activator treatment times (68.11 minutes CTA, 81.36 minutes NCHCT; P=0.577). In the 157 patients who underwent CTA, 16 (10.2%) vascular anomalies and 55 (35.0%) high-grade stenoses or occlusions were identified. CONCLUSIONS—: CTA acquisition during acute stroke evaluation was safe with regards to renal function and did not delay appropriate therapy delivery. Acute CTA acquisition offers additional clinical value in rapid identification of vascular abnormalities. © 2016 American Heart Association, Inc.

Mugler J.P.,University of Virginia
Journal of Magnetic Resonance Imaging | Year: 2014

Spin-echo-based acquisitions are the workhorse of clinical MRI because they provide a variety of useful image contrasts and are resistant to image artifacts from radio-frequency or static field inhomogeneity. Three-dimensional (3D) acquisitions provide datasets that can be retrospectively reformatted for viewing in freely selectable orientations, and are thus advantageous for evaluating the complex anatomy associated with many clinical applications of MRI. Historically, however, 3D spin-echo-based acquisitions have not played a significant role in clinical MRI due to unacceptably long acquisition times or image artifacts associated with details of the acquisition method. Recently, optimized forms of 3D fast/turbo spin-echo imaging have become available from several MR-equipment manufacturers (for example, CUBE [GE], SPACE [Siemens], and VISTA [Philips]). Through specific design strategies and optimization, including short non-spatially selective radio-frequency pulses to significantly shorten the echo spacing and variable flip angles for the refocusing radio-frequency pulses to suppress blurring or considerably lengthen the useable duration of the spin-echo train, these techniques permit single-slab 3D imaging of sizeable volumes in clinically acceptable acquisition times. These optimized fast/turbo spin-echo pulse sequences provide a robust and flexible approach for 3D spin-echo-based imaging with a broad range of clinical applications. © 2014 Wiley Periodicals, Inc.

Fairchild K.D.,University of Virginia
Current Opinion in Pediatrics | Year: 2013

PURPOSE OF REVIEW: Predictive monitoring is an exciting new field involving analysis of physiologic data to detect abnormal patterns associated with critical illness. The first example of predictive monitoring being taken from inception (proof of concept) to reality (demonstration of improved outcomes) is the use of heart rate characteristics (HRC) monitoring to detect sepsis in infants in the neonatal ICU. The commercially available 'HeRO' monitor analyzes electrocardiogram data from existing bedside monitors for decreased HR variability and transient decelerations associated with sepsis, and converts these changes into a score (the HRC index or HeRO score). This score is the fold increase in probability that a patient will have a clinical deterioration from sepsis within 24h. This review focuses on HRC monitoring and discusses future directions in predictive monitoring of ICU patients. RECENT FINDINGS: In a randomized trial of 3003 very low birthweight infants, display of the HeRO score reduced mortality more than 20%. Ongoing research aims to combine respiratory and HR analysis to optimize care of ICU patients. SUMMARY: Predictive monitoring has recently been shown to save lives. Harnessing and analyzing the vast amounts of physiologic data constantly displayed in ICU patients will lead to improved algorithms for early detection, prognosis, and therapy of critical illnesses. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Izotov Y.I.,Ukrainian Academy of Sciences | Thuan T.X.,University of Virginia | Guseva N.G.,Ukrainian Academy of Sciences
Monthly Notices of the Royal Astronomical Society | Year: 2014

We present near-infrared (NIR) spectroscopic observations of the high-intensity He I λ10830 Å emission line in 45 low-metallicity HII regions. We combined these NIR data with spectroscopic data in the optical range to derive the primordial He abundance. The use of the He I λ10830 Å line, the intensity of which is very sensitive to the density of the HII region, greatly improves the determination of the physical conditions in the He+ zone. This results in a considerably tighter Y-O/H linear regression compared to all previous studies.We extracted a final sample of 28 HII regions with Hβ equivalent width EW(Hβ) = 150 Å, excitation parameter O2 +/O = 0.8, and with helium mass fraction Y derived with an accuracy better than 3 per cent. With this final sample we derived a primordial 4He mass fraction Yp = 0.2551 ± 0.0022. The derived value of Yp is higher than the one predicted by the standard big bang nucleosynthesis model. Using our derived Yp together with D/H = (2.53 ± 0.04) × 10-5, and the x2 technique, we found that the best agreement between these light element abundances is achieved in a cosmological model with a baryon mass density Ωbh2 = 0.0240 ± 0.0017 (68 per cent confidence level, CL), ± 0.0028 (95.4 per cent CL), ± 0.0034 (99 per cent CL) and an effective number of neutrino species Neff = 3.58 ± 0.25 (68 per cent CL), ± 0.40 (95.4 per cent CL), ± 0.50 (99 per cent CL). A non-standard value of Neff is preferred at the 99 per cent CL, implying the possible existence of additional types of neutrino species. © 2014 The Authors.

Saad W.E.A.,University of Virginia
Seminars in Interventional Radiology | Year: 2011

The concept of obliterating varices that complicate portal hypertension dates back to the 1970s, but its minimally invasive clinical utilization was probably lost with the advent of the transjugular intrahepatic portosystemic shunt (TIPS). The conception of retrograde obliteration of a gastrorenal shunt via the left renal vein was reported by Olson et al from the University of Indiana. However, the definition, development, technical perfection, and clinical implementation of the balloon-occluded retrograde transvenous obliteration (BRTO) occurred in Japan (by Kanagawa et al and others). The BRTO-procedure is currently undergoing a renaissance in the United States particularly for patients who are not TIPS candidates. © 2011 by Thieme Medical Publishers, Inc.

Herbst E.,University of Virginia
Physical Chemistry Chemical Physics | Year: 2014

The interdisciplinary science of astrochemistry is 45 years of age, if we pinpoint its origin to have occurred when the first polyatomic molecules were detected in the interstellar gas. Since that time, the field has grown remarkably from an esoteric area of research to one that unites scientists around the globe. Almost 200 different molecules have been detected in the gas-phase of interstellar clouds, mainly by rotational spectroscopy, while dust particles and their icy mantles in colder regions can be probed by vibrational spectroscopy. Astrochemistry is exciting to scientists in a number of different fields. Astronomers are interested in molecular spectra from the heavens because such spectra are excellent probes of the physical conditions where molecules exist, while chemists are interested in the exotic molecules, their spectra, and the unusual chemical processes that produce and destroy them under conditions often very different from those on our home planet. Chemical simulations involving thousands of reactions are now used to calculate concentrations and spectra of interstellar molecules as functions of time. Even biologists share an interest in the subject, because the interstellar clouds of gas and dust, portions of which collapse to form stars and planetary systems, contain organic molecules that may become part of the initial inventory of new planets and may indeed be the precursors of life. An irresistible subject to its practitioners, astrochemistry is proving to be exciting to a much wider audience. In this perspective article, the field is first introduced, and the emphasis is then placed on the three environments in which chemistry occurs in the interstellar medium: the gas phase, the surfaces of bare dust particles, and the ice mantles that cover bare grains in cold dense interstellar clouds. What we do know and what we do not know is distinguished. The status of chemical simulations for a variety of interstellar sources having to do with stellar and planetary evolution is surveyed. An optimistic view of the future of astrochemistry ends the article. © 2014 the Owner Societies.

Pu L.,University of Virginia
Accounts of Chemical Research | Year: 2014

ConspectusChiral alcohols are ubiquitous in organic structures. One efficient method to generate chiral alcohols is the catalytic asymmetric addition of a carbon nucleophile to a carbonyl compound since this process produces a C-C bond and a chiral center simultaneously. In comparison with the carbon nucleophiles such as an organolithium or a Grignard reagent, an organozinc reagent possesses the advantages of functional group tolerance and more mild reaction conditions. Catalytic asymmetric reactions of aldehydes with arylzincs, vinylzincs, and alkynylzincs to generate functional chiral alcohols are discussed in this Account.Our laboratory has developed a series of 1,1′-bi-2-naphthol (BINOL)-based chiral catalysts for the asymmetric organozinc addition to aldehydes. It is found that the 3,3′-dianisyl- substituted BINOLs are not only highly enantioselective for the alkylzinc addition to aldehydes, but also highly enantioselective for the diphenylzinc addition to aldehydes. A one-step synthesis has been achieved to incorporate Lewis basic amine groups into the 3,3′-positions of the partially hydrogenated H8BINOL. These H8BINOL-amine compounds have become more generally enantioselective and efficient catalysts for the diphenylzinc addition to aldehydes to produce various types of chiral benzylic alcohols. The application of the H8BINOL-amine catalysts is expanded by using in situ generated diarylzinc reagents from the reaction of aryl iodides with ZnEt2, which still gives high enantioselectivity and good catalytic activity. Such a H8BINOL-amine compound is further found to catalyze the highly enantioselective addition of vinylzincs, in situ generated from the treatment of vinyl iodides with ZnEt2, to aldehydes to give the synthetically very useful chiral allylic alcohols.We have discovered that the unfunctionalized BINOL in combination with ZnEt2 and Ti(O iPr)4 can catalyze the terminal alkyne addition to aldehydes to produce chiral propargylic alcohols of high synthetic utility. The reaction was conducted by first heating an alkyne with ZnEt2 in refluxing toluene to generate an alkynylzinc reagent, which can then add to a broad range of aldehydes at room temperature in the presence of BINOL and Ti(OiPr)4 with high enantioselectivity. It was then found that the addition of a catalytic amount of dicyclohexylamine (Cy2NH) allows the entire process to be conducted at room temperature without the need to generate the alkynylzincs at elevated temperature. This BINOL-ZnEt 2-Ti(OiPr)4-Cy2NH catalyst system can be used to catalyze the reaction of structurally diverse alkynes with a broad range of aldehydes at room temperature with high enantioselectivity and good catalytic activity.The work described in this Account demonstrates that BINOL and its derivatives can be used to develop highly enantioselective catalysts for the asymmetric organozinc addition to aldehydes. These processes have allowed the efficient synthesis of many functional chiral alcohols that are useful in organic synthesis. © 2014 American Chemical Society.

Gurung P.,St Jude Childrens Research Hospital | Lukens J.R.,St Jude Childrens Research Hospital | Lukens J.R.,University of Virginia | Kanneganti T.-D.,St Jude Childrens Research Hospital
Trends in Molecular Medicine | Year: 2015

Recent studies have identified new roles for mitochondria in the regulation of autoinflammatory processes. Emerging data suggests that the release of danger signals from mitochondria in response to stress and infection promotes the formation of the inflammatory signaling platform known as inflammasomes. Activation of inflammasomes by damaged mitochondria results in caspase-1-dependent secretion of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18, and an inflammatory form of cell death referred to as pyroptosis. Here, we review recently described mechanisms that have been proposed to be involved in mitochondria-mediated regulation of inflammasome activation and inflammation. In addition, we highlight how aberrant regulation of mitochondria-induced inflammasome activation centrally contributes to the inflammatory process that is responsible for obesity and associated metabolic diseases. © 2014 Elsevier Ltd.

Miller J.L.,University of Virginia
Sub-cellular biochemistry | Year: 2013

Although the field of genetics has grown by leaps and bounds within the last decade due to the completion and availability of the human genome sequence, transcriptional regulation still cannot be explained solely by an individual's DNA sequence. Complex coordination and communication between a plethora of well-conserved chromatin modifying factors are essential for all organisms. Regulation of gene expression depends on histone post translational modifications (HPTMs), DNA methylation, histone variants, remodeling enzymes, and effector proteins that influence the structure and function of chromatin, which affects a broad spectrum of cellular processes such as DNA repair, DNA replication, growth, and proliferation. If mutated or deleted, many of these factors can result in human disease at the level of transcriptional regulation. The common goal of recent studies is to understand disease states at the stage of altered gene expression. Utilizing information gained from new high-throughput techniques and analyses will aid biomedical research in the development of treatments that work at one of the most basic levels of gene expression, chromatin. This chapter will discuss the effects of and mechanism by which histone modifications and DNA methylation affect transcriptional regulation.

Haimes Y.Y.,University of Virginia
Risk Analysis | Year: 2011

This article highlights the complexity of the quantification of the multidimensional risk function, develops five systems-based premises on quantifying the risk of terrorism to a threatened system, and advocates the quantification of vulnerability and resilience through the states of the system. The five premises are: (i) There exists interdependence between a specific threat to a system by terrorist networks and the states of the targeted system, as represented through the system's vulnerability, resilience, and criticality-impact. (ii) A specific threat, its probability, its timing, the states of the targeted system, and the probability of consequences can be interdependent. (iii) The two questions in the risk assessment process: "What is the likelihood?" and "What are the consequences?" can be interdependent. (iv) Risk management policy options can reduce both the likelihood of a threat to a targeted system and the associated likelihood of consequences by changing the states (including both vulnerability and resilience) of the system. (v) The quantification of risk to a vulnerable system from a specific threat must be built on a systemic and repeatable modeling process, by recognizing that the states of the system constitute an essential step to construct quantitative metrics of the consequences based on intelligence gathering, expert evidence, and other qualitative information. The fact that the states of all systems are functions of time (among other variables) makes the time frame pivotal in each component of the process of risk assessment, management, and communication. Thus, risk to a system, caused by an initiating event (e.g., a threat) is a multidimensional function of the specific threat, its probability and time frame, the states of the system (representing vulnerability and resilience), and the probabilistic multidimensional consequences. © 2011 Society for Risk Analysis.

Columbus L.,University of Virginia
Current Opinion in Structural Biology | Year: 2015

Currently, membrane proteins only comprise 1.5% of the protein data bank and, thus, still remain a challenge for structural biologists. Expression, stabilization in membrane mimics (e.g. detergent), heterogeneity (conformational and chemical), and crystallization in the presence of a membrane mimic are four major bottlenecks encountered. In response, several post-expression protein modifications have been utilized to facilitate structure determination of membrane proteins. This review highlights four approaches: limited proteolysis, deglycosylation, cysteine alkylation, and lysine methylation. Combined these approaches have facilitated the structure determination of more than 40 membrane proteins and, therefore, are a useful addition to the membrane protein structural biologist's toolkit. © 2015 Elsevier Ltd.

Santos W.L.,Virginia Polytechnic Institute and State University | Lynch K.R.,University of Virginia
ACS Chemical Biology | Year: 2015

The transfer of the gamma phosphate from ATP to sphingosine (Sph) to generate a small signaling molecule, sphingosine 1-phosphate (S1P), is catalyzed by sphingosine kinases (SphK), which exist as two isoforms, SphK1 and SphK2. SphK is a key regulator of S1P and the S1P:Sph/ceramide ratio. Increases in S1P levels have been linked to diseases including sickle cell disease, cancer, and fibrosis. Therefore, SphKs are potential targets for drug discovery. However, the current chemical biology toolkit needed to validate these enzymes as drug targets is inadequate. With this review, we survey in vivo active SphK inhibitors and highlight the need for developing more potent and selective inhibitors. © 2014 American Chemical Society.

Egelman E.H.,University of Virginia
Archives of Biochemistry and Biophysics | Year: 2015

The field of three-dimensional electron microscopy began more than 45 years ago with a reconstruction of a helical phage tail, and helical polymers continue to be important objects for three-dimensional reconstruction due to the centrality of helical protein and nucleoprotein polymers in all aspects of biology. We are now witnessing a fundamental revolution in this area, made possible by direct electron detectors, which has led to near-atomic resolution for a number of important helical structures. Most importantly, the possibility of achieving such resolution routinely for a vast number of helical samples is within our reach. One of the main problems in helical reconstruction, ambiguities in assigning the helical symmetry, is overcome when one reaches a resolution where secondary structure is clearly visible. However, obstacles still exist due to the intrinsic variability within many helical filaments. © 2015 Elsevier Inc. All rights reserved.

Community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) strains have emerged as major human pathogens. CA-MRSA virulence appears to be distinct from healthcare-associated (HA) MRSA with several factors [α-hemolysin (Hla), Panton-Valentine leukocidin (PVL), α-type phenol soluble modulins (PSMα) and SCCmec IV] postulated to enhance virulence or fitness. Using the Caenorhabditis elegans infection model, we compared the virulence of clinical and laboratory isolates of CA-MRSA and HA-MRSA and explored the contribution of CA-MRSA associated virulence factors to nematode killing. All CA-MRSA strains were highly pathogenic to nematodes, while HA-MRSA strains demonstrated variable nematode killing. Nematode killing by isogenic mutants of hla or the loci for PVL, PSMα, PSMβ, PSMδ or SCCmec IV was not different than the parental strains. These results demonstrate that CA-MRSA is highly virulent, shows some strains of HA-MRSA are equally virulent toward nematodes and suggests CA-MRSA virulence in C. elegans is not linked to a single virulence factor.

Rychak J.J.,Targeson Inc. | Klibanov A.L.,University of Virginia
Advanced Drug Delivery Reviews | Year: 2014

Nucleic acid-based therapy is a growing field of drug delivery research. Although ultrasound has been suggested to enhance transfection decades ago, it took a combination of ultrasound with nucleic acid carrier systems (microbubbles, liposomes, polyplexes, and viral carriers) to achieve reasonable nucleic acid delivery efficacy. Microbubbles serve as foci for local deposition of ultrasound energy near the target cell, and greatly enhance sonoporation. The major advantage of this approach is in the minimal transfection in the non-insonated non-target tissues. Microbubbles can be simply co-administered with the nucleic acid carrier or can be modified to carry nucleic acid themselves. Liposomes with embedded gas or gas precursor particles can also be used to carry nucleic acid, release and deliver it by the ultrasound trigger. Successful testing in a wide variety of animal models (myocardium, solid tumors, skeletal muscle, and pancreas) proves the potential usefulness of this technique for nucleic acid drug delivery. © 2014 Elsevier B.V.

Horwitz A.R.,University of Virginia
Nature Reviews Molecular Cell Biology | Year: 2012

Recognition of the importance of cell adhesion grew steadily during the twentieth century as it promised answers to fundamental questions in diverse fields that included cell biology, developmental biology, tumorigenesis, immunology and neurobiology. However, the route towards a better understanding of its molecular basis was long and difficult, with many false starts. Major progress was made in the late 1970s to late 1980s with the identification of the major families of adhesion molecules, including integrins and cadherins. This in turn set the stage for the explosive growth in adhesion research over the past 25 years. © 2012 Macmillan Publishers Limited. All rights reserved.

Zuo Z.,University of Virginia
Medical Gas Research | Year: 2012

Volatile anesthetics are one class of the most commonly used drugs. However, the mechanisms for these drugs to induce anesthesia are not fully understood and have been under intensive investigation. Two other effects of these anesthetics on the central nervous system, volatile anesthetics-induced neuroprotection and neurotoxicity, currently are hot research fields. Although data from animal studies for these two effects are extensive and convincing, clinical data for volatile anesthetics-induced neuroprotection are relatively weak. There is essentially lack of evidence to suggest volatile anesthetics-induced neurotoxicity in humans. In this regard, the contribution of general anesthesia/anesthetics to postoperative cognitive decline, a clinical entity whose existence has been supported by substantial evidence, also has not been established. This paper will be focused on reviewing the evidence, especially the clinical evidence, for volatile anesthetics-induced neuroprotection and neurotoxicity. Efforts will be devoted to facilitating the understanding of the two seemingly contradictory effects of these important drugs on the brain. © 2012 Zuo; licensee BioMed Central Ltd.

Salthouse T.A.,University of Virginia
Journal of Experimental Psychology: General | Year: 2014

Although there has been considerable interest in identifying potential correlates of cognitive change, results of past studies have been inconsistent. The present study incorporated a number of methodological features intended to maximize sensitivity to detect characteristics of individuals with different amounts of cognitive change. Cognitive change in 5 cognitive abilities was analyzed with 2nd-order latent growth curve models applied to data from a moderately large sample of healthy adults ranging from 18 to 99 years of age (Ns of 4,802 with 1 occasion, 2,265 with 2 occasions, and 1,128 with 3 occasions). There was significant individual difference variance in the longitudinal changes in several cognitive abilities, even in separate analyses of individuals between 18 years of age and 39, between 40 and 64, and 65 and over. Potential correlates of change included measures of self-rated health, vision, mood, personality, and lifestyle. Most of the potential correlates of change had high reliability, and several analyses were based on even more reliable factors determined by the variance common to multiple measures. Despite favorable conditions for detecting correlates of change, there was little evidence that cognitive change was moderated by any of the variables examined. Possible reasons for the inconsistent results regarding correlates of cognitive change are discussed. © 2013 American Psychological Association.

Dunn S.P.,University of Virginia
Journal of the American Heart Association | Year: 2013

Proton pump inhibitors (PPIs) may interfere with the metabolic activation of clopidogrel via inhibition of cytochrome P450 2C19, but the clinical implications remain unclear. The impact of PPI use on the 1-year primary end point (ischemic stroke, myocardial infarction [MI], or vascular death) in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial and the 28-day (all-cause death, MI, or urgent target vessel revascularization) and 1-year (all-cause death, MI, or stroke) primary end points in the Clopidogrel for Reduction of Events During Observation (CREDO) trial were examined. Clopidogrel appeared to elevate risk for the primary end point in CAPRIE among PPI users (estimated hazard ratio [EHR] 2.66, 95% CI 0.94 to 7.50) while lowering it for non-PPI users (EHR 0.90, 95% CI 0.83 to 0.99, interaction P=0.047). Moreover, PPI use was associated with worse outcomes in patients receiving clopidogrel (EHR 2.39, 95% CI 1.74 to 3.28) but not aspirin (EHR 1.04, 95% CI 0.70 to 1.57, interaction P=0.001). Clopidogrel did not significantly alter risk for the 1-year primary end point in CREDO among PPI users (EHR 0.82, 95% CI 0.48 to 1.40) while lowering it for non-PPI users (EHR 0.71, 95% CI 0.52 to 0.98, interaction P=0.682). Also, PPI use was associated with worse outcomes in both patients receiving clopidogrel (EHR 1.67, 95% CI 1.06 to 2.64) and those receiving placebo (EHR 1.56, 95% CI 1.06 to 2.30, interaction P=0.811). In CREDO, the efficacy of clopidogrel was not significantly affected by PPI use. However, in CAPRIE, clopidogrel was beneficial to non-PPI users while apparently harmful to PPI users. Whether this negative interaction is clinically important for patients receiving clopidogrel without aspirin needs further study.

Kooyers N.J.,University of Virginia
Plant Science | Year: 2015

While the functional genetics and physiological mechanisms controlling drought resistance in crop plants have been intensely studied, less research has examined the genetic basis of adaptation to drought stress in natural populations. Drought resistance adaptations in nature reflect natural rather than human-mediated selection and may identify novel mechanisms for stress tolerance. Adaptations conferring drought resistance have historically been divided into alternative strategies including drought escape (rapid development to complete a life cycle before drought) and drought avoidance (reducing water loss to prevent dehydration). Recent studies in genetic model systems such as Arabidopsis, Mimulus, and Panicum have begun to elucidate the genes, expression profiles, and physiological changes responsible for ecologically important variation in drought resistance. Similar to most crop plants, variation in drought escape and avoidance is complex, underlain by many QTL of small effect, and pervasive gene by environment interactions. Recently identified major-effect alleles point to a significant role for genetic constraints in limiting the concurrent evolution of both drought escape and avoidance strategies, although these constraints are not universally found. This progress suggests that understanding the mechanistic basic and fitness consequences of gene by environment interactions will be critical for crop improvement and forecasting population persistence in unpredictable environments. © 2015.

Wallace K.L.,University of Virginia | Linden J.,La Jolla Institute for Allergy and Immunology
Blood | Year: 2010

We showed previously that pulmonary function and arterial oxygen saturation in NY1DD mice with sickle cell disease (SCD) are improved by depletion of invariant natural killer T (iNKT) cells or blockade of their activation. Here we demonstrate that SCD causes a 9- and 6-fold induction of adenosine A 2A receptor (A2AR) mRNA in mouse pulmonary iNKT and natural killer (NK) cells, respectively. Treating SCD mice with the A 2AR agonist ATL146e produced a dose-dependent reversal of pulmonary dysfunction with maximal efficacy at 10 ng/kg/minute that peaked within 3 days and persisted throughout 7 days of continuous infusion. Crossing NY1DD mice with Rag1-/- mice reduced pulmonary injury that was restored by adoptive transfer of 106 purified iNKT cells. Reconstituted injury was reversed by ATL146e unless the adoptively transferred iNKT cells were pretreated with the A2AR alkylating antagonist, FSPTP (5-amino-7-[2-(4- fluorosulfonyl)phenylethyl]-2-(2-furyl)-pryazolo[4,3-∈]-1,2,4-triazolo[1, 5-c]pyrimidine), which completely prevented protection. In NY1DD mice exposed to hypoxia-reoxygenation, treatment with ATL146e at the start of reoxygenation prevented further lung injury. Together, these data indicate that activation of induced A2ARs on iNKT and NK cells in SCD mice is sufficient to improve baseline pulmonary function and prevent hypoxia-reoxygenation-induced exacerbation of pulmonary injury. A2A agonists have promise for treating diseases associated with iNKT or NK cell activation. © 2010 by The American Society of Hematology.

Van Der Marel R.P.,US Space Telescope Science Institute | Kallivayalil N.,Yale Center for Astronomy and Astrophysics | Kallivayalil N.,University of Virginia
Astrophysical Journal | Year: 2014

We present the first detailed assessment of the large-scale rotation of any galaxy based on full three-dimensional velocity measurements. We do this for the LMC by combining our Hubble Space Telescope average proper motion (PM) measurements for stars in 22 fields, with existing line-of-sight (LOS) velocity measurements for 6790 individual stars. We interpret these data with a model of circular rotation in a flat disk. The PM and LOS data paint a consistent picture of the LMC rotation, and their combination yields several new insights. The PM data imply a stellar dynamical center that coincides with the H I dynamical center, and a rotation curve amplitude consistent with that inferred from LOS velocity studies. The implied disk viewing angles agree with the range of values found in the literature, but continue to indicate variations with stellar population and/or radius. Young (red supergiant) stars rotate faster than old (red and asymptotic giant branch) stars due to asymmetric drift. Outside the central region, the circular velocity is approximately flat at V circ = 91.7 ± 18.8 km s-1. This is consistent with the baryonic Tully-Fisher relation and implies an enclosed mass M(8.7 kpc) = (1.7 ± 0.7) × 1010 M·. The virial mass is larger, depending on the full extent of the LMC's dark halo. The tidal radius is 22.3 ± 5.2 kpc (24.°0 ± 5.°6). Combination of the PM and LOS data yields kinematic distance estimates for the LMC, but these are not yet competitive with other methods. © 2014. The American Astronomical Society. All rights reserved.

Roland A.V.,University of Virginia | Moenter S.M.,University of Michigan
Molecular Endocrinology | Year: 2011

GnRH neurons integrate steroidal and metabolic cues to regulate fertility centrally. Central glucopri- vation reduces LH secretion, which is governed by GnRH release, suggesting GnRH neuron activity is modulated by glucose availability. Here we tested whether GnRH neurons can sense changes in extracellular glucose, and whether glucosensing is altered by the steroids dihydrotestosterone (DHT) and/or estradiol (E). Extracellular recordings were made from GnRH neurons in brain slices from ovariectomized (OVX) mice DHT and/or E implants. Firing rate was reduced by a switch from 4.5 to 0.2 mM glucose in cells from OVX, OVX E, and OVX DHT E mice, but not OVX DHT mice. This suggests that androgens reduce the sensitivity of GnRH neurons to changes in extracellular glucose, but E mitigates this effect. Next we investigated potential mechanisms. In the presence of the ATP- sensitivepotassiumchannelantagonisttolbutamide,glucosensingpersisted.Incontrast,glucosensing was attenuated in the presence of compound C, an antagonist of AMP-activated protein kinase (AMPK), suggesting a role for AMPK in glucosensing. The AMPK activator N1-(b-D-ribofuranosyl)-5- aminoimidazole-4-carboxamide (AICAR) mimicked the effect of low glucose and was less effective in cells from DHT-treated mice. The effect of DHT to diminish responses to low glucose and AICAR was abolished by blockade of fast synaptic transmission. Both AICAR and low glucose activated a current with a reversal potential near 50 mV, suggesting a nonspecific cation current. These studies indicate thatglucosensingisonemechanismbywhichGnRHneuronssensefuelavailabilityandpointtoanovel role for AMPK in the central regulation of fertility. © 2011 by The Endocrine Society.

Reynolds P.P.,University of Virginia
Academic Medicine | Year: 2012

The community health center (CHC), or neighborhood health center as it was originally known, was an innovation developed under President Lyndon Johnson's War on Poverty to address the needs of poor urban and rural Americans. The ranks of CHCs have grown from 8 pilot health centers in 1965 to more than 1,100 health centers serving over 19 million Americans in 2012. The capacity of CHCs is limited by the availability of primary care clinicians (physicians, nurse practitioners, and physician assistants) who are trained to work in these settings. Primary care residency program faculties have long recognized the value and importance of educating physicians in CHCs, but productivity pressures over the past decade forced the dissolution of many CHC-medical school and residency program partnerships. Advocacy and research conducted in the 1990s and 2000s laid the groundwork for the Teaching Health Center Graduate Medical Education (THCGME) program, funded under the 2010 Patient Protection and Affordable Care Act, which enables funding for residency training to flow directly to CHCs. This new federal initiative aligns the graduate medical education (GME) mission of preparing competent professionals with the CHC mission of providing quality and comprehensive care; it also helps address health care reform and the need for more primary care clinicians. Of the first 21 THCGME grants, 15 (71%) were awarded for family medicine residency training. As Chen and colleagues suggest in this issue of Academic Medicine, the THCGME program is an important step in reform of GME financing and training.

Rosner M.H.,University of Virginia
Clinics in Geriatric Medicine | Year: 2013

Most patients who develop acute kidney injury (AKI) are older than 65 years. Specific structural and functional changes that occur in the aging kidney predispose the elderly patient to AKI. This risk is further compounded by comorbid conditions, polypharmacy, and the need for invasive procedures. When AKI does occur, it is associated with significant morbidity and mortality. Although morbidity and mortality increases with advancing age, many elderly patients can survive AKI and do well. Thus, decision making should be thoughtful and individualized, and not dependent on age. Whenever possible, preventive approaches should be pursued to lessen the burden of AKI. © 2013 Elsevier Inc.

Beitz K.M.,University of Colorado at Colorado Springs | Salthouse T.A.,University of Virginia | Davis H.P.,University of Colorado at Colorado Springs
Journal of Experimental Psychology: General | Year: 2014

The present study focuses on the role of frequency bias and expected value on the learning processes driving performance on the Iowa Gambling Task (IGT) in individuals between 5 and 89 years of age. As in previous studies, children performed poorly on the IGT, were increasingly influenced by frequency of losses during learning, and constantly changed their decisions. Decision-making strategies changed after childhood from erratic behavior to more consistent strategies that promoted expected value of deck choices. Performance deficits as well as a loss frequency bias were found in older adults. However, age-related deficits were distinct between children and older adults. Cognitive modeling analysis indicated that older adults were more likely to forget about recent outcomes and were more consistent than children when selecting decks. Cognitive ability was associated with a modeling parameter for memory as well as IGT performance, suggesting the involvement of a cognitive component in young and middle-aged adult decision making. The interactions of modeling parameters suggested that cognitive changes were the cause of lowered performance in older adults. These analyses suggest critical developments in decision processes during the adolescent years and decline in a cognitive process leading to decision-making deficits after age 60. © 2014 American Psychological Association.

Krushkal V.,University of Virginia
Combinatorics Probability and Computing | Year: 2011

We introduce a polynomial invariant of graphs on surfaces, PG, generalizing the classical Tutte polynomial. Topological duality on surfaces gives rise to a natural duality result for PG, analogous to the duality for the Tutte polynomial of planar graphs. This property is important from the perspective of statistical mechanics, where the Tutte polynomial is known as the partition function of the Potts model. For ribbon graphs, PG specializes to the well-known Bollobás-Riordan polynomial, and in fact the two polynomials carry equivalent information in this context. Duality is also established for a multivariate version of the polynomial PG. We then consider a 2-variable version of the Jones polynomial for links in thickened surfaces, taking into account homological information on the surface. An analogue of Thistlethwaite's theorem is established for these generalized Jones and Tutte polynomials for virtual links. © 2010 Cambridge University Press.

Prevention of invasive Candida infections (ICI) is an achievable goal for every NICU and supported by A-1 evidence. Due to the incidence of ICI, high infection-associated mortality and neurodevelopmental impairment, antifungal prophylaxis should be targeted to infants <1000 g or ≤27 weeks gestation. There is A-1 evidence for both fluconazole and nystatin prophylaxis for the prevention of ICI. Evidence currently would favour fluconazole prophylaxis in high-risk preterm infants since intravenous fluconazole prophylaxis has greater efficacy compared to enteral nystatin prophylaxis, efficacy in the most immature patients in whom mortality is the highest, requires less dosing, and can be given to infants with gastrointestinal disease or haemodynamic instability. All NICUs caring for extremely preterm infants should use antifungal prophylaxis. Even in NICUs with low rates of ICI, antifungal prophylaxis is crucial to improving survival and neurodevelopmental outcomes for this vulnerable population. For infants 1000-1500 g if there is concern for ICI in the NICU, either drug could be chosen for prophylaxis. Fluconazole prophylaxis administered at 3 mg/kg twice a week, while intravenous access is required, appears to be the safest and most effective schedule in preventing ICI while attenuating the emergence of fungal resistance. Invasive Candida infections are one group of infections we can prevent. © 2012 Elsevier Ireland Ltd.

Cafiso D.S.,University of Virginia
Accounts of Chemical Research | Year: 2014

ConspectusProtein structures are not static but sample different conformations over a range of amplitudes and time scales. These fluctuations may involve relatively small changes in bond angles or quite large rearrangements in secondary structure and tertiary fold. The equilibrium between discrete structural substates on the microsecond to millisecond time scale is sometimes termed conformational exchange. Protein dynamics and conformational exchange are believed to provide the basis for many important activities, such as protein-protein and protein-ligand interactions, enzymatic activity and protein allostery; however, for many proteins, the dynamics and conformational exchange that lead to function are poorly defined.Spectroscopic methods, such as NMR, are among the most important methods to explore protein dynamics and conformational exchange; however, they are difficult to implement in some systems and with some types of exchange events. Site-directed spin labeling (SDSL) is an EPR based approach that is particularly well-suited to high molecular-weight systems such as membrane proteins. Because of the relatively fast time scale for EPR spectroscopy, it is an excellent method to examine exchange. Conformations that are in exchange are captured as distinct populations in the EPR spectrum, and this feature when combined with the use of methods that can shift the free energy of conformational substates allows one to identify regions of proteins that are in dynamic exchange. In addition, modern pulse EPR methods have the ability to examine conformational heterogeneity, resolve discrete protein states, and identify the substates in exchange.Protein crystallography has provided high-resolution models for a number of membrane proteins; but because of conformational exchange, these models do not always reflect the structures that are present when the protein is in a native bilayer environment. In the case of the Escherichia coli vitamin B12 transporter, BtuB, the energy coupling segment of this protein undergoes a substrate-dependent unfolding, which acts to couple this outer-membrane protein to the inner-membrane protein TonB. EPR spectroscopy demonstrates that the energy coupling segment is in equilibrium between ordered and disordered states, and that substrate binding shifts this equilibrium to favor an unfolded state. However, in crystal structures of BtuB, this segment is resolved and folded within the protein, and neither the presence of this equilibrium nor the substrate-induced change is revealed. This is a result of the solute environment and the crystal lattice, both of which act to stabilize one conformational substate of the transporter.Using SDSL, it can be shown that conformational exchange is present in other regions of BtuB and in other members of this transporter family. Conformational exchange has also been examined in systems such as the plasma membrane SNARE protein, syntaxin 1A, where dynamics are controlled by regulatory proteins such as munc18. Regulating the microsecond to millisecond time scale dynamics in the neuronal SNAREs is likely to be a key feature that regulates assembly of the SNAREs and neurotransmitter release. © 2014 American Chemical Society.

Curran J.C.,University of Virginia
Geomorphology | Year: 2010

Mobility of large woody debris (LWD) in low gradient channels is an important but often overlooked transport process. The majority of studies on LWD have focused on its role in geomorphic and ecologic river processes. When jams extend across the width of the channel, they have the potential to retain sediment and alter the channel profile. When jams obstruct only a portion of the channel, they can re-direct flow, altering patterns of scour and deposition. The boundary complexity created by LWD has a recognized role in riverine ecosystems which has led to programs of replacing LWD in-channel corridors where it was previously removed. Although LWD jams are common in rivers around the world, they have been studied most intensely in steep, forested channel reaches where they are often found to be stable channel features. It is not fully known how much of the information on LWD from steep forested channels will transfer to other channel types. Whereas it may be reasonable to assume that the ecological benefits of LWD are similar in low gradient channels, research has shown that a much higher rate of LWD transport occurs in low gradient channels, with jams mobilized on timescales of 100-102 years. This study evaluates the distribution and mobility of LWD over 72 km of the San Antonio River, a low gradient channel in southeast Texas. LWD jam locations were identified for 2003 and 2007 using a combination of aerial photography and field mapping. Each jam was cataloged according to its location in the channel cross-section and the amount of channel area blocked. During the four-year period, all the LWD jams were mobilized, including those jams extending across the channel width. Although easily mobilized, 34 jams re-form in the same locations, creating 34 channel locations with persistent LWD jams. Data from the San Antonio River are applied to two models developed to predict LWD mobility and transport distances to assess the applicability of each model to a low gradient channel. The locations of stable (or recurring) LWD jams were matched to model results where predicted LWD transport distances were equal to measured LWD jam spacing. Model results showed good agreement with the mean and median spacing of LWD jams when given input parameters specific to the channel and wood species. The ability to predict where LWD jams will persist over time in a low gradient channel has application in watershed management. Persistent LWD jams can exert a greater influence on channel morphology and may require active management. © 2009 Elsevier B.V. All rights reserved.

Norton P.,University of Virginia
Technology and Culture | Year: 2015

Traffic safety, once neglected within the larger history of the automobile in the United States, has finally been getting the attention it always deserved. Nevertheless, historians still sometimes misappraise traffic safety in one era by the standards of another. Ahistorical assumptions have contributed to misinterpretations—for example, that Americans of the 1920s were extraordinarily tolerant of traffic casualties because they did not respond to them as more recent traffic-safety paradigms would prescribe. As a corrective, four paradigms, approximately sequential, are proposed: Safety First, Control, Crashworthiness, and Responsibility. Historians are invited to borrow, modify, or replace them, and to consider their applicability to other countries. Whether these particular paradigms survive review or not, historians who are alert to safety paradigms will produce more reliable scholarship on the history of traffic safety. © 2015 by the Society for the History of Technology. All rights reserved.

Horgan C.O.,University of Virginia
International Journal of Non-Linear Mechanics | Year: 2015

In 1996, Alan Gent published a short paper that proposed the use of a very simple two parameter phenomenological constitutive model for hyperelastic isotropic incompressible materials. The model is empirical but has the advantages of mathematical simplicity, reflects the severe strain-stiffening at large strains observed experimentally, reduces to the classic neo-Hookean model for small strains and involves just two material parameters namely the shear modulus for infinitesimal deformations and a parameter that measures a maximum allowable value of strain. The model reflects the limiting chain extensibility characteristic of non-Gaussian molecular models for rubber. Here we review some of the numerous developments, extensions and widespread applications that have resulted from that groundbreaking paper not only in rubber elasticity but also in the area of biomechanics of soft biomaterials. The Gent model is remarkably robust: its mathematical simplicity combined with physical basis has ensured that it has reached status as a fundamental canonical phenomenological constitutive model for hyperelastic materials. © 2014 Elsevier Ltd. All rights reserved.

Shin J.,University of Virginia
Annals of biomedical engineering | Year: 2012

A finite element (FE) model of the foot and leg was developed to improve understanding of injury mechanisms of the ankle and subtalar joints during vehicle collisions and to aid in the design of injury countermeasures. The FE model was developed based on the reconstructed geometry of a male volunteer close to the anthropometry of a 50th percentile male and a commercial anatomical database. While the forefoot bones were defined as rigid bodies connected by ligament models, the surrounding bones of the ankle and subtalar joints and the leg bones were modeled as deformable structures. The material and structural properties were selected based on a synthesis of current knowledge of the constitutive models for each tissue. The whole foot and leg model was validated in different loading conditions including forefoot impact, axial rotation, dorsiflexion, and combined loadings. Overall results obtained in the model validation indicated improved biofidelity relative to previous FE models. The developed model was used to investigate the injury tolerance of the ankle joint under brake pedal loading for internally and externally rotated feet. Ligament failures were predicted as the main source of injury in this loading condition. A 12% variation of failure moment was observed in the range of axial foot rotations (±15°). The most vulnerable position was the internally rotated (15°) posture among three different foot positions. Furthermore, the present foot and ankle model will be coupled together with other body region FE models into the state-of-art human FE model to be used in the field of automotive safety.

Chevalier R.A.,University of Virginia
Astrophysical Journal Letters | Year: 2012

A variety of supernova events, including TypeIIn supernovae and ultraluminous supernovae, appear to have lost up to solar masses of their envelopes in tens to hundreds of years leading up to the explosion. In order to explain the close timing of the mass loss and supernova events, we explore the possibility that the mass loss is driven by common envelope evolution of a compact object (neutron star or black hole) in the envelope of a massive star and the supernova is triggered by the inspiral of the compact object to the central core of the companion star. The expected rate of such events is smaller than the observed rate of TypeIIn supernovae but the rates may agree within the uncertainties. The mass loss velocity is related to the escape velocity from the common envelope system and is comparable to the observed velocity of hundreds of kilometers per second in TypeIIn events. The mass loss is expected to be denser near the equatorial plane of the binary system and there is good evidence that the circumstellar media in TypeIIn supernovae are asymmetric. Some of these supernova types show evidence for energies in excess of the canonical 1051 erg, which might be the result of explosions from rapid accretion onto a compact object through a disk. © 2012. The American Astronomical Society. All rights reserved.

Cherepanova O.A.,University of Virginia
Nature Medicine | Year: 2016

Although somatic cell activation of the embryonic stem cell (ESC) pluripotency factor OCT4 has been reported, this previous work has been controversial and has not demonstrated a functional role for OCT4 in somatic cells. Here we demonstrate that smooth muscle cell (SMC)-specific conditional knockout of Oct4 in Apoe-/- mice resulted in increased lesion size and changes in lesion composition that are consistent with decreased plaque stability, including a thinner fibrous cap, increased necrotic core area, and increased intraplaque hemorrhage. Results of SMC-lineage-tracing studies showed that these effects were probably the result of marked reductions in SMC numbers within lesions and SMC investment within the fibrous cap, which may result from impaired SMC migration. The reactivation of Oct4 within SMCs was associated with hydroxymethylation of the Oct4 promoter and was hypoxia inducible factor-1α (HIF-1α, encoded by HIF1A) and Krüppel-like factor-4 (KLF4)-dependent. These results provide the first direct evidence that OCT4 has a functional role in somatic cells, and they highlight the potential role of OCT4 in normal and diseased somatic cells. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Okusa M.D.,University of Virginia
Transactions of the American Clinical and Climatological Association | Year: 2012

Dendritic cells (DCs) and macrophages are critical early initiators of innate immunity in the kidney; they also orchestrate inflammation subsequent to ischemia-reperfusion injury. Hence, these cells hold great promise as targets for pharmacological interventions. Macrophages and DCs are the most abundant leukocytes present in the kidney, and they represent a heterogeneous population of cells that are capable of inducing sterile inflammation after reperfusion, directly through the production of proinflammatory cytokines, chemokines, and other soluble inflammatory mediators, or indirectly through activation of effector T lymphocytes and natural killer T cells. In addition, recent studies have indicated that macrophages participate in tissue repair and DCs possess tolerogenic functions in normal and disease states. Understanding the function of DCs and macrophages as well as the microenvironment that governs their phenotype will shed light on the pathogenesis of kidney disease and offer novel drug targets.

Loman N.J.,University of Birmingham | Quinlan A.R.,University of Virginia
Bioinformatics | Year: 2014

Motivation: Nanopore sequencing may be the next disruptive technology in genomics, owing to its ability to detect single DNA molecules without prior amplification, lack of reliance on expensive optical components, and the ability to sequence long fragments. The MinION™ from Oxford Nanopore Technologies (ONT) is the first nanopore sequencer to be commercialized and is now available to early-access users. The MinION™ is a USB-connected, portable nanopore sequencer that permits real-time analysis of streaming event data. Currently, the research community lacks a standardized toolkit for the analysis of nanopore datasets. Results: We introduce poretools, a flexible toolkit for exploring datasets generated by nanopore sequencing devices from MinION™ for the purposes of quality control and downstream analysis. Poretools operates directly on the native FAST5 (an application of the HDF5 standard) file format produced by ONT and provides a wealth of format conversion utilities and data exploration and visualization tools. © The Author 2014. Published by Oxford University Press.

Rosner M.H.,University of Virginia
Kidney International | Year: 2012

Hyponatremia, the most common electrolyte disorder encountered in clinical practice, is associated with significant morbidity and mortality. The introduction of medications that specifically antagonize the vasopressin V2 receptor (vaptans) has provided a safe and effective means of therapy. Lixivaptan is the newest of these agents that reliably increase serum sodium levels in patients with euvolemic hyponatremia. However, significant questions remain regarding the specific indications for vaptans, and their potential impact on morbidity and mortality associated with hyponatremia. © 2012 International Society of Nephrology.

Schenk III W.G.,University of Virginia
American Surgeon | Year: 2010

An autologous arteriovenous (AV) fistula is the preferred form of angioaccess for chronic hemodialysis. A prospective study was carried out to evaluate the potential of regional anesthesia to improve AV fistula prevalence. One hundred ninety-three patients underwent preoperative duplex ultrasound evaluation over a 14-month period. The qualification of each patient to receive either an autologous AV fistula or a prosthetic graft was based on specific sonographic criteria. Patients scheduled for placement of a graft received an ultrasound-directed supraclavicular brachial plexus block, which produces dense sympathetic blockade. After the regional block, those patients who met criteria for primary fistula construction on repeat ultrasound received a fistula instead of a graft. Of 62 patients scheduled to receive an AV graft, 23 or 37 per cent were recruited to receive a fistula instead. The outcome of the recruited fistulas was compared with the 121 planned fistulas. There was no statistically significant difference in primary failure rate (4.3 vs 5.8%). The recruited fistulas had a shorter average maturation time, 83 ± 48 versus 132 ± 82 days (P = 0.023). Within the study population, functioning fistula prevalence was increased from 61.7 to 79.8 per cent. Regional anesthesia and immediate preoperative ultrasound is a useful strategy for increasing fistula prevalence.

Beans C.M.,University of Virginia
Ecology and Evolution | Year: 2014

The evidence for character displacement as a widespread response to competition is now building. This progress is largely the result of the establishment of rigorous criteria for demonstrating character displacement in the animal literature. There are, however, relatively few well-supported examples of character displacement in plants. This review explores the potential for character displacement in plants by addressing the following questions: (1) Why aren't examples of character displacement in plants more common? (2) What are the requirements for character displacement to occur and how do plant populations meet those requirements? (3) What are the criteria for testing the pattern and process of character displacement and what methods can and have been used to address these criteria in the plant literature? (4) What are some additional approaches for studying character displacement in plants? While more research is needed, the few plant systems in which character displacement hypotheses have been rigorously tested suggest that character displacement may play a role in shaping plant communities. Plants are especially amenable to character displacement studies because of the experimental ease with which they can be used in common gardens, selection analyses, and breeding designs. A deeper investigation of character displacement in plants is critical for a more complete understanding of the ecological and evolutionary processes that permit the coexistence of plant species. © 2014 The Author. Ecology and Evolution published by John Wiley & Sons Ltd.

Burns T.M.,University of Virginia
Annals of the New York Academy of Sciences | Year: 2012

The myasthenia gravis composite (MGC) was constructed by selecting the best performing items from three commonly used, MG-specific scales. The response categories of the items were subsequently weighted for importance. The MGC, which takes less than five minutes to complete, is made up of three ocular, three bulbar, one respiratory, one neck, and two limb items. After its construction, the MGC was validated in an 11-center scale validity study. During the validation study, which included test-retest analysis, it was determined that a 3-point improvement in MGC score reliably indicates clinical improvement. A 3-point improvement in MGC also appears to be meaningful to the patient. Rasch analysis of the MGC confirmed that all 10 items belong and can be summed to provide a total score, and that the weights given to the response categories of the items are appropriate. © 2012 New York Academy of Sciences.

Fessler T.A.,University of Virginia
Nutrition in Clinical Practice | Year: 2013

Parenteral nutrition (PN) is a life-sustaining therapy for hundreds of thousands of people who have severe impairment of gastrointestinal function. Trace elements are a small but very important part of PN that can be overlooked during busy practice. Serious complications can result from trace element deficiencies and toxicities, and this is especially problematic during times of product shortages. Practical information on parenteral trace element use can be gleaned from case reports, some retrospective studies, and very few randomized controlled trials. A general knowledge of trace element metabolism and excretion, deficiency and toxicity symptoms, products, optimal dosages, and strategies for supplementation, restriction, and monitoring will equip practitioners to provide optimal care for their patients who depend on PN. © 2013 American Society for Parenteral and Enteral Nutrition.

Ruhm C.J.,University of Virginia
Journal of Health Economics | Year: 2015

Over the 1976-2010 period, total mortality shifted from strongly procyclical to being weakly or unrelated to macroeconomic conditions. The association is likely to be poorly measured when using short (less than 15 year) analysis periods. Deaths from cardiovascular disease and transport accidents continue to be procyclical; however, countercyclical patterns have emerged for fatalities from cancer mortality and external causes. Among the latter, non-transport accidents, particularly accidental poisonings, play an important role. © 2015 Elsevier B.V.

Perez-Reyes E.,University of Virginia
Channels | Year: 2010

Our interest was drawn to the I-II loop of CaV3 channels for two reasons: (1) transfer of the I-II loop from a high voltage-activated channel (CaV2.2) to a low voltage-activated channel (CaV3.1) unexpectedly produced an ultra-low voltage activated channel; and (2) sequence variants of the I-II loop found in childhood absence epilepsy patients altered channel gating and increased surface expression of CaV3.2 channels. To determine the roles of this loop we have studied the structure of the loop and the biophysical consequences of altering its structure. Deletions localized the gating brake to the first 62 amino acids after IS6 in all three Ca V3 channels, establishing the evolutionary conservation of this region and its function. Circular dichroism was performed on a purified fragment of the I-II loop from CaV3.2 to reveal a high α-helical content. De novo computer modeling predicted the gating brake formed a helix-loop-helix structure. This model was tested by replacing the helical regions with poly-proline-glycine (PGPGPG), which introduces kinks and flexibility. These mutations had profound effects on channel gating, shifting both steady-state activation and inactivation curves, as well as accelerating channel kinetics. Mutations designed to preserve the helical structure (poly-alanine, which forms α-helices) had more modest effects. Taken together, we conclude the second helix of the gating brake establishes important contacts with the gating machinery, thereby stabilizing a closed state of T-channels, and that this interaction is disrupted by depolarization, allowing the S6 segments to spread open and Ca2+ ions to flow through. © 2010 Landes Bioscience.

Carey R.M.,University of Virginia
Current Opinion in Endocrinology, Diabetes and Obesity | Year: 2010

Purpose of Review: The renin-angiotensin-aldosterone system is a co-ordinated hormonal cascade of major importance in the control of fluid and electrolyte homeostasis and blood pressure. During the past decade, the scientific community has realized that this system is also of paramount importance in pathophysiology of cardiovascular and renal target organ damage. In particular, inappropriately elevated aldosterone levels in the face of body sodium expansion have been incriminated in cardiac and vascular inflammation and fibrosis leading to remodeling and disease. Substantial advances on the role and mechanisms of aldosterone-induced tissue damage and novel findings on the genetic control of aldosterone secretion have been reported during the past year, and these are the subjects of this brief review. Recent Findings: A novel control mechanism for aldosterone secretion may be circadian clock genes, disruption of which leads to increased aldosterone secretion and hypertension. Animal models for human idiopathic hyperaldosteronism have been reported for the first time. Glucocorticoids have now been found to activate cardiac mineralocorticoid receptors during certain cardiovascular disease states. Crosstalk between mineralocorticoid and angiotensin AT1 receptors contributes to target organ damage. Endogenous cardiotonic steroids may explain at least some of the tissue damage during sodium loading previously attributed to aldosterone. Summary: Insights on aldosterone and cardiovascular disease gained during the past year provide new avenues for research and applications for treatment in the future. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Platts-Mills T.A.E.,University of Virginia
Journal of Allergy and Clinical Immunology | Year: 2015

Before the first description of hay fever in 1870, there was very little awareness of allergic disease, which is actually similar to the situation in prehygiene villages in Africa today. The best explanation for the appearance and subsequent increase in hay fever at that time is the combination of hygiene and increased pollen secondary to changes in agriculture. However, it is important to remember that the major changes in hygiene in Northern Europe and the United States were complete by 1920. Asthma in children did not start to increase until 1960, but by 1990, it had clearly increased to epidemic numbers in all countries where children had adopted an indoor lifestyle. There are many features of the move indoors that could have played a role; these include increased sensitization to indoor allergens, diet, and decreased physical activity, as well as the effects of prolonged periods of shallow breathing. Since 1990, there has been a remarkable increase in food allergy, which has now reached epidemic numbers. Peanut has played a major role in the food epidemic, and there is increasing evidence that sensitization to peanut can occur through the skin. This suggests the possibility that changes in lifestyle in the last 20 years could have influenced the permeability of the skin. Overall, the important conclusion is that sequential changes in lifestyle have led to increases in different forms of allergic disease. Equally, it is clear that the consequences of hygiene, indoor entertainment, and changes in diet or physical activity have never been predicted. © 2015 American Academy of Allergy, Asthma & Immunology.

Keeley E.C.,University of Virginia
Advances in cancer research | Year: 2010

The tumor microenvironment is extremely complex that depends on tumor cell interaction with the responding host cells. Angiogenesis, or new blood vessel growth from preexisting vasculature, is a preeminent feature of successful tumor growth of all solid tumors. While a number of factors produced by both the tumor cells and host responding cells have been discovered that regulate angiogenesis, increasing evidence is growing to support the important role of CXC chemokines in this process. As a family of cytokines, the CXC chemokines are pleiotropic in their ability to regulate tumor-associated angiogenesis, as well as cancer cell metastases. In this chapter, we will discuss the disparate activity that CXC chemokines play in regulating cancer-associated angiogenesis and metastases. Copyright 2010 Elsevier Inc. All rights reserved.

Ruhm C.J.,University of Virginia
Journal of Health Economics | Year: 2012

The combination of economic and biological factors is likely to result in overeating in the current environment of cheap and readily available food. This propensity is shown using a "dual decision" approach where choices reflect the interaction of a "deliberative" system, operating as in standard economic models, and an "affective" system that responds rapidly to stimuli without considering long-term consequences. This framework is characterized by excess food consumption and body weight, in that individuals prefer both ex-ante and ex-post to eat and weigh less than they actually do, with weight loss attempts being common but often unsuccessful or only partially successful. As in the standard model, weight is related to prices. However, another potentially important reason for rising obesity is that food producers have incentives to engineer products to stimulate the affective system so as to encourage overeating. Data from several sources are used to investigate predictions of the dual decision model, with the evidence providing broad support for at least some irrationality in food consumption. Most importantly, there is little indication that the large secular increases in body mass index have been accompanied by corresponding growth in utility-maximizing weight. One result is that efforts to reduce weight have become more common as obesity has increased. © 2012 Elsevier B.V.

Neuroendocrine mechanisms underlying the progression of sleep-wake gonadotrophin-releasing hormone (GnRH) pulse secretion across puberty have remained enigmatic. Here, the changes of sleep-wake luteinising hormone (LH) (and, by inference, GnRH) pulse secretion across puberty in normal girls are reviewed, primarily focusing on available human data. It is suggested that the primary control of GnRH pulse frequency changes across puberty, with sex steroid feedback exerting minimal control during childhood, but primary control during adulthood. A working model is proposed regarding how such a transfer of GnRH pulse frequency control may partly account for the prominent day-night differences of GnRH pulse frequency characteristic of puberty. How this model may be relevant to the genesis of abnormal GnRH secretion in peripubertal girls with hyperandrogenaemia is then described. © 2010 The Author. Journal Compilation © 2010 Blackwell Publishing Ltd.

The pathologic anatomy and hemodynamics of the left-sided portal circulation that is associated with gastric varices (GVs) are complex and highly variable. Understanding the pathologic anatomy and hemodynamics associated with GVs is important for clinical management decisions and for the technical descriptive details of the balloon-occluded retrograde transvenous obliteration (BRTO) and balloon-occluded antegrade transvenous obliteration procedures. A reflection of the considerable variability in anatomy, pathology, and hemodynamics is the numerous descriptive and categorical classifications that have been described in the past 2 decades. This article reviews the detailed descriptive gross anatomy, radiographic anatomy, and portosystemic venous hemodynamics that are associated with GVs and that can be encountered during the BRTO or balloon-occluded antegrade transvenous obliteration procedure(s) or both. Definitions are also set to clarify this detailed anatomy that received limited description in the prior literature. Moreover, all the classifications that have been described (to the best of the author's knowledge) that are relevant to the BRTO procedure are detailed in the article. © 2013 Elsevier Inc.

Hart J.M.,University of Virginia
Journal of athletic training | Year: 2010

Arthrogenic muscle inhibition is an important underlying factor in persistent quadriceps muscle weakness after knee injury or surgery. To determine the magnitude and prevalence of volitional quadriceps activation deficits after knee injury. Web of Science database. Eligible studies involved human participants and measured quadriceps activation using either twitch interpolation or burst superimposition on patients with knee injuries or surgeries such as anterior cruciate ligament deficiency (ACLd), anterior cruciate ligament reconstruction (ACLr), and anterior knee pain (AKP). Means, measures of variability, and prevalence of quadriceps activation (QA) failure (<95%) were recorded for experiments involving ACLd (10), ACLr (5), and AKP (3). A total of 21 data sets from 18 studies were initially identified. Data from 3 studies (1 paper reporting data for both ACLd and ACLr, 1 on AKP, and the postarthroscopy paper) were excluded from the primary analyses because only graphical data were reported. Of the remaining 17 data sets (from 15 studies), weighted mean QA in 352 ACLd patients was 87.3% on the involved side, 89.1% on the uninvolved side, and 91% in control participants. The QA failure prevalence ranged from 0% to 100%. Weighted mean QA in 99 total ACLr patients was 89.2% on the involved side, 84% on the uninvolved side, and 98.5% for the control group, with prevalence ranging from 0% to 71%. Thirty-eight patients with AKP averaged 78.6% on the involved side and 77.7% on the contralateral side. Bilateral QA failure was commonly reported in patients. Quadriceps activation failure is common in patients with ACLd, ACLr, and AKP and is often observed bilaterally.

Kong J.,Korea University | Chung S.W.,Korea University | Skadron K.,University of Virginia
ACM Computing Surveys | Year: 2012

Microprocessor design has recently encountered many constraints such as power, energy, reliability, and temperature. Among these challenging issues, temperature-related issues have become especially important within the past several years. We summarize recent thermal management techniques for microprocessors, focusing on those that affect or rely on themicroarchitecture. We categorize thermal management techniques into sixmain categories: temperaturemonitoring, microarchitectural techniques, floorplanning, OS/compiler techniques, liquid cooling techniques, and thermal reliability/security. Temperature monitoring, a requirement for Dynamic Thermal Management (DTM), includes temperature estimation and sensor placement techniques for accurate temperature measurement or estimation. Microarchitectural techniques include both static and dynamic thermal management techniques that control hardware structures. Floorplanning covers a range of thermal-aware floorplanning techniques for 2D and 3D microprocessors. OS/compiler techniques include thermal-aware task scheduling and instruction scheduling techniques. Liquid cooling techniques are higher-capacity alternatives to conventional air cooling techniques. Thermal reliability/security issues cover temperature-dependent reliability modeling, Dynamic Reliability Management (DRM), and malicious codes that specifically cause overheating. Temperature-related issues will only become more challenging as process technology continues to evolve and transistor densities scale up faster than power per transistor scales down. The overall objective of this survey is to give microprocessor designers a broad perspective on various aspects of designing thermal-aware microprocessors and to guide future thermal management studies. © 2012 ACM.

Saha M.V.,University of Virginia
American Journal of Epidemiology | Year: 2014

Mortality rates increase immediately after periods of high air temperature. In the days and weeks after heat events, time series may exhibit mortality displacement - periods of lower than expected mortality. We examined all-cause mortality and meteorological data from 1980 to 2009 in the cities of Atlanta, Georgia; Boston, Massachusetts; Minneapolis-St. Paul, Minnesota; Philadelphia, Pennsylvania; Phoenix, Arizona; Seattle, Washington; and St. Louis, Missouri. We modeled baseline mortality using a generalized additive model. Heat waves were defined as periods of 3 or more consecutive days in which the apparent temperature exceeded a variable percentile. For each heat wave, we calculated the sum of excess and deficit mortality. Mortality displacement, which is the ratio of grand sum deficit to grand sum excess mortality, decreased as a function of event strength in all cities. Displacement was close to 1.00 for the weakest events. At the highest temperatures, displacement varied from 0.35 (95% confidence interval: 0.21, 0.55) to 0.75 (95% confidence interval: 0.54, 0.97). We found strong evidence of acclimatization across cities. Without consideration of displacement effects, the net impacts of heat-wave mortality are likely to be significant overestimations. A statistically significant positive relationship between the onset temperature of nondisplaced heat mortality and mean warm-season temperature (R2 = 0.78, P < 0.01) suggests that heat mortality thresholds may be predictable across cities. © The Author 2013.

Hasan F.M.,University of Virginia | Alsahli M.,University of Toronto | Gerich J.E.,University of Rochester
Diabetes Research and Clinical Practice | Year: 2014

The kidney plays an important role in glucose homeostasis via its production, utilization, and, most importantly, reabsorption of glucose from glomerular filtrate which is largely mediated via the sodium glucose co-transporter 2 (SGLT2). Pharmacological inhibition of SGLT2 increases urinary glucose excretion and decreases plasma glucose levels in an insulin-independent manner. Agents that inhibit SGLT2 represent a novel class of drugs, which has recently become available for treatment of type 2 diabetes. This article summarizes the rationale for use of these agents and reviews available clinical data on their efficacy, safety, and risks/benefits. © 2014 Elsevier Ireland Ltd.

Liechti G.,University of Virginia
Frontiers in cellular and infection microbiology | Year: 2012

The bacterial pathogen Helicobacter pylori is capable of colonizing the gastric mucosa of the human stomach using a variety of factors associated with or secreted from its outer membrane (OM). Lipopolysaccharide (LPS) and numerous OM proteins have been shown to be involved in adhesion and immune stimulation/evasion. Many of these factors are essential for colonization and/or pathogenesis in a variety of animal models. Despite this wide array of potential targets present on the bacterial surface, the ability of H. pylori to vary its OM profile limits the effectiveness of vaccines or therapeutics that target any single one of these components. However, it has become evident that the proteins comprising the complexes that transport the majority of these molecules to the OM are highly conserved and often essential. The field of membrane biogenesis has progressed remarkably in the last few years, and the possibility now exists for targeting the mechanisms by which β-barrel proteins, lipoproteins, and LPS are transported to the OM, resulting in loss of bacterial fitness and significant altering of membrane permeability. In this review, the OM transport machinery for LPS, lipoproteins, and outer membrane proteins (OMPs) are discussed. While the principal investigations of these transport mechanisms have been conducted in Escherichia coli and Neisseria meningitidis, here these systems will be presented in the genetic context of ε proteobacteria. Bioinformatic analysis reveals that minimalist genomes, such as that of Helicobacter pylori, offer insight into the smallest number of components required for these essential pathways to function. Interestingly, in the majority of ε proteobacteria, while the inner and OM associated apparatus of LPS, lipoprotein, and OMP transport pathways appear to all be intact, most of the components associated with the periplasmic compartment are either missing or are almost unrecognizable when compared to their E. coli counterparts. Eventual targeting of these pathways would have the net effect of severely limiting the delivery/transport of components to the OM and preventing the bacterium's ability to infect its human host.

Santen R.J.,University of Virginia
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: Two common strategies are used to treat estrogen receptor-positive breast cancer in women: tamoxifen to inhibit estrogen action, and aromatase inhibitors (AIs) to block estrogen biosynthesis. Recent data suggest that AIs are more effective than tamoxifen in the adjuvant and advanced disease settings and are now being more commonly used. Tamoxifen, as a selective estrogen receptor modulator, exerts estrogenic effects to preserve bone, whereas the AIs profoundly lower estrogen levels and cause bone loss. Recent comparative studies of these agents provide extensive data on fracture rates, bone mineral density, and markers of bone formation and resorption. Objective: The aim of the study was to review the mechanistic effects of estrogen on bone and clinical data regarding bone density, bone turnover markers, and fracture rates in women with breast cancer taking tamoxifen or AIs. Evidence Acquisition and Synthesis: Data presented reflect a review of the literature and data integration from the perspective of the author's knowledge of the field. Results: Tamoxifen increases bone density and reduces fractures in postmenopausal women with breast cancer, whereas AIs increase rate of fracture, accelerate loss of bone mineral density, and enhance levels of markers of bone formation and resorption. Bisphosphonates and denosumab counteract the effects of the AIs on bone. Guidelines for management of AI-induced bone loss are available from several sources, but a simple algorithm guides decision making most effectively. Conclusions: Endocrine therapy for postmenopausal women with breast cancer exerts substantial effects on bone, and guidelines are available to assist in the management of bone-related problems. Copyright © 2011 by The Endocrine Society.

Mikami A.Y.,University of Virginia
Clinical Child and Family Psychology Review | Year: 2010

It is well-established that youth with attention-deficit/hyperactivity disorder (ADHD) are often peer-rejected and rated by parents, teachers, and observers to have poor social skills, when compared to typically developing peers. Significantly less research, however, has been devoted to the experiences youth with ADHD have in their close friendships. The aim of this article is to draw attention to friendship as a distinct construct from peer rejection and social skills and to summarize what is known about youth with ADHD in their friendships. The potential for stable, high-quality friendships to buffer the negative outcomes typically conferred by peer rejection in this population is discussed. This article concludes with recommendations for interventions that specifically target improving the close friendships of youth with ADHD as a treatment strategy. © 2010 Springer Science+Business Media, LLC.

Durbin Jr. C.G.,University of Virginia
Respiratory Care | Year: 2010

Tracheostomy is one of the most frequent procedures performed in intensive care unit (ICU) patients. Of the many purported advantages of tracheostomy, only patient comfort, early movement from the ICU, and shorter ICU and hospital stay have significant supporting data. Even the belief of increased safety with tracheostomy may not be correct. Various techniques for tracheostomy have been developed; however, use of percutaneous dilation techniques with bronchoscopic control continue to expand in popularity throughout the world. Tracheostomy should occur as soon as the need for prolonged intubation (longer than 14 d) is identified. Accurate prediction of this duration by day 3 remains elusive. Mortality is not worse with tracheotomy and may be improved with earlier provision, especially in head-injured and critically ill medical patients. The timing of when to perform a tracheostomy continues to be individualized, should include daily weaning assessment, and can generally be made within 7 days of intubation. Bedside techniques are safe and efficient, allowing timely tracheostomy with low morbidity. © 2010 Daedalus Enterprises.

Williams M.E.,University of Virginia
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2013

Mantle cell lymphoma (MCL) is a unique subtype of non-Hodgkin lymphoma that is both biologically and clinically heterogeneous. A variety of biomarkers, the achievement of minimal residual disease negativity after initial therapy, and the MCL International Prognostic Index (MIPI) are associated with patient outcome, although none has as yet been used for routine treatment stratification. Given the lack of widely accepted and standardized treatment approaches, clinical trial enrollment should always be considered for the initial therapy of MCL. Outside of the trial setting, younger and transplantation-eligible patients with newly diagnosed MCL who require treatment should first be considered for a rituximab+a high-dose cytarabine-containing regimen, followed by autologous stem cell transplantation consolidation in first remission. Symptomatic elderly and nontransplantation-eligible individuals typically receive rituximab+bendamustine, or R-CHOP (rituximab+cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone/prednisolone) followed by maintenance rituximab, the latter a treatment plan that has demonstrated extended response duration and survival. Promising early results for consolidation approaches with proteasome inhibitors and immunomodulatory drugs are now being tested in randomized clinical trials. The availability of highly active BCR signaling pathway inhibitors and cell death pathway modulation via BH3 mimetics, among other novel agents, promise to rapidly expand treatment options, change existing treatment paradigms, and further improve outcomes for MCL patients.

Fountain N.B.,University of Virginia
Current Opinion in Neurology | Year: 2013

Purpose of Review: The science of quality of care in medicine has been emerging for the past decade, but it has only recently addressed epilepsy care. Quality of care in this sense refers to implementation of policies in large populations to improve care. This can have a large impact on epilepsy patients, as much of their care is delivered by generalists who can improve their care through the explicit direct requirements of quality measures. Purpose of Review: Eight epilepsy quality performance measures were recently approved by national organizations, but only three were adopted by Medicare and only one by the National Quality Forum. The main reason for not adopting them is the lack of high-level evidence. However, there is high-level evidence for the efficacy of epilepsy surgery and use of newer antiepileptic drugs for the treatment of intractable epilepsy. Other problems are the lack of information about gaps in care and the imprecision in epilepsy diagnosis coding. Summary: Quality measurement will continue in epilepsy care, so a working knowledge of the topic is required by healthcare providers. Implementation of standardized quality measures can improve the care of people with epilepsy if the measures have demonstrated efficacy and can address gaps in care, and implementation is feasible. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Moore J.M.,NASA | Howard A.D.,University of Virginia
Geophysical Research Letters | Year: 2010

Features observed in the low-latitude basins of Hotei Regio and Tui Regio on Titan have attracted the attention of the Cassini-era investigators. At both locations, Visual Infrared Mapping Spectrometer (VIMS) observed isolated 5-μm bright ∼500 km wide features described as lobate in shape. Several studies have proposed that these materials are cryo-volcanic flows. We propose an alternative explanation. Recently published topographic profiles across Hotei Regio and Tui Regio indicate these features appear to occur in large regional basins, at least along the direction of the profiles. Cassini Synthetic Aperture Radar (SAR) images show that the terrains surrounding both topographically low-lying 5-μm bright features exhibit fluvial networks that appear to converge into the probable basins. The 5-μm bright features themselves correspond to fields of discrete radar-bright depressions whose bounding edges are commonly rounded and cumulate in planform in SAR images. These fields of discrete radar-bright depressions strongly resemble fields of features seen at Titan's high latitudes identified as dry lakes. Thus the combination of (1) the resemblance to high-latitude dry lakes, (2) location in the centers of regional depressions, and (3) convergence of fluvial networks are inferred by us to best explain the features of Hotei Regio and Tui Regio as sites of paleolake clusters (and perhaps former, now dry seas). These low-latitude paleolake clusters or former seas, if real, may be evidence of substantially larger inventories of liquid alkanes in Titan's past. Copyright 2010 by the American Geophysical Union.

Carr D.E.,University of Virginia | Eubanks M.D.,Texas A&M University
Annual Review of Entomology | Year: 2014

Self-pollination is common in plants, and limited seed and pollen dispersal can create localized inbreeding even within outcrossing plants. Consequently, insects regularly encounter inbred plants in nature. Because inbreeding results in elevated homozygosity, greater expression of recessive alleles, and subsequent phenotypic changes in inbred plants, inbreeding may alter plant-insect interactions. Recent research has found that plant inbreeding alters resistance and tolerance to herbivores, alters the attraction and susceptibility of plants to insects that vector plant pathogens, and alters visitation rates of insect pollinators. These results suggest that interactions with insects can increase or decrease inbreeding depression (the loss of fitness due to self-fertilization) and subsequently alter the evolution of selfing within plant populations. Future work needs to focus on the mechanisms underlying genetic variation in the effects of inbreeding on plant-insect interactions and the consequences of altered plant-insect interactions on the evolution of plant defense and plant mating systems. © Copyright ©2014 by Annual Reviews. All rights reserved.

Griggs M.S.,University of Virginia | Mikami A.Y.,University of British Columbia
Journal of the American Academy of Child and Adolescent Psychiatry | Year: 2011

Objective: This study investigated the impact of parental attention-deficit/hyperactivity disorder (ADHD) symptoms on the peer relationships and parentchild interaction outcomes of children with ADHD among families completing a randomized controlled trial of parental friendship coaching (PFC) relative to control families. Method: Participants were 62 children with ADHD (42 boys and 20 girls, 6 through 10 years old) and their parents. Approximately half of the families received PFC (a 3-month parent training intervention targeting the peer relationships of children with ADHD), and the remainder represented a no-treatment control group. Results: Parental inattention predicted equivalent declines in children's peer acceptance in both treatment and control families. However, treatment amplified differences between parents with high versus low ADHD symptoms for some outcomes: Control families declined in functioning regardless of parents' symptom levels. However, high parental inattention predicted increased child peer rejection and high parental inattention and impulsivity predicted decreased parental facilitation among treated families (indicating reduced treatment response). Low parental symptoms among treated families were associated with improved functioning in these areas. For other outcomes, treatment attenuated differences between parents with high versus low ADHD symptoms: Among control parents, high parental impulsivity was associated with increasing criticism over time, whereas all treated parents showed reduced criticism regardless of symptom levels. Follow-up analyses indicated that the parents experiencing poor treatment response are likely those with clinical levels of ADHD symptoms. Conclusions: Results underscore the need to consider parental ADHD in parent training treatments for children with ADHD. © 2011 American Academy of Child and Adolescent Psychiatry.

Janes K.A.,University of Virginia | Lauffenburger D.A.,Massachusetts Institute of Technology
Journal of Cell Science | Year: 2013

Computational models of cell signalling are perceived by many biologists to be prohibitively complicated. Why do math when you can simply do another experiment? Here, we explain how conceptual models, which have been formulated mathematically, have provided insights that directly advance experimental cell biology. In the past several years, models have influenced the way we talk about signalling networks, how we monitor them, and what we conclude when we perturb them. These insights required wet-lab experiments but would not have arisen without explicit computational modelling and quantitative analysis. Today, the best modellers are crosstrained investigators in experimental biology who work closely with collaborators but also undertake experimental work in their own laboratories. Biologists would benefit by becoming conversant in core principles of modelling in order to identify when a computational model could be a useful complement to their experiments. Although the mathematical foundations of a model are useful to appreciate its strengths and weaknesses, they are not required to test or generate a worthwhile biological hypothesis computationally. © 2013. Published by The Company of Biologists Ltd.

Tustison N.J.,University of Virginia | Avants B.B.,University of Pennsylvania
Frontiers in Neuroinformatics | Year: 2013

Diffeomorphic mappings are central to image registration due largely to their topological properties and success in providing biologically plausible solutions to deformation and morphological estimation problems. Popular diffeomorphic image registration algorithms include those characterized by time-varying and constant velocity fields, and symmetrical considerations. Prior information in the form of regularization is used to enforce transform plausibility taking the form of physics-based constraints or through some approximation thereof, e.g., Gaussian smoothing of the vector fields [a la Thirion's Demons (Thirion, 1998)]. In the context of the original Demons' framework, the so-called directly manipulated free-form deformation (DMFFD) (Tustison et al., 2009) can be viewed as a smoothing alternative in which explicit regularization is achieved through fast B-spline approximation. This characterization can be used to provide B-spline "flavored" diffeomorphic image registration solutions with several advantages. Implementation is open source and available through the Insight Toolkit and our Advanced Normalization Tools (ANTs) repository. A thorough comparative evaluation with the well-known SyN algorithm (Avants et al., 2008), implemented within the same framework, and its B-spline analog is performed using open labeled brain data and open source evaluation tools. © 2013 Tustison and Avants.

Liu X.,University of California at Los Angeles | Lin Z.,University of Virginia
IEEE Transactions on Automatic Control | Year: 2011

The nonlinear equivalences of both finite and infinite zero structures of linear systems have been well understood for single input single output systems and have found many applications in nonlinear control theory. The extensions of these notions to multiple input multiple output systems have proven to be highly sophisticated. In this paper, we propose constructive algorithms for decomposing a nonlinear system that is affine in control. These algorithms require modest assumptions on the system and apply to general multiple input multiple output systems that do not necessarily have the same number of inputs and outputs. They lead to various normal form representations and reveal the structure at infinity, the zero dynamics and the invertibility properties, all of which represent nonlinear equivalences of relevant linear system structural properties. © 2006 IEEE.

BACKGROUND: Axon degeneration is a characteristic feature of multiple neuropathologic states and is also a mechanism of physiological neurodevelopmental pruning. The vast majority of in vivo studies looking at axon degeneration have relied on the use of classical silver degeneration stains, which have many limitations including lack of molecular specificity and incompatibility with immunolabeling methods. Because Wallerian degeneration is well known to involve cytoskeletal disassembly and because caspases are recently implicated in aspects of this process, we asked whether antibodies directed at caspase-generated neoepitopes of beta-actin and alpha-tubulin would be useful immunohistochemical markers of pathological and developmental axon degeneration.RESULTS: Here we demonstrate that several forms of axon degeneration involve caspase-mediated cleavage of these cytoskeletal elements and are well-visualized using this approach. We demonstrate the generation of caspase-induced neoepitopes in a) an in vitro neuronal culture model using nerve growth factor-deprivation-induced degeneration and b) an in vivo model using ethanol-induced neuronal apoptosis, and c) during normal developmental pruning and physiological turnover of neurons.CONCLUSIONS: Our findings support recent experimental data that suggests caspase-3 and caspase-6 have specific non-redundant roles in developmental pruning. Finally, these findings may have clinical utility, as these markers highlight degenerating neurites in human hypoxic-ischemic injury. Our work not only confirms a common downstream mechanism involved in axon degeneration, but also illuminates the potential utility of caspase-cleavage-neoepitope antibodies as markers of neurodegeneration.

Okusa M.D.,University of Virginia | Davenport A.,University College London
Kidney International | Year: 2014

The KDIGO guidelines for acute kidney injury (AKI) are designed to assist health-care providers around the world in managing patients with AKI. Clinical guidelines are intended to help the clinician make an informed decision based on review of the currently available evidence. Due to the generic nature of guidelines, it is sometimes difficult to translate a guideline for a particular individual patient who may have specific clinical circumstances. To illustrate this point, we have discussed the interpretation of the KDIGO guideline in patients who have subtleties in their clinical presentation, which may make treatment decisions less than straightforward © 2013 International Society of Nephrology.

Background and Objective: Heart failure patient mortality rates are a focus of hospital quality assessment. This study examines whether comprehensive use of diagnoses identified as present on admission improves Methods for comparing hospital mortality rates. Research Design: California hospital mortality rates are assessed using the Agency for Healthcare Research and Quality Inpatient Quality Indicator for heart failure, which uses selected diagnoses identified as present on admission. These rates are compared with rates calculated using comprehensive adjustments for diagnoses identified as present on admission. Models are compared to assess the accuracy of classification and to compare differences in hospitals identified with lower or higher than expected mortality. SUBJECTS: The study included 91,511 discharge records for patients with heart failure from 365 California hospitals for patients discharged in 2007. Results: Every aspect of statistical model performance (discrimination, classification, calibration, and explanatory power) was improved by using more comprehensive adjustments for diagnoses identified as present on admission. The number of hospitals originally identified with higher than expected mortality was reduced by 50%. Conclusions: More comprehensive use of diagnoses identified as present on admission improves the performance of mortality risk adjustment Methods, and these improvements meaningfully change the Results of hospital mortality rate comparisons. Copyright © 2011 by Lippincott Williams & Wilkins.

Adler P.N.,University of Virginia
Current topics in developmental biology | Year: 2012

Drosophila has been the key model system for studies on planar cell polarity (PCP). The rich morphology of the insect exoskeleton contains many structures that display PCP. Among these are the trichomes (cuticular hairs) that cover much of the exoskeleton, sensory bristles, and ommatidia. Many genes have been identified that must function for the development of normal PCP. Among these are the genes that comprise the frizzled/starry night (fz/stan) and dachsous/fat pathways. The mechanisms that underlie the function of the fz/stan pathway are best understood. All of the protein products of these genes accumulate asymmetrically in wing cells and there is good evidence that this involves local intercellular signaling between protein complexes on the distal edge of one cell and the juxtaposed proximal edge of its neighbor. It is thought that a feedback system, directed transport, and stabilizing protein-protein interactions mediate the formation of distal and proximal protein complexes. These complexes appear to recruit downstream proteins that function to spatially restrict the activation of the cytoskeleton in wing cells. This leads to the formation of the array of distally pointing hairs found on wings. Copyright © 2012 Elsevier Inc. All rights reserved.

Schwarzbauer J.E.,Princeton University | DeSimone D.W.,University of Virginia
Cold Spring Harbor Perspectives in Biology | Year: 2011

Fibronectin (FN) is a multidomain protein with the ability to bind simultaneously to cell surface receptors, collagen, proteoglycans, and other FN molecules. Many of these domains and interactions are also involved in the assembly of FN dimers into a multimeric fibrillar matrix. When, where, and how FN binds to its various partners must be controlled and coordinated during fibrillogenesis. Steps in the process of FN fibrillogenesis including FN self-association, receptor activities, and intracellular pathways have been under intense investigation for years. In this review, the domain organization of FN including the extra domains and variable region that are controlled by alternative splicing are described. We discuss how FN-FN and cell-FN interactions play essential roles in the initiation and progression of matrix assembly using complementary results from cell culture and embryonic model systems that have enhanced our understanding of this process. © 2011 Cold Spring Harbor Laboratory Press.

Hoffman D.M.,University of Virginia
Health, Risk and Society | Year: 2010

In recent years, consciousness of high levels of societal and familial risk have made raising a 'resilient child' a key theme in parenting culture. Using evidence from the popular literature on parenting resilient children, this interpretive discourse-based critique explores the ways resilience has been conceptualised in the parenting advice literature. It suggests that this literature advocates a 'resilience pedagogy' that reflects social class differentials and dramatically expands the possibilities for parental intervention in children's lives. The analysis identifies clear links between resilience pedagogy and an emphasis on parenting strategies focused on fostering children's emotional competencies. While ostensibly legitimising and valuing children's emotional worlds, the underlying message of resilience pedagogy is more one of social control and conformity, in which parents become a primary means for the delivery of rationalised and therapeutic models of parent-child relationships that respond to larger political, cultural, and class-based visions of social order. © 2010 Taylor & Francis.

Geroleo F.G.,U.S. Army | Brandt-Pearce M.,University of Virginia
IEEE Transactions on Aerospace and Electronic Systems | Year: 2012

The Wigner-Ville Hough transform (WVHT) is suboptimal in the detection and parameter estimation of linear frequency-modulated (LFM) continuous wave (LFMCW) low probability of intercept (LPI) radar waveforms because they are composed of concatenated LFM pulses. We formulate the detection and estimation problem to take into account the multiple pulses that are available in an observation interval at the intercept receiver. The new algorithm, called the periodic WVHT (PWVHT), significantly outperforms the WVHT for LFMCW signals. © 2006 IEEE.

Minkoff H.,Maimonides Medical Center | Marshall M.F.,University of Virginia
American Journal of Bioethics | Year: 2016

Several factors related to fetal risk render it more or less acceptable in justifying constraints on the behavior of pregnant women. Risk is an unavoidable part of pregnancy and childbirth, one that women must balance against other vital personal and family interests. Two particular issues relate to the fairness of claims that pregnant women are never entitled to put their fetuses at risk: relative risks and relatives' risks. The former have been used—often spuriously—to advance arguments against activities, such as home birth, that may incur risk; the latter implicate the nature of relationships in determining the acceptability of coercing or precluding activities. Motivated reasoning by clinicians and judges leads to inaccurate risk assessments, and judgments based on false claims to objectivity. Such judgments undermine the moral and legal standing of pregnant women and do not advance the interests of fetuses, pregnant women, families, or states. © 2016, Copyright © Taylor & Francis Group, LLC.

Lamacraft A.,University of Virginia
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2011

We study a spin-1 Bose-Einstein condensate small enough to be treated as a single magnetic domain: a system that we term a microcondensate. Because all particles occupy a single spatial mode, this quantum many-body system has a well-defined classical limit consisting of three degrees of freedom, corresponding to the three macroscopically occupied spin states. We study both the classical limit and its quantization, finding an integrable system in both cases. Depending on the sign of the ratio of the spin interaction energy and the quadratic Zeeman energy, the classical limit displays either a separatrix in phase space or Hamiltonian monodromy corresponding to nontrivial phase space topology. We discuss the quantum signatures of these classical phenomena using semiclassical quantization as well as an exact solution using the Bethe ansatz. © 2011 American Physical Society.

Lamacraft A.,University of Virginia
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2011

We consider the one-dimensional expansion of a system of interacting bosons, starting from a regular array. Without interactions the familiar Hanbury Brown and Twiss effect for bosons gives rise to a series of peaks in the density-density correlations of the expanded system. Infinitely repulsive particles likewise give a series of dips, a signature of the underlying description in terms of free fermions. In the intermediate case of finite interaction, the noise correlations consist of a set of Fano resonance lineshapes, with an asymmetry parameter determined by the scattering phase shift of a pair of particles and a width depending on the initial momentum spread of the particles. © 2011 American Physical Society.

Guan X.,University of Virginia | Gammie C.F.,University of Illinois at Urbana - Champaign
Astrophysical Journal | Year: 2011

We consider local, stratified, numerical models of isothermal accretion disks. The novel feature of our treatment is that radial extent Lx and azimuthal extent Ly satisfy H « Lx, L y « R, where H is the scale height and R is the local radius. This enables us to probe mesoscale structure in stratified thin disks. We evolve the model at several resolutions, sizes, and initial magnetic field strengths. Consistent with earlier work, we find that the saturated, turbulent state consists of a weakly magnetized disk midplane coupled to a strongly magnetized corona, with a transition at |z| ∼ 2H. The saturated α ≈ 0.01-0.02. A two-point correlation function analysis reveals that the central 4H of the disk is dominated by small-scale turbulence that is statistically similar to unstratified disk models, while the coronal magnetic fields are correlated on scales ∼ 10H. Nevertheless angular momentum transport through the corona is small. A study of magnetic field loops in the corona reveals few open field lines and predominantly toroidal loops with a characteristic distance between footpoints that is ∼ H. Finally, we find quasiperiodic oscillations with characteristic timescale ∼ 30 Ω-1 in the magnetic field energy density. These oscillations are correlated with oscillations in the mean azimuthal field; we present a phenomenological, alpha-dynamo model that captures most aspects of the oscillations. © 2011. The American Astronomical Society. All rights reserved. Printed in the U.S.A.

Janes K.A.,University of Virginia
Current Opinion in Biotechnology | Year: 2016

Recent advances have created new opportunities to dissect cellular heterogeneity at the omics level. The enthusiasm for deep single-cell profiling has obscured a discussion of different types of heterogeneity and the most-appropriate techniques for studying each type. Here, I distinguish heterogeneity in regulation from heterogeneity in lineage. Snapshots of lineage heterogeneity provide a cell atlas that catalogs cellular diversity within complex tissues. Profiles of regulatory heterogeneity seek to interrogate one lineage deeply to capture an ensemble of single-cell states. Single-cell atlases require molecular signatures from many cells at a throughput afforded by mass cytometry-based, microfluidic-based, and microencapsulation-based methods. Single-cell states are more dependent on time, microenvironment, and low-abundance transcripts, emphasizing in situ methods that stress depth of profiling and quantitative accuracy. © 2016 Elsevier Ltd.

Glanowska K.M.,University of Virginia | Moenter S.M.,University of Michigan
Journal of Neurophysiology | Year: 2011

Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway for central control of fertility. Regulation of GnRH neurons by long-loop gonadal steroid feedback through steroid receptor-expressing afferents such as GABAergic neurons is well studied. Recently, local central feedback circuits regulating GnRH neurons were identified. GnRH neuronal depolarization induces short-term inhibition of their GABAergic afferents via a mechanism dependent on metabotropic glutamate receptor (mGluR) activation. GnRH neurons are enveloped in astrocytes, which express mGluRs. GnRH neurons also produce endocannabinoids, which can be induced by mGluR activation. We hypothesized the local GnRH-GABA circuit utilizes glia-derived and/or cannabinoid mechanisms and is altered by steroid milieu. Whole cell voltageclamp was used to record GABAergic postsynaptic currents (PSCs) from GnRH neurons before and after action potential-like depolarizations were mimicked. In GnRH neurons from ovariectomized (OVX) mice, this depolarization reduced PSC frequency. This suppression was blocked by inhibition of prostaglandin synthesis with indomethacin, by a prostaglandin receptor antagonist, or by a specific glial metabolic poison, together suggesting the postulate that prostaglandins, potentially glia-derived, play a role in this circuit. This circuit was also inhibited by a CB1 receptor antagonist or by blockade of endocannabinoid synthesis in GnRH neurons, suggesting an endocannabinoid element, as well. In females, local circuit inhibition persisted in androgen-treated mice but not in estradiol-treated mice or young ovary-intact mice. In contrast, local circuit inhibition was present in gonad-intact males. These data suggest GnRH neurons interact with their afferent neurons using multiple mechanisms and that these local circuits can be modified by both sex and steroid feedback. © 2011 the American Physiological Society.

Shirts M.R.,University of Virginia
Journal of Chemical Theory and Computation | Year: 2013

It is often difficult to quantitatively determine if a new molecular simulation algorithm or software properly implements sampling of the desired thermodynamic ensemble. We present some simple statistical analysis procedures to allow sensitive determination of whether the desired thermodynamic ensemble is properly sampled. These procedures use paired simulations to cancel out system dependent densities of state and directly test the extent to which the Boltzmann distribution associated with the ensemble (usually canonical, isobaric-isothermal, or grand canonical) is satisfied. We demonstrate the utility of these tests for model systems and for molecular dynamics simulations in a range of situations and describe an implementation of the tests designed for end users. © 2012 American Chemical Society.

Klich I.,University of Virginia
Physical Review Letters | Year: 2012

In this Letter we study the entanglement of a quantum radiation field interacting with a dielectric medium. In particular, we describe the quantum mixed state of a field interacting with a dielectric through plasma and Drude models and show that these generate very different entanglement behavior, as manifested in the entanglement entropy of the field. We also present a formula for a "Casimir" entanglement entropy, i.e., the distance dependence of the field entropy. Finally, we study a toy model of the interaction between two plates. In this model, the field entanglement entropy is divergent; however, as in the Casimir effect, its distance-dependent part is finite, and the field matter entanglement is reduced when the objects are far. © 2012 American Physical Society.

Huntsinger J.R.,Loyola University Chicago | Isbell L.M.,University of Massachusetts Amherst | Clore G.L.,University of Virginia
Psychological Review | Year: 2014

Despite decades of research demonstrating a dedicated link between positive and negative affect and specific cognitive processes, not all research is consistent with this view. We present a new overarching theoretical account as an alternative-one that can simultaneously account for prior findings, generate new predictions, and encompass a wide range of phenomena. According to our proposed affect-ascognitive- feedback account, affective reactions confer value on accessible information processing strategies (e.g., global vs. local processing) and other responses, goals, concepts, and thoughts that happen to be accessible at the time. This view underscores that the relationship between affect and cognition is not fixed but, instead, is highly malleable. That is, the relationship between affect and cognitive processing can be altered, and often reversed, by varying the mental context in which it is experienced. We present evidence that supports this account, along with implications for specific affective states and other subjective experiences. © 2014 American Psychological Association.

Derewenda Z.S.,University of Virginia
Acta Crystallographica Section D: Biological Crystallography | Year: 2010

Until recently, protein crystallization has mostly been regarded as a stochastic event over which the investigator has little or no control. With the dramatic technological advances in synchrotron-radiation sources and detectors and the equally impressive progress in crystallographic software, including automated model building and validation, crystallization has increasingly become the rate-limiting step in X-ray diffraction studies of macromolecules. However, with the advent of recombinant methods it has also become possible to engineer target proteins and their complexes for higher propensity to form crystals with desirable X-ray diffraction qualities. As most proteins that are under investigation today are obtained by heterologous overexpression, these tech-niques hold the promise of becoming routine tools with the potential to transform classical crystallization screening into a more rational high-success-rate approach. This article presents an overview of protein-engineering methods designed to enhance crystallizability and discusses a number of examples of their successful application. © 2010 International Union of Crystallography. Printed in Singapore-all rights reserved.

Roulston T.H.,University of Virginia | Goodell K.,Ohio State University
Annual Review of Entomology | Year: 2011

Recent declines of bee species have led to great interest in preserving and promoting bee populations for agricultural and wild plant pollination. Many correlational studies have examined the indirect effects of factors such as landscape context and land management practices and found great variation in bee response. We focus here on the evidence for effects of direct factors (i.e., food resources, nesting resources, and incidental risks) regulating bee populations and then interpret varied responses to indirect factors through their species-specific and habitat-specific effects on direct factors. We find strong evidence for food resource availability regulating bee populations, but little clear evidence that other direct factors are commonly limiting. We recommend manipulative experiments to illuminate the effects of these different factors. We contend that much of the variation in impact from indirect factors, such as grazing, can be explained by the relationships between indirect factors and floral resource availability based on environmental circumstances. © 2011 by Annual Reviews. All rights reserved.

Winckler B.,University of Virginia
Cold Spring Harbor perspectives in biology | Year: 2010

Wiring of the brain relies initially on the correct outgrowth of axons to reach the appropriate target area for innervation. A large number of guidance receptors present in the plasma membrane of axonal growth cones and elsewhere on the neuron read and execute directional cues present in the extracellular environment of the navigating growth cone. The exact timing, levels, and localization of expression of the guidance receptors in the plasma membrane therefore determine the outcome of guidance decisions. Many guidance receptors are localized in exquisitely precise spatial and temporal patterns. The cellular mechanisms ensuring these localization patterns include spatially accurate sorting after synthesis in the secretory pathway, retrieval of inappropriately expressed receptors by endocytosis followed by degradation or recycling, and restriction of diffusion. This article will discuss the machinery and regulation underlying the restricted distribution of membrane receptors, focusing on the currently best-studied example, the L1 cell adhesion molecule. In addition to the long-range mechanisms ensuring appropriate localization, the same mechanisms can act locally to adjust levels and localization of receptors. These local mechanisms are regulated by ligand binding and subsequent activation of local signaling cascades. It is likely that the localization of all guidance receptors is regulated by a combination of sorting, retrieval, recycling and retention, similar to the ones we discuss here for L1.

Ruhm C.J.,University of Virginia
Future of Children | Year: 2011

The struggle to balance work responsibilities with family obligations may be most difficult for working parents of the youngest children, those five and under. Any policy changes designed to ease the difficulties for these families are likely to be controversial, requiring a careful effort to weigh both the costs and benefits of possible interventions while respecting diverse and at times conflicting American values. In this article, Christopher Ruhm looks at two potential interventions- parental leave and early childhood education and care (ECEC)-comparing differences in policies in the United States, Canada, and several European nations and assessing their consequences for important parent and child outcomes. By and large, Canadian and European policies are more generous than those in the United States, with most women eligible for paid maternity leave, which in a few countries can last for three years or more. Many of these countries also provide for paid leave that can be used by either the mother or the father. And in many European countries ECEC programs are nearly universal after the child reaches a certain age. In the United States, parental leave, if it is available, is usually short and unpaid, and ECEC is generally regarded as a private responsibility of parents, although some federal programs help defray costs of care and preschool education. Ruhm notes that research on the effects of differences in policies is not completely conclusive, in part because of the difficulty of isolating consequences of leave and ECEC policies from other influences on employment and children's outcomes. But, he says, the comparative evidence does suggest desirable directions for future policy in the United States. Policies establishing rights to short parental leaves increase time at home with infants and slightly improve the job continuity of mothers, with small, but positive, long-run consequences for mothers and children. Therefore, Ruhm indicates that moderate extensions of existing U.S. leave entitlements (up to several months in duration) make sense. He also suggests that some form of paid leave would facilitate its use, particularly among less advantaged parents, and that efforts to improve the quality of ECEC, while maintaining or enhancing affordability, are desirable.

Gernsheimer T.,University of Washington | James A.H.,University of Virginia | Stasi R.,St. Georges Hospital
Blood | Year: 2013

A mild thrombocytopenia is relatively frequent during pregnancy and has generally no consequences for either the mother or the fetus. Although representing no threat in the majority of patients, thrombocytopenia may result from a range of pathologic conditions requiring closer monitoring and possible therapy. Two clinical scenarios are particularly relevant for their prevalence and the issues relating to their management. The first is the presence of isolated thrombocytopenia and the differential diagnosis between primary immune thrombocytopenia and gestational thrombocytopenia. The second is thrombocytopenia associated with preeclampsia and its lookalikes and their distinction from thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome. In this review, we describe a systematic approach to the diagnosis and treatment of these disease entities using a case presentation format. Our discussion includes the antenatal and perinatal management of both the mother and fetus. © 2013 by The American Society of Hematology.

Blackhall L.J.,University of Virginia
Muscle and Nerve | Year: 2012

Patients with amyotrophic lateral sclerosis (ALS) have high symptom burdens, including pain, fatigue, dyspnea, and sialorrhea, and they must make difficult decisions about the use of life-prolonging therapies, such as long-term mechanical ventilation. The impact of ALS is also felt by family caregivers who often struggle to meet the heavy physical, financial, and emotional demands associated with the illness. Expert multidisciplinary care may improve both quality and length of life of patients with ALS. However, although advances have been made in the treatment of some symptoms, others, including pain management, remain poorly studied. Involvement of palliative care specialists as part of the ALS multidisciplinary team is recommended, as we continue to work toward improving the quality of life for patients and their families. © 2011 Wiley Periodicals, Inc.

Lowe D.E.,University of Virginia
Frontiers in cellular and infection microbiology | Year: 2012

Bacillus anthracis, the causative agent of anthrax, secretes a tri-partite exotoxin that exerts pleiotropic effects on the host. The purification of the exotoxin components, protective antigen, lethal factor, and edema factor allowed the rapid characterization of their physiologic effects on the host. As molecular biology matured, interest focused on the molecular mechanisms and cellular alterations induced by intoxication. Only recently have researchers begun to connect molecular and cellular knowledge back to the broader physiological effects of the exotoxin. This review focuses on the progress that has been made bridging molecular knowledge back to the exotoxin's physiological effects on the host.

Porter J.H.,University of Virginia | Hanson P.C.,University of Wisconsin - Madison | Lin C.-C.,Taiwan Forestry Research Institute
Trends in Ecology and Evolution | Year: 2012

Developments in sensor design, electronics, computer technology and networking have converged to provide new ways of collecting environmental data at rates hitherto impossible to achieve. To translate this 'data deluge' into scientific knowledge requires comparable advances in our ability to integrate, process and analyze massive data sets. We review the experience of one large project in ingesting and analyzing sensor data from global lakes and provide a synopsis of innovative approaches being used to confront the information management and analytical challenges posed by massive volumes of data. © 2011 Elsevier Ltd.

McCaffrey L.M.,McGill University | Macara I.G.,University of Virginia
Trends in Cell Biology | Year: 2011

Epithelial cells comprise the foundation for the majority of organs in the mammalian body, and are the source of approximately 90% of all human cancers. Characteristically, epithelial cells form intercellular adhesions, exhibit apical/basal polarity, and orient their mitotic spindles in the plane of the epithelial sheet. Defects in these attributes result in the tissue disorganization associated with cancer. Epithelia undergo self-renewal from stem cells, which might in some cases be the cell of origin for cancers. The PAR polarity proteins are master regulators of epithelial organization, and are closely linked to signaling pathways such as Hippo, which orchestrate proliferation and apoptosis to control organ size. 3D ex vivo culture systems can now faithfully recapitulate epithelial organ morphogenesis, providing a powerful approach to study both normal development and the initiating events in carcinogenesis. © 2011 Elsevier Ltd.

Peng Y.-N.,University of Virginia
Communications in Mathematical Physics | Year: 2011

Associated to a composition of M and a composition of N, a new presentation of the super Yangian of the general linear Lie superalgebra Y(glM{pipe}N) is obtained. © 2011 Springer-Verlag.

Browne J.A.,University of Virginia | Hanssen A.D.,Mayo Medical School
Journal of Bone and Joint Surgery - Series A | Year: 2011

Background: Patellar tendon disruption associated with total knee arthroplasty is an uncommon but potentially disastrous complication. Repair with isolated suture fixation is insufficient, and autograft and allograft tendon reconstruction techniques have variable results. The purpose of this study was to determine the results of a novel surgical technique in which readily available synthetic mesh is used for patellar tendon reconstruction. Methods: We retrospectively reviewed thirteen consecutive patients who underwent extensor mechanism reconstruction for subacute or chronic patellar tendon disruption following total knee arthroplasty at an average age of sixty years (range, thirty-seven to seventy-seven years). Five patients had already been treated unsuccessfully with an allograft extensor mechanism reconstruction and eight had a prior revision knee arthroplasty. The surgical technique included use of a knitted monofilament polypropylene graft to reconstruct the patellar tendon and to facilitate fixation of adjacent host tissue into the graft. Follow-up was available for all patients at a mean of forty-two months (range, eleven to 118 months). Results: Three patients had evidence of failure of the graft reconstruction, all within six months. One patient with previous sepsis had recurrent infection and was treated with a knee arthrodesis. The remaining nine patients all demonstrated an extensor lag of no greater than 10° and have had no loss of extension at the time of final follow-up. Knee flexion was maintained in all patients (a mean of 103° preoperatively versus a mean of 107° postoperatively). The mean Knee Society scores for pain and function improved significantly (p < 0.01). Synthetic mesh was significantly less expensive than allograft for this reconstruction. Conclusions: The use of synthetic mesh to reconstruct a disrupted patellar tendon is a straightforward surgical procedure that was successful and durable in the majority of patients in our series. Compared with the use of an allograft, this technique eliminates the possibility of disease transmission and may be more cost-effective. No complications unique to the synthetic mesh were observed. Level of Evidence: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence. Copyright © 2011 by The Journal of Bone and Joint Surgery, Incorporated.

Roach D.A.,University of Virginia
Experimental Gerontology | Year: 2012

Individuals in a large experimental field population, of the short-lived perennial species Plantago lanceolata, were followed to determine the sources of variation that influence mortality and life span. The design included multiple age groups with initially similar genetic structure, which made it possible to separate age effects from period effects and to identify the genetic component to variation in life span. During a period of stress, individuals of all ages showed parallel increases in mortality but different cohorts experienced this period of high mortality at different ages. This then influenced the distribution of life spans across cohorts. Age and size-age interactions influenced mortality during the period of stress. Smaller individuals died but only if they were old. Additionally, growth and age interacted with stress such that older individuals had negative growth and high mortality whereas younger individuals had positive growth and relatively lower mortality during stress. The results of this study show that it is not simply the environment that can have a major impact on demography in natural populations; rather, age, size and growth can interact with the environment to influence mortality and life span when the environment is stressful. © 2012 Elsevier Inc.

Gray M.,University of Virginia
American Journal of Clinical Dermatology | Year: 2010

Incontinence-associated dermatitis (IAD), sometimes referred to as perineal dermatitis, is an inflammation of the skin associated with exposure to urine or stool. Elderly adults, and especially those in long-term care facilities, are at risk for urinary or fecal incontinence and IAD. Traditionally, IAD has received little attention as a distinct disorder, and it is sometimes confused with stage I or II pressure ulcers. However, a modest but growing body of research is beginning to provide insights into the epidemiology, etiology, and pathophysiology of IAD. In addition, recent changes in reimbursement policies from the US Center for Medicare and Medicaid Services regarding pressure ulcer prevention has focused attention on the differential diagnosis of IAD versus pressure ulcer, and its influence on pressure ulcer risk. Color, location, depth, and the presence or absence of necrotic tissue are visual indicators used to differentiate IAD from pressure-related skin damage. Prevention is based on avoiding or minimizing exposure to stool or urine combined with a structured skin-care program based on principles of gentle cleansing, moisturization, preferably with an emollient, and application of a skin protectant. Treatment of IAD focuses on three main goals: (i) removal of irritants from the affected skin; (ii) eradication of cutaneous infections such as candidiasis; and (iii) containment or diversion of incontinent urine or stool. © 2010 Adis Data Information BV. All rights reserved.

Pearson W.R.,University of Virginia
Current Protocols in Bioinformatics | Year: 2013

Protein sequence similarity searching programs like BLASTP, SSEARCH, and FASTA use scoring matrices that are designed to identify distant evolutionary relationships (BLOSUM62 for BLAST, BLOSUM50 for SSEARCH and FASTA). Different similarity scoring matrices are most effective at different evolutionary distances. "Deep" scoring matrices like BLOSUM62 and BLOSUM50 target alignments with 20% to 30% identity, while "shallow" scoring matrices (e.g., VTML10 to VTML80) target alignments that share 90% to 50% identity, reflecting much less evolutionary change. While "deep" matrices provide very sensitive similarity searches, they also require longer sequence alignments and can sometimes produce alignment overextension into nonhomologous regions. Shallower scoring matrices are more effective when searching for short protein domains, or when the goal is to limit the scope of the search to sequences that are likely to be orthologous between recently diverged organisms. Likewise, in DNA searches, the match and mismatch parameters set evolutionary look-back times and domain boundaries. In this unit, we will discuss the theoretical foundations that drive practical choices of protein and DNA similarity scoring matrices and gap penalties. Deep scoring matrices (BLOSUM62 and BLOSUM50) should be used for sensitive searches with full-length protein sequences, but short domains or restricted evolutionary look-back require shallower scoring matrices. © 2013 by John Wiley & Sons, Inc.

Carta G.,University of Virginia
Biotechnology Journal | Year: 2012

The dynamic binding capacity (DBC) and its dependence on residence time influence the design and productivity of adsorption columns used in protein capture applications. This paper offers a very simple approach to predict the DBC of an adsorption column based on a measurement of the equilibrium binding capacity (EBC) and of the time needed to achieve one-half of the EBC in a batch adsorption test. The approach is based on a mass transfer kinetics model that assumes pore diffusion with a rectangular isotherm; however, the same approach is also shown to work for other systems where solute transport inside the particle occurs through other transport mechanisms. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pinkerton J.V.,University of Virginia
Menopause | Year: 2014

Unsubstantiated claims, lack of scientific safety and efficacy data, and lack of quality control surround customcompounded bioidentical hormone products. FDA-approved hormone therapy provides tested and regulated therapy without the risks of unregulated and untested custom preparations. © 2014 by The North American Menopause Society.

Howard A.D.,University of Virginia | Moore J.M.,NASA
Journal of Geophysical Research E: Planets | Year: 2011

Numerous shallowly incised valleys extend from the upper interior rims of Newton and Gorgonum basins across smooth interior basin deposits. These valleys are a few meters to 300 m wide and may have experienced discharges over all or most of their width, implying that they are, in fact, incised channels. In Newton Crater these valleys extend up to 75 km, to near the center of the basin floor. In Gorgonum basin the valleys terminate at what we interpret to be a former ice-covered lake. These valleys appear to be examples of scattered, shallowly incised valleys found throughout the midlatitudes of Mars superimposed upon the widespread mantling deposits within the region. On the basis of crater count age dating, the interior valleys in Newton and Gorgonum basins were formed at about the Hesperian to Amazonian transition. The runoff through the valleys may have occurred due to episodic melting of snow and ice that had accumulated on the crater rims. Temperatures warm enough to cause extensive melting may have occurred during optimal orbital and obliquity configurations because of intensive volcanism releasing greenhouse gasses or as a result of a brief episode of warming from a large impact somewhere on Mars. The valleys were formed at about the same time as major outflow channels were active along the highlands-lowlands boundary. Water delivered to the northern lowlands by the outflow channels may have been recycled as snow and ice deposits within the Martian midlatitudes. The episodic melting of such deposits may have formed the midlatitude valleys. Copyright 2011 by the American Geophysical Union.

Santen R.J.,University of Virginia
The Journal of clinical endocrinology and metabolism | Year: 2010

OBJECTIVE: Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement. EVIDENCE: Each expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence. CONSENSUS PROCESS: A consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors. CONCLUSIONS: The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

Gress D.R.,University of Virginia
Journal of the American College of Cardiology | Year: 2012

Cerebral embolic events related to carotid and cardiac disease have been known for decades. Recently, cerebral embolic events have become a focus of clinical importance as complications of vascular procedures. Further, the development of new technologies and procedures has increased the overall clinical significance. Although the relative safety of these procedures is usually defined by acute stroke risk, it is also becoming clear that far more subclinical events are occurring. Recent reports provided substantial evidence of memory loss, cognitive decline, and dementia related to these so-called silent infarcts. Literature reports of magnetic resonance imaging events lead to an estimate of as many as 600,000 patients with new brain injury each year in the United States alone. Given the magnitude of the numbers involved, the impact of accelerated cognitive loss and premature senescence in a vulnerable at-risk population could well be significant. © 2012 American College of Cardiology Foundation.

Abdesselam A.,University of Virginia
Annales Henri Poincare | Year: 2011

We provide an explicit combinatorial expansion for the ground state energy of the massless spin-Boson model as a power series in the coupling parameter. Our method uses the technique of cluster expansion in constructive quantum field theory and takes as a starting point the functional integral representation and its reduction to an Ising model on the real line with long range interactions. We prove the analyticity of our expansion and provide an explicit lower bound on the radius of convergence. We do not need multiscale nor renormalization group analysis. A connection to the loop-erased random walk is indicated. © 2011 Springer Basel AG.

We questioned whether the use of p16(INK4a) immunohistochemistry in endocervical curettage (ECC) specimens would improve the detection of high-grade squamous intraepithelial lesions (HSIL) in a high-risk patient population. Papanicolaou test results were retrieved in 58 consecutive ECC specimens that were previously diagnosed as no histopathologic abnormality in patients with antecedent HSIL or atypical squamous cells, cannot exclude HSIL. An H&E recut and immunohistochemistry for p16(INK4a) were performed on all cases. HSIL were found in 18 (31%) ECC specimens originally interpreted as negative. Of these 18 cases, three had moderate-sized fragments of ectocervical epithelium with HSIL seen on the recut H&E with concurrent positivity for p16(INK4a). Fourteen cases had rare to occasional clusters of atypical cells with strong immunoreactivity for p16(INK4a). A single case showed a medium-sized fragment of HSIL on the p16(INK4a)-stained section. The use of recuts and adjunct p16(INK4a) should be considered when evaluating ECC specimens in high-risk patient populations.

We showed previously that pulmonary function and arterial oxygen saturation in NY1DD mice with sickle cell disease (SCD) are improved by depletion of invariant natural killer T (iNKT) cells or blockade of their activation. Here we demonstrate that SCD causes a 9- and 6-fold induction of adenosine A(2A) receptor (A(2A)R) mRNA in mouse pulmonary iNKT and natural killer (NK) cells, respectively. Treating SCD mice with the A(2A)R agonist ATL146e produced a dose-dependent reversal of pulmonary dysfunction with maximal efficacy at 10 ng/kg/minute that peaked within 3 days and persisted throughout 7 days of continuous infusion. Crossing NY1DD mice with Rag1(-/-) mice reduced pulmonary injury that was restored by adoptive transfer of 10(6) purified iNKT cells. Reconstituted injury was reversed by ATL146e unless the adoptively transferred iNKT cells were pretreated with the A(2A)R alkylating antagonist, FSPTP (5-amino-7-[2-(4-fluorosulfonyl)phenylethyl]-2-(2-furyl)-pryazolo[4,3-ε]-1,2,4-triazolo[1,5-c]pyrimidine), which completely prevented pro-tection. In NY1DD mice exposed to hypoxia-reoxygenation, treatment with ATL146e at the start of reoxygenation prevented further lung injury. Together, these data indicate that activation of induced A(2A)Rs on iNKT and NK cells in SCD mice is sufficient to improve baseline pulmonary function and prevent hypoxia-reoxygenation-induced exacerbation of pulmonary injury. A(2A) agonists have promise for treating diseases associated with iNKT or NK cell activation.

Lu A.,Harvard University | Magupalli V.G.,Harvard University | Ruan J.,Harvard University | Yin Q.,Harvard University | And 7 more authors.
Cell | Year: 2014

Inflammasomes elicit host defense inside cells by activating caspase-1 for cytokine maturation and cell death. AIM2 and NLRP3 are representative sensor proteins in two major families of inflammasomes. The adaptor protein ASC bridges the sensor proteins and caspase-1 to form ternary inflammasome complexes, achieved through pyrin domain (PYD) interactions between sensors and ASC and through caspase activation and recruitment domain (CARD) interactions between ASC and caspase-1. We found that PYD and CARD both form filaments. Activated AIM2 and NLRP3 nucleate PYD filaments of ASC, which, in turn, cluster the CARD of ASC. ASC thus nucleates CARD filaments of caspase-1, leading to proximity-induced activation. Endogenous NLRP3 inflammasome is also filamentous. The cryoelectron microscopy structure of ASCPYD filament at near-atomic resolution provides a template for homo- and hetero-PYD/PYD associations, as confirmed by structure-guided mutagenesis. We propose that ASC-dependent inflammasomes in both families share a unified assembly mechanism that involves two successive steps of nucleation-induced polymerization. PaperFlick © 2014 Elsevier Inc.

Glanowska K.M.,University of Virginia | Moenter S.M.,University of Michigan
Endocrinology | Year: 2015

GnRH release in the median eminence (ME) is the central output for control of reproduction. GnRH processes in the preoptic area (POA) also release GnRH.Weexamined region-specific regulation of GnRH secretion using fast-scan cyclic voltammetry to detect GnRH release in brain slices from adult male mice. Blocking endoplasmic reticulum calcium reuptake to elevate intracellular calcium evokes GnRH release in both the ME and POA. This release is action potential dependent in the ME but not the POA. Locally applied kisspeptin induced GnRH secretion in both theMEand POA. Local blockade of inositol triphospate-mediated calcium release inhibited kisspeptin-induced GnRH release in the ME, but broad blockade was required in the POA. In contrast, kisspeptin-evoked secretion in the POA was blocked by local gonadotropin-inhibitory hormone, but broad gonadotropin-inhibitory hormone application was required in the ME. Although action potentials are required for GnRH release induced by pharmacologically-increased intracellular calcium in theMEand kisspeptin-evoked release requires nositol triphosphate-mediated calcium release, blocking action potentials did not inhibit kisspeptin-induced GnRH release in the ME. Kisspeptin-induced GnRH release was suppressed after blocking both action potentials and plasma membrane Ca2+ channels. This suggests that kisspeptin action in theMErequiresbothincreased intracellular calciumandinfluxfromthe outside of the cell but not action potentials. Local interactions among kisspeptin and GnRH processes in the ME could thus stimulate GnRH release without involving perisomatic regions of GnRH neurons. Coupling between action potential generation and hormone release in GnRH neurons is thus likely physiologically labile and may vary with region. © 2015 by the Endocrine Society Received April 18, 2014.

Noshad M.,University of Virginia | Jamshidi K.,University of Applied Sciences of Leipzig
Journal of Lightwave Technology | Year: 2011

In this paper, two lower and upper bounds for the bit error rate of codes with fixed cross correlation in spectral-amplitude-coding optical code-division multiple access systems are offered. In this study, we consider only the phase-induced intensity noise and neglect other noises such as shot and thermal noises, in the performance analysis. Also, it is assumed that users are synchronous. This bound is obtained using combinatorics approach and utilizing simple inequalities. In numerical results, the comparison between the upper bound, lower bound, and simulation results for MQC, MFH, BIBD, and Hadamard codes is presented, and the tightness of the bounds is evaluated. © 2011 IEEE.

Morris P.B.,Medical University of South Carolina | Ballantyne C.M.,Baylor College of Medicine | Birtcher K.K.,University of Houston | Dunn S.P.,University of Virginia | Urbina E.M.,Cincinnati Childrens Hospital Medical Center
Journal of the American College of Cardiology | Year: 2014

Managing risk related to low-density lipoprotein (LDL) is vital in therapy for patients at risk for atherosclerotic cardiovascular disease (ASCVD) events given its important etiologic role in atherogenesis. Despite decades of research showing reduction of ASCVD risk with multiple approaches to lowering of LDL cholesterol, there continue to be significant gaps in care with inadequate numbers of patients receiving standard of care lipid-lowering therapy. Confusion regarding implementation of the multiple published clinical practice guidelines has been identified as one contributor to suboptimal management of LDL-related risk. This review summarizes the current guidelines for reduction of LDL-related cardiovascular risk provided by a number of major professional societies, which have broad applicability to diverse populations worldwide. Statements have varied in the process and methodology of development of recommendations, the grading system for level and strength of evidence, the inclusion or exclusion of expert opinion, the suggested ASCVD risk assessment tool, the lipoproteins recommended for risk assessment, and the lipoprotein targets of therapy. The similarities and differences among important guidelines in the United States and internationally are discussed, with recommendations for future strategies to improve consistency in approaches to LDL-related ASCVD risk and to reduce gaps in implementation of evidence-based therapies. © 2014 By The American College of Cardiology Foundation Published By Elsevier Inc.

Mathers A.J.,University of Virginia | Peirano G.,University of Calgary | Pitout J.D.D.,University of Calgary | Pitout J.D.D.,University of Pretoria
Clinical Microbiology Reviews | Year: 2015

Escherichia coli sequence type 131 (ST131) and Klebsiella pneumoniae ST258 emerged in the 2000s as important human pathogens, have spread extensively throughout the world, and are responsible for the rapid increase in antimicrobial resistance among E. coli and K. pneumoniae strains, respectively. E. coli ST131 causes extraintestinal infections and is often fluoroquinolone resistant and associated with extended-spectrum β-lactamase production, especially CTX-M-15. K. pneumoniae ST258 causes urinary and respiratory tract infections and is associated with carbapenemases, most often KPC-2 and KPC-3. The most prevalent lineage within ST131 is named fimH30 because it contains the H30 variant of the type 1 fimbrial adhesin gene, and recent molecular studies have demonstrated that this lineage emerged in the early 2000s and was then followed by the rapid expansion of its sublineages H30-R and H30-Rx. K. pneumoniae ST258 comprises 2 distinct lineages, namely clade I and clade II. Moreover, it seems that ST258 is a hybrid clone that was created by a large recombination event between ST11 and ST442. Epidemic plasmids with blaCTX-M and blaKPC belonging to incompatibility group F have contributed significantly to the success of these clones. E. coli ST131 and K. pneumoniae ST258 are the quintessential examples of international multidrug-resistant high-risk clones. © 2015, American Society for Microbiology. All Rights Reserved.

Ruddiman W.F.,University of Virginia
Annual Review of Earth and Planetary Sciences | Year: 2013

The start of the period of large-scale human effects on this planet (the Anthropocene) is debated. The industrial view holds that most significant impacts have occurred since the early industrial era (∼1850), whereas the early-Anthropogenic view recognizes large impacts thousands of years earlier. This review focuses on three indices of global-scale human influence: forest clearance (and related land use), emissions of greenhouse gases (CO2 and CH4), and effects on global temperature. Because reliable, systematic land-use surveys are rare prior to 1950, most reconstructions for early-industrial centuries and prior millennia are hind casts that assume humans have used roughly the same amount of land per person for 7,000 years. But this assumption is incorrect. Historical data and new archeological databases reveal much greater per-capita land use in preindustrial than in recent centuries. This early forest clearance caused much greater preindustrial greenhouse-gas emissions and global temperature changes than those proposed within the industrial paradigm. © Copyright ©2013 by Annual Reviews. All rights reserved.

Culp S.H.,University of Virginia | Schellhammer P.F.,Eastern Virginia Medical School | Williams M.B.,Eastern Virginia Medical School
European Urology | Year: 2014

Background Few data exist regarding the impact on survival of definitive treatment of the prostate in men diagnosed with metastatic prostate cancer (mPCa). Objective To evaluate the survival of men diagnosed with mPCa based on definitive treatment of the prostate. Design, setting, and participants Men with documented stage IV (M1a-c) PCa at diagnosis identified using Surveillance Epidemiology and End Results (SEER) (2004-2010) and divided based on definitive treatment of the prostate (radical prostatectomy [RP] or brachytherapy [BT]) or no surgery or radiation therapy (NSR). Outcome measurements and statistical analysis Kaplan-Meier methods were used to calculate overall survival (OS). Multivariable competing risks regression analysis was used to calculate disease-specific survival (DSS) probability and identify factors associated with cause-specific mortality (CSM). Results and limitations A total of 8185 patients were identified: NSR (n = 7811), RP (n = 245), and BT (n = 129). The 5-yr OS and predicted DSS were each significantly higher in patients undergoing RP (67.4% and 75.8%, respectively) or BT (52.6 and 61.3%, respectively) compared with NSR patients (22.5% and 48.7%, respectively) (p < 0.001). Undergoing RP or BT was each independently associated with decreased CSM (p < 0.01). Similar results were noted regardless of the American Joint Committee on Cancer (AJCC) M stage. Factors associated with increased CSM in patients undergoing local therapy included AJCC T4 stage, high-grade disease, prostate-specific antigen ≤20 ng/ml, age ≤70 yr, and pelvic lymphadenopathy (p < 0.05). The major limitation of this study was the lack of variables from SEER known to influence survival of patients with mPCa, including treatment with systemic therapy. Conclusions Definitive treatment of the prostate in men diagnosed with mPCa suggests a survival benefit in this large population-based study. These results should serve as a foundation for future prospective trials. Patient summary We used a large population-based cancer database to examine survival in men diagnosed with metastatic prostate cancer (mPCa) undergoing definitive therapy for the prostate. Local therapy (LT) appeared to confer a survival benefit. Therefore, we conclude that prospective trials are needed to further evaluate the role of LT in mPCa. © 2013 European Association of Urology.

Pu L.,University of Virginia
Accounts of chemical research | Year: 2012

The development of automated, high-throughput organic synthesis and screening techniques has created an urgent demand for methods that rapidly determine the enantiomeric composition of chiral compounds. Enantioselective fluorescent sensors offer the potential for real-time, high-sensitivity techniques for determining enantiomeric data in high-throughput chiral assays. In this Account, we describe a range of fluorescent sensors derived from 1,1'-bi-2-naphthol (BINOL), a readily available biaryl compound with axial chirality. We show that BINOL can be used to construct structurally diverse, chiral fluorescent sensors to carry out highly enantioselective, sensitive recognition of chiral amino alcohols, α-hydroxycarboxylic acids, and amino acid derivatives. For example, we prepared an (S)-BINOL derivative whose 3,3'-positions are attached to two chiral amino alcohol units, each having two phenyl substituents. This compound shows a fluorescence enhancement of 950-fold in the presence of (S)-mandelic acid but very little change in the presence of (R)-mandelic acid. It also allows the enantiomers of this α-hydroxycarboxylic acid to be visually discriminated by an enantioselective precipitation process. A structurally similar (S)-BINOL-amino alcohol molecule, but with three rather than two phenyl substitutents in each of the two amino alcohol units, was found to exhibit generally enantioselective fluorescence responses toward structurally diverse α-hydroxycarboxylic acids. We further prepared a pseudoenantiomeric analogue of this compound from (R)-H(8)BINOL, which has the opposite chiral configuration at both the biaryl center as well as the pendant amino alcohols. These two compounds have opposite enantioselectivity in the recognition of a chiral substrate, with distinctly different fluorescence emission wavelengths. By mixing them together, we developed a pseudoenantiomeric sensor pair to facilitate chiral assays. Using this pseudoenantiomeric sensor pair allows both the concentration and the enantiomeric composition of a substrate to be determined in a single fluorescence measurement. We synthesized another compound by ligating a terpyridine unit to BINOL and found that coordination of a Cu(II) ion to the terpyridine unit almost completely quenched its fluorescence. Displacement of the Cu(2+) ion from this complex by chiral amino alcohols leads to enantioselective fluorescence enhancement. This BINOL-terpyridine-Cu(II) complex also exhibits enantioselective gel collapsing in the presence of chiral amino alcohols, providing a new visual chiral discrimination method. When a series of light-absorbing conjugated units are attached to the BINOL structure, the resulting multiarmed dendritic molecules show greatly amplified fluorescence responses. Thus, the light harvesting effect of dendrimers can be used to greatly increase the sensitivity of the fluorescent sensors. The progress described here demonstrates that highly enantioselective and sensitive fluorescent sensors can be obtained through a systematic investigation of the structure-property relation between the sensors and the substrates. These sensors show great potential for the development of rapid assays of chiral organic compounds.

Jaswal V.K.,University of Virginia
Cognitive Psychology | Year: 2010

How do children resolve conflicts between a self-generated belief and what they are told? Four studies investigated the circumstances under which toddlers would trust testimony that conflicted with their expectations about the physical world. Thirty-month-olds believed testimony that conflicted with a naive bias (Study 1), and they also repeatedly trusted testimony that conflicted with an event they had just seen (Study 2)-even when they had an incentive to ignore the testimony (Study 3). Children responded more skeptically if they could see that the testimony was wrong as it was being delivered (Study 3), or if they had the opportunity to accumulate evidence confirming their initial belief before hearing someone contradict it (Study 4). Together, these studies demonstrate that toddlers have a robust bias to trust even surprising testimony, but this trust can be influenced by how much confidence they have in their initial belief. © 2010 Elsevier Inc.

Egelman E.H.,University of Virginia
eLife | Year: 2014

Helical polymers are found throughout biology and account for a substantial fraction of the protein in a cell. These filaments are very attractive for three-dimensional reconstruction from electron micrographs due to the fact that projections of these filaments show many different views of identical subunits in identical environments. However, ambiguities exist in defining the symmetry of a helical filament when one has limited resolution, and mistakes can be made. Until one reaches a near-atomic level of resolution, there are not necessarily reality-checks that can distinguish between correct and incorrect solutions. A recent paper in eLife (Xu et al., 2014) almost certainly imposed an incorrect helical symmetry and this can be seen using filament images posted by Xu et al. A comparison between the atomic model proposed and the published three-dimensional reconstruction should have suggested that an incorrect solution was found.

Gerber M.S.,University of Virginia
Decision Support Systems | Year: 2014

Twitter is used extensively in the United States as well as globally, creating many opportunities to augment decision support systems with Twitter-driven predictive analytics. Twitter is an ideal data source for decision support: its users, who number in the millions, publicly discuss events, emotions, and innumerable other topics; its content is authored and distributed in real time at no charge; and individual messages (also known as tweets) are often tagged with precise spatial and temporal coordinates. This article presents research investigating the use of spatiotemporally tagged tweets for crime prediction. We use Twitter-specific linguistic analysis and statistical topic modeling to automatically identify discussion topics across a major city in the United States. We then incorporate these topics into a crime prediction model and show that, for 19 of the 25 crime types we studied, the addition of Twitter data improves crime prediction performance versus a standard approach based on kernel density estimation. We identify a number of performance bottlenecks that could impact the use of Twitter in an actual decision support system. We also point out important areas of future work for this research, including deeper semantic analysis of message content, temporal modeling, and incorporation of auxiliary data sources. This research has implications specifically for criminal justice decision makers in charge of resource allocation for crime prevention. More generally, this research has implications for decision makers concerned with geographic spaces occupied by Twitter-using individuals. ©2014 Elsevier B.V. All rights reserved.

BACKGROUND:: Few reports have focused on treatment of adult cervical deformity (ACD). OBJECTIVE:: To present early complication rates associated with ACD surgery. METHODS:: A prospective multicenter database of consecutive operative ACD patients was reviewed for early (≤30 days from surgery) complications. Enrollment required at least 1 of the following: cervical kyphosis >10 degrees, cervical scoliosis >10 degrees, C2-7 sagittal vertical axis >4 cm, or chin-brow vertical angle >25 degrees. RESULTS:: Seventy-eight patients underwent surgical treatment for ACD (mean age, 60.8 years). Surgical approaches included anterior-only (14%), posterior-only (49%), anterior-posterior (35%), and posterior-anterior-posterior (3%). Mean numbers of fused anterior and posterior vertebral levels were 4.7 and 9.4, respectively. A total of 52 early complications were reported, including 26 minor and 26 major. Twenty-two (28.2%) patients had at least 1 minor complication, and 19 (24.4%) had at least 1 major complication. Overall, 34 (43.6%) patients had at least 1 complication. The most common complications included dysphagia (11.5%), deep wound infection (6.4%), new C5 motor deficit (6.4%), and respiratory failure (5.1%). One (1.3%) mortality occurred. Early complication rates differed significantly by surgical approach: anterior-only (27.3%), posterior-only (68.4%), and anterior-posterior/posterior-anterior-posterior (79.3%) (P = .007). CONCLUSION:: This report provides benchmark rates for overall and specific ACD surgery complications. Although the surgical approach(es) used were likely driven by the type and complexity of deformity, there were significantly higher complication rates associated with combined and posterior-only approaches compared with anterior-only approaches. These findings may prove useful in treatment planning, patient counseling, and ongoing efforts to improve safety of care. ABBREVIATIONS:: 3CO, 3-column osteotomiesACD, adult cervical deformityEBL, estimated blood lossISSG, International Spine Study groupSVA, sagittal vertical axis Copyright © by the Congress of Neurological Surgeons

Spotnitz W.D.,University of Virginia
American Surgeon | Year: 2012

Hemostats, sealants, and adhesives are useful adjuncts to modern surgical procedures. To maximize their benefit, a surgeon needs to understand the safety, efficacy, usability, and cost of these agents. To be truly added to a surgeon's own toolbox, the operator must also have knowledge of when and how to best use these materials. This commentary is designed to succinctly facilitate this understanding and knowledge. A nomenclature and classification system based on group, category, and class has been created to help with this process and is provided here. By using this system, materials consisting of similar design and for common indications can be compared. For example, in this system, the three functional groups are hemostats, sealants, and adhesives. The hemostats may be divided into four categories: mechanical, active, flowable, and fibrin sealant. These hemostat categories are further subdivided into generic classes based on the composition of the approved materials. Similarly, categories and classes are provided for sealants and adhesives. In this commentary, the salient points with respect to the characteristics of these agents are presented. A discussion of when these agents can be used in specific indications and how they may be applied to achieve the best results is also provided. Copyright Southeastern Surgical Congress. All rights reserved.

Koenig M.A.,University of Minnesota | Jaswal V.K.,University of Virginia
Child Development | Year: 2011

Do children expect an expert in one domain to also be an expert in an unrelated domain? In Study 1, 32 three- and four-year-olds learned that one informant was an expert about dogs relative to another informant. When presented with pictures of new dogs or of artifacts, children who could remember which informant was the dog expert preferred her over the novice as an informant about the names of dogs, but they had no preference when the informants presented artifact labels. In Study 2, 32 children learned that one informant was incompetent about dogs whereas another was neutral. In this case, children preferred the neutral speaker over the incompetent one about both dogs and artifacts. Taken together, these results suggest that for children, expertise is not subject to a "halo effect," but incompetence may be subject to a "pitchfork effect". © 2011 The Authors. Child Development © 2011 Society for Research in Child Development, Inc.

Keller D.,University of Virginia
Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment | Year: 2013

A comprehensive investigation into the measurement uncertainty in polarization produced by Dynamic Nuclear Polarization is outlined. The polarization data taken during Jefferson Lab experiment E08-007 is used to obtain error estimates and to develop an algorithm to minimize uncertainty of the measurement of polarization in irradiated NH314 targets, which is readily applied to other materials. The target polarization and corresponding uncertainties for E08-007 are reported. The resulting relative uncertainty found in the target polarization is determined to be less than or equal to 3.9%. © 2013 The Authors.

Benjamin D.,Harvard University | Klich I.,University of Virginia | Demler E.,Harvard University
Physical Review Letters | Year: 2014

We show that a simple model of noninteracting quasiparticles accurately describes resonant inelastic x-ray scattering (RIXS) experiments in the hole-doped cuprate superconductors. Band structure alone yields signatures previously attributed to collective magnetic modes, such as the dispersing peaks and nontrivial polarization dependence found in several experiments. We conclude that RIXS data can be explained without positing the existence of magnetic excitations that persist with increasing doping. In so doing we develop a formalism for RIXS in itinerant electron systems that accounts for the positively charged core hole exactly and discover a mechanism by which the core hole produces polarization dependence mimicking that of a magnetic system. © 2014 American Physical Society.

Ransom T.S.,University of Virginia
Oecologia | Year: 2011

Ecosystem engineers create habitat that can be used by other species in multiple ways, such as refuges from predators, places to breed, or areas with increased prey resources. I conducted a series of enclosure experiments to: (1) determine if salamanders use earthworm burrows, and (2) examine the potential influence of earthworm burrow use and indirect effects on salamander intra- and interspecific competition, predator avoidance, and seasonal performance. I found that one species of woodland salamander, Plethodon cinereus, used earthworm burrows 50% of the time when burrows were present. Neither adults nor juveniles of the congeneric P. glutinosus used earthworm burrows. Intraspecific, but not interspecific, competition by P. cinereus affected salamander behavior when earthworms were absent, with P. cinereus found under cover objects >70% of the time when alone or with a P. glutinosus, but only 40% of the time when with another P. cinereus. When earthworms were present, the behavior of P. cinereus was similar across salamander treatments. Earthworms decreased the amount of leaf litter and microinvertebrates, although this did not affect salamander mass. In subsequent experiments using only P. cinereus, the refuge provided by earthworm burrows increased the survival of P. cinereus over the winter and allowed P. cinereus to avoid being consumed by the common garter snake (Thamnophis sirtalis). Because earthworm burrows provide a refuge for P. cinereus during intraspecific encounters, in the presence of a predator and over the winter, they may serve as an important belowground-aboveground linkage in eastern forests where salamanders are common. © 2010 Springer-Verlag.

Chevalier R.L.,University of Virginia
Current Medicinal Chemistry | Year: 2012

The renin-angiotensin system is highly conserved through evolutionary history, and has multiple functions in addition to maintaining cardiovascular homeostasis: these include the regulation of renal cell survival and cell death, and development of the kidney. The importance of angiotensin (ANG) in normal kidney development was first recognized in infants with renal maldevelopment born to mothers treated with angiotensin converting enzyme (ACE) inhibitors or with ANG AT1 receptor blockers. The molecular role of ANG in renal development has been elucidated using gene targeting in mice, revealing major effects in branching morphogenesis, vasculogenesis, development of the papilla and renal concentrating mechanism. Although exposure of the fetus to ANG inhibitors is potentially harmful throughout pregnancy, effects are greater in late compared to early gestation. Significant differences between humans and rodents in placental transfer of ANG and timing of renal development contributed to initial delays in recognizing the teratogenic effects of ANG inhibitors. Although administration of ACE or AT1 receptor inhibitors can slow progression of renal disease in older children, ANG inhibition in the neonatal period can aggravate renal injury due to congenital urinary tract obstruction. Neonates are also far more sensitive than older children to the hypotensive actions these agents and doses must be markedly reduced to avoid precipitating oliguria. Understanding the complex interactions of the maturing renin-angiotensin system in the perinatal period is essential in the use of ANG or renin inhibitors in women during childbearing years or in neonates with cardiovascular or renal disease. © 2012 Bentham Science Publishers.

Taylor R.P.,University of Virginia
Blood | Year: 2013

In this issue of Blood, Rossi et al provide convincing evidence that extends and generalizes the importance of trogocytosis, a process in which effector cells use Fcγ receptors to remove Immunoglobulin G (IgG)-chelated antigens from donor cells. Their work suggests that the process may be beneficial in the context of epratuzumab treatment of autoimmune diseases.

Moskaluk C.A.,University of Virginia
Head and Neck Pathology | Year: 2013

The clinical features and common molecular alterations of adenoid cystic carcinoma (ACC) are reviewed in this paper. ACC is an uncommon neoplasm that most frequently arises in salivary glands and related tissue in the head and neck region. ACC has distinct histologic features, with cribriform and tubular growth patterns of basaloid cells displaying a predominantly myoepithelial cellular phenotype. This neoplasm also has uncommon clinical features of rare regional lymph node metastasis and a prolonged but relentlessly progressive clinical course. Clinical outcome in ACC is correlated to histologic grade, which is correlated to the degree of aneuploidy and genetic alterations present in the tumor genomes. Recent studies have identified that the majority of ACC contain alterations of the MYB gene, usually resulting in a fusion gene product with the NFIB gene by a t(6;9) translocation event. The molecular consequences of this alteration are incompletely understood, as are secondary molecular alterations that contribute to the neoplastic phenotype of ACC. © 2013 Springer Science+Business Media New York.

Salthouse T.A.,University of Virginia
Journal of the International Neuropsychological Society | Year: 2012

Two major challenges facing researchers interested in cognitive change are that measures of change are often not very reliable, and they may reflect effects of prior test experience in addition to the factors of primary interest. One approach to dealing with these problems is to obtain multiple measures of change on parallel versions of the same tests in a measurement burst design. A total of 783 adults performed three parallel versions of cognitive tests on two occasions separated by an average of 2.6 years. Performance increased substantially across the three sessions within each occasion, and for all but vocabulary ability these within-occasion improvements were considerably larger than the between-occasion changes. Reliabilities of the changes in composite scores were low, but averages of the three changes had larger, albeit still quite modest, reliabilities. In some cognitive abilities individual differences were evident in the relation of prior test experience and the magnitude of longitudinal change. Although multiple assessments are more time consuming than traditional measurement procedures, the resulting estimates of change are more robust than those from conventional methods, and also allow the influence of practice on change to be systematically investigated. © 2012 INS. Published by Cambridge University Press.

Winstead-Derlega C.,University of Virginia
Telemedicine journal and e-health : the official journal of the American Telemedicine Association | Year: 2012

This pilot study tested the feasibility and impact of using mobile media devices to present peer health messages to human immunodeficiency virus (HIV)-positive patients. A convenience sample of 30 adult patients from an outpatient HIV clinic serving a mostly rural catchment area in central Virginia volunteered for the study. Participants viewed short videos of people discussing HIV health topics on an Apple (Cupertino, CA) iPod® touch® mobile device. Pre- and post-intervention surveys assessed attitudes related to engagement in care and disease disclosure. Participants found delivery of health information by the mobile device acceptable in a clinic setting. They used the technology without difficulty. Participants reported satisfaction with and future interest in viewing such videos after using the mobile devices. The majority of participants used the device to access more videos than requested, and many reported the videos "hit home." There were no significant changes in participant perceptions about engagement in care or HIV disclosure after the intervention. This pilot study demonstrates the feasibility and acceptability of using mobile media technology to deliver peer health messages. Future research should explore how to best use mobile media to improve engagement in care and reduce perceptions of stigma.

Ragosta M.,University of Virginia
Journal of Cardiovascular Translational Research | Year: 2011

The catheterization laboratory is an excellent resource for translational research projects requiring phenotypic analysis of coronary artery disease. Coronary angiography, a traditional method of quantifying coronary disease, remains useful for describing the extent and the severity of angiographic coronary disease but is limited by the fact that angiography only depicts the effect of atherosclerosis on the arterial lumen. For this reason, quantitative coronary angiography has been supplemented by intravascular ultrasound and other catheter-based techniques and non-invasive methods for studies involving atherosclerosis progression and regression. Other angiographic based techniques potentially useful in research include the semi-quantification of collateral circulation, thrombolysis in myocardial infarction (TIMI) frame count, and TIMI blush score. The invasive assessment of coronary flow reserve and fractional flow reserve is a valuable adjunctive technique and can be used to precisely quantify the extent of ischemia or the presence of microvascular disease. Intravascular ultrasound (IVUS) is currently considered the gold standard for early diagnosis of coronary atherosclerosis and for measuring plaque burden. The serial measurements of changes in plaque volume over time are a valuable method of discerning plaque progression and regression. Similarly, radiofrequency backscatter IVUS, a relatively new imaging modality, can be used to describe and track changes in plaque composition. © 2011 Springer Science+Business Media, LLC.

Sheehan J.P.,University of Virginia
Journal of Neurosurgery | Year: 2010

Object. Neurosurgical training is critical in providing residents with the skill set, knowledge, and confidence to perform challenging neurosurgical procedures. Radiosurgery, which neurosurgeons helped define and refine, differs from more traditional, open neurosurgical approaches. This study evaluates the opinions of residents on current radiosurgical training and the effect of a focused educational course on those residents. Methods. The American Association of Neurological Surgeons sponsored a 3-day course focused on intracranial and spinal radiosurgery. Senior-level residents were nominated by US program directors to participate in the course. Twenty-eight residents from distinct training programs were surveyed before and after the course to discern current training practices in radiosurgery and the effect of the focused educational program. The median training level of the participants was postgraduate Year 5 (mean 5.3 years, range 3-7 years). Results. Two-thirds of residents reported that their training institutions had no formal radiosurgery rotation. Twenty-five percent planned to obtain postresidency fellowship training that would include radiosurgery. Before the course, 79% of the residents expected to include radiosurgery in their practice. However, prior to the course, those describing themselves as "very uncomfortable" with performing intracranial or spinal radiosurgery were 33.3 and 45.8%, respectively. After the course, mean self-assessment scores for understanding the indications and performing intracranial radiosurgery increased by 43 and 89%, respectively. The mean scores for understanding the indications and comfort with performing spinal radiosurgery increased by 79 and 200%, respectively. Following the course, there was a 12.3% increase in the number of residents planning to perform radiosurgery following residency. Conclusions. Current neurosurgical residents appear uneasy about their grasp of radiosurgical indications and their ability to perform the procedure. Focused training courses sponsored by professional societies may improve resident education and training in this area of neurosurgery, which has a skill set and basis of knowledge different from traditional open neurosurgical procedures. Further evaluation of the radiosurgical training process for residents must be performed so as to ensure competency and sufficient workforce to meet expanding demands for neurosurgeons performing radiosurgery in a multidisciplinary climate.

Evan A.T.,University of Virginia | Camargo S.J.,Lamont Doherty Earth Observatory
Journal of Climate | Year: 2011

On average 1-2 tropical cyclones form over the Arabian Sea each year, and few of these storms are intense enough to be classified as very severe or super cyclonic storms. As such, few studies have explicitly identified the seasonal to interannual changes in environmental conditions that are associated with Arabian Sea tropical cyclogenesis. However, over the last 30 yr several intense Arabian storms did form and make landfall, with large impacts, which motivates this new study of the basin. The conclusions of earlier studies are visited by utilizing modern observational and reanalysis data to identify the large-scale features associated with Arabian tropical cyclone variability on seasonal time scales. Then year-to-year changes in environmental conditions that are related to interannual variability in Arabian storms during the pre- and postmonsoon periods are elucidated. The analysis of the relationship between large-scale environmental variables and seasonal storm frequency supports conclusions from work completed more than 40 yr prior. Investigation of the year-to-year changes in premonsoon storm frequency suggests that May (June) storms are associated with an early (late) onset of the southwest monsoon. Thefindings also demonstrate that November cyclones (the month when the majority of postmonsoon cyclogenesis occurs) primarily form during periods when the Bay of Bengal experiences a broad region of high sea level pressure, implying that November storms form in either the Arabian Sea or the Bay of Bengal but not in both during the same year. Finally, the analysis of changes in a genesis potential index suggests that long-term variability in the potential for a storm to form is dictated by changes in midlevel moisture. © 2011 American Meteorological Society.

Schwartz M.A.,University of Virginia
Cold Spring Harbor perspectives in biology | Year: 2010

Integrins bind extracellular matrix fibrils and associate with intracellular actin filaments through a variety of cytoskeletal linker proteins to mechanically connect intracellular and extracellular structures. Each component of the linkage from the cytoskeleton through the integrin-mediated adhesions to the extracellular matrix therefore transmits forces that may derive from both intracellular, myosin-generated contractile forces and forces from outside the cell. These forces activate a wide range of signaling pathways and genetic programs to control cell survival, fate, and behavior. Additionally, cells sense the physical properties of their surrounding environment through forces exerted on integrin-mediated adhesions. This article first summarizes current knowledge about regulation of cell function by mechanical forces acting through integrin-mediated adhesions and then discusses models for mechanotransduction and sensing of environmental forces.

Diabetes mellitus (DM) and hypertension may be associated with complications following fractionated radiotherapy. To date no studies have determined the risk of radiation toxicity in patients with DM or hypertension who have undergone Gamma Knife surgery (GKS) for brain arteriovenous malformations (AVMs). The goal of the present study was to determine associations between DM or hypertension and other factors in the development of radiotoxicity, as measured by radiation-induced changes (RICs) on MR images following radiosurgery for AVM. Using univariate methods and multivariate logistic regression, the authors compared the RIC status in patients 18 years of age and older with these patients' history of, or medication use for, DM or hypertension; tobacco use; patient age and sex; AVM volume; Spetzler-Martin AVM severity scale (Grades I and II vs Grades III-V); AVM surgery, AVM embolization, or hemorrhage prior to radiosurgery; AVM location; number of draining veins; and radiosurgery margin dose. Radiation-induced changes occurred in 38% of 539 adults within a mean (± standard deviation) of 12 ± 10 months after radiosurgery, as observed during a median follow-up time of 55 months. Among patients in whom RICs occurred, 34% had headaches, neurological deficits, or new-onset seizures. Larger RICs were associated with worse symptoms. According to a univariate analysis, DM (3% of patients), larger AVM volume, worse Spetzler-Martin grade, lack of AVM surgery prior to radiosurgery, lack of hemorrhage prior to radiosurgery, and smaller margin dose of radiation had significant associations with the presence of RICs. Hypertension (20%), patient sex, tobacco use, number of draining veins, superficial or deep location of the lesion, and AVM embolization prior to radiosurgery had no association with the presence of RICs. According to a multivariate analysis, larger AVM volume, worse Spetzler-Martin grade, and no AVM surgery prior to radiosurgery predicted the occurrence of an RIC. Diabetes mellitus had borderline significance. Vascular factors such as hypertension, patient sex, and tobacco use did not convey additional risks of radiotoxicity, but DM remained a possible cardiovascular risk factor in the development of RICs.

Rulli M.C.,Polytechnic of Milan | D'Odorico P.,University of Virginia
Geophysical Research Letters | Year: 2013

The increasing global demand for food, fibers, and biofuels has made investments in agriculture a priority for some governments and corporations eager to expand their agricultural production while securing good profits. Here we calculate the water appropriation associated with land deals at different negotiation and implementation stages. Using estimates of actual and potential evapotranspiration for the crops planted in the acquired land, we calculate the green and blue water appropriated by land investors under a variety of irrigation scenarios. We also determine the grey water footprint as the amount of water required to dilute to allowable standards the pollution resulting from fertilizer applications. We found that about 380 × 109 m 3 yr-1 of rainwater is appropriated with the 43 million ha of reported contract area acquired by agri-investors (>240 × 10 9 m3 yr-1 in the 29 million ha of foreign acquisitions only). This water would be sufficient to feed ≈ 300-390 million people. Key Points Land and water grabbing are occurring at alarming rates. Grabbed water would be sufficient to improve food security in grabbed countries. Water grabbing is associated with water withdrawals increase ©2013. American Geophysical Union. All Rights Reserved.

Yu J.,University of Virginia
Pediatric Nephrology | Year: 2014

The collecting duct network and the urothelium of the ureter of the metanephric kidney are derived from the ureteric bud epithelium, initially an outgrowth from the caudal end of the Wolffian duct at the onset of the metanephric kidney development. The tips of the ureteric bud epithelium undergo reiterative branching morphogenesis, which generates more tips and trunks, whereas the ureteric trunks grow and differentiate into principal cells and intercalated cells of the collecting ducts that regulate body water and acid-base homeostasis. microRNAs (miRNAs) are a family of small non-coding RNAs that regulate a diversity of biological processes including organogenesis, mostly by negatively regulating their target gene expression. In this review, I will summarize the current knowledge on the critical roles of miRNAs expressed in the ureteric bud epithelium in ureteric bud morphogenesis and differentiation, including ureteric bud branching morphogenesis, collecting duct terminal differentiation, cystogenesis of the collecting ducts, and ureter development. © 2014 IPNA.

Bloom G.S.,University of Virginia
JAMA Neurology | Year: 2014

The defining features of Alzheimer disease (AD) include conspicuous changes in both brain histology and behavior. The AD brain is characterized microscopically by the combined presence of 2 classes of abnormal structures, extracellular amyloid plaques and intraneuronal neurofibrillary tangles, both of which comprise highly insoluble, densely packed filaments. The soluble building blocks of these structures are amyloid-β (Aβ) peptides for plaques and tau for tangles. Amyloid-β peptides are proteolytic fragments of the transmembrane amyloid precursor protein, whereas tau is a brain-specific, axon-enriched microtubule-associated protein. The behavioral symptoms of AD correlate with the accumulation of plaques and tangles, and they are a direct consequence of the damage and destruction of synapses that mediate memory and cognition. Synapse loss can be caused by the failure of live neurons to maintain functional axons and dendrites or by neuron death. During the past dozen years, a steadily accumulating body of evidence has indicated that soluble forms of Aβ and tau work together, independently of their accumulation into plaques and tangles, to drive healthy neurons into the diseased state and that hallmark toxic properties of Aβ require tau. For instance, acute neuron death, delayed neuron death following ectopic cell cycle reentry, and synaptic dysfunction are triggered by soluble, extracellular Aβ species and depend on soluble, cytoplasmic tau. Therefore, Aβ is upstream of tau in AD pathogenesis and triggers the conversion of tau from a normal to a toxic state, but there is also evidence that toxic tau enhances Aβ toxicity via a feedback loop. Because soluble toxic aggregates of both Aβ and tau can self-propagate and spread throughout the brain by prionlike mechanisms, successful therapeutic intervention for AD would benefit from detecting these species before plaques, tangles, and cognitive impairment become evident and from interfering with the destructive biochemical pathways that they initiate. Copyright 2014 American Medical Association. All rights reserved.

Panzer M.B.,University of Virginia | Wood G.W.,Duke University | Bass C.R.,Duke University
Experimental Neurology | Year: 2014

Scaling is an essential component for translating the clinical outcomes of a neurotrauma model to the human equivalent. This article reviews the principles of biomechanical scaling for traumatic brain injuries, and a number of different approaches to scaling the dose (inputs) and response (outputs) of an animal model to humans are highlighted. A particular focus on blast injury scaling is given as an ongoing area of research, and discussion on the implications of scaling on the current blast TBI literature is provided. The risk of using neurotrauma models without considering an appropriate scaling method is that injuries may be induced with non-realistic loading conditions, and the injury mechanisms produced in the laboratory may not be consistent with those in the clinical setting. © 2014 Elsevier Inc.

Grimes R.N.,University of Virginia
Dalton Transactions | Year: 2015

Once seldom encountered outside of a few laboratories, carboranes are now everywhere, playing a role in the development of a broad range of technologies encompassing organic synthesis, radionuclide handling, drug design, heat-resistant polymers, cancer therapy, nanomaterials, catalysis, metal-organic frameworks, molecular machines, batteries, electronic devices, and more. This perspective highlights selected examples in which the special attributes of carboranes and metallacarboranes are being exploited for targeted purposes in the laboratory and in the wider world. This journal is © The Royal Society of Chemistry 2015.

Kaufman D.A.,University of Virginia
Current medical research and opinion | Year: 2010

In an era of quality improvement and 'getting to zero (infections and/or related mortality),' neonatal candidiasis is ripe for evidence-based initiatives. Knowledge of each institution's invasive Candida infection (ICI) incidence and infection-related mortality is critical to evaluate disease burden and effective interventions. Evidenced-based interventions include: antifungal prophylaxis, starting with appropriate dosing, and prompt removal of central venous catheters (CVC). There is A-I evidence supporting antifungal prophylaxis with fluconazole, and it should be considered in every neonatal intensive care unit (NICU). The literature supports targeting infants <1000 g and/or 1000 g and >or=28 weeks not receiving antifungal prophylaxis. Evaluation of ICI incidence and mortality by gestational age and birth week should be followed in each NICU, to evaluate infection control and prevention.

Mortensen M.,University of Virginia
Current Opinion in Otolaryngology and Head and Neck Surgery | Year: 2010

Purpose of Review: Vocal fold scar is generally caused by trauma or from iatrogenic causes such as intubation, radiation therapy or phonomicrosurgery. Once a vocal fold scar has occurred it becomes a difficult problem to treat. There are many different tools that otolaryngologists use for vocal fold scar treatment. This study reviews the literature and discusses the usefulness of laryngeal steroid injection for the treatment of vocal fold scar. Recent Findings: Steroid injection can be performed on an outpatient basis using a rigid laryngeal telescope or with a flexible laryngoscope under topical anesthesia. This technique allows easy surgical manipulation with a good visual field and an easy accurate approach to the lesion. The literature is limited regarding the benefits of steroid injection for vocal fold scar. Summary: Steroid injection of the scarred vocal fold using an office-based technique is one of the ways that we can treat vocal fold scarring that may improve the patient's voice outcomes with minimal side effects or complications. Copyright © 2010 Lippincott Williams & Wilkins.

Hayden F.G.,University of Virginia
Influenza and other Respiratory Viruses | Year: 2013

Progress in the development of antivirals for non-influenza respiratory viruses has been slow with the result that many unmet medical needs and few approved agents currently exist. This commentary selectively reviews examples of where specific agents have provided promising clinical benefits in selected target populations and also considers potential therapeutics for emerging threats like the SARS and Middle East respiratory syndrome coronaviruses. Recent studies have provided encouraging results in treating respiratory syncytial virus infections in lung transplant recipients, serious parainfluenza virus and adenovirus infections in immunocompromised hosts, and rhinovirus colds in outpatient asthmatics. While additional studies are needed to confirm the efficacy and safety of the specific agents tested, these observations offer the opportunity to expand therapeutic studies to other patient populations.© 2013 Blackwell Publishing Ltd.

Dekosky S.T.,University of Virginia | Blennow K.,Gothenburg University | Ikonomovic M.D.,University of Pittsburgh | Gandy S.,Mount Sinai School of Medicine
Nature Reviews Neurology | Year: 2013

Over the past decade, public awareness of the long-term pathological consequences of traumatic brain injury (TBI) has increased. Such awareness has been stimulated mainly by reports of progressive neurological dysfunction in athletes exposed to repetitive concussions in high-impact sports such as boxing and American football, and by the rising number of TBIs in war veterans who are now more likely to survive explosive blasts owing to improved treatment. Moreover, the entity of chronic traumatic encephalopathy (CTE) - which is marked by prominent neuropsychiatric features including dementia, parkinsonism, depression, agitation, psychosis, and aggression - has become increasingly recognized as a potential late outcome of repetitive TBI. Annually, about 1% of the population in developed countries experiences a clinically relevant TBI. The goal of this Review is to provide an overview of the latest understanding of CTE pathophysiology, and to delineate the key issues that are challenging clinical and research communities, such as accurate quantification of the risk of CTE, and development of reliable biomarkers for single-incident TBI and CTE. © 2013 Macmillan Publishers Limited. All rights reserved.

DeBoer M.D.,University of Virginia
Expert Review of Endocrinology and Metabolism | Year: 2011

Pediatric obesity threatens the future health of a growing number of children worldwide. An added challenge in identifying the patients at greatest need for intervention due to their elevated risk for future disease is that pediatric obesity and the associated metabolic syndrome manifest differently among different ethnic groups. African-Americans and Hispanics are more likely to exhibit obesity and insulin resistance and are at a higher risk for developing Type 2 diabetes. Nevertheless, using current criteria, African-American adolescents are much less likely to be diagnosed with metabolic syndrome, largely owing to lower rates of dyslipidemia. Further development is needed in ethnicity-inclusive means of risk identification among adolescents to accurately target treatment toward children at highest risk for future disease and to motivate adolescent patients and their families towards lifestyle improvement. Effective targeting and intensive treatment efforts may help in avoiding future sequelae of obesity among all ethnicities. © 2011 Expert Reviews Ltd.

Davies J.M.,University of Queensland | Platts-Mills T.A.,University of Virginia | Aalberse R.C.,University of Amsterdam
Journal of Allergy and Clinical Immunology | Year: 2013

Our understanding of the origin and fate of the IgE-switched B cell has been markedly improved by studies in mouse models. The immediate precursor of the IgE-switched B cell is either a relatively naive nonswitched B cell or a mature IgG-switched B cell. These 2 routes are referred to as the direct and indirect pathways, respectively. IgE responses derived from each pathway differ significantly, largely reflecting the difference in time spent in a germinal center and thus time for clonal expansion, somatic hypermutation, affinity maturation, and acquisition of a memory phenotype. The clinical and therapeutic implications for IgE responses in human subjects are still a matter of debate, largely because the immunization procedures used in the animal models are significantly different from classical atopic sensitization to allergens from pollen and mites. On the basis of the limited information available, it seems likely that these atopic IgE responses are characterized by a relatively low IgG/IgE ratio, low B-cell memory, and modest affinity maturation, which fits well with the direct switching pathway. It is still unresolved how the IgE response evolves to cover a wide epitope repertoire involving many epitopes per allergen, as well as many different allergens from a single allergen source. © 2013 American Academy of Allergy, Asthma & Immunology.

Hayden F.G.,University of Virginia | Hayden F.G.,Wellcome Trust Sanger Institute
Influenza and other Respiratory Viruses | Year: 2013

Please cite this paper as: Hayden FG. (2012) Newer Influenza Antivirals, Biotherapeutics and Combinations. Influenza and Other Respiratory Viruses 7(Suppl. 1), 63-75. This summary provides an overview of investigational antiviral agents for influenza and of future directions for development of influenza therapeutics. While progress in developing clinically useful antiviral agents for influenza has been generally slow, especially with respect to seriously ill and high-risk patients, important clinical studies of intravenous neuraminidase inhibitors, antibodies and drug combinations are currently in progress. The current decade offers the promise of developing small molecular weight inhibitors with novel mechanisms of action, including host-directed therapies, new biotherapeutics and drug combinations, that should provide more effective antiviral therapies and help mitigate the problem of antiviral resistance. Immunomodulatory interventions also offer promise but need to be based on better understanding of influenza pathogenesis, particularly in seriously ill patients. The development of combination interventions, immunomodulators and host-directed therapies presents unique clinical trial design and regulatory hurdles that remain to be addressed. © 2012 Blackwell Publishing Ltd.

Oishi S.,University of Virginia | Schimmack U.,University of Toronto
Journal of Personality and Social Psychology | Year: 2010

We tested the relation between residential mobility and well-being in a sample of 7,108 American adults who were followed for 10 years. The more residential moves participants had experienced as children, the lower the levels of well-being as adults. As predicted, however, the negative association between the number of residential moves and well-being was observed among introverts but not among extraverts. We further demonstrated that the negative association between residential mobility and well-being among introverts was explained by the relative lack of close social relationships. Finally, we found that introverts who had moved frequently as children were more likely to have died during the 10-year follow-up. Among extraverts, childhood residential mobility was unrelated to their mortality risk as adults. These findings indicate that residential moves can be a risk factor for introverts and that extraversion can be an interpersonal resource for social relationships and well-being in mobile societies. © 2010 American Psychological Association.

Hirashita H.,Academia Sinica, Taiwan | Li Z.,University of Virginia
Monthly Notices of the Royal Astronomical Society: Letters | Year: 2013

We investigate the condition for the formation of micron-sized grains in dense cores of molecular clouds. This ismotivated by the detection ofmid-infrared emission from deep inside a number of dense cores, the so-called 'coreshine,' which is thought to come from scattering by micron (μm)-sized grains. Based on numerical calculations of coagulation starting from the typical grain-size distribution in the diffuse interstellar medium, we obtain a conservative lower limit to the time t to form μm-sized grains: t/tff 3(5/S)(nH/105 cm-3)-1/4 (where tff is the free-fall time at hydrogen number density nH in the core and S the enhancement factor of the grain-grain collision cross-section to account for non-compact aggregates). At the typical core density nH = 105 cm-3, it takes at least a few free-fall times to form the μm-sized grains responsible for coreshine. The implication is that those dense cores observed in coreshine are relatively long-lived entities in molecular clouds, rather than dynamically transient objects that last for one free-fall time or less. © 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.

Hu S.,University of Virginia
Current Opinion in Chemical Biology | Year: 2016

Providing the specific imaging contrast of optical absorption and excellent spatial scalability across the optical and ultrasonic dimensions, photoacoustic imaging has been rapidly emerging and expanding in the past two decades. In this review, I focus on a few latest advances in this enabling technology that hold the potential to transform in vivo functional and molecular imaging at multiple length scales. Specifically, multi-parametric photoacoustic microscopy enables simultaneous high-resolution mapping of hemoglobin concentration, oxygen saturation and blood flow - opening up the possibility of quantifying the metabolic rate of oxygen at the microscopic level. The pump-probe approach harnesses a variety of photoinduced transient optical absorption as novel contrast mechanisms for high-specificity molecular imaging at depth and as nonlinear excitation strategies for high-resolution volumetric microscopy beyond the conventional limit. Novel magneto-optical and photochromic probes lead to contrast-enhanced molecular photoacoustic imaging through differential detection. © 2016 Elsevier Ltd.

Qiao H.,McMaster University | Agnew S.R.,University of Virginia | Wu P.D.,McMaster University
International Journal of Plasticity | Year: 2015

A recently developed crystal plasticity model for describing twinning and detwinning behavior is employed to simulate the behavior of extruded Mg alloy, ZK60A. Notably, accounting for the initial texture and calibrating the model using tension and compression along one direction permits prediction of the strength anisotropy, strength asymmetry, and strain hardening behavior along other directions, for cases for which the contribution of twinning is large, small and intermediate. The model discriminates between the stress required to initiate twinning and that required to grow (thicken) previously existing twins. This enables the model to simulate the unusual stress-strain hysteresis behavior during twinning (e.g., sharp yielding behavior) as well as that of detwinning (characterized by quite gradual yielding). The strain hardening plateau which occurs during both twinning and detwinning are captured, as are the rapid hardening induced by the exhaustion of these mechanisms. Finally, the modeling is validated using previously published in-situ neutron diffraction data. The predicted diffracted intensity evolution, which is indicative of the volume fraction of twinning compares well with the experimental data. For the first time, the lattice strain evolutions during cyclic loading (involving twinning and detwinning) of an extruded magnesium alloy are predicted. Most features of the experimentally observed internal strain evolution are well-described. In particular, the inflections which may be associated with the initiation of particular deformation mechanisms: basal and non-basal slips, as well as deformation twinning are predicted. Careful analysis of the lattice strains reveals greater than expected load sharing by the precipitate phase. © 2014 Elsevier Ltd.

Chevalier R.L.,University of Virginia
Advances in Chronic Kidney Disease | Year: 2015

Maldevelopment of the collecting system resulting in urinary tract obstruction (UTO) is the leading identifiable cause of CKD in children. Specific etiologies are unknown; most cases are suspected by discovering hydronephrosis on prenatal ultrasonography. Congenital UTO can reduce nephron number and cause bladder dysfunction, which contribute to ongoing injury. Severe UTO can impair kidney growth in utero, and animal models of unilateral ureteral obstruction show that ischemia and oxidative stress cause proximal tubular cell death, with later development of interstitial fibrosis. Congenital obstructive nephropathy, therefore, results from combined developmental and obstructive kidney injury. Because of inadequacy of available biomarkers, criteria for surgical correction of upper tract obstruction are poorly established. Lower tract obstruction requires fetal or immediate postnatal intervention, and the rate of progression of CKD is highly variable. New biomarkers based on proteomics and determination of glomerular number by magnetic resonance imaging should improve future care. Angiotensin inhibitors have not been effective in slowing progression, although avoidance of nephrotoxins and timely treatment of hypertension are important. Because congenital UTO begins in fetal life, smooth transfer of care from perinatologist to pediatric and adult urology and nephrology teams should optimize quality of life and ultimate outcomes for these patients. © 2015 National Kidney Foundation, Inc.

As a discipline, chronobiology has come of age in the last 25 years. There has been an exponential increase in our understanding of the molecular mechanism underlying circadian rhythms of gene expression, physiology, and behavior. While the mammalian clock mechanism has not yet been fully described, most of the primary gears have probably been identified; however, there remains a large submerged portion of this physiological iceberg. What is the extent of "clock-controlled gene" expression in the myriad cell types in mammals? What are the cell specific physiological processes that depend either directly or indirectly on the clock? These questions remain largely unanswered, but recent advances suggest a substantial link between basic clock function and physiology in several systems. In the reproductive system, there has been a recent surge in research on molecular clock function in neuroendocrine and endocrine tissues. This makes sense a priori, given the established link between the circadian clock, behavior (including reproductive behavior), and endocrine physiology. By understanding the role of the clock in basic mammalian reproductive physiology, we can begin to explore its role in the onset and progression of diseases that negatively affect fertility. Advances in this area will certainly yield novel insights into the etiology of these disorders and may provide new and exciting avenues for clinical research in reproduction and fertility.

Okusa M.D.,University of Virginia
Contributions to Nephrology | Year: 2010

Acute kidney injury (AKI) is frequently encountered in the intensive care unit, and from its inception, morbidity and mortality increase in these patients compared to those without AKI. Despite numerous clinical trials and newer pharmacological agents, very little progress has been made to reduce the deaths that occur in this population. An important emerging concept is that AKI does not occur in isolation and it frequently involves other organs. Clinical conditions such as shock, trauma, and sepsis lead to an increase in fluid volume, cytokines/chemokines, uremic toxins and other soluble mediators that are known to affect distant organs. This critical loss of balance of these mediators appears to be due both to a reduction in clearance and increase in production as demonstrated by experimental studies of bilateral nephrectomy and ischemia-reperfusion, respectively. The evidence and mechanisms for distant organ injury following AKI will be discussed. Copyright © 2010 S. Karger AG, Basel.

Pearson W.R.,University of Virginia
Current Protocols in Bioinformatics | Year: 2013

Sequence similarity searching, typically with BLAST, is the most widely used and most reliable strategy for characterizing newly determined sequences. Sequence similarity searches can identify "homologous" proteins or genes by detecting excess similarity- statistically significant similarity that reflects common ancestry. This unit provides an overview of the inference of homology from significant similarity, and introduces other units in this chapter that provide more details on effective strategies for identifying homologs. © 2013 by John Wiley & Sons, Inc.

Harland R.M.,University of California at Berkeley | Grainger R.M.,University of Virginia
Trends in Genetics | Year: 2011

Research using Xenopus takes advantage of large, abundant eggs and readily manipulated embryos in addition to conserved cellular, developmental and genomic organization with mammals. Research on Xenopus has defined key principles of gene regulation and signal transduction, embryonic induction, morphogenesis and patterning as well as cell cycle regulation. Genomic and genetic advances in this system, including the development of Xenopus tropicalis as a genetically tractable complement to the widely used Xenopus laevis, capitalize on the classical strengths and wealth of achievements. These attributes provide the tools to tackle the complex biological problems of the new century, including cellular reprogramming, organogenesis, regeneration, gene regulatory networks and protein interactions controlling growth and development, all of which provide insights into a multitude of human diseases and their potential treatments. © 2011 Elsevier Ltd.

Schwartz M.A.,University of Virginia
Current Biology | Year: 2011

Super-resolution light microscopy images of integrin-mediated adhesions have revealed that signaling and cytoskeletal proteins reside at characteristic vertical distances between the plasma membrane and F-actin. © 2011 Elsevier Ltd.

Jin L.,University of Virginia
Journal of Muscle Research and Cell Motility | Year: 2011

Palladin is an actin associated protein serving as a cytoskeleton scaffold, and actin cross linker, localizing at stress fibers, focal adhesions, and other actin based structures. Recent studies showed that palladin plays a critical role in smooth muscle differentiation, migration, contraction, and more importantly contributes to embryonic development. This review will focus on the functions and possible mechanisms of palladin in smooth muscle and in pathological conditions such as cardiovascular diseases and cancers. © 2011 Springer Science+Business Media B.V.

Seto C.K.,University of Virginia
Clinics in Sports Medicine | Year: 2011

The evolution of the preparticipation physical examination (PPE) in the United States continues to advance. In May 2010, the fourth edition of the Preparticipation Physical Examination Evaluation (PPE-4) monograph was published. The monograph is a product reflecting the collaborative efforts of 6 author societies. This article provides a brief historical review of the PPE and then highlights the recent changes and updates contained in the PPE-4 monograph, including cardiovascular screening in athletes. New recommendations to include the PPE in all well-child care visits and the need to develop a nationwide standard for the PPE are discussed. © 2011 Elsevier Inc.

Imbrie J.Z.,University of Virginia
Physical Review Letters | Year: 2016

We consider a weakly interacting quantum spin chain with random local interactions. We prove that many-body localization follows from a physically reasonable assumption that limits the extent of level attraction in the statistics of eigenvalues. In a Kolmogorov-Arnold-Moser-style construction, a sequence of local unitary transformations is used to diagonalize the Hamiltonian by deforming the initial tensor-product basis into a complete set of exact many-body eigenfunctions. © 2016 American Physical Society.

BACKGROUND: The 30-day readmission rate is a quality metric under the Affordable Care Act. Readmission rates after thyroidectomy and parathyroidectomy and associated factors remain ill-defined. We evaluated patient and perioperative factors for association with readmission after thyroidectomy and parathyroidectomy.METHODS: The American College of Surgeons National Surgical Quality Improvement Program Participant Use File (2011) data for thyroid (n = 3,711) and parathyroid (n = 3,358) resections were analyzed. Patient- and operation-related factors were assessed by univariate and multivariate analyses.RESULTS: Among 7,069 patients, 30-day readmission rate was 4.0%: 4.1% after thyroidectomy and 3.8% after parathyroidectomy. Significant associations for 30-day readmission included declining functional status (odds ratio [OR], 6.4-10.1), preoperative hemodialysis (OR, 2.6; 95% CI, 1.5-4.7), malnutrition (OR, 3.4; 95% CI, 1.2-10.1), increasing American Society of Anesthesiologists class (OR 1.3-4.7), unplanned reoperation (OR, 61.6), and length of stay (LOS) <24 hours (OR, 0.61; 95% CI, 0.45-0.85; all P < .05). Readmission was associated with greater total and postoperative LOS and major postoperative complications, including renal insufficiency (all P < .01).CONCLUSION: Thirty-day readmission after cervical endocrine resection occurs in 4% of patients. Discharge within 24 hours of operation does not affect the likelihood of readmission. Risk factors for readmission are multifactorial and driven by preoperative conditions. Decreasing the index hospital stay and preventing major postoperative complications may decrease readmissions and improve quality metrics. Copyright © 2014 Elsevier Inc. All rights reserved.

Farrell-Carnahan L.,University of Virginia
Telemedicine journal and e-health : the official journal of the American Telemedicine Association | Year: 2013

Alcohol-exposed pregnancy (AEP) is a leading cause of birth defects. Effective face-to-face preconception interventions based on motivational interviewing (MI) exist and should be translated into remote formats for maximum public health impact. This study investigated the feasibility and promise of a one-session, remote-delivered, preconception, MI-based AEP intervention (EARLY Remote) for non-treatment-seeking community women. This was a single-arm, prospective pilot intervention study. All participants received the intervention via telephone and mail. Feasibility of remote-delivery methods, treatment engagement, treatment credibility, MI treatment integrity, and therapeutic alliance were examined. Outcomes were 3- and 6-month drinks per drinking day (DDD), rate of unreliable contraception, and proportion of women at risk for AEP due to continued risk drinking and no or unreliable contraception use. Feasibility of remote delivery was established; participants were engaged by the intervention and rated it as credible. Integrity to MI and therapeutic alliance were good. Both DDD and rate of unreliable contraception decreased significantly over time. Proportions of women who drank at risk levels, used unreliable or no contraception, and/or were at risk for AEP in the past 90 days decreased significantly from baseline to 6 months. Remote delivery was feasible, and the translated remote intervention may reduce AEP risk. Refinement of EARLY Remote may facilitate its placement within a spectrum of effective MI-based preconception AEP interventions as part of a stepped-care approach. EARLY Remote may have an important role within a stepped-care model for dissemination to geographically disperse women at risk for AEP. This could result in substantial public health impact through reduction of AEP on a larger scale.

Courtoy A.,University of Liege | Liuti S.,University of Virginia
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2013

We present an analysis of the role of the running coupling constant at the intersection of perturbative and non-perturbative QCD. Although the approaches that have been considered so far in these two regimes appear to be complementary to each other, a unified description might be derived through the definition of the effective coupling, as they both provide ways of analyzing its freezing at low values of the scale. We extract the effective coupling from all available experimental data on the unpolarized structure function of the proton, F2p, at large values of Bjorken x, including the resonance region. We suggest that parton-hadron duality observed in this region can be explained if non-perturbative effects are included in the coupling constant. The outcome of our analysis is a smooth transition from perturbative to non-perturbative QCD physics, embodied in the running of the coupling constant at intermediate scales. © 2013 Elsevier B.V.

Deboer M.D.,University of Virginia
Current Pharmaceutical Design | Year: 2012

Ghrelin is a stomach-derived hormone that acts at the ghrelin receptor (formerly called the Growth Hormone Secretagogue (GHS)-1a receptor) in multiple tissues throughout the body, exhibiting pleotropic effects potentially beneficial as a treatment in human disease states. Given its properties including increasing appetite, decreasing systemic inflammation, decreasing vascular resistance, increasing cardiac output, and increasing growth hormone and IGF-1 levels, ghrelin has been tested as a treatment in animal models of multiple disease states that produce the deficits in these processes. Thus, the efficacy of ghrelin has been testing in diseases involving anorexia, negative energy balance, cardiovascular compromise, systemic inflammation and gastroparesis. These diseases include cancer cachexia, chronic heart failure, chronic renal failure, chemotherapy, arthritis, gastroparesis and inflammatory bowel disease. Across this wide variety of diseases treatment with ghrelin and ghrelin agonists have produced benefits, though given ghrelin's widespread effects, the exact mechanisms behind ghrelin's action in these settings is frequently difficult to determine. Further investigation using animal models may help to determine mechanisms that are most operative in these disease states and narrow treatment parameters helpful for human application. © 2012 Bentham Science Publishers.

DeBoer M.D.,University of Virginia
Nutrition | Year: 2010

Cachexia is a devastating syndrome of body wasting that is associated with multiple common chronic diseases including cancer, chronic kidney disease, and chronic heart failure. These underlying diseases are associated with increased levels of inflammatory cytokines and result in anorexia, increased resting energy expenditure, and loss of fat and lean body mass. Prior experiments have implicated the central melanocortin system in the hypothalamus with the propagation of these symptoms of cachexia. Pharmacologic blockade of this system using melanocortin antagonists causes attenuation of the signs of cachexia in laboratory models. Recent advances in our knowledge of this disease process have involved further elucidation of the pathophysiology of melanocortin activation and demonstration of the efficacy of melanocortin antagonists in new models of cachexia, including cardiac cachexia. In addition, small molecule antagonists of the melanocortin-4 receptor continue to be introduced, including ones with oral bioavailability. These developments generate optimism that melanocortin antagonism will be used to treat humans with disease-associated cachexia. However, to date, human application has remained elusive and it is unclear when we will know whether humans with cachexia would benefit from treatment with these compounds. © 2010 Elsevier Inc. All rights reserved.

Marshall J.C.,University of Virginia | Dunaif A.,Northwestern University
Fertility and Sterility | Year: 2012

PRO - A large majority of women with PCOS have insulin resistance, compensatory hyperinsulinemia with consequent reproductive and metabolic abnormalities. Metformin has been shown to be effective therapy and could be used more widely in obese adolescents with hyperandrogenemia, a forerunner of PCOS. CON - The severity of insulin resistance is highly variable in women with PCOS and may not be clinically relevant in milder phenotypes. Treatment should be directed at specific metabolic or reproductive problems and insulin sensitizing drugs are not always the optimum therapy.

Egorov S.A.,University of Virginia
Soft Matter | Year: 2012

We present a self-consistent field theoretical study of phase separation in binary polymer brushes physisorbed on cylindrical surfaces under good solvent conditions. In agreement with earlier simulation and experimental work, we find that macrophase separation occurs for two immiscible polymers of the same length, while a chain length mismatch between two polymer types promotes microphase separation, with ring-shaped alternating stripes forming perpendicular to the cylinder axis. We observe that the width of the stripes increases with increasing immiscibility, increasing substrate curvature, decreasing mismatch in the chain length, and decreasing the amount of adsorbed polymer. We rationalize these observations by analyzing entropic and energetic contributions to the Helmholtz free energy of the system. © 2012 The Royal Society of Chemistry.

Li Y.S.,University of Virginia
Superconductor Science and Technology | Year: 2015

We have studied the magnetic field or disorder induced insulating and metallic phases in amorphous Ta superconducting thin films. The evolution of the nonlinear transport in the insulating phase exhibits a non-monotonic behavior as the magnetic field is increased. We suggest that this observation could be evidence of the presence of localized Cooper pairs in the insulating phase. As the metallic phase intervenes the superconducting and insulating states in Ta films, this result further reveals that Cooper pairs also exist in the metallic ground state. © 2015 IOP Publishing Ltd.

Evans E.C.,University of Virginia
Midwifery | Year: 2013

Objective: identify research examining the effect of culture on maternal mortality rates. Design: literature review of CINAHL, Cochrane, PsychInfo, OVID Medline and Web of Science databases. Setting: developing countries with typically higher rates of maternal mortality. Participants: women, birth attendants, family members, nurse midwives, health-care workers, and community members. Measurements and findings: reviews, qualitative and mixed-methods research have identified components of culture that have a direct impact on maternal mortality. Examples of culture are given in the text and categorised according to the way in which they impact maternal mortality. Key conclusions: cultural customs, practices, beliefs and values profoundly influence women's behaviours during the perinatal period and in some cases increase the likelihood of maternal death in childbirth. The four ways in which culture may increase MMR are as follows: directly harmful acts, inaction, use of care and social status. Implications for practice: understanding the specifics of how the culture surrounding childbirth contributes to maternal mortality can assist nurses, midwives and other health-care workers in providing culturally competent care and designing effective programs to help decrease MMR, especially in the developing world. Interventions designed without accounting for these cultural factors are likely to be less effective in reducing maternal mortality. © 2012 Elsevier Ltd.

Ma L.,Malvern Inc. | Danoff T.M.,Malvern Inc. | Borish L.,University of Virginia
Journal of Allergy and Clinical Immunology | Year: 2014

Background Anaphylaxis is a serious allergic reaction that can cause death; however, the actual risk of death is unclear. Objective We sought to estimate the case fatality rate among hospitalizations or emergency department (ED) presentations for anaphylaxis and the mortality rate associated with anaphylaxis for the general population. Methods This was a population-based epidemiologic study using 3 national databases: the Nationwide Inpatient Sample (NIS; 1999-2009), the Nationwide Emergency Department Sample (NEDS; 2006-2009), and Multiple Cause of Death Data (MCDD; 1999-2009). Sources for these databases are hospital and ED discharge records and death certificates, respectively. Results Case fatality rates were between 0.25% and 0.33% among hospitalizations or ED presentations with anaphylaxis as the principal diagnosis (NIS+NEDS, 2006-2009). These rates represent 63 to 99 deaths per year in the United States, approximately 77% of which occurred in hospitalized patients. The rate of anaphylaxis-related hospitalizations increased from 21.0 to 25.1 per million population between 1999 and 2009 (annual percentage change, 2.23%; 95% CI, 1.52% to 2.94%), contrasting with a decreasing case fatality rate among hospitalizations (annual percentage change, -2.35%; 95% CI, -4.98% to 0.34%). Overall mortality rates ranged from 0.63 to 0.76 per million population (186-225 deaths per year, MCDD) and appeared stable in the last decade (annual percentage change, -0.31%; 95% CI, -1.54% to 0.93%). Conclusion From 2006 to 2009, the overwhelming majority of hospitalizations or ED presentations for anaphylaxis did not result in death, with an average case fatality rate of 0.3%. Anaphylaxis-related hospitalizations increased steadily in the last decade (1999-2009), but this increase was offset by the decreasing case fatality rate among those hospitalized; both inpatient and overall mortality rates associated with anaphylaxis appeared stable and were well under 1 per million population. Although anaphylactic reactions are potentially life-threatening, the probability of dying is actually very low. With the prevalence of anaphylaxis on the increase, practitioners need to stay vigilant and follow the treatment guidelines to further reduce anaphylaxis-related deaths. © 2013 American Academy of Allergy, Asthma & Immunology.

Knochenmuss R.,Tofwerk AG | Zhigilei L.V.,University of Virginia
Analytical and Bioanalytical Chemistry | Year: 2012

Ion recombination in matrix-assisted laser desorption/ionization (MALDI) is as important as any ion formation process in determining the quantity of ions observed but has received comparatively little attention. Molecular dynamics simulations are used here to investigate some models for recombination, including a Langevin-type model, a soft threshold model and a tunneling model. The latter was found to be superior due to its foundations in a widespread physical phenomenon, and its lack of excessive sensitivity to parameter choice. Tunneling recombination in the Marcus inverted region may be a major reason why MALDI is a viable analytical method, by allowing ion formation to exceed ion loss on the time scale of the plume expansion. Ion velocities, photoacoustic transients and pump-probe measurements might be used to investigate the role of recombination in different MALDI matrices, and to select new matrices. [Figure not available: see fulltext.] © 2011 Springer-Verlag.

Gray M.,University of Virginia
AACN Advanced Critical Care | Year: 2010

Changes in reimbursement policies have focused attention on the use of indwelling catheters in the critical care unit as well as their role in hospital-acquired urinary tract infections. Implementation of an evidencebased prevention program can significantly reduce both the prevalence of indwelling catheterization and the incidence of hospitalacquired catheter-associated urinary tract infection. This article describes the epidemiology and pathophysiology of catheterassociated urinary tract infection, and outlines essential elements of an evidence-based prevention program for the critical care unit. © 2010 AACN.

Ratziu V.,University Pierre and Marie Curie | Caldwell S.,University of Virginia | Neuschwander-Tetri B.A.,Saint Louis University
Hepatology | Year: 2010

Insulin sensitizers are attractive candidate therapies for nonalcoholic steatohepatitis mainly because of the strong association between this disease and insulin resistance. This review provides a critical overview of the mechanisms of action, clinical trial results, and safety issues of metformin and glitazones in nonalcoholic steatohepatitis. It also highlights methodological challenges for trial design and proposes endpoints for future proof of principle, registrational, and postmarketing trials. Copyright © 2010 American Association for the Study of Liver Diseases.

Miller A.R.,University of Virginia | Tucker C.,Massachusetts Institute of Technology
Information Systems Research | Year: 2013

Given the demand for authentic personal interactions over social media, it is unclear how much firms should actively manage their social media presence. We study this question empirically in a health care setting. We show that active social media management drives more user-generated content. However, we find that this is due to an incremental increase in user postings from an organization's employees rather than from its clients. This result holds when we explore exogenous variation in social media policies, employees, and clients that are explained by medical marketing laws, medical malpractice laws, and distortions in Medicare incentives. Further examination suggests that content being generated mainly by employees can be avoided if a firm's postings are entirely client focused. However, most firm postings seem not to be specifically targeted to clients' interests, instead highlighting more general observations or achievements of the firm itself. We show that untargeted postings like these provoke activity by employees rather than clients. This may not be a bad thing because employee-generated content may help with employee motivation, recruitment, or retention, but it does suggest that social media should not be funded or managed exclusively as a marketing function of the firm. © 2013 INFORMS.

Wang Y.,Acadia University | Meister D.B.,University of Western Ontario | Gray P.H.,University of Virginia
MIS Quarterly: Management Information Systems | Year: 2013

Theory suggests that coworkers may influence individuals' technology use behaviors, but there is limited research in the technology diffusion literature that explicates how such social influence processes operate after initial adoption. We investigate how two key social influence mechanisms (identification and internalization) may explain the growth over time in individuals' use of knowledge management systems (KMS)-a technology that because of its publicly visible use provides a rich context for investigating social influence. We test our hypotheses using longitudinal KMS usage data on over 80,000 employees of a management consulting firm. Our approach infers the presence of identification and internalization from associations between actual system use behaviors by a focal individual and prior system use by a range of reference groups. Evidence of these kinds of associations between system use behaviors helps construct a more complete picture of social influence mechanisms, and is to our knowledge novel to the technology diffusion literature. Our results confirm the utility of this approach for understanding social influence effects and reveal a fine-grained pattern of influence across different social groups: we found strong support for bottom-up social influence across hierarchical levels, limited support for peer-level influence within levels, and no support for top-down influence. Copyright © 2013 by the Management Information Systems Research Center (MISRC) of the University of Minnesota.

Hazen K.C.,University of Virginia
Diagnostic Microbiology and Infectious Disease | Year: 2013

Dimethylsulfoxide (DMSO) binds within the plasma membrane of cells and increases membrane permeability. DMSO is used in antifungal (AF) susceptibility assays for water insoluble agents. DMSO was observed to cause Candida albicans to express enhanced, diminished, or no change in growth compared to control medium, suggesting DMSO could influence the efficacy of water-insoluble AF agents. The activity of 4 water soluble AF agents against 6 yeast species was tested under conditions similar to the CSLI M27-A3 method. Growth response to 0.5% and 1% DMSO was variable. In 15 of 67 AF assays, DMSO resulted in a different MIC-2 (substantial inhibition of growth) value compared to control. Two of these involved differences of two doubling dilutions. The results imply that, in some cases of water-insoluble AF drug-yeast combinations, the MIC-2 may be skewed from the more clinically relevant MIC, providing one reason for possible discordance between MIC results and clinical outcomes. © 2013 Elsevier Inc..

Joseph K.L.,University of Virginia
Energy Policy | Year: 2010

Ongoing theft, corruption, and an artificially decreased pricing structure have made it nearly impossible for the state utilities in India to improve power service. As a result, industrial consumers across India exit the state-run system and rely on their own on-site power generation in order to ensure a consistent and reliable source of electricity. The 2003 Electricity Act encourages further power production from these captive plants through its open access clause. By encouraging the growth of these captive power plants, politicians in India set up a dual-track economy, whereby state-run and market-run production exist side-by-side. This strategy allows politicians to encourage private sector involvement in the electricity market, without jeopardizing the support of key political constituencies at the state level. © 2009 Elsevier Ltd. All rights reserved.

Bateman P.J.,Youngstown State University | Gray P.H.,University of Virginia | Butler B.S.,University of Pittsburgh
Information Systems Research | Year: 2011

Online discussion communities have become a widely used medium for interaction, enabling conversations Oacross a broad range of topics and contexts. Their success, however, depends on participants' willingness to invest their time and attention in the absence of formal role and control structures. Why, then, would individuals choose to return repeatedly to a particular community and engage in the various behaviors that are necessary to keep conversation within the community going? Some studies of online communities argue that individuals are driven by self-interest, while others emphasize more altruistic motivations. To get beyond these inconsistent explanations, we offer a model that brings dissimilar rationales into a single conceptual framework and shows the validity of each rationale in explaining different online behaviors. Drawing on typologies of organizational commitment, we argue that members may have psychological bonds to a particular online community based on (a) need, (b) affect, and/or (c) obligation. We develop hypotheses that explain how each form of commitment to a community affects the likelihood that a member will engage in particular behaviors (reading threads, posting replies, moderating the discussion). Our results indicate that each form of community commitment has a unique impact on each behavior, with need-based commitment predicting thread reading, affect-based commitment predicting reply posting and moderating behaviors, and obligation-based commitment predicting only moderating behavior. Researchers seeking to understand how discussion-based communities function will benefit from this more precise theorizing of how each form of member commitment relates to different kinds of online behaviors. Community managers who seek to encourage particular behaviors may use our results to target the underlying form of commitment most likely to encourage the activities they wish to promote. © 2011 INFORMS.

Saulsbury F.T.,University of Virginia
Current Opinion in Rheumatology | Year: 2010

Purpose Of Review: To provide an update on recent advances in the genetic susceptibility, pathogenesis and treatment of Henoch-Schönlein purpura. Recent Findings: Recent work has advanced our understanding of the genetic susceptibility and pathogenesis of Henoch-Schönlein purpura, but there are still significant gaps in our knowledge. Information concerning the most effective treatment of Henoch-Schönlein purpura has begun to emerge. Corticosteroid therapy reduces the duration and severity of abdominal and joint pain, but corticosteroids do not prevent the development of nephritis, or alter the natural history of Henoch-Schönlein purpura. The most effective treatment for severe nephritis remains unclear despite multiple, mostly retrospective reports investigating a variety of drugs. Summary: Despite recent progress, our understanding of the genetic susceptibility, pathogenesis and treatment of Henoch-Schönlein purpura remains incomplete. Further research is necessary in order to clearly define the genetic susceptibility and the pathogenesis of Henoch-Schönlein purpura. Multicenter clinical trials are needed to determine the most effective treatment of Henoch-Schönlein purpura, particularly for patients with severe nephritis. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Arras P.,University of Virginia | Socrates A.,Institute for Advanced Study
Astrophysical Journal | Year: 2010

Asynchronous rotation and orbital eccentricity lead to time-dependent irradiation of the close-in gas giant exoplanets - the hot Jupiters. This time-dependent surface heating gives rise to fluid motions which propagate throughout the planet. We investigate the ability of this "thermal tide" to produce a quadrupole moment which can couple to the stellar gravitational tidal force. While previous investigations discussed planets with solid surfaces, here we focus on entirely fluid planets in order to understand gas giants with small cores. The Coriolis force, thermal diffusion, and self-gravity of the perturbations are ignored for simplicity. First, we examine the response to thermal forcing through analytic solutions of the fluid equations which treat the forcing frequency as a small parameter. In the "equilibrium tide" limit of zero frequency, fluid motion is present but does not induce a quadrupole moment. In the next approximation, finite frequency corrections to the equilibrium tide do lead to a nonzero quadrupole moment, the sign of which torques the planet away from synchronous spin. We then numerically solve the boundary value problem for the thermally forced, linear response of a planet with neutrally stratified interior and a stably stratified envelope. The numerical results find quadrupole moments in agreement with the analytic non-resonant result at a sufficiently long forcing period. Surprisingly, in the range of forcing periods of 1-30 days, the induced quadrupole moments can be far larger than the analytic result due to response of internal gravity waves which propagate in the radiative envelope. We discuss the relevance of our results for the spin, eccentricity, and thermal evolution of hot Jupiters. © 2010. The American Astronomical Society. All rights reserved.

Siragy H.M.,University of Virginia
Vascular Health and Risk Management | Year: 2011

The safety of angiotensin II receptor blockers (ARBs) for the treatment of hypertension and cardiovascular and renal diseases has been well documented in numerous randomized clinical trials involving thousands of patients. However, recent concerns have surfaced about possible links between ARBs and increased risks of myocardial infarction and cancer. Less is known about the safety of the direct renin inhibitor aliskiren, which was approved as an antihypertensive in 2007. This article provides a detailed review of the safety of ARBs and aliskiren, with an emphasis on the risks of cancer and myocardial infarction associated with ARBs. Safety data were identified by searching PubMed and Food and Drug Administration (FDA) Web sites through April 2011. ARBs are generally well tolerated, with no known class-specific adverse events. The possibility of an increased risk of myocardial infarction associated with ARBs was suggested predominantly because the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial reported a statistically significant increase in the incidence of myocardial infarction with valsartan compared with amlodipine. However, no large-scale, randomized clinical trials published after the VALUE study have shown a statistically significant increase in the incidence of myocardial infarction associated with ARBs compared with placebo or non-ARBs. Meta-analyses examining the risk of cancer associated with ARBs have produced conflicting results, most likely due to the inherent limitations of analyzing heterogeneous data and a lack of published cancer data. An ongoing safety investigation by the FDA has not concluded that ARBs increase the risk of cancer. Pooled safety results from clinical trials indicate that aliskiren is well tolerated, with a safety profile similar to that of placebo. ARBs and aliskiren are well tolerated in patients with hypertension and certain cardiovascular and renal conditions; their benefits outweigh possible safety concerns. © 2011 Siragy, publisher and licensee Dove Medical Press Ltd.

Farber C.R.,University of Virginia
Current Osteoporosis Reports | Year: 2012

From the early 1990s to the middle of the last decade, the search for genes influencing osteoporosis proved difficult with few successes. However, over the last 5 years this has begun to change with the introduction of genome-wide association (GWA) studies. In this short period of time, GWA studies have significantly accelerated the pace of gene discovery, leading to the identification of nearly 100 independent associations for osteoporosisrelated traits. However, GWA does not specifically pinpoint causal genes or provide functional context for associations. Thus, there is a need for approaches that provide systemslevel insight on how associated variants influence cellular function, downstream gene networks, and ultimately disease. In this review we discuss the emerging field of 'systems genetics' and how it is being used in combination with and independent of GWA to improve our understanding of the molecular mechanisms involved in bone fragility. © Springer Science+Business Media, LLC 2012.

Nakamura F.,Japan National Astronomical Observatory | Li Z.-Y.,University of Virginia
Astrophysical Journal | Year: 2014

Protostellar outflows have been shown theoretically to be capable of maintaining supersonic turbulence in cluster-forming clumps and keeping the star formation rate per free-fall time as low as a few percent. We aim to test two basic predictions of this outflow-regulated cluster formation model, namely, (1) the clump should be close to virial equilibrium and (2) the turbulence dissipation rate should be balanced by the outflow momentum injection rate, using recent outflow surveys toward eight nearby cluster-forming clumps (B59, L1551, L1641N, Serpens Main Cloud, Serpens South, ρ Oph, IC 348, and NGC 1333). We find, for almost all sources, that the clumps are close to virial equilibrium and the outflow momentum injection rate exceeds the turbulence momentum dissipation rate. In addition, the outflow kinetic energy is significantly smaller than the clump gravitational energy for intermediate and massive clumps with M cl ≳ a few × 102 M ⊙, suggesting that the outflow feedback is not enough to disperse the clump as a whole. The number of observed protostars also indicates that the star formation rate per free-fall time is as small as a few percent for all clumps. These observationally based results strengthen the case for outflow-regulated cluster formation. © 2014. The American Astronomical Society. All rights reserved.

Miller A.R.,University of Virginia | Tucker C.,Massachusetts Institute of Technology
Journal of Health Economics | Year: 2014

There are many technology platforms that bring benefits only when users share data. In healthcare, this is a key policy issue, because of the potential cost savings and quality improvements from 'big data' in the form of sharing electronic patient data across medical providers. Indeed, one criterion used for federal subsidies for healthcare information technology is whether the software has the capability to share data. We find empirically that larger hospital systems are more likely to exchange electronic patient information internally, but are less likely to exchange patient information externally with other hospitals. This pattern is driven by instances where there may be a commercial cost to sharing data with other hospitals. Our results suggest that the common strategy of using 'marquee' large users to kick-start a platform technology has an important drawback of potentially creating information silos. This suggests that federal subsidies for health data technologies based on 'meaningful use' criteria, that are based simply on the capability to share data rather than actual sharing of data, may be misplaced. © 2013 Elsevier B.V.

McCall A.L.,University of Virginia
Endocrinology and Metabolism Clinics of North America | Year: 2012

Hypoglycemia is the most important and common side effect of insulin therapy. It is also the rate limiting factor in safely achieving excellent glycemic control. A three-fold increased risk of severe hypoglycemia occurs in both type 1 and type 2 diabetes with tight glucose control. This dictates a need to individualize therapy and glycemia goals to minimize this risk. Several ways to reduce hypoglycemia risk are recognized and discussed. They include frequent monitoring of blood sugars with home blood glucose tests and sometimes continuous glucose monitoring (CGM) in order to identify hypoglycemia particularly in hypoglycemia unawareness. Considerations include prompt measured hypoglycemia treatment, attempts to reduce glycemic variability, balancing basal and meal insulin therapy, a pattern therapy approach and use of a physiological mimicry with insulin analogues in a flexible manner. Methods to achieve adequate control while focusing on minimizing the risk of hypoglycemia are delineated in this article. © 2012 Elsevier Inc.

Ratliff C.R.,University of Virginia
Journal of Wound, Ostomy and Continence Nursing | Year: 2014

PURPOSE:: The purpose of this study was to describe demographic and clinical variables related to ostomy pouch leakage from those discharged from a major medical center during a 2-year period. SUBJECTS AND SETTINGS:: A convenience sample of 198 persons with an ostomy was obtained using the ICD-9 (International Classification of Diseases, Ninth Revision) codes for colostomy, ileostomy, and ileal conduit for patients who were discharged from the medical center within the time frame of July 2009 to July 2011. One hundred seven participants (55%) returned a completed survey. Respondents included 57 men (53%) and 50 women (47%). The mean age was 60 years with age range from 23 to 91 years. Fecal ostomies made up the majority of the stomas representing 71 patients (66%). METHODS:: A descriptive, cross-sectional research design was used to describe clinical variables related to ostomy pouch leakage for those discharged from a major academic medical center over a 2-year period of time. Participants were mailed an introductory letter from the principal investigator, a self-Administered questionnaire, and a prepaid return envelope. RESULTS:: Ninety-three patients (87%) reported leakage; however, 48 patients (45%) stated that they did not leak often. A logistic regression was estimated to determine which variables were significant predictors of the dependent variable of leaking status (no/seldom leaking vs more frequent leaking). Two variables were individually significant predictors, sex (P = .021) and 2-piece pouch (P = .015). Women were 4 times more likely to be in the more frequent leaking group than were men. Those who were wearing 2-piece pouches were 78% less likely to be in the more frequent leaking group. Participants with ileostomies or urostomies were more likely to be in the more frequent leaking group and those with peristomal skin irritation were more likely to be in the more frequent leaking group. CONCLUSION:: Findings from this study reveal that women were more likely to experience leakage than men and that wearing a 2-piece pouch was associated with no leakage or seldom leakage group. Additional studies looking at specific characteristics of patients with ostomy leakage are needed to validate these results. Copyright © 2014 by the Wound, Ostomy and Continence Nurses Society.

Ungewitter E.,Kogod Center on Aging | Ungewitter E.,University of Virginia | Scrable H.,Kogod Center on Aging
Genes and Development | Year: 2010

Δ40p53 is a transactivation-deficient isoform of the tumor suppressor p53. We discovered that Δ40p53, in addition to being highly expressed in embryonic stem cells (ESCs), is the major p53 isoform during early stages of embryogenesis in the mouse. By altering the dose of Δ40p53 in ESCs, we identified a critical role for this isoform in maintaining the ESC state. Haploinsufficiency for Δ40p53 causes a loss of pluripotency in ESCs and acquisition of a somatic cell cycle, while increased dosage of Δ40p53 prolongs pluripotency and inhibits progression to a more differentiated state. Δ40p53 controls the switch from pluripotent ESCs to differentiated somatic cells by controlling the activity of full-length p53 at critical targets such as Nanog and the IGF-1 receptor (IGF-1R). The IGF axis plays a central role in the switch between pluripotency and differentiation in ESCs - and Δ40p53, by controlling the level of the IGF-1R, acts as a master regulator of this switch. We propose that this is the primary function of Δ40p53 in cells of the early embryo and stem cells, which are the only normal cells in which this isoform is expressed. © 2010 by Cold Spring Harbor Laboratory Press.

Noonan D.,University of Virginia
Public Health Nursing | Year: 2010

Popularity of waterpipe smoking or hookah smoking in the United States has been growing for some time now among youth and young adults. Currently, many cities and states have exemptions that allow hookah bars to remain in operation despite the passage of clean indoor air legislation. From a public health perspective this is concerning for many reasons. One public health concern with the increase in popularity of this type of tobacco use is the associated health effects. Another concern is that hookah smoke produces a sweet smelling aroma making it less obvious that patrons and employees of hookah bars are inhaling noxious fumes from mainstream smoke, as well as the toxins from the charcoal that is used to heat the tobacco. The purpose of this paper is to discuss smoke-free air legislation in relation to hookah use, the public health implications of exempting hookah bars from current smoke-free legislation, and implications for the public health nurse in protecting the public from the dangers of second-hand smoke, and limiting this new form of tobacco use. © 2009 Wiley Periodicals, Inc.

Myers N.L.,University of Virginia
Culture, Medicine and Psychiatry | Year: 2010

This cultural case study investigates one U. S. psychosocial rehabilitation organization's (Horizons) attempt to implement the recovery philosophy of the U. S. Recovery Movement and offers lessons from this local attempt that may inform global mental health care reform. Horizons' "recovery-oriented" initiatives unwittingly mobilized stressful North American discourses of valued citizenship. At times, efforts to "empower" people diagnosed with schizophrenia to become esteemed self-made citizens generated more stressful sociocultural conditions for people whose daily lives were typically remarkably stressful. A recovery-oriented mental health system must account for people diagnosed with schizophrenia's sensitivity to stress and offer consumers contextually relevant coping mechanisms. Any attempt to export U. S. mental health care practices to the rest of the world must acknowledge that (1) sociocultural conditions affect schizophrenia outcomes; (2) schizophrenia outcomes are already better in the developing world than in the United States; and (3) much of what leads to "better" outcomes in the developing world may rely on the availability of locally relevant techniques to address stress. © 2010 Springer Science+Business Media, LLC.

Herakovich C.T.,University of Virginia
Mechanics Research Communications | Year: 2012

This review is concerned with mechanics of continuous fiber composites. The earliest and most important advancements in the field are emphasized. No doubt the coverage is limited to some extent by the interests and experiences of the writer as well as time and space considerations. The advancements in mechanics of composites have been influenced to a great extent by the development of advanced composites through materials science. No attempt is made to discuss these developments. This review emphasizes the use of theoretical and applied mechanics in the development of theories, confirmed by experimentation, to predict the response of composite materials and structures. Citations have been given for many published works, but certainly not all. Apologies to those not listed; numerous additional references can be found in the works cited. © 2012 Elsevier Ltd.

Kalantari K.,University of Virginia
Journal of Clinical Apheresis | Year: 2012

Therapeutic apheresis (TA) is performed using either centrifugation-based or filter-based systems. The blood flow rate (BFR) used for TA using centrifugation-based systems is less than 100 mL/min. Because of this low BFR requirement, even peripheral veins can be considered as an option for TA, especially for less-frequent treatments and those performed for short periods. Other options for vascular access (VA) include central venous catheters (temporary or tunneled), totally implantable ports, and arteriovenous fistulae (AVF) or grafts (AVG). Nontunneled catheters should be considered as the choice of VA for relatively short-term treatments mainly in the inpatient settings. For long-term treatments, ports and tunneled catheters should be considered because of lower rates of infections compared to nontunneled catheters. However, studies in hemodialysis (HD) patients have demonstrated significantly higher morbidity and mortality rates associated with the use of tunneled catheters as compared to AVF. Therefore, if TA is being considered for several years, AVG and AVF would be the preferred options of VA. Studies in HD population indicate far better outcomes with the use of AVF as compared to AVG. This article, as presented at the Therapeutic Apheresis Academy in September 2011, is an overview of the available VA options for TA based on indication and duration of treatment. Pros and cons of each option are mentioned briefly. Finally, for those considered for AVF placement for chronic TA, specific recommendations are made for the care of AVF based on our own experience at University of Virginia. Copyright © 2012 Wiley Periodicals, Inc.

Salthouse T.A.,University of Virginia
Journal of Clinical and Experimental Neuropsychology | Year: 2011

A total of 1,576 adults between 18 and 95 years of age performed a battery of cognitive tests and the Connections version of the Trail Making Test twice, with an average interval between assessments of 2.5 years. Consistent with previous results, speed ability and fluid cognitive ability were strongly correlated with trail making performance. Neither speed nor fluid cognitive ability at the first occasion predicted longitudinal changes in trail making performance, but there were significant correlations between the changes in these abilities and the changes in trail making performance. These results indicate that individual differences in speed and fluid cognitive abilities are associated with individual differences in trail making performance both at a single point in time (cross-sectional differences) and in the changes over time (longitudinal changes). © 2010 Psychology Press, an imprint of the Taylor & Francis Group, an Informa business.

Szepietowski P.,University of Virginia
Journal of High Energy Physics | Year: 2012

In this paper we study the holographic dual to a-maximization in five-dimensional N=2 gauged supergravity. In particular, we apply the procedure described by Tachikawa in [1] to specific examples consisting of holographic duals to gauge theories arising as the IR limit of N M5-branes wrapping a Riemann surface. A key element of this analysis is a consistent truncation of seven-dimensional N=4 SO(5) gauged supergravity reduced on a Riemann surface. We demonstrate the consistency of this truncation and match to a sector of five-dimensional matter-coupled N=2 gauged supergravity. We determine the U(1) R symmetry and central charge of these theories and find agreement with the literature. The final results provide a nontrivial illustration of the holographic interpretation of a-maximization. © 2012 SISSA, Trieste, Italy.

Stroupe C.,University of Virginia
Current Biology | Year: 2011

Autophagosomes sequester cytosolic constituents and deliver this cargo to lysosomes for destruction. Two groups now report that autophagosome maturation requires homotypic membrane fusion catalyzed by SNARE proteins. © 2011 Elsevier Ltd. All rights reserved.

Hurd N.M.,University of Virginia | Stoddard S.A.,University of Michigan | Zimmerman M.A.,University of Michigan
Child Development | Year: 2013

This study explored how neighborhood characteristics may relate to African American adolescents' internalizing symptoms via adolescents' social support and perceptions of neighborhood cohesion. Participants included 571 urban, African American adolescents (52% female; M age = 17.8). A multilevel path analysis testing both direct and indirect effects of neighborhood characteristics on adolescents' mental health outcomes was conducted. Higher neighborhood poverty and unemployment rates predicted greater internalizing symptoms via lower cumulative social support and perceptions of neighborhood cohesion. In contrast, higher concentrations of African American and residentially stable residents in one's neighborhood related to fewer internalizing symptoms among adolescent residents via greater cumulative social support and perceptions of neighborhood cohesion. Implications of these findings are discussed. © 2012 Society for Research in Child Development, Inc.

Keller R.,University of Virginia
Science | Year: 2012

Understanding how cells coordinately shape an organism is grounded in a history of biophysical analyses of the molecules, mechanics, and forces that govern cell movements.

Mahadevan M.S.,University of Virginia
Current Opinion in Neurology | Year: 2012

Purpose of Review: The myotonic dystrophies (DM1 and DM2) are the paradigm for RNA toxicity in disease pathogenesis. The emphasis of this review will be on recent developments and issues in understanding the pathogenesis of DM1 and how this is driving the accelerated pace of translational and therapeutic developments. Recent Findings: RNA toxicity in myotonic dystrophy is now associated with bi-directional antisense transcription, dysregulation of microRNAs and potentially non-ATG-mediated translation of homopolymeric toxic proteins. The role of other RNA-binding proteins beyond MBNL1 and CUGBP1, such as Staufen 1 and DDX5, are being identified and studied with respect to their role in myotonic dystrophy. New functions for MBNL1 in miR-1 biogenesis might have a clinically relevant role in myotonic dystrophy cardiac conduction defects and pathology. Advances are being made in identifying and characterizing small molecules with the potential to disrupt CUG-MBNL1 interactions. Summary: Mechanisms of RNA toxicity are moving beyond a simplistic 'foci-centric' view of DM1 pathogenesis as a spliceopathy due to MBNL1 sequestration. Therapeutic development for myotonic dystrophy is moving rapidly with the development of antisense and small molecule therapies. Clinically, significant emphasis is being placed on biomarker discovery and outcome measures as an essential prelude to clinical trials. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Voinov A.,University of Twente | Shugart H.H.,University of Virginia
Environmental Modelling and Software | Year: 2013

In many cases model integration treats models as software components only, ignoring the fluid relationship between models and reality, the evolving nature of models and their constant modification and recalibration. As a result, with integrated models we find increased complexity, where changes that used to impact only relatively contained models of subsystems, now propagate throughout the whole integrated system. This makes it harder to keep the overall complexity under control and, in a way, defeats the purpose of modularity, when efficiency is supposed to be gained from independent development of modules. Treating models only as software in solving the integration challenge may give birth to 'integronsters' - constructs that are perfectly valid as software products but ugly or even useless as models. We argue that one possible remedy is to learn to use data sets as modules and integrate them into the models. Then the data that are available for module calibration can serve as an intermediate linkage tool, sitting between modules and providing a module-independent baseline dynamics, which is then incremented when scenarios are to be run. In this case it is not the model output that is directed into the next model input, but model output is presented as a variation around the baseline trajectory, and it is this variation that is then fed into the next module down the chain. However still with growing overall complexity, calibration can become an important limiting factor, giving more promise to the integral approach, when the system is modeled and simplified as a whole. © 2012 Elsevier Ltd.

Mulloy D.P.,University of Virginia
The Journal of thoracic and cardiovascular surgery | Year: 2012

Ex vivo lung perfusion (EVLP) is a promising modality for the evaluation and treatment of marginal donor lungs. The optimal timing of EVLP initiation and the potential for rehabilitation of donor lungs with extended warm ischemic times is unknown. The present study compared the efficacy of different treatment strategies for uncontrolled non-heart-beating donor lungs. Mature swine underwent hypoxic arrest, followed by 60 minutes of no-touch warm ischemia. The lungs were harvested and flushed with 4°C Perfadex. Three groups (n = 5/group) were stratified according to the preservation method: cold static preservation (CSP; 4 hours of 4°C storage), immediate EVLP (I-EVLP: 4 hours EVLP at 37°C), and delayed EVLP (D-EVLP; 4 hours of CSP followed by 4 hours of EVLP). The EVLP groups were perfused with Steen solution supplemented with heparin, methylprednisolone, cefazolin, and an adenosine 2A receptor agonist. The lungs then underwent allotransplantation and 4 hours of recipient reperfusion before allograft assessment for resultant ischemia-reperfusion injury. The donor blood oxygenation (partial pressure of oxygen/fraction of inspired oxygen ratio) before death was not different between the groups. The oxygenation after transplantation was significantly greater in the D-EVLP group than in the I-EVLP or CSP groups. The mean airway pressure, pulmonary artery pressure, and expression of interleukin-8, interleukin-1β, and tumor necrosis factor-α were all significantly reduced in the D-EVLP group. Post-transplant oxygenation exceeded the acceptable clinical levels only in the D-EVLP group. Uncontrolled non-heart-beating donor lungs with extended warm ischemia can be reconditioned for successful transplantation. The combination of CSP and EVLP in the D-EVLP group was necessary to obtain optimal post-transplant function. This finding, if confirmed clinically, will allow expanded use of nonheart-beating donor lungs. Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Burns T.M.,University of Virginia
Muscle and Nerve | Year: 2010

This review illustrates how measurements of clinical status in patients with myasthenia gravis have evolved from clinical descriptions and estimates of mortality rates to more sophisticated evaluative instruments, including numerical rating scales that measure strength, endurance, quality of life, and activities of daily living. The rationale and use of weighting and the importance of patient-reported outcomes are also discussed. The measurement of the steroid-sparing effect of an immunosuppressant is also reviewed. © 2010 Wiley Periodicals, Inc.

Brown J.C.,University of Virginia
Genomics | Year: 2014

In cells latently infected with a herpesvirus, the viral DNA is present in the cell nucleus, but it is not extensively replicated or transcribed. In this suppressed state the virus DNA is vulnerable to mutagenic events that affect the host cell and have the potential to destroy the virus' genetic integrity. Despite the potential for genetic damage, however, herpesvirus sequences are well conserved after reactivation from latency. To account for this apparent paradox, I have tested the idea that host cell-encoded mechanisms of DNA repair are able to control genetic damage to latent herpesviruses. Studies were focused on homologous recombination-dependent DNA repair (HR). Methods of DNA sequence analysis were employed to scan herpesvirus genomes for DNA features able to activate HR. Analyses were carried out with a total of 39 herpesvirus DNA sequences, a group that included viruses from the alpha-, beta- and gamma-subfamilies. The results showed that all 39 genome sequences were enriched in two or more of the eight recombination-initiating features examined. The results were interpreted to indicate that HR can stabilize latent herpesvirus genomes. The results also showed, unexpectedly, that repair-initiating DNA features differed in alpha- compared to gamma-herpesviruses. Whereas inverted and tandem repeats predominated in alpha-herpesviruses, gamma-herpesviruses were enriched in short, GC-rich initiation sequences such as CCCAG and depleted in repeats. In alpha-herpesviruses, repair-initiating repeat sequences were found to be concentrated in a specific region (the S segment) of the genome while repair-initiating short sequences were distributed more uniformly in gamma-herpesviruses. The results suggest that repair pathways are activated differently in alpha- compared to gamma-herpesviruses. © 2014.

Surgical management of degenerative cervical myelopathy requires careful pathoanatomic consideration to select between various surgical options from both anterior and posterior approach. Hitherto, unexplored is the relevance of cervical deformity to the pathophysiology of such neurological disability, and whether correction of that deformity should be a surgical objective when planning for reconstruction after spinal cord decompression. Such correction could address both the static cord compression and the dynamic repetitive cord injury, while also restoring more normal biomechanics to the cervical spine. The articles in this focus issue's section on cervical spinal deformity reveal that cervical sagittal alignment is geometrically related to thoracolumbar spinal pelvic alignment and to T1 slope, and that it is further clinically correlated to regional disability and general health scores and to myelopathy severity. These conclusions are based on narrative reviews and a selection of primary research data, reflecting the nascency of this field. They further recommend for preoperative assessment of spinal alignment when significant deformity is suspected, and that correction of cervical kyphosis should be an objective when surgery is planned.

Zhou B.,Harbin Institute of Technology | Li Z.-Y.,Harbin Institute of Technology | Lin Z.,University of Virginia
Automatica | Year: 2013

This paper is concerned with observer based output feedback control of linear systems with both (multiple) input and output delays. Our recently developed truncated predictor feedback (TPF) approach for state feedback stabilization of time-delay systems is generalized to the design of observers. By imposing some restrictions on the open-loop system, two classes of observer based output feedback controllers, one being finite dimensional and the other infinite dimensional, are constructed. It is further shown that, the infinite dimensional observer based output feedback controllers can be generalized to linear systems with both time-varying input and output delays. It is also shown that the separation principle holds for the infinite dimensional observer based output feedback controllers, but does not hold for the finite dimensional ones. Numerical examples are worked out to illustrate the effectiveness of the proposed approaches. © 2013 Published by Elsevier Ltd.

McCaffrey L.M.,McGill University | Macara I.G.,University of Virginia
Cold Spring Harbor Perspectives in Biology | Year: 2012

A key function of signal transduction during cell polarization is the creation of spatially segregated regions of the cell cortex that possess different lipid and protein compositions and have distinct functions. Polarity can be initiated spontaneously or in response to signaling inputs from adjacent cells or soluble factors and is stabilized by positive-feedback loops. A conserved group of proteins, the Par proteins, plays a central role in polarity establishment and maintenance in many contexts. These proteins generate and maintain their distinct locations in cells by actively excluding one another from specific regions of the plasma membrane. The Par signaling pathway intersects with multiple other pathways that control cell growth, death, and organization. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.

Keith D.S.,University of Virginia
Seminars in Dialysis | Year: 2012

Recurrent idiopathic focal segmental glomerulosclerosis (FSGS) after renal transplantation can lead to a rapid failure of the allograft. A circulating, nonimmunoglobulin factor appears to be important in the pathogenesis of this complication in many cases. Between 30% and 50% of transplant recipients with FSGS develop recurrent disease. Three major risk factors for recurrence have been identified: short duration of native kidney disease, history of recurrence with previous kidney transplant, and pediatric aged recipients. Although no properly controlled trials have been conducted, plasmapheresis has emerged as one of the important treatment modalities for this entity. Retrospective studies prior to the routine use of plasmapheresis showed graft loss rates as high as 80%, a rate much higher than that seen in more recent series managed with plasmapheresis. Duration and intensity of treatment of plasmaphersis have not been studied rigorously, but in most case series, plasmapheresis was continued until a clear diminution of proteinuria was seen. The benefit of other adjuvant therapies for this condition remains unclear, but also may play a role in the treatment of this entity. © 2011 Wiley Periodicals, Inc.

Recent studies suggest that the effects of attending preschool vary by race. These findings are difficult to interpret because the likelihood of enrolling a child in preschool also differs across groups. This study used newly released, nationally representative data to examine whether the impact of preschool participation at age 4 varies across racial groups after accounting for selection differences (N = 7,400). Among a subsample of children living below a poverty threshold, no racial differences in preschool impact are detected. However, findings suggest that nonpoor Black children benefit substantially more from preschool than their nonpoor White or Hispanic peers. Implications of these findings are discussed toward understanding the potential of large-scale preschool interventions for narrowing racial achievement gaps. © 2010 The Author. Child Development © 2010 Society for Research in Child Development, Inc.

Rust R.S.,University of Virginia
Seminars in Pediatric Neurology | Year: 2012

Worldwide, arboviral illnesses constitute the most important international infectious threat to human neurological health and welfare. Before the availability of effective immunizations, approximately 50,000 cases of Japanese encephalitis occurred in the world each year, one-fifth of which cases proved lethal and a much larger number were left with severe neurological handicaps. With global climate change and perhaps other factors, the prevalences of some arboviral illnesses appear to be increasing. Arboviral illnesses, including Japanese encephalitis, tick-borne encephalitis, Yellow fever, and others, are emerging as possible global health care threats because of biological warfare. This chapter will review ecology, pathophysiology, diagnosis, management, and outcome of the forms of arboviral encephalitis that are of greatest importance in North America, together with some of the most important arboviral encephalitides prevalent in other parts of the world. © 2012 Elsevier Inc.

Brautigan D.L.,University of Virginia
FEBS Journal | Year: 2013

This review traces the historical origins and conceptual developments leading to the current state of knowledge of the three superfamilies of protein Ser/Thr phosphatases. 'PR enzyme' was identified as an enzyme that inactivates glycogen phosphorylase, although it took 10 years before this ugly duckling was recognized for its true identity as a protein Ser/Thr phosphatase. Ethanol denaturation for purification in the 1970s yielded a phosphatase that exhibited broad specificity, which was resolved into type-1 and type-2 phosphatases in the 1980s. More recent developments show that regulation and specificity are achieved through assembly of multisubunit holoenzymes, transient phosphorylation and the action of inhibitor proteins. Still not widely appreciated, there are hundreds of discrete protein Ser/ Thr phosphatases available to counteract protein kinases, offering potential therapeutic targets. Signalling networks and modelling schemes need to incorporate the full gamut of protein Ser/ Thr phosphatases and their interconnections. © 2012 The Author Journal compilation © 2012 FEBS.

Blake K.,Center for Pharmacogenomics and Translational Research | Teague W.G.,University of Virginia
Current Opinion in Pulmonary Medicine | Year: 2013

PURPOSE OF REVIEW: Gastroesophageal reflux disease (GERD) is common in children with asthma and may be present with or without symptoms. Clinicians, influenced by position statements in national guidelines, have routinely treated children with poorly controlled asthma with various anti-GERD medications. This practice is based on the pervasive but unproven belief that GERD is an important determinant of poor asthma control. RECENT FINDINGS: Clinical studies show that GERD is highly prevalent in children with asthma, with estimates as high as 80%, but nearly half of the children are asymptomatic. However, there is no conclusive evidence per se that asymptomatic GERD informs asthma control, and treatment of GERD in the few controlled trials available for review does not substantively improve asthma outcomes. In a recent large controlled clinical trial, treatment with a proton-pump inhibitor (PPI) was not only ineffective, but adverse effects were common, including an increased prevalence of symptomatic respiratory infections. SUMMARY: Current evidence does not support the routine use of anti-GERD medications in the treatment of poorly controlled asthma of childhood. However large controlled trials of children symptomatic of both GERD and asthma have not been conducted, and in this case the benefits of treatment, although unproven, might outweigh the risks. Copyright © 2012 Lippincott Williams &Wilkins.

Agrawal R.,University of Virginia
Current allergy and asthma reports | Year: 2014

Atopic dermatitis (AD) is a chronic inflammatory skin condition with complex etiology that is dependent upon interactions between the host and the environment. Acute skin lesions exhibit the features of a Th2-driven inflammatory disorder, and many patients are highly atopic. The skin barrier plays key roles in immune surveillance and homeostasis, and in preventing penetration of microbial products and allergens. Defects that compromise the structural integrity or else the immune function of the skin barrier play a pivotal role in the pathogenesis of AD. This article provides an overview of the array of molecular building blocks that are essential to maintaining healthy skin. The basis for structural defects in the skin is discussed in relation to AD, with an emphasis on filaggrin and its genetic underpinnings. Aspects of innate immunity, including the role of antimicrobial peptides and proteases, are also discussed.