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Duke University is a private research university located in Durham, North Carolina, United States. Founded by Methodists and Quakers in the present-day town of Trinity in 1838, the school moved to Durham in 1892. In 1924, tobacco and electric power industrialist James B. Duke established The Duke Endowment, at which time the institution changed its name to honor his deceased father, Washington Duke.The university's campus spans over 8,600 acres on three contiguous campuses in Durham as well as a marine lab in Beaufort. Duke's main campus—designed largely by African American architect Julian Abele—incorporates Gothic architecture with the 210-foot Duke Chapel at the campus' center and highest point of elevation. The first-year-populated East Campus contains Georgian-style architecture, while the main Gothic-style West Campus 1.5 miles away is adjacent to the Medical Center.Duke's research expenditures in the 2012 fiscal year were $1.01 billion, the seventh largest in the nation. Competing in the Atlantic Coast Conference, Duke's athletic teams, known as the Blue Devils, have captured 15 team national championships, including four by its high profile men's basketball team. Duke was ranked among the world's best universities by both THE and QS, while tying for 8th in the 2015 U.S. News & World Report "Best National Universities Rankings." In 2014, Thomson Reuters named 32 Duke professors to its list of Highly Cited Researchers. The only schools with more primary affiliations were Harvard, Stanford, and UC Berkeley. Wikipedia.

Keefe F.J.,Duke University
Annals of Behavioral Medicine | Year: 2011

This paper discusses trends and future directions in behavioral medicine. It is divided into three sections. The first briefly reviews key developments in the history of behavioral medicine. The second section highlights trends and future directions in pain research and practice as a way of illustrating future directions for behavioral medicine. Consistent with the biopsychosocial model of pain, this section focuses on trends and future directions in three key areas: biological, psychological, and social. The third section describes recent Society of Behavioral Medicine initiatives designed to address some of the key challenges facing our field as we prepare for the future. © The Society of Behavioral Medicine 2011.

Andolsek K.M.,Duke University
Academic Medicine | Year: 2015

The author reflects on the chapter titled "Preserving Excellence in Residency Training and Medical Care" in Dr. Kenneth Ludmerer's book Let Me Heal: The Opportunity to Preserve Excellence in American Medicine. Rather than assuming that the status quo represents excellence, however, the author asserts that we must make an informed judgment regarding the quality of graduate medical education (GME) by applying an evidence-based approach, carefully measuring performance against specific criteria. But what are the right criteria to judge excellence in GME? The author posits that the first criterion for excellence is the foundational concept identified by the Josiah Macy Jr. Foundation, that of accountability to the public. The author argues that for GME to be truly excellent it must produce a workforce "of sufficient size, specialty mix, and skill" needed to serve the public good. For GME to be truly excellent it must produce the right composition (reflecting the population it serves), use the right pedagogy, and be embedded within the right clinical learning environment. Implementation of competency-based education must be bolder and accelerated. The process of culling out service from education in GME must be more honest, not because all service cannot in some ways be educational but because it is simply too expensive to squander a single minute of time in training. Finally, the epidemic of burnout must be addressed urgently and innovatively. © 2015 by the Association of American Medical Colleges.

Exercise, considered a mainstay of cardiac rehabilitation, has been shown to reduce cardiac risk factors such as hyperlipidemia and hypertension. Growing evidence also suggests that exercise has beneficial effects on mental health, which is relevant for cardiac patients because of the prognostic significance of depression in patients with coronary heart disease (CHD). Depression has been associated with increased mortality and nonfatal cardiac events in patients with CHD; it is also associated with worse outcomes in patients who undergo coronary artery bypass graft surgery and those who have heart failure. The standard therapy for depression is pharmacologic treatment, often with second-generation antidepressants such as selective serotonin reuptake inhibitors. Despite their widespread use, antidepressants have only modest effects on depression for many patients compared with placebo controls. Exercise therapy, already an established component of cardiac rehabilitation, has potential efficacy as a treatment for depression in cardiac disease patients. Randomized controlled trials are needed to determine the clinical effects of exercise in this population and to compare the effects of exercise with those of antidepressants.

Urban T.J.,Duke University | Daly A.K.,Northumbria University | Aithal G.P.,University of Nottingham
Seminars in Liver Disease | Year: 2014

There is considerable evidence that susceptibility to idiosyncratic drug-induced liver injury (DILI) is genetically determined. Though genetic associations with DILI have been reported since the 1980s, the development of genome-wide association studies has enabled genetic risk factors for DILI, in common with other diseases, to be detected and confirmed more confidently. Human leukocyte antigen (HLA) genotype has been demonstrated to be a strong risk factor for development of DILI with a range of drugs and the underlying mechanism, probably involving presentation of a drug-peptide complex to T cells is increasingly well understood. However, specific HLA alleles are not associated with all forms of DILI and non-HLA genetic risk factors, especially those relating to drug disposition, also appear to contribute. For some drugs, there is evidence of a dual role for HLA and drug metabolism genes. Though the associations with non-HLA genes have been less well replicated than the HLA associations, there is increasing evidence that drug metabolism genes such as NAT2 and UGT2B7 contribute to some forms of DILI. Translating current genetic findings on DILI susceptibility to the clinic has been relatively slow, but some progress is now being made. In the future, DNA sequencing may lead to the identification of rare variants that contribute to DILI. Developments in the related area of epigenomics and in the development of improved models for DILI by use of genetically defined induced pluripotent stem cells should improve understanding of the biology of DILI and inform drug development. Copyright © 2014 by Thieme Medical Publishers, Inc.

Zenn M.R.,Duke University
Clinics in Plastic Surgery | Year: 2011

Fluorescent angiography is a simple and effective real-time tool for measurement of tissue perfusion both in and out of the operating room. It has multiple uses including: (1) identifying perforating vessels during flap planning; (2) locating primary and secondary angiosomes within a prepared flap; (3) as an aid in decision making for tissue debridement and flap creation; (4) intraoperative evaluation of microanastomoses; (5) postoperative flap monitoring, and (6) documentation of perfusion. The technology is easy to use in the hands of the operating surgeon and is safe for the patient, as it requires no radiation exposure. © 2011 Elsevier Inc.

Costanzo P.R.,Duke University
Developmental Psychology | Year: 2014

In this commentary, the common themes from the interesting articles in this special section of Developmental Psychology are considered as they illuminate the potential ontogenetic sources of the conscientiousness-well-being-longevity interconnections that have emerged in recent research. In particular, consideration is given to the changing nature of the expression of conscientiousness over the life course and the importance of the causally linked chain of developmental events associated with the sustenance of this trait from early childhood to later life. Methodological as well as conceptual issues are part of the common thematic analysis provided. In addition, several more or less neglected issues are addressed in the commentary. These include an examination of the potential roles of self-presentation social context and social aggregation in the developmentally emergent conscientiousness-well-being relationship. Further, the potential downside of the moral tinge of the conscientiousness construct is considered, as is the cultural variation in the benefits of conscientiousness to well-being. Finally, the applied significance of research on the conscientiousness-well-being link to health promotion over the life course is addressed. The commentary concludes with reflections on the transformation of 1970s trait-like conceptions as unbending tautological predictors of behavior into the situationally and developmentally nuanced conceptions of conscientiousness provided in these collected articles. © 2012 American Psychological Association.

Green J.B.,Duke University
Postgraduate Medicine | Year: 2012

The dipeptidyl peptidase-4 (DPP-4) inhibitors are a relatively new class of oral anti-diabetic agents that improve glycemic control in patients with type 2 diabetes mellitus. These agents differ in structure, but all act by inhibiting the DPP-4 enzyme. Dipeptidyl peptidase-4 inhibition increases levels of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which in turn stimulate insulin secretion in a glucose-dependent fashion. Clinical trials have shown that DPP-4 inhibitors provide significant reductions in glycated hemoglobin levels, with a low risk of hypoglycemia. Animal model experiments and proof-of-concept studies suggest that the incretins favorably affect the cardiovascular system; it is possible that these same effects may be conveyed by DPP-4 inhibitor therapy. Pooled and meta-analyses of DPP-4 inhibitor clinical trial data have shown no increase in major adverse cardiovascular events, and, in fact, suggest a potential cardiovascular benefit to such therapy. Long-term cardiovascular safety trials are currently underway to more fully define and understand the cardiovascular impact of DPP-4 therapy in patients with type 2 diabetes mellitus. © Postgraduate Medicine.

The impact of the Fast Track intervention on externalizing disorders across childhood was examined. Eight hundred-ninety-one early-starting children (69% male; 51% African American) were randomly assigned by matched sets of schools to intervention or control conditions. The 10-year intervention addressed parent behavior-management, child social cognitive skills, reading, home visiting, mentoring, and classroom curricula. Outcomes included psychiatric diagnoses after grades 3, 6, 9, and 12 for conduct disorder, oppositional defiant disorder, attention deficit hyperactivity disorder, and any externalizing disorder. Significant interaction effects between intervention and initial risk level indicated that intervention prevented the lifetime prevalence of all diagnoses, but only among those at highest initial risk, suggesting that targeted intervention can prevent externalizing disorders to promote the raising of healthy children. © 2011 The Authors. Child Development © 2011 Society for Research in Child Development, Inc.

Runcie D.E.,Duke University
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

Variation in the social environment can have profound effects on survival and reproduction in wild social mammals. However, we know little about the degree to which these effects are influenced by genetic differences among individuals, and conversely, the degree to which social environmental variation mediates genetic reaction norms. To better understand these relationships, we investigated the potential for dominance rank, social connectedness and group size to modify the effects of genetic variation on gene expression in the wild baboons of the Amboseli basin. We found evidence for a number of gene-environment interactions (GEIs) associated with variation in the social environment, encompassing social environments experienced in adulthood as well as persistent effects of early life social environment. Social connectedness, maternal dominance rank and group size all interacted with genotype to influence gene expression in at least one sex, and either in early life or in adulthood. These results suggest that social and behavioural variation, akin to other factors such as age and sex, can impact the genotype-phenotype relationship. We conclude that GEIs mediated by the social environment are important in the evolution and maintenance of individual differences in wild social mammals, including individual differences in responses to social stressors.

McFadden K.,Duke University
Current topics in microbiology and immunology | Year: 2013

Viruses encounter many challenges within host cells in order to replicate their nucleic acid. In the case of DNA viruses, one challenge that must be overcome is recognition of viral DNA structures by the host DNA damage response (DDR) machinery. This is accomplished in elegant and unique ways by different viruses as each has specific needs and sensitivities dependent on its life cycle. In this review, we focus on three DNA tumor viruses and their interactions with the DDR. The viruses Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and human papillomavirus (HPV) account for nearly all of the virus-associated human cancers worldwide. These viruses have also been excellent models for the study of oncogenic virus-mediated cell transformation. In this review, we will discuss how each of these viruses engage and subvert aspects of the host DDR. The first level of DDR engagement is a result of the genetic linkage between the oncogenic potential of these viruses and their ability to replicate. Namely, the promotion of cells from quiescence into the cell cycle to facilitate virus replication can be sensed through aberrant cellular DNA replication structures which activate the DDR and hinder cell transformation. DNA tumor viruses subvert this growth-suppressive DDR through changes in viral oncoprotein expression which ultimately facilitate virus replication. An additional level of DDR engagement is through direct detection of replicating viral DNA. These interactions parallel those observed in other DNA virus systems in that the need to subvert these intrinsic sensors of aberrant DNA structure in order to replicate must be in place. DNA tumor viruses are no exception. This review will cover the molecular features of DNA tumor virus interactions with the host DDR and the consequences for virus replication.

Lanasa M.C.,Duke University
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2010

Significant advancements in the care of patients with chronic lymphocytic leukemia (CLL) have occurred over the past decade. Nonetheless, CLL remains incurable outside of allogeneic transplantation. CLL is the most common leukemia in the United States and Europe, and new treatments and therapeutic strategies are clearly needed. To address this need, the pathogenesis of CLL has been an area of intense ongoing investigation. These international efforts illuminate a complex biology that is reliant on the interplay of inherited, environmental, and host factors. This broad review will discuss the recent advances in our understanding of CLL biology including the elucidation of inherited and acquired genetic changes; the role of the B-cell receptor and B-cell receptor signaling; CLL cell kinetics; and the interactions in the microenvironment between CLL cells, other immune cells, and stromal elements. This improved understanding of disease pathogenesis is facilitating the development of novel therapeutic treatment strategies.

China is quickly building up its nuclear power capacity while the hailed nuclear renaissance in the United States has been largely stagnant. The political and industrial structures explain the divergent paths. This paper draws lessons from the French experiences in deploying nuclear power and uses the lessons in comparing Chinese and U.S. policies. An authoritative political system and state-owned utility industry allow China to emulate the French approaches such as government-backed financing and broad-scale deployment with standardized design. The democratic political system and fragmented utility industry, and the laissez-faire ideology in the United States, on the other hand, are unfavorable to a nuclear renaissance. The prospect of a nuclear revival in the United States remains highly uncertain.As China builds up its nuclear industry, it will be able to reduce carbon emissions without a carbon price through a national plan to deploy low-carbon nuclear electricity, while the United States cannot implement a climate policy without a carbon price. American politicians should stop using China's lack of carbon cap as an excuse for postponing the legislation of a carbon price. © 2011 Elsevier Ltd.

Dichter G.S.,University of North Carolina at Chapel Hill | Dichter G.S.,Duke University
Dialogues in Clinical Neuroscience | Year: 2012

This review presents an overview of functional magnetic resonance imaging findings in autism spectrum disorders (ASDs). Although there is considerable heterogeneity with respect to results across studies, common themes have emerged, including: (i) hypoactivation in nodes of the "social brain" during social processing tasks, including regions within the prefrontal cortex, the posterior superior temporal sulcus, the amygdala, and the fusiform gyrus; (ii) aberrant frontostriatal activation during cognitive control tasks relevant to restricted and repetitive behaviors and interests, including regions within the dorsal prefrontal cortex and the basal ganglia; (iii) differential lateralization and activation of language processing and production regions during communication tasks; (iv) anomalous mesolimbic responses to social and nonsocial rewards; (v) task-based long-range functional hypoconnectivity and short-range hyper-connectivity; and (vi) decreased anterior-posterior functional connectivity during resting states. These findings provide mechanistic accounts of ASD pathophysiology and suggest directions for future research aimed at elucidating etiologic models and developing rationally derived and targeted treatments. © 2012, LLS SAS.

Aldabagh B.,Duke University
Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.] | Year: 2013

The role of human papillomavirus (HPV) in the induction and maintenance of cervical, anogenital, and some oropharyngeal carcinomas is well recognized, but its role in cutaneous squamous cell carcinoma (SCC) remains to be elucidated. HPV is thought to act as a possible cocarcinogen in the development of SCC. To review the literature assessing the correlation between and possible causation of HPV and cutaneous SCC in immunocompetent and immunocompromised populations. We reviewed HPV sampling and detection methods, epidemiologic studies examining HPV carriage in immunocompetent and immunosuppressed individuals, and evidence asserting an association between HPV and cutaneous SCC. Although an abundant body of evidence points toward a link between HPV and cutaneous SCC, many studies indicate otherwise. Recent studies have focused on viral activity in addition to DNA presence. The possibility exists that HPV may play a role in the induction but not maintenance of cutaneous SCC. © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc.

PURPOSE:: To report the intraoperative use of microscope-integrated optical coherence tomography (MIOCT) to enable visualization for Descemetʼs stripping automated endothelial keratoplasty (DSAEK) in 2 patients with advanced bullous keratopathy. METHODS:: Patient 1 was an 83-year-old female and patient 2 was a 28-year-old male both with limited vision and significant pain from bullous keratopathy who underwent palliative DSAEK. Because of the severity and chronicity of the corneal decompensation in both patients, the view past the anterior cornea was negligible using standard microscope illumination techniques. We used spectral-domain (Patient 1) and swept-source (Patient 2) MIOCT, both of which rely on infrared illumination, to visualize key parts of the DSAEK procedure. RESULTS:: Graft insertion, unfolding, tamponade, and attachment could be dynamically visualized intraoperatively despite the nearly opaque nature of the host corneas. Postoperatively, the grafts remained attached with significant corneal clearing, and there was improvement in visual acuity, and pain relief for both patients. CONCLUSIONS:: MIOCT is a valuable tool for the corneal surgeon, allowing for DSAEK to be successfully performed even when the surgical microscope view is limited from severe corneal edema, as is often the case in patients with advanced bullous keratopathy. By using MIOCT, these patients can benefit from the advantages of DSAEK despite a clinically opaque cornea, which would otherwise be treated with a penetrating keratoplasty. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Yoder A.D.,Duke University
Genome biology and evolution | Year: 2014

Vomeronasal receptor genes have frequently been invoked as integral to the establishment and maintenance of species boundaries among mammals due to the elaborate one-to-one correspondence between semiochemical signals and neuronal sensory inputs. Here, we report the most extensive sample of vomeronasal receptor class 1 (V1R) sequences ever generated for a diverse yet phylogenetically coherent group of mammals, the tooth-combed primates (suborder Strepsirrhini). Phylogenetic analysis confirms our intensive sampling from a single V1R subfamily, apparently unique to the strepsirrhine primates. We designate this subfamily as V1Rstrep. The subfamily retains extensive repertoires of gene copies that descend from an ancestral gene duplication that appears to have occurred prior to the diversification of all lemuriform primates excluding the basal genus Daubentonia (the aye-aye). We refer to the descendent clades as V1Rstrep-α and V1Rstrep-β. Comparison of the two clades reveals different amino acid compositions corresponding to the predicted ligand-binding site and thus potentially to altered functional profiles between the two. In agreement with previous studies of the mouse lemur (genus, Microcebus), the majority of V1Rstrep gene copies appear to be intact and under strong positive selection, particularly within transmembrane regions. Finally, despite the surprisingly high number of gene copies identified in this study, it is nonetheless probable that V1R diversity remains underestimated in these nonmodel primates and that complete characterization will be limited until high-coverage assembled genomes are available.

Understanding the impact of obesity on elective total joint arthroplasty (TJA) remains critical. Perioperative outcomes were reviewed in 316 patients undergoing primary TJA. Higher percent body fat (PBF) was associated with postoperative blood transfusion, increased hospital length of stay (LOS) >3 days, and discharge to an extended care facility while no significant differences existed for BMI. Additionally, PBF of 43.5 was associated with a 2.4× greater likelihood of blood transfusion, PBF of 36.5 with a 1.9× greater likelihood for LOS >3 days, and PBF of 36.0 with a 1.4× greater likelihood for discharge to an extended care facility. PBF may be a more effective measure than BMI to use in screening for perioperative risks and acute outcomes associated with obese total joint patients. Copyright © 2014 Elsevier Inc. All rights reserved.

Lee G.M.,Duke University
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2013

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder caused by antibodies that recognize complexes of platelet factor 4 (PF4) and heparin. HIT is frequently considered in the differential diagnosis of thrombocytopenia occurring in patients on heparin therapy. HIT is a challenging diagnosis because of routine heparin use in hospitalized patients, the common occurrence of thrombocytopenia, and high rates of anti-PF4/heparin seroconversions in patients treated with heparin. Our diagnostic approach to HIT is presented here, underscoring critical elements of clinical and laboratory evaluation.

Dave S.S.,Duke University
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2013

The application of high-throughput genomic approaches in lymphomas has generated a wealth of data regarding the molecular underpinnings of these cancers. In this review, key findings from recent studies are discussed, as well as the genetic heterogeneity that underlies common lymphomas including diffuse large B-cell lymphoma, Burkitt lymphoma, and chronic lymphocytic leukemia, and the implications for identifying new therapeutic opportunities and personalized medicine.

Rosoff P.M.,Duke University
American Journal of Bioethics | Year: 2012

Periodic and unexpected shortages of drugs, biologics, and even medical devices have become commonplace in the United States. When shortages occur, hospitals and clinics need to decide how to ration their available stock. When such situations arise, institutions can choose from several different allocation schemes, such as first-come, first-served, a lottery, or a more rational and calculated approach. While the first two approaches sound reasonable at first glance, there are a number of problems associated with them, including the inability to make fine, individual patient-centered decisions. They also do not discriminate between what kinds of patients and what types of uses may be more deserving or reasonable than others. In this article I outline an ethically acceptable procedure for rationing drugs during a shortage in which demand outstrips supply. © 2012 Copyright Taylor and Francis Group, LLC.

Majumder A.,Ohio State University | Muller B.,Duke University
Physical Review Letters | Year: 2010

Finite temperature lattice simulations of quantum chromodynamics (QCD) are sensitive to the hadronic mass spectrum for temperatures below the "critical" temperature Tc≈160MeV. We show that a recent precision determination of the QCD trace anomaly shows evidence for the existence of a large number of hadron states beyond those known from experiment. The lattice results are well represented by an exponentially growing mass spectrum up to a temperature T=155MeV. Using simple parametrizations of the hadron mass spectrum we show how one may estimate the total spectral weight in these yet undermined states. © 2010 The American Physical Society.

Havrilesky L.J.,Duke University
Obstetrics and Gynecology | Year: 2010

Objective: To estimate the ratio of gynecologic cancer cases to practicing gynecologic oncologists in the United States over the next 40 years. Methods: Using population projections from the U.S. Census Bureau and incidence and mortality rates from Surveillance, Epidemiology and End Results surveys, we estimated the annual number of new gynecologic cancer cases through 2050; the effects of human papillomavirus (HPV) vaccination was included in cervical cancer estimates. The number of practicing gynecologic oncologists was projected through 2050 using data from the 2005 Society of Gynecologic Oncologists Practice Survey, current Society of Gynecologic Oncologists membership information, American Board of Obstetrics and Gynecology and Gynecologic Oncology oral examination results, and mortality estimates from U.S. life tables. Projected time in practice was sex-dependent based on Society of Gynecologic Oncologists Practice Survey. For sensitivity analyses, we varied annual number and sex distribution of fellowship graduates, HPV vaccination coverage rates, and future incidence of overweight and obesity. Results: At constant training rates, the annual number of new cancer cases per practicing gynecologic oncologist will rise from 112 in 2010 to 133 in 2050, a 19% increase. If the annual number of fellowship graduates increases by 25%, the ratio of cancer cases per gynecologic oncologist will decrease to 106, a 5% decrease. Projections are more sensitive to changes in physician demographics than to changes in HPV vaccination coverage rates. Conclusion: The gynecologic cancer caseload of practicing gynecologic oncologists will increase by almost 20% over the next 40 years at constant training rates. Changes in the projected sex distribution of fellowship graduates and their time in practice affect these projections. © 2010 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins.

Muir A.J.,Duke University
Clinics in Liver Disease | Year: 2012

Patients with chronic liver disease face greater risk of perioperative morbidity and mortality, with the greatest risk among patients with cirrhosis. Both the Child-Pugh score and the Model for End-Stage Liver Disease have been evaluated as predictors of postoperative mortality. Other comorbidities, age, and American Society of Anesthesiologists physical status classification are also important predictors of these outcomes. In patients with liver disease, elective surgeries should be delayed to allow complete evaluation of the severity of liver disease, including the role of transplantation in the event of hepatic decompensation postoperatively. © 2012 Elsevier Inc.

Frances A.J.,Duke University | Widiger T.,University of Kentucky
Annual Review of Clinical Psychology | Year: 2012

The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders provides the authoritative list of what are considered to be mental disorders. This list has a tremendous impact on research, funding, and treatment, as well as a variety of civil and forensic decisions. The development of this diagnostic manual is an enormous responsibility. Provided herein are lessons learned during the course of the development of the fourth edition. Noted in particular is the importance of obtaining and publishing critical reviews, restraining the unbridled creativity of experts, conducting field trials that address key issues and concerns, and conducting forthright risk-benefit analyses. It is suggested that future editions of the diagnostic manual be developed under the auspices of the Institute of Medicine. The goal would be broad representation, an evidence-based approach, disinterested recommendations, and a careful attention to the risks and benefits of each suggestion for change to the individual patient, to public policy, and to forensic applications. © Copyright ©2012 by Annual Reviews. All rights reserved.

Bernal A.J.,Duke University
Birth defects research. Part A, Clinical and molecular teratology | Year: 2010

Through DNA methylation, histone modifications, and small regulatory RNAs the epigenome systematically controls gene expression during development, both in utero and throughout life. The epigenome is also a very reactive system; its labile nature allows it to sense and respond to environmental perturbations to ensure survival during fetal growth. This pliability can lead to aberrant epigenetic modifications that persist into later life and induce numerous disease states. Endocrine-disrupting compounds (EDCs) are ubiquitous chemicals that interfere with growth and development. Several EDCs also interfere with epigenetic programming. The investigation of the epigenotoxic effects of bisphenol A (BPA), an EDC used in the production of plastics and resins, has further raised concern over the impact of EDCs on the epigenome. Using the Agouti viable yellow (A(vy)) mouse model, dietary BPA exposure was shown to hypomethylate both the A(vy) and the Cabp(IAP) metastable epialleles. This hypomethylating effect was counteracted with dietary supplementation of methyl donors or genistein. These results are consistent with reports of BPA and other EDCs causing epigenetic effects. Epigenotoxicity could lead to numerous developmental, metabolic, and behavioral disorders in exposed populations. The heritable nature of epigenetic changes also increases the risk for transgenerational inheritance of phenotypes. Thus, epigenotoxicity must be considered when assessing these compounds for safety. © 2010 Wiley-Liss, Inc.

Moran T.P.,Duke University | Vickery B.P.,University of North Carolina at Chapel Hill | Burks A.W.,University of North Carolina at Chapel Hill
Current Opinion in Immunology | Year: 2013

Food allergies are increasing in prevalence and present an emerging epidemic for westernized countries. Strict dietary avoidance is the only approved management for food allergy, but accidental exposures regularly occur, leading to significant patient anxiety and decreased quality of life. Over the past decade, oral and sublingual immunotherapies have emerged as potential treatments for food allergy. While several small clinical trials have demonstrated that immunotherapy can desensitize food-allergic individuals, strategies for further enhancing safety and definitively establishing long-term efficacy are needed. This review presents an overview of recent oral and sublingual immunotherapy trials, and provides a glimpse into what the next generation of food immunotherapy may entail. © 2013 Elsevier Ltd.

Bartels K.,Duke University
Critical care (London, England) | Year: 2013

Intravenous fluid therapy has evolved significantly over time. From the initial report of the first intravenous administration of sodium-chloride-based solution to the development of goal-directed fluid therapy using novel dynamic indices, efforts have focused on improving patient outcomes. The goal of this review is to provide a brief overview of current concepts for intravenous fluid administration in the ICU. Results of recently published clinical trials suggesting harmful effects of starch-based solutions on critically ill patients are discussed. Concepts for goal-directed fluid therapy and new modalities for the assessment of fluid status as well as for the prediction of responsiveness to different interventions will continue to emerge. Advances in technology will have to be critically evaluated for their ability to improve outcomes in different clinical scenarios.

Frances A.J.,Duke University
British Journal of Psychiatry | Year: 2013

Having two systems of psychiatric diagnosis creates unnecessary confusion therefore it would be desirable to achieve increased consistency between ICD-11 and DSM-5. Unfortunately, however, DSM-5 has included many controversial suggestions that have weak scientific support and insufficient risk-benefit analysis. As a result ICD-11 should learn from the DSM-5 mistakes rather than repeating them.

Background: Patients with brain tumors report experiencing elevated levels of stress across the disease continuum. Massage therapy is a commonly used complementary therapy and is employed in cancer care to reduce psychological stress and to improve quality of life (QoL). The purpose of this pilot study was to obtain a preliminary assessment of the efficacy of massage therapy on patient reported psychological outcomes and QoL. Materials and methods: The design of the study was a prospective, single-arm intervention. Participants were newly diagnosed primary brain tumor patients who reported experiencing stress and who received a total of eightmassages over a period of 4 weeks. Participants completed the Perceived Stress Scale (PSS-10) and the Functional Assessment of Cancer Therapy - Brain to assess their stress level and QoL. Results: As a group, levels of stress dropped significantly between weeks 2 and 3 (M=12.3, SD=3.09, P≤0.010). A trend for the reduction in stress continued through week 4 (P≤0.063). At the end of week 4, PSS-10 scores of all participants were below the threshold for being considered stressed. By the end of the intervention, participants reported significant improvements in three test domains, emotional well-being, additional brain tumor concerns, and social/family well-being. Conclusion: This study indicates that participation in a massage therapy program is both feasible and acceptable to newly diagnosed brain tumor patients experiencing stress. Furthermore, participants in this study reported improvements in stress and their QoL while receiving massage therapy. © Springer-Verlag 2010.

Dabigatran is a novel oral anticoagulant approved for thromboprophylaxis in atrial fibrillation. Adoption patterns of this new agent in community practice are unknown. We studied patterns of dabigatran use among patients enrolled in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry between June 2010 and August 2011 and followed for 12 months. Among 9974 atrial fibrillation patients included, 1217 (12%) were treated with dabigatran during the study. Overall, patients receiving dabigatran were younger (median age 72 versus 75 years, P<0.0001), more likely to be white (92% versus 89%, P=0.005), more likely to have private insurance (33% versus 25%, P<0.0001), and less likely to have prior cardiovascular disease (4% versus 33%, P<0.0001). They had more new-onset atrial fibrillation (8.8% versus 4.1%, P<0.0001), lower CHADS2 scores (estimated risk based on the presence of congestive heart failure, hypertension, aged ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack; mean 2.0 versus 2.3, P<0.0001), and lower Anticoagulation and Risk Factors in Atrial Fibrillation scores (mean 2.4 versus 2.8, P<0.0001). More than half (n=14/25, 56%) of patients with severe kidney disease were not prescribed reduced dosing, whereas 10% (n=91/920) with preserved renal function received lower dosing. Among patients not on dabigatran at baseline, 8% had dabigatran initiated during follow-up. Patient education was significantly associated with switching from warfarin to dabigatran (adjusted odds ratio for postgraduate 1.73, P=0.007), whereas antiarrhythmic drug use significantly correlated with de novo adoption of dabigatran (adjusted odds ratio 2.4, P<0.0001). Patients receiving dabigatran were younger and at a lower risk of stroke and bleeding. Patients appeared to drive switching from warfarin, whereas clinical characteristics influenced de novo start of dabigatran. These data suggest cautious early uptake of dabigatran, and more careful attention to dosing adjustments is warranted. Clinicaltrials.gov. Unique identifier: NCT01165710.

Thomas K.L.,Duke University
Journal of the American Heart Association | Year: 2013

The intersection of heart failure (HF) and atrial fibrillation (AF) is common, but the burden of AF among black patients with HF is poorly characterized. We sought to determine the prevalence of AF, characteristics, in-hospital outcomes, and warfarin use associated with AF in patients hospitalized with HF as a function of race. We analyzed data on 135 494 hospitalizations from January 2006 through January 2012 at 276 hospitals participating in the American Heart Association's Get With The Guidelines HF Program. Multivariable logistic regression models using generalized estimating equations approach for risk-adjusted comparison of AF prevalence, in-hospital outcomes, and warfarin use. In this HF population, 53 389 (39.4%) had AF. Black patients had markedly less AF than white patients (20.8% versus 44.8%, P < 0.001). Adjusting for risk factors and hospital characteristics, black race was associated with significantly lower odds of AF (adjusted odds ratio 0.52, 95% CI 0.48 to 0.55, P < 0.0001). There were no racial differences in in-hospital mortality; however, black patients had a longer length of stay relative to white patients. Black patients compared with white patients with AF were less likely to be discharged on warfarin (adjusted odds ratio 0.76, 95% CI 0.69 to 0.85, P < 0.001). Despite having many risk factors for AF, black patients, relative to white patients hospitalized for HF, had a lower prevalence of AF and lower prescription of guideline-recommended warfarin therapy.

Vickery B.P.,Duke University
Current Opinion in Allergy and Clinical Immunology | Year: 2012

Purpose of Review: Egg allergy is one of the most common food allergies of childhood and no interventional therapy is currently approved by the Food and Drug Administration. Much recent research has focused on the safety, efficacy, and mechanism of oral immunotherapy (OIT) as a disease-modifying treatment. Recent Findings: Small pilot studies with varying protocol designs have shown egg OIT to be relatively well tolerated, and efficacy is suggested but not formally demonstrated. At this time, no placebo-controlled randomized trial has been published confirming desensitization and no published study has convincingly demonstrated the development of OIT-induced tolerance to egg. Summary: Egg OIT is a promising modality for providing temporary protection from reactions caused by accidental egg exposure. However, the overall strength of the evidence in favor of egg OIT is limited by small sample sizes and the lack of controls, both of which are important considerations given the spontaneous resolution expected in egg allergy. More high-quality studies are necessary before egg OIT can be recommended as a viable treatment option. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Gersbach C.A.,Duke University | Gaj T.,Scripps Research Institute | Barbas C.F.,Scripps Research Institute
Accounts of Chemical Research | Year: 2014

ConspectusThe understanding of gene regulation and the structure and function of the human genome increased dramatically at the end of the 20th century. Yet the technologies for manipulating the genome have been slower to develop. For instance, the field of gene therapy has been focused on correcting genetic diseases and augmenting tissue repair for more than 40 years. However, with the exception of a few very low efficiency approaches, conventional genetic engineering methods have only been able to add auxiliary genes to cells. This has been a substantial obstacle to the clinical success of gene therapies and has also led to severe unintended consequences in several cases. Therefore, technologies that facilitate the precise modification of cellular genomes have diverse and significant implications in many facets of research and are essential for translating the products of the Genomic Revolution into tangible benefits for medicine and biotechnology. To address this need, in the 1990s, we embarked on a mission to develop technologies for engineering protein-DNA interactions with the aim of creating custom tools capable of targeting any DNA sequence. Our goal has been to allow researchers to reach into genomes to specifically regulate, knock out, or replace any gene. To realize these goals, we initially focused on understanding and manipulating zinc finger proteins. In particular, we sought to create a simple and straightforward method that enables unspecialized laboratories to engineer custom DNA-modifying proteins using only defined modular components, a web-based utility, and standard recombinant DNA technology. Two significant challenges we faced were (i) the development of zinc finger domains that target sequences not recognized by naturally occurring zinc finger proteins and (ii) determining how individual zinc finger domains could be tethered together as polydactyl proteins to recognize unique locations within complex genomes. We and others have since used this modular assembly method to engineer artificial proteins and enzymes that activate, repress, or create defined changes to user-specified genes in human cells, plants, and other organisms. We have also engineered novel methods for externally controlling protein activity and delivery, as well as developed new strategies for the directed evolution of protein and enzyme function. This Account summarizes our work in these areas and highlights independent studies that have successfully used the modular assembly approach to create proteins with novel function. We also discuss emerging alternative methods for genomic targeting, including transcription activator-like effectors (TALEs) and CRISPR/Cas systems, and how they complement the synthetic zinc finger protein technology. © 2014 American Chemical Society.

Scholberg K.,Duke University
Annual Review of Nuclear and Particle Science | Year: 2012

A core-collapse supernova will produce an enormous burst of neutrinos of all flavors in the few-tens-of-MeV range. Measurement of the flavor, time, and energy structure of a nearby core-collapse neutrino burst will yield answers to many physics and astrophysics questions. The neutrinos left over from past cosmic supernovae are also observable, and their detection will improve knowledge of core-collapse rates and average neutrino emission. This review describes experimental techniques for detection of core-collapse neutrinos, as well as the sensitivities of current and future detectors. © 2012 by Annual Reviews.

Mating in basidiomycetous fungi is often controlled by two unlinked, multiallelic loci encoding homeodomain transcription factors or pheromones/pheromone receptors. In contrast to this tetrapolar organization, Cryptococcus neoformans/Cryptococcus gattii have a bipolar mating system, and a single biallelic locus governs sexual reproduction. The C. neoformans MAT locus is unusually large (>100 kb), contains >20 genes, and enhances virulence. Previous comparative genomic studies provided insights into how this unusual MAT locus might have evolved involving gene acquisitions into two unlinked loci and fusion into one contiguous locus, converting an ancestral tetrapolar system to a bipolar one. Here we tested this model by studying Cryptococcus heveanensis, a sister species to the pathogenic Cryptococcus species complex. An extant sexual cycle was discovered; co-incubating fertile isolates results in the teleomorph (Kwoniella heveanensis) with dikaryotic hyphae, clamp connections, septate basidia, and basidiospores. To characterize the C. heveanensis MAT locus, a fosmid library was screened with C. neoformans/C. gattii MAT genes. Positive fosmids were sequenced and assembled to generate two large probably unlinked MAT gene clusters: one corresponding to the homeodomain locus and the other to the pheromone/receptor locus. Strikingly, two divergent homeodomain genes (SXI1, SXI2) are present, similar to the bE/bW Ustilago maydis paradigm, suggesting one or the other homeodomain gene was recently lost in C. neoformans/C. gattii. Sequencing MAT genes from other C. heveanensis isolates revealed a multiallelic homeodomain locus and at least a biallelic pheromone/receptor locus, similar to known tetrapolar species. Taken together, these studies reveal an extant C. heveanensis sexual cycle, define the structure of its MAT locus consistent with tetrapolar mating, and support the proposed evolutionary model for the bipolar Cryptococcus MAT locus revealing transitions in sexuality concomitant with emergence of a pathogenic clade. These studies provide insight into convergent processes that independently punctuated evolution of sex-determining loci and sex chromosomes in fungi, plants, and animals.

Muller B.,Duke University | Schukraft J.,CERN | Wyslouch B.,Massachusetts Institute of Technology
Annual Review of Nuclear and Particle Science | Year: 2012

At the end of 2010, the Large Hadron Collider (LHC) at CERN started operation with heavy-ion beams, colliding lead nuclei at a center-of-mass energy of 2.76 TeV per nucleon. These collisions ushered in a new era in ultrarelativistic heavy-ion physics at energies exceeding that of previous accelerators by more than an order of magnitude. This review summarizes the results from the first year of heavy-ion physics at the LHC obtained by the three experiments participating in the heavy-ion program: ALICE, ATLAS, and CMS. © 2012 by Annual Reviews.

Pilowsky D.J.,Columbia University | Wu L.-T.,Duke University
Addictive Behaviors | Year: 2013

Background: A review of the literature was conducted to examine substance use screening instruments commonly used with adolescents in medical settings, their comparative usefulness, and SBIRT (Screening, Brief Intervention, and Referral to Treatment). Methods: We screened two databases (Ovid MEDLINE and PsycINFO) targeting journal articles dealing with screening for alcohol and drug use in adolescence as well as adolescent SBIRT. Results: Adolescents preferred paper forms and computerized questionnaires over interviews with physicians or nurses. The CRAFFT was the best studied instrument for screening for alcohol/drug use and related problems, and is the only tool with data to support its use in medical settings. Other screening instruments require more testing/evaluation in more representative samples of adolescents in primary care settings. Long term follow-up data to establish the efficacy of SBIRT in adolescence are not available. Innovative computerized approaches to screening for substance use in this population have recently been proposed. Although promising, they require further evaluation. Conclusions: The CRAFFT has the most consistent data to support its use in primary care settings. The effects of SBIRT in adolescence have not been adequately evaluated. Adolescents' opinions and preferences for SBIRT should be studied to improve their acceptance. © 2013 Elsevier Ltd.

Terhune C.E.,Duke University
American Journal of Physical Anthropology | Year: 2013

Behavioral observations of great apes have consistently identified differences in feeding behavior among species, and these differences have been linked to variation in masticatory form. As the point at which the mandible and cranium articulate, the temporomandibular joint (TMJ) is an important component of the masticatory apparatus. Forces are transmitted between the mandible and cranium via the TMJ, and this joint helps govern mandibular range of motion. This study examined the extent to which TMJ form covaries with feeding behavior in the great apes by testing a series of biomechanical hypotheses relating to specific components of joint shape using linear measurements extracted from three-dimensional coordinate data. Results of these analyses found that taxa differ significantly in TMJ shape, particularly in the mandibular fossa. Chimpanzees have relatively more anteroposteriorly elongated joint surfaces, whereas gorillas tend to have relatively anteroposteriorly compressed joints. Orangutans were most commonly intermediate in form between Pan and Gorilla, perhaps reflecting a trade-off between jaw gape and load resistance capabilities. Importantly, much of the observed variation among taxa reflects differences in morphologies that facilitate gape over force production. These data therefore continue to emphasize the unclear relationship between mandibular loading and bony morphology, but highlight the need for further data regarding food material properties, jaw gape, and ingestive/food processing behaviors. Copyright © 2012 Wiley Periodicals, Inc.

Felker G.M.,Duke University
Heart Failure Reviews | Year: 2012

Congestion is a major component of the clinical syndrome of heart failure, and diuretic therapy remains the cornerstone of congestion management. Despite being widely used, there is very limited evidence from prospective randomized studies to guide the prescription and titration of diuretics. A thorough understanding of the pharmacology of loop diuretics is crucial to the optimal use of these agents. Although multiple observational studies have suggested that high doses of diuretics may be harmful, all such analyses are confounded by the association of higher diuretic doses with greater severity of illness and comorbidity. Recent data from randomized trials suggest that higher doses of diuretics may be more effective at relieving congestion and that associated changes in renal function are typically transient. Data from other ongoing trials will continue to inform our understanding of the optimal role for loop diuretics in the treatment of heart failure. © 2011 Springer Science+Business Media, LLC.

Draelos Z.D.,Duke University
Clinics in Dermatology | Year: 2010

The use of nutrition, including vitamins and antioxidants, to enhance youthful-appearing skin is presented. The most current references in the area are included, but much of the material discussed has not been well studied. The use of nutricosmetics is supported by testimonial, assumption, inference, and vague language. This contribution provides an overview of the current nutricosmetic marketplace and also substantiates the lack of available scientific data. © 2010 Elsevier Inc.

Cassidy F.,Duke University
Bipolar Disorders | Year: 2010

The recently released preliminary proposal for the DSM-5 diagnostic system includes modification of the mixed mania diagnosis symptom set. That definition includes the long-overdue exclusion of nonspecific signs and symptoms, as well as the inclusion of psychomotor retardation. Anxiety is specifically excluded from the definition. The current report reviews studies to establish that psychomotor retardation would have limited utility in the definition, in contrast to anxiety, which is a core symptom of the mixed manic subtype. © 2010 The Author. Journal compilation © 2010 John Wiley & Sons A/S.

McMullin D.,Duke University
Epilepsia | Year: 2012

A major challenge in epilepsy research is to unravel the complex genetic mechanisms underlying both common and rare forms of epilepsy, as well as the genetic determinants of response to treatment. To accelerate progress in this area, the National Institute of Neurological Disorders and Stroke (NINDS) recently offered funding for the creation of a "Center without Walls" to focus on the genetics of human epilepsy. This article describes Epi4K, the collaborative study supported through this grant mechanism and having the aim of analyzing the genomes of a minimum 4,000 subjects with highly selected and well-characterized epilepsy. © 2012 International League Against Epilepsy.

As swollen polymer networks in water, hydrogels are usually brittle. However, hydrogels with high toughness play critical roles in many plant and animal tissues as well as in diverse engineering applications. Here we review the intrinsic mechanisms of a wide variety of tough hydrogels developed over the past few decades. We show that tough hydrogels generally possess mechanisms to dissipate substantial mechanical energy but still maintain high elasticity under deformation. The integrations and interactions of different mechanisms for dissipating energy and maintaining elasticity are essential to the design of tough hydrogels. A matrix that combines various mechanisms is constructed for the first time to guide the design of next-generation tough hydrogels. We further highlight that a particularly promising strategy for the design is to implement multiple mechanisms across multiple length scales into nano-, micro-, meso-, and macro-structures of hydrogels. © The Royal Society of Chemistry 2014.

Lyman G.H.,Duke University | Sparreboom A.,St Jude Childrens Research Hospital
Nature Reviews Clinical Oncology | Year: 2013

Retrospective and prospective preclinical and clinical data have demonstrated an association between chemotherapy dose intensity and both clinical efficacy and toxicity. The optimum tolerable and effective dose and schedule of chemotherapeutic agents is based on data from dose-finding studies and early clinical trials. There is considerable evidence that reductions in the recommended dose intensity often occurs in actual clinical practice, particularly among overweight and obese patients with cancer. With increasing rates of obesity, and variation and uncertainty about appropriate dosing of chemotherapy in obese patients, ASCO has generated clinical practice guidelines for appropriate chemotherapy dosing for obese adult patients with cancer. Without evidence of any increase in treatment-related toxicity among obese patients receiving chemotherapy, the guidelines recommend that, after considering any accompanying comorbidities, chemotherapy dosing should be calculated based on body surface area using actual weight, rather than an estimate or idealization of weight. While further research is needed, pharmacokinetic studies support the use of actual body weight to calculate chemotherapy doses for most chemotherapy drugs in obese patients. We highlight the issue of chemotherapy dosing in this population, how a more personalized approach can be achieved, as well as discussing areas for further research. © 2013 Macmillan Publishers Limited. All rights reserved.

Egan P.J.,New York University | Mullin M.,Duke University
Nature | Year: 2016

As climate change unfolds, weather systems in the United States have been shifting in patterns that vary across regions and seasons. Climate science research typically assesses these changes by examining individual weather indicators, such as temperature or precipitation, in isolation, and averaging their values across the spatial surface. As a result, little is known about population exposure to changes in weather and how people experience and evaluate these changes considered together. Here we show that in the United States from 1974 to 2013, the weather conditions experienced by the vast majority of the population improved. Using previous research on how weather affects local population growth to develop an index of people's weather preferences, we find that 80% of Americans live in counties that are experiencing more pleasant weather than they did four decades ago. Virtually all Americans are now experiencing the much milder winters that they typically prefer, and these mild winters have not been offset by markedly more uncomfortable summers or other negative changes. Climate change models predict that this trend is temporary, however, because US summers will eventually warm more than winters. Under a scenario in which greenhouse gas emissions proceed at an unabated rate (Representative Concentration Pathway 8.5), we estimate that 88% of the US public will experience weather at the end of the century that is less preferable than weather in the recent past. Our results have implications for the public's understanding of the climate change problem, which is shaped in part by experiences with local weather. Whereas weather patterns in recent decades have served as a poor source of motivation for Americans to demand a policy response to climate change, public concern may rise once people's everyday experiences of climate change effects start to become less pleasant. © 2016 Macmillan Publishers Limited. All rights reserved.

Sevim V.,Duke University
PLoS computational biology | Year: 2010

A recently published transcriptional oscillator associated with the yeast cell cycle provides clues and raises questions about the mechanisms underlying autonomous cyclic processes in cells. Unlike other biological and synthetic oscillatory networks in the literature, this one does not seem to rely on a constitutive signal or positive auto-regulation, but rather to operate through stable transmission of a pulse on a slow positive feedback loop that determines its period. We construct a continuous-time Boolean model of this network, which permits the modeling of noise through small fluctuations in the timing of events, and show that it can sustain stable oscillations. Analysis of simpler network models shows how a few building blocks can be arranged to provide stability against fluctuations. Our findings suggest that the transcriptional oscillator in yeast belongs to a new class of biological oscillators.

Molecular data have converged on a consensus about the genus-level phylogeny of extant platyrrhine monkeys, but for most extinct taxa and certainly for those older than the Pleistocene we must rely upon morphological evidence from fossils. This raises the question as to how well anatomical data mirror molecular phylogenies and how best to deal with discrepancies between the molecular and morphological data as we seek to extend our phylogenies to the placement of fossil taxa.Here I present parsimony-based phylogenetic analyses of extant and fossil platyrrhines based on an anatomical dataset of 399 dental characters and osteological features of the cranium and postcranium. I sample 16 extant taxa (one from each platyrrhine genus) and 20 extinct taxa of platyrrhines. The tree structure is constrained with a "molecular scaffold" of extant species as implemented in maximum parsimony using PAUP with the molecular-based 'backbone' approach. The data set encompasses most of the known extinct species of platyrrhines, ranging in age from latest Oligocene (~26. Ma) to the Recent. The tree is rooted with extant catarrhines, and Late Eocene and Early Oligocene African anthropoids.Among the more interesting patterns to emerge are: (1) known early platyrrhines from the Late Oligocene through Early Miocene (26-16.5. Ma) represent only stem platyrrhine taxa; (2) representatives of the three living platyrrhine families first occur between 15.7. Ma and 13.5. Ma; and (3) recently extinct primates from the Greater Antilles (Cuba, Jamaica, Hispaniola) are sister to the clade of extant platyrrhines and may have diverged in the Early Miocene. It is probable that the crown platyrrhine clade did not originate before about 20-24. Ma, a conclusion consistent with the phylogenetic analysis of fossil taxa presented here and with recent molecular clock estimates.The following biogeographic scenario is consistent with the phylogenetic findings and climatic and geologic evidence: Tropical South America has been a center for platyrrhine diversification since platyrrhines arrived on the continent in the middle Cenozoic. Platyrrhines dispersed from tropical South America to Patagonia at ~25-24. Ma via a "Paraná Portal" through eastern South America across a retreating Paranense Sea. Phylogenetic bracketing suggests Antillean primates arrived via a sweepstakes route or island chain from northern South America in the Early Miocene, not via a proposed land bridge or island chain (GAARlandia) in the Early Oligocene (~34. Ma). Patagonian and Antillean platyrrhines went extinct without leaving living descendants, the former at the end of the Early Miocene and the latter within the past six thousand years. Molecular evidence suggests crown platyrrhines arrived in Central America by crossing an intermittent connection through the Isthmus of Panama at or after 3.5. Ma. Any more ancient Central American primates, should they be discovered, are unlikely to have given rise to the extant Central American taxa in situ. © 2013 Elsevier Inc.

Pavlisko E.N.,Duke University
American Journal of Surgical Pathology | Year: 2015

Peritoneal mesothelioma is rare, and the sarcomatoid variant is more infrequent, with <30 cases reported to date in the literature. Several case series have described the morphologic features of sarcomatoid peritoneal mesothelioma (SPe); however, the clinicopathologic features are not well characterized. To our knowledge, this is the first large series reporting the clinicopathologic features of SPe. We reviewed our database of 3106 malignant mesothelioma cases. Of 248 peritoneal mesotheliomas, 15 (4%) were sarcomatoid variant (0.5% of all mesotheliomas). Only cases with 100% sarcomatoid morphology diagnosed by open surgical biopsy and/or autopsy were included. Thus, 4 cases were excluded leaving 11 cases of SPe. Two additional cases of SPe previously published by 1 of the authors (V.L.R.), not included in the database, are added yielding 13 cases total. The median age at diagnosis was 66 years (range=48 to 85 y), and there was a male predominance (M:F=3.25:1). Survival from date of diagnosis to date of death was 5 months (range=0 to 12 mo). The most common presenting symptom was abdominal pain, and 3 of 4 women were suspected to have cholecystitis/cholelithiasis. All cases stained positive for cytokeratins, and 2 contained heterologous elements. Seven cases had objective markers of asbestos exposure, and 2 additional cases had occupations strongly associated with mesothelioma. Two cases with alleged household contact exposures could not be confirmed to be asbestos related by lung fiber analysis. SPe is a rare variant of mesothelioma attributed to asbestos exposure in 69% of our cases. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Carleton A.,University of Geneva | Accolla R.,Firmenich | Simon S.A.,Duke University
Trends in Neurosciences | Year: 2010

To understand gustatory physiology and associated dysfunctions it is important to know how oral taste stimuli are encoded both in the periphery and in taste-related brain centres. The identification of distinct taste receptors, together with electrophysiological recordings and behavioral assessments in response to taste stimuli, suggest that information about distinct taste modalities (e.g. sweet versus bitter) are transmitted from the periphery to the brain via segregated pathways. By contrast, gustatory neurons throughout the brain are more broadly tuned, indicating that ensembles of neurons encode taste qualities. Recent evidence reviewed here suggests that the coding of gustatory stimuli is not immutable, but is dependant on a variety of factors including appetite-regulating molecules and associative learning. © 2010 Elsevier Ltd.

Yu L.,Duke University
PLoS genetics | Year: 2010

Drosophila is a well recognized model of several human diseases, and recent investigations have demonstrated that Drosophila can be used as a model of human heart failure. Previously, we described that optical coherence tomography (OCT) can be used to rapidly examine the cardiac function in adult, awake flies. This technique provides images that are similar to echocardiography in humans, and therefore we postulated that this approach could be combined with the vast resources that are available in the fly community to identify new mutants that have abnormal heart function, a hallmark of certain cardiovascular diseases. Using OCT to examine the cardiac function in adult Drosophila from a set of molecularly-defined genomic deficiencies from the DrosDel and Exelixis collections, we identified an abnormally enlarged cardiac chamber in a series of deficiency mutants spanning the rhomboid 3 locus. Rhomboid 3 is a member of a highly conserved family of intramembrane serine proteases and processes Spitz, an epidermal growth factor (EGF)-like ligand. Using multiple approaches based on the examination of deficiency stocks, a series of mutants in the rhomboid-Spitz-EGF receptor pathway, and cardiac-specific transgenic rescue or dominant-negative repression of EGFR, we demonstrate that rhomboid 3 mediated activation of the EGF receptor pathway is necessary for proper adult cardiac function. The importance of EGF receptor signaling in the adult Drosophila heart underscores the concept that evolutionarily conserved signaling mechanisms are required to maintain normal myocardial function. Interestingly, prior work showing the inhibition of ErbB2, a member of the EGF receptor family, in transgenic knock-out mice or individuals that received herceptin chemotherapy is associated with the development of dilated cardiomyopathy. Our results, in conjunction with the demonstration that altered ErbB2 signaling underlies certain forms of mammalian cardiomyopathy, suggest that an evolutionarily conserved signaling mechanism may be necessary to maintain post-developmental cardiac function.

Haddad E.,University of Montreal | Leroy S.,Institute Pasteur Paris | Buckley R.H.,Duke University
Journal of Allergy and Clinical Immunology | Year: 2013

Bone marrow transplantation has resulted in life-saving sustained T-cell reconstitution in many infants with severe combined immunodeficiency (SCID), but correction of B-cell function has been more problematic. At the annual meeting of the Primary Immunodeficiency Treatment Consortium held in Boston, Massachusetts, on April 27, 2012, a debate was held regarding the use of pretransplantation conditioning versus no pretransplantation conditioning in an effort to address this problem. Reviews of the literature were made by both debaters, and there was agreement that there was a higher rate of B-cell chimerism and a lower number of patients who required ongoing immunoglobulin replacement therapy in centers that used pretransplantation conditioning. However, there were still patients who required immunoglobulin replacement in those centers, and therefore pretransplantation conditioning did not guarantee development of B-cell function. Dr Rebecca H. Buckley presented data on B-cell function according to the molecular defect of the patient, and showed that patients with IL-7 receptor α, ADA, and CD3 chain gene mutations can have normal B-cell function after transplantation with only host B cells. Dr Elie Haddad presented a statistical analysis of B-cell function in published reports and showed that only a conditioning regimen that contained busulfan was significantly associated with better B-cell function after transplantation. The question is whether the risk of immediate and long-term toxicity with use of busulfan is justified, particularly in patients with SCID with DNA repair defects and in very young newborns with SCID who will be detected by using newborn screening. © 2013 American Academy of Allergy, Asthma & Immunology.

Steinbach W.J.,Duke University
Current medical research and opinion | Year: 2010

This case-based review examines the growing literature on critical issues related to the epidemiology, diagnosis, and treatment of pediatric invasive aspergillosis. Immunocompromised children are at heightened risk for invasive aspergillosis. Children at highest risk include those with new-onset or relapsed hematologic malignancy and recipients of allogeneic stem cell transplants. Additional risk factors in stem cell transplant recipients include impaired lymphocyte engraftment and graft-versus-host disease. Pediatric invasive aspergillosis is associated with a high mortality rate (generally >50%) and requires prompt diagnosis and treatment to prevent dissemination and death. Tools available for diagnosis include radiologic examinations (primarily computed tomography), the galactomannan assay, bronchoalveolar lavage, and tissue biopsy. Age-related differences in computed tomography and galactomannan assay results have been suggested. Recommended primary therapy for pediatric invasive aspergillosis is voriconazole (7 mg/kg IV q12 hours). Currently approved alternative therapies include liposomal amphotericin B, amphotericin B lipid complex, and caspofungin. Posaconazole and itraconazole are also possibilities, but there is no established pediatric dose for posaconazole, and itraconazole dosing is difficult in children. In patients who do not benefit from initial antifungal therapy, options include switching to another agent with a different mechanism of action or combination therapy. Further research is required to better establish optimal approaches to the management of pediatric patients with invasive aspergillosis recalcitrant to initial primary therapy.

Charney E.,Duke University
Behavioral and Brain Sciences | Year: 2012

The science of genetics is undergoing a paradigm shift. Recent discoveries, including the activity of retrotransposons, the extent of copy number variations, somatic and chromosomal mosaicism, and the nature of the epigenome as a regulator of DNA expressivity, are challenging a series of dogmas concerning the nature of the genome and the relationship between genotype and phenotype. According to three widely held dogmas, DNA is the unchanging template of heredity, is identical in all the cells and tissues of the body, and is the sole agent of inheritance. Rather than being an unchanging template, DNA appears subject to a good deal of environmentally induced change. Instead of identical DNA in all the cells of the body, somatic mosaicism appears to be the normal human condition. And DNA can no longer be considered the sole agent of inheritance. We now know that the epigenome, which regulates gene expressivity, can be inherited via the germline. These developments are particularly significant for behavior genetics for at least three reasons: First, epigenetic regulation, DNA variability, and somatic mosaicism appear to be particularly prevalent in the human brain and probably are involved in much of human behavior; second, they have important implications for the validity of heritability and gene association studies, the methodologies that largely define the discipline of behavior genetics; and third, they appear to play a critical role in development during the perinatal period and, in particular, in enabling phenotypic plasticity in offspring. I examine one of the central claims to emerge from the use of heritability studies in the behavioral sciences, the principle of minimal shared maternal effects, in light of the growing awareness that the maternal perinatal environment is a critical venue for the exercise of adaptive phenotypic plasticity. This consideration has important implications for both developmental and evolutionary biology. © 2012 Cambridge University Press.

Stimuli responsive (or "smart") polymer brushes represent a non-toxic approach for achieving release of biofouling layers. Thermo-responsive poly(N-isopropylacrylamide) (PNIPAAm) polymer brushes have been shown to modulate bacterial adhesion and release through transition between temperatures above and below the lower critical solution temperature (LCST ~32 °C) of PNIPAAm in water. In this article, we describe a convenient method to synthesize grafted PNIPAAm brushes over large areas for biological studies using a relatively simple and rapid method which allows atom transfer radical polymerization (ATRP) in presence of air using the activator regenerated electron transfer (ARGET) mechanism. PNIPAAm brushes were characterized using X-ray photoelectron spectroscopy, time-of-flight secondary ion mass spectroscopy, Fourier transform infrared spectroscopy, ellipsometry, and contact angle measurements. Our studies demonstrate that uniform, high purity PNIPAAm brushes with controlled and high molecular weight can be easily produced over large areas using ARGET-ATRP. We also report the use of a spinning disk apparatus to systematically and quantitatively study the detachment profiles of bacteria from PNIPAAm surfaces under a range (0-400 dyne/cm(2)) of shear stresses.

Chordoma is a rare bone cancer that is believed to originate from notochordal remnants. We previously identified germline T duplication as a major susceptibility mechanism in several chordoma families. Recently, a common genetic variant in T (rs2305089) was significantly associated with the risk of sporadic chordoma. We sequenced all T exons in 24 familial cases and 54 unaffected family members from eight chordoma families (three with T duplications), 103 sporadic cases, and 160 unrelated controls. We also measured T copy number variation in all sporadic cases. We confirmed the association between the previously reported variant rs2305089 and risk of familial [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 0.93, 7.25, P = 0.067] and sporadic chordoma (OR = 2.85, 95% CI = 1.89, 4.29, P < 0.0001). We also identified a second common variant, rs1056048, that was strongly associated with chordoma in families (OR = 4.14, 95% CI = 1.43, 11.92, P = 0.0086). Among sporadic cases, another common variant (rs3816300) was significantly associated with risk when jointly analyzed with rs2305089. The association with rs3816300 was significantly stronger in cases with early age onset. In addition, we identified three rare variants that were only observed among sporadic chordoma cases, all of which have potential functional relevance based on in silico predictions. Finally, we did not observe T duplication in any sporadic chordoma case. Our findings further highlight the importance of the T gene in the pathogenesis of both familial and sporadic chordoma and suggest a complex susceptibility related to T.

Gentile M.A.,Duke University
Respiratory Care | Year: 2011

The mixture of oxygen and nitrogen is usually sufficient to achieve the therapeutic objective of supporting adequate gas exchange. Pediatric and neonatal patients have an assortment of physiologic conditions that may require adjunctive inhaled gases to treat the wide variety of diseases seen in this heterogeneous population. Inhaled nitric oxide, helium oxygen mixtures, inhaled anesthetics, hypercarbic mixtures, hypoxic mixtures, inhaled carbon monoxide, and hydrogen sulfide have been used to alter physiology in an attempt to improve patient outcomes. Balancing the therapeutic potential, possible adverse effects, and the complexity of the technical aspects of gas delivery, it is essential that clinicians thoroughly understand the application of medical gas therapy beyond the traditional nitrogen/oxygen mixture. © 2011 Daedalus Enterprises.

Hong J.,Duke University | Luesch H.,University of Florida
Natural Product Reports | Year: 2012

Covering up to 2011 The cyclic depsipeptide largazole from a cyanobacterium of the genus Symploca is a marine natural product with a novel chemical scaffold and potently inhibits class I histone deacetylases (HDACs). Largazole possesses highly differential growth-inhibitory activity, preferentially targeting transformed over non-transformed cells. The intriguing structure and biological activity of largazole have attracted strong interest from the synthetic chemistry community to establish synthetic routes to largazole and to investigate its potential as a cancer therapeutic. This Highlight surveys recent advances in this area with a focus on the discovery, synthesis, target identification, structure-activity relationships, HDAC8-largazole thiol crystal structure, and biological studies, including in vivo anticancer and osteogenic activities. This journal is © The Royal Society of Chemistry 2012.

Jewell Z.,Duke University
Conservation Biology | Year: 2013

Monitoring free-ranging animals in their natural habitat is a keystone of ecosystem conservation and increasingly important in the context of current rates of loss of biological diversity. Data collected from individuals of endangered species inform conservation policies. Conservation professionals assume that these data are reliable-that the animals from whom data are collected are representative of the species in their physiology, ecology, and behavior and of the populations from which they are drawn. In the last few decades, there has been an enthusiastic adoption of invasive techniques for gathering ecological and conservation data. Although these can provide impressive quantities of data, and apparent insights into animal ranges and distributions, there is increasing evidence that these techniques can result in animal welfare problems, through the wide-ranging physiological effects of acute and chronic stress and through direct or indirect injuries or compromised movement. Much less commonly, however, do conservation scientists consider the issue of how these effects may alter the behavior of individuals to the extent that the data they collect could be unreliable. The emerging literature on the immediate and longer-term effects of capture and handling indicate it can no longer be assumed that a wild animal's survival of the process implies the safety of the procedure, that the procedure is ethical, or the scientific validity of the resulting data. I argue that conservation professionals should routinely assess study populations for negative effects of their monitoring techniques and adopt noninvasive approaches for best outcomes not only for the animals, but also for conservation science. © 2013 Society for Conservation Biology.

Chandrasekharan S.,Duke University | Li A.,University of Washington
Physical Review Letters | Year: 2012

The recently proposed fermion-bag approach is a powerful technique to solve some four-fermion lattice field theories. Because of the existence of a duality between strong and weak couplings, the approach leads to efficient Monte-Carlo algorithms in both these limits. The new method allows us for the first time to accurately compute quantities close to the quantum critical point in the three dimensional lattice Thirring model with massless fermions on large lattices. The critical exponents at the quantum critical point are found to be ν=0.85(1), η=0.65(1), and η ψ=0.37(1). © 2012 American Physical Society.

Van Dover C.L.,Duke University
Marine Environmental Research | Year: 2014

Deep-sea hydrothermal-vent ecosystems have stimulated decades of scientific research and hold promise of mineral and genetic resources that also serve societal needs. Some endemic taxa thrive only in vent environments, and vent-associated organisms are adapted to a variety of natural disturbances, from tidal variations to earthquakes and volcanic eruptions. In this paper, physicochemical and biological impacts of a range of human activities at vents are considered. Mining is currently the only anthropogenic activity projected to have a major impact on vent ecosystems, albeit at a local scale, based on our current understanding of ecological responses to disturbance. Natural recovery from a single mining event depends on immigration and larval recruitment and colonization; understanding processes and dynamics influencing life-history stages may be a key to effective minimization and mitigation of mining impacts. Cumulative impacts on benthic communities of several mining projects in a single region, without proper management, include possible species extinctions and shifts in community structure and function. © 2014 The Author.

Franz K.J.,Duke University
Current Opinion in Chemical Biology | Year: 2013

The traditional notion of chelation therapy is the administration of a chemical agent to remove metals from the body. But formation of a metal-chelate can have biological ramifications that are much broader than metal elimination. Exploring these other possibilities could lead to pharmacological interventions that alter the concentration, distribution, or reactivity of metals in targeted ways for therapeutic benefit. This review highlights recent examples that showcase four general strategies of using principles of metal chelation in medicinal contexts beyond the traditional notion of chelation therapy. These strategies include altering metal biodistribution, inhibiting specific metalloenzymes associated with disease, enhancing the reactivity of a metal complex to promote cytotoxicity, and conversely, passivating the reactivity of metals by site-activated chelation to prevent cytotoxicity. © 2013 Elsevier Ltd.

Riboh J.C.,Duke University
Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association | Year: 2014

PURPOSE: To provide a synthesis of the highest-quality literature available comparing early passive motion (EPM) with strict sling immobilization during the first 4 to 6 weeks after surgery.METHODS: The Medline, Cochrane, and Embase databases were searched for eligible studies. We reviewed 886 citations, and 5 randomized clinical trials (RCTs) (Level II) met the inclusion criteria for meta-analysis. Four RCTs contributed to the analysis of range of motion, and 5 contributed to the analysis of retear rates. A single Level IV study was available for qualitative review. Random-effects models were used for meta-analysis, computing mean differences for continuous variables and risk ratios for dichotomous variables.RESULTS: EPM resulted in improved shoulder forward flexion at 3 months (mean difference, 14.70°; 95% confidence interval [CI], 5.52° to 23.87°; P = .002), 6 months (mean difference, 4.31°; 95% CI, 0.17° to 8.45°; P = .04), and 12 months (mean difference, 4.18°; 95% CI, 0.36° to 8.00°; P = .03). External rotation at the side was only superior with EPM at 3 months (mean difference, 10.43°; 95% CI, 4.51° to 16.34°; P = .0006). Rotator cuff retear rates (16.3% for immobilization v 21.1% for EPM; risk ratio, 0.82; 95% CI, 0.57 to 1.20; P = .31) were not significantly different between EPM and immobilization at a minimum of 1 year of follow-up.CONCLUSIONS: A small number of RCTs with low to moderate risks of bias are currently available. Meta-analysis suggests that after primary arthroscopic rotator cuff repair of small to medium tears, EPM results in 15° of improved forward flexion at 3 months and approximately 5° at 6 and 12 months. External rotation is improved by 10° with EPM at 3 months only. The clinical importance of these differences has yet to be determined. Retear rates at a minimum of 1 year of follow-up are not clearly affected by type of rehabilitation.LEVEL OF EVIDENCE: Level II, meta-analysis of Level II studies and qualitative review of Level IV study. Copyright © 2014 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Cullen B.R.,Duke University | Cherry S.,University of Pennsylvania | Tenoever B.R.,Mount Sinai School of Medicine
Cell Host and Microbe | Year: 2013

While RNA interference (RNAi) functions as an antiviral response in plants, nematodes, and arthropods, a similar antiviral role in mammals has remained controversial. Three recent papers provide evidence that either favors or challenges this hypothesis. Here, we discuss these new findings in the context of previous research. © 2013 Elsevier Inc.

Ahearne J.F.,Duke University
Energy Economics | Year: 2011

Support for a growth in nuclear power has been seen in China and the United States. Obstacles to further growth include cost, concerns about links to proliferation of nuclear weapons, public attitudes, how to handle nuclear waste, and workforce shortages. More than 20 countries are considering building nuclear power plants. Among new designs being considered are pebble-bed reactors and small reactors. Continued growth will require addressing the obstacles and continued safe operation of plants worldwide. © 2010 Elsevier B.V.

Olsen E.A.,Duke University
Dermatologic Therapy | Year: 2011

The reported efficacy of various treatments for alopecia is difficult to compare based on a general lack of consideration in case reports/series and clinical trials of the spontaneous regrowth or baseline prognostic factors seen in alopecia areata and a general lack of quantification of hair growth. This report will give both the investigator and clinician guidelines for clinical trial design that will take into account variables known to effect efficacy results such as baseline severity, pattern, and duration of hair loss, age of the subject, and concomitant conditions that may impact on potential regrowth. Reliable methods of assessment of efficacy and response criteria that will enable direct comparison of results between agents will also be discussed. © 2011 Wiley Periodicals, Inc.

Macintyre N.R.,Duke University
Respiratory Care | Year: 2011

Assisted (interactive) breathing is generally preferred to controlled breaths in patients on mechanical ventilators. Assisted breaths allow the patient's respiratory muscles to be used, and ventilatory muscle atrophy can be prevented. Moreover, the respiratory drive of the patient does not have to be aggressively blunted. However, interactive breaths need to be synchronized with the patient's efforts during the trigger, the flow delivery, and the cycling phases. Asynchrony during any of these can put an intolerable load on the respiratory muscles, leading to fatigue and the need for a high level of sedation or even paralysis. Current ventilation modes have a number of features that can monitor and enhance synchrony, including adjustment of the trigger variable, the use of pressuretargeted versus fixed-flow-targeted breaths, and manipulations of the cycle variable. Clinicians need to know how to use these ventilation mode and monitor them properly, especially understanding the airway pressure and flow graphics. The clinical challenge is synchronizing ventilator gas delivery with patient effort. © 2011 Daedalus Enterprises.

Gentile M.A.,Duke University
Respiratory Care | Year: 2011

Patient-ventilator interaction is a key element in optimizing mechanical ventilation. The change from inspiration to expiration is a crucial point in the mechanically ventilated breath, and is termed "cycling." Patient-ventilator asynchrony may occur if the flow at which the ventilator cycles to exhalation does not coincide with the termination of neural inspiration. Ideally, the ventilator terminates inspiratory flow in synchrony with the patient's neural timing, but frequently the ventilator terminates inspiration either early or late. Most current mechanical ventilators include adjustable cycling features that, when used in conjunction with waveform graphics, can enhance patient-ventilator synchrony. © 2011 Daedalus Enterprises.

Ticknor J.L.,Duke University
Expert Systems with Applications | Year: 2013

In this paper a Bayesian regularized artificial neural network is proposed as a novel method to forecast financial market behavior. Daily market prices and financial technical indicators are utilized as inputs to predict the one day future closing price of individual stocks. The prediction of stock price movement is generally considered to be a challenging and important task for financial time series analysis. The accurate prediction of stock price movements could play an important role in helping investors improve stock returns. The complexity in predicting these trends lies in the inherent noise and volatility in daily stock price movement. The Bayesian regularized network assigns a probabilistic nature to the network weights, allowing the network to automatically and optimally penalize excessively complex models. The proposed technique reduces the potential for overfitting and overtraining, improving the prediction quality and generalization of the network. Experiments were performed with Microsoft Corp. and Goldman Sachs Group Inc. stock to determine the effectiveness of the model. The results indicate that the proposed model performs as well as the more advanced models without the need for preprocessing of data, seasonality testing, or cycle analysis. © 2013 Elsevier Ltd. All rights reserved.

Many neuropsychiatric disorders are associated with a strong dysregulation of the immune system, and several have a striking etiology in development as well. Our recent evidence using a rodent model of neonatal Escherichia coli infection has revealed novel insight into the mechanisms underlying cognitive deficits in adulthood, and suggests that the early-life immune history of an individual may be critical to understanding the relative risk of developing later-life mental health disorders in humans. A single neonatal infection programs the function of immune cells within the brain, called microglia, for the life of the rodent such that an adult immune challenge results in exaggerated cytokine production within the brain and associated cognitive deficits. I describe the important role of the immune system, notably microglia, during brain development, and discuss some of the many ways in which immune activation during early brain development can affect the later-life outcomes of neural function, immune function, and cognition. Microglia and many immune molecules are critical for normal brain development. Immune activation during brain development can impact behavior throughout life. The developmental immune history of an individual may predict risk of neuropsychiatric disorders. A model of neonatal infection may inform diverse environmental challenges which impact the developing immune system. © 2013 Elsevier Inc.

Muoio D.M.,Duke University
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2010

The term lipotoxicity elicits visions of steatotic liver, fat laden skeletal muscles and engorged lipid droplets that spawn a number of potentially harmful intermediates that can wreak havoc on signal transduction and organ function. Prominent among these so-called lipotoxic mediators are signaling molecules such as long chain acyl-CoAs, ceramides and diacyglycerols; each of which is thought to engage serine kinases that disrupt the insulin signaling cascade, thereby causing insulin resistance. Defects in skeletal muscle fat oxidation have been implicated as a driving factor contributing to systemic lipid imbalance, whereas exercise-induced enhancement of oxidative potential is considered protective. The past decade of diabetes research has focused heavily on the foregoing scenario, and indeed the model is grounded in strong experimental evidence, albeit largely correlative. This review centers on mechanisms that connect lipid surplus to insulin resistance in skeletal muscle, as well as those that underlie the antilipotoxic actions of exercise. Emphasis is placed on recent studies that challenge accepted paradigms. © 2009.

Yang Y.,Stanford University | Calakos N.,Duke University
Frontiers in Synaptic Neuroscience | Year: 2013

Long-term synaptic plasticity is a major cellular substrate for learning, memory, and behavioral adaptation. Although early examples of long-term synaptic plasticity described a mechanism by which postsynaptic signal transduction was potentiated, it is now apparent that there is a vast array of mechanisms for long-term synaptic plasticity that involve modifications to either or both the presynaptic terminal and postsynaptic site. In this article, we discuss current and evolving approaches to identify presynaptic mechanisms as well as discuss their limitations. We next provide examples of the diverse circuits in which presynaptic forms of long-term synaptic plasticity have been described and discuss the potential contribution this form of plasticity might add to circuit function. Finally, we examine the present evidence for the molecular pathways and cellular events underlying presynaptic long-term synaptic plasticity. © 2013 Yang and Calakos.

Ohler U.,Duke University | Wassarman D.A.,University of Wisconsin - Madison
Development | Year: 2010

Animal growth and development depend on the precise control of gene expression at the level of transcription. A central role in the regulation of developmental transcription is attributed to transcription factors that bind DNA enhancer elements, which are often located far from gene transcription start sites. Here, we review recent studies that have uncovered significant regulatory functions in developmental transcription for the TFIID basal transcription factors and for the DNA core promoter elements that are located close to transcription start sites.

Haynes B.F.,Duke University
Current Opinion in Immunology | Year: 2015

Development of a safe and effective vaccine for HIV is a major global priority. However, to date, efforts to design an HIV vaccine with methods used for development of other successful viral vaccines have not succeeded due to HIV diversity, HIV integration into the host genome, and ability of HIV to consistently evade anti-viral immune responses. Recent success in isolation of potent broadly neutralizing antibodies (bnAbs), in discovery of mechanisms of bnAb induction, and in discovery of atypical mechanisms of CD8T cell killing of HIV-infected cells, have opened new avenues for strategies for HIV vaccine design. © 2015 Elsevier Ltd.

Forrester M.T.,Harvard University | Foster M.W.,Duke University
Free Radical Biology and Medicine | Year: 2012

Nitric oxide (NO) is an inevitable product of life in an oxygen- and nitrogen-rich environment. This reactive diatomic molecule exhibits microbial cytotoxicity, in large part by facilitating nitrosative stress and inhibiting heme-containing proteins within the aerobic respiratory chain. Metabolism of NO is therefore essential for microbial life. In many bacteria, fungi, and protozoa, the evolutionarily ancient flavohemoglobin (flavoHb) converts NO and O 2 to inert nitrate (NO 3 -) and undergoes catalytic regeneration via flavin-dependent reduction. Since its identification, widespread efforts have characterized roles for flavoHb in microbial nitrosative stress protection. Subsequent genomic studies focused on flavoHb have elucidated the transcriptional machinery necessary for inducible NO protection, such as NsrR in Escherichia coli, as well as additional proteins that constitute a nitrosative stress protection program. As an alternative strategy, flavoHb has been heterologously employed in higher eukaryotic organisms such as plants and human tumors to probe the function(s) of endogenous NO signaling. Such an approach may also provide a therapeutic route to in vivo NO depletion. Here we focus on the molecular features of flavoHb, the hitherto characterized NO-sensitive transcriptional machinery responsible for its induction, the roles of flavoHb in resisting mammalian host defense systems, and heterologous applications of flavoHb in plant/mammalian systems (including human tumors), as well as unresolved questions surrounding this paradigmatic NO-consuming enzyme. © 2012 Elsevier Inc. All rights reserved.

Schumacher M.A.,Duke University
Current Opinion in Structural Biology | Year: 2012

The accurate segregation or partition of replicated DNA is essential for ensuring stable genome transmission. Partition of bacterial plasmids requires only three elements: a centromere-like DNA site and two proteins, a partition NTPase, and a centromere-binding protein (CBP). Because of this simplicity, partition systems have served as tractable model systems to study the fundamental molecular mechanisms required for DNA segregation at an atomic level. In the last few years, great progress has been made in this endeavor. Surprisingly, these studies have revealed that although the basic partition components are functionally conserved between three types of plasmid partition systems, these systems employ distinct mechanisms of DNA segregation. This review summarizes the molecular insights into plasmid segregation that have been achieved through these recent structural studies. © 2011 Elsevier Ltd.

Cullen B.R.,Duke University
Cell Host and Microbe | Year: 2013

In a recent issue of Cell, Gomez et al. (2013) describe a long intergenic noncoding RNA, called NeST, that regulates the ability of mice to respond to viral and bacterial infections. NeST recruits histone H3 lysine 4 methyltransferases to the IFN-γ gene locus, enhancing IFN-γ expression in key T cell subsets. © 2013 Elsevier Inc.

Guo X.,University of California at San Diego | Wang X.-F.,Duke University
Cell | Year: 2012

An unexpected role for a Mediator subunit, MED12, in resistance to multiple anticancer agents is revealed by Huang et al. Loss of MED12 confers drug resistance by activating transforming growth factor β (TGF-β) signaling. Inhibition of the TGF-β pathway resensitizes cells to therapeutic drugs, suggesting a new combinatorial cancer treatment. © 2012 Elsevier Inc.

Soft tissue sarcomas (STS) are a rare, heterogeneous group of solid tumors in need of improved therapeutic options. First-line chemotherapy is considered the current standard of care for patients with advanced, symptomatic STS, but the median survival is only 8 to 12 months. Efforts to increase response rates by using combination or dose-dense regimens have largely failed to improve patient outcomes. However, increasing evidence supports the use of specific treatments for certain histological subtypes of STS, and novel therapies, including tyrosine kinase and mammalian target of rapamycin inhibitors, are currently under active investigation. In addition, novel treatment approaches (such as maintenance therapy) designed to prolong the duration of response to chemotherapy and delay disease progression are being explored. This article provides an overview of current systemic therapies for patients with advanced STS and discusses ongoing efforts designed to improve patient outcomes through the use of novel therapeutic agents and treatment strategies. © 2011 American Cancer Society.

Lo H.W.,Duke University
Current cancer drug targets | Year: 2010

Malignant gliomas are the most common and the deadliest brain malignancies in adults. Despite the lack of a complete understanding of the biology of these tumors, significant advances have been made in the past decades. One of the key discoveries made in the area of malignant gliomas is that these tumors can be induced and maintained by aberrant signaling networks. In this context, the Ras pathway has been extensively exploited, from both basic and translational perspectives. Although somatic oncogenic mutations of Ras genes are frequent in several cancer types, early investigations on gliomas revealed disappointing facts that the Ras mutations are nearly absent in malignant gliomas and that the BRAF mutations are present in a very small percentage of gliomas. Therefore, the observed deregulation of the Ras-RAF-ERK signaling pathway in gliomas is attributed to its upstream positive regulators, including, EGFR and PDGFR known to be highly active in the majority of malignant gliomas. In contrast to the initial negative results on the somatic mutations of H-Ras, K-Ras and BRAF, recent breakthrough studies on pediatric low-grade astrocytomas uncovered genetic alterations of the BRAF gene involving copy number gains and rearrangements. The 7q34 rearrangements result in a novel in-frame KIAA1549:BRAF fusion gene that possesses constitutive BRAF kinase activity resembling oncogenic BRAF (V600E). In light of the earlier findings and recent breakthroughs, this review summarizes our current understanding of the Ras-RAF-ERK signaling pathway in gliomas and the outcome of preclinical and clinical studies that evaluated the efficacy of Ras-targeted therapy in malignant gliomas.

Objectives/Hypothesis: This study's objectives are to 1) to assess the prevalence of dysphonia in the primary care community, 2) evaluate the severity of dysphonia, 3) explore potential risk factors for dysphonia, 4) examine the treatment of dysphonic patients,and 5) assess treatment-related barriers. The hypotheses are that 1) dysphonia is common in the primary care community, 2) it adversely impacts patients' quality of life (QOL), and 3) patients are underevaluated and experience obstacles with respect to seeking treatment. Study Design: Cross-sectional, practice-based study in the primary care population. Methods: English-speaking patients 18 years of age and older were recruited from a primary care research network. Patients presenting to their primary care practices were given a packet of questionnaires to complete that documented demographic information, risk factors, presence of dysphonia, prior treatment, and reasons for not seeking treatment. The Voice-Related Quality of Life (VRQOL) and Center for Epidemiological Studies-Depression Scale (CES-D) served as quality-of-life outcome measures. A priori sample size calculations were performed indicating a sample size of 780. Univariate analyses, descriptive statistics, odds ratios and 95% confidence intervals, and multivariate analyses were performed. Results: A total of 789 patients with a mean age of 49.9 years and range of 18 to 94 years participated. Lifetime prevalence of dysphonia was 29.1%,point prevalence of dysphonia 7.5%, and 4.3% had had dysphonia for <4 weeks. Of those with current dysphonia, only 46% had not missed work. Of those with current dysphonia, 73.3% had had dysphonia more than once. Patients with dysphonia had lower VRQOL scores and higher CES-D scores (t test, P ≥.001). Risk factors for dysphonia and impaired VRQOL on multivariate analysis included neurologic disease, dry mouth, family history of dysphonia, college or postgraduate level education, allergies or sinus problems, neck pain, medication for depression/ anxiety, more than three upper respiratory infections per year, gastroesophageal reflux at least monthly, and asthma or lung disease. Of the patients who had ever had dysphonia, 22.1% received treatment. Common treatment modalities included antireflux treatment, antiallergy treatment, and antibiotics. Speech-language pathology evaluation was rare. Compared to those not interested in treatment, patients wanting treatment were more likely to have chronic dysphonia <4 weeks (30.6% vs. 8.1%; v2, P ≥.001), more likely to have dysphonia more than once (85.1% vs. 58.0%; v2, P ≥.001), and lower VRQOL scores (median 67.5 vs. 97.5; rank sum test, P >l.001). Reasons for not seeking treatment included thinking the dysphonia would go away, physicians did not ask about voice problems, and being unaware of treatment options. Conclusions: At the time one in 13 primary care patients had dysphonia resulting in significant functional impairment with reduced voice-specific QOL and greater depression scores. Risk factors for dysphonia and voice-specific QOL impairment were identified and might be useful for identifying patients at risk for dysphonia. Barriers exist that prevent dysphonic patients from receiving evaluation and treatment. Whether improved methods of dysphonia screening leads to better outcomes and reduced societal impact needs investigation. © 2010 The American Laryngological.

PURPOSE OF REVIEW: To summarize recent studies on combination regimens that employ a statin with added niacin, ezetimibe, and/or bile acid sequestrants, and to understand the implications of these studies for clinical practice. RECENT FINDINGS: Combinations of statin, niacin, and/or intestinally active LDL-lowering drug have demonstrated safety and favorable effects on plasma low and high-density lipoproteins. Niacin and bile acid sequestrants appear to exert beneficial effects on atherosclerotic lesions, whereas results with ezetimibe are uncertain. Moreover, the use of niacin and bile acid sequestrants is supported by clinical outcome results from large monotherapy trials and small combination therapy trials. Three large randomized trials currently are evaluating clinical outcomes with the addition of niacin or ezetimibe to statin treatment. SUMMARY: Until the results of ongoing trials are known, it is reasonable to favor the use of niacin and bile acid sequestrants in combination with statins, based on safety and efficacy with regard to effects on lipoproteins, atherosclerotic lesions, and, to a limited extent, clinical outcomes. The effect of ezetimibe on carotid atherosclerosis is indeterminate, but ezetimibe can be reasonably added to statin therapy as a secondary option for LDL-lowering. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

George L.K.,Duke University
The journals of gerontology. Series B, Psychological sciences and social sciences | Year: 2010

OBJECTIVES. Understanding the factors that promote quality of life in old age has been a staple of social gerontology since its inception and remains a significant theme in aging research. The purpose of this article was to review the state of the science with regard to subjective well-being (SWB) in later life and to identify promising directions for future research. METHODS: This article is based on a review of literature on SWB in aging, sociological, and psychological journals. Although the materials reviewed date back to the early 1960s, the emphasis is on publications in the past decade. RESULTS: Research to date paints an effective portrait of the epidemiology of SWB in late life and the factors associated with it. Although the research base is large, causal inferences about the determinants of SWB remain problematic. Two recent contributions to the research base are highlighted as emerging issues: studies of secular trends in SWB and cross-national studies. Discussion. The review ends with discussion of priority issues for future research.

Nightingale K.,Duke University
Current Medical Imaging Reviews | Year: 2011

Acoustic radiation force based elasticity imaging methods are under investigation by many groups. These methods differ from traditional ultrasonic elasticity imaging methods in that they do not require compression of the transducer, and are thus expected to be less operator dependent. Methods have been developed that utilize impulsive (i.e. < 1 ms), harmonic (pulsed), and steady state radiation force excitations. The work discussed in this paper utilizes impulsive methods, for which two imaging approaches have been pursued: 1) monitoring the tissue response within the radiation force region of excitation (ROE) and generating images of relative differences in tissue stiffness (Acoustic Radiation Force Impulse (ARFI) imaging); and 2) monitoring the speed of shear wave propagation away from the ROE to quantify tissue stiffness (Shear Wave Elasticity Imaging (SWEI)). For these methods, a single ultrasound transducer on a commercial ultrasound system can be used to both generate acoustic radiation force in tissue, and to monitor the tissue displacement response. The response of tissue to this transient excitation is complicated and depends upon tissue geometry, radiation force field geometry, and tissue mechanical and acoustic properties. Higher shear wave speeds and smaller displacements are associated with stiffer tissues, and slower shear wave speeds and larger displacements occur with more compliant tissues. ARFI images have spatial resolution comparable to that of B-mode, often with greater contrast, providing matched, adjunctive information. SWEI images provide quantitative information about the tissue stiffness, typically with lower spatial resolution. A review these methods and examples of clinical applications are presented herein. © 2011 Bentham Science Publishers.

Dexter K.G.,Duke University
Journal of Biogeography | Year: 2010

Aim- Dispersal is often assumed to be a major force in shaping macroecological patterns, but this is rarely tested Here I describe macroecological patterns for two groups of Lesser Antillean birds and then use population genetic data to assess if differences in dispersal ability could be responsible for the groups' contrasting patterns Importantly, the population genetic data are derived independently from any data used to generate the macroecological patterns.Location- The Lesser Antilles, Caribbean.Methods- I used data from the literature to construct species-area curves and evaluate the decline in species compositional similarity with geographic distance (hereafter distance-decay) for two sets of bird communities in the Lesser Antilles, those found in rain forest and those in dry forest I then used mitochondrial DNA sequences from island populations to assess the dispersal ability of rain forest and dry forest species.Results- Rain forest species show steeper species-area curves and greater distance-decay in community similarity than dry forest species, patterns that could be explained by rain forest species having more limited dispersal ability Both conventional analyses of M, the number of migrants per generation between populations, and alternative analyses of DA, the genetic distance between populations, suggest that rain forest species disperse between islands less frequently than dry forest species.Main conclusions- Differences in dispersal ability are a plausible explanation for the contrasting macroecological patterns of rain forest and dry forest species Additionally, historical factors, such as the taxon cycle and Pleistocene climate fluctuations, may have played a role in shaping the distribution patterns of Lesser Antillean birds. © 2010 Blackwell Publishing Ltd.

Szczech L.A.,Duke University
Kidney International | Year: 2012

The prevalence of atrial fibrillation is much greater among persons with end-stage renal disease (ESRD) than among the general population. While significant advances have been made recently in the treatment of atrial fibrillation in the general population, we know very little about the treatment of atrial fibrillation among those with ESRD. This Commentary explores gaps in our knowledge of how to treat this vulnerable and sick population. © 2012 International Society of Nephrology.

Zylinski S.,Duke University
Proceedings. Biological sciences / The Royal Society | Year: 2012

Cuttlefish rapidly change their appearance in order to camouflage on a given background in response to visual parameters, giving us access to their visual perception. Recently, it was shown that isolated edge information is sufficient to elicit a body pattern very similar to that used when a whole object is present. Here, we examined contour completion in cuttlefish by assaying body pattern responses to artificial backgrounds of 'objects' formed from fragmented circles, these same fragments rotated on their axis, and with the fragments scattered over the background, as well as positive (full circles) and negative (homogenous background) controls. The animals displayed similar responses to the full and fragmented circles, but used a different body pattern in response to the rotated and scattered fragments. This suggests that they completed the broken circles and recognized them as whole objects, whereas rotated and scattered fragments were instead interpreted as small, individual objects in their own right. We discuss our findings in the context of achieving accurate camouflage in the benthic shallow-water environment.

Long R.,Anhui University of Science and Technology | Zhou S.,Anhui University of Science and Technology | Wiley B.J.,Duke University | Xiong Y.,Anhui University of Science and Technology
Chemical Society Reviews | Year: 2014

Since the discovery of the role of oxidative etching in shape-controlled metal nanostructure synthesis in 2004, it has become a versatile tool to precisely manipulate the nucleation and growth of metal nanocrystals at the atomic level. Subsequent research has shown that oxidative etching can be used to reshape nanocrystals via atomic addition and subtraction. This research has attracted extensive attention from the community because of its promising practical applications and theoretical value, and as a result, tremendous efforts from numerous research groups have been made to expand and apply this method to their own research. In this review, we first outline the merits of oxidative etching for the controlled synthesis of metal nanocrystals. We then summarize recent progress in the use of oxidative etching to control the morphology of a nanostructure during and after its synthesis, and analyze its specific functions in controlling a variety of nanocrystal parameters. Applications enabled by oxidative etching are also briefly presented to show its practical impact. Finally, we discuss the challenges and opportunities for further development of oxidative etching in nanocrystals synthesis. © The Royal Society of Chemistry 2014.

Bryan A.R.,Duke University
Current allergy and asthma reports | Year: 2014

The complement system is a major, multifunctional part of innate immunity and serves as a bridge between the innate and adaptive immune systems. It consists of more than 30 distinct proteins that interact with one another in a specific sequence. There are three pathways of complement activation: the classical, the lectin, and the alternative pathways. The three pathways are initiated by distinct mechanisms, but they all generate the same core set of effector molecules. Inherited complete deficiencies in complement components are generally very rare and predispose to infections and autoimmune disease. One of the better described associations is between deficiencies in early classical pathway components and the development of systemic lupus erythematosus. The goal of this review will be to discuss the associations between and the causal mechanisms of complement deficiencies and systemic lupus erythematosus.

Female ring-tailed lemurs (Lemur catta) are Malagasy primates that are size monomorphic with males, socially dominate males, and exhibit a long, pendulous clitoris, channeled by the urethra. These masculine traits evoke certain attributes of female spotted hyenas (Crocuta crocuta) and draw attention to the potential role of androgens in lemur sexual differentiation. Here, hormonal correlates of prenatal development were assessed to explore the possibility that maternal androgens may shape the masculine morphological and behavioral features of developing female lemurs. Maternal serum 17α-hydroxyprogesterone, dehydroepiandrosterone sulphate (DHEA-S), Δ4 androstenedione (androst-4-ene-3,17,dione), testosterone, and 17β-estradiol were charted throughout the 19 pregnancies of 11 ring-tailed lemurs. As in spotted hyenas, lemur pregnancies were associated with an immediate increase in androgen concentrations (implicating early maternal derivation), followed by continued increases across stages of gestation. Pregnancies that produced singleton males, twin males, or mixed-sex twins were marked by greater androgen and estrogen concentrations than were pregnancies that produced singleton or twin females, especially in the third trimester, implicating the fetal testes in late-term steroid profiles. Concentrations of DHEA-S were mostly below detectable limits, suggesting a minor role for the adrenals in androgen biosynthesis. Androgen concentrations of pregnant lemurs bearing female fetuses, although less than those of pregnant hyenas, exceeded preconception and postpartum values and peaked in the third trimester. Although a maternal (and, on occasion, fraternal) source of androgen may exist for fetal lemurs, further research is required to confirm that these steroids would reach the developing female and contribute to her masculinization. © 2010 Elsevier Inc.

BACKGROUND AND PURPOSE-: Statewide assessments of stroke prevention and treatment services were performed in North Carolina in 1998 and 2003. The 2003 survey found certain technologies, but not stroke-related programs, were more widely available. The survey was repeated in 2008 to determine whether there was an interval change in accessibility. METHODS-: A 2-page questionnaire was sent to each North Carolina hospital. Results were compared with the 1998 and 2003 surveys. RESULTS-: Complete responses were obtained from each of the state's emergent stroke care hospitals. The proportions providing CT angiography and diffusion-weighted MRI increased between each period (each P<0.05); the use of care maps and intravenous tissue plasminogen activator protocols increased between 2003 and 2008 but not between 1998 and 2003. There were no changes in availability of MRI, MR angiography, catheter angiography, carotid ultrasound, transcranial Doppler, transthoracic echocardiography, or in the proportions of hospitals having a stroke unit, having a neurologist or neurointerventionalist readily available, or providing stroke-related public education (each P>0.05). The proportions of hospitals having a group of "basic" stroke capabilities did not change (18%, 21%, and 20%, respectively, P>0.05). In 2008, 41% of North Carolina's population resided in a county with at least 1 Primary Stroke Center and an additional 40% in a county using telemedicine or having a transfer plan for patients with acute stroke. CONCLUSIONS-: The availability of certain diagnostic tests, but not specialty staff or stroke units, increased in North Carolina hospitals between 1998 and 2008. Although there was no change in stroke-related hospital-based organizational features between 1998 and 2003, there were improvements between 2003 and 2008, possibly reflecting programs aimed at developing stroke care systems. © 2010 American Heart Association, Inc.

Identifying biological mechanisms through which the experience of adversity emerges as individual risk for mental illness is an important step toward developing strategies for personalized treatment and, ultimately, prevention. Preclinical studies have identified epigenetic modification of gene expression as one such mechanism. Recent clinical studies have suggested that epigenetic modification, particularly methylation of gene regulatory regions, also acts to shape human brain function associated with risk for mental illness. However, it is not yet clear whether differential gene methylation as a function of adversity contributes to the emergence of individual risk for mental illness. Using prospective longitudinal epigenetic, neuroimaging and behavioral data from 132 adolescents, we demonstrate that changes in gene methylation associated with lower socioeconomic status (SES) predict changes in risk-related brain function. Specifically, we find that lower SES during adolescence is associated with an increase in methylation of the proximal promoter of the serotonin transporter gene, which predicts greater increases in threat-related amygdala reactivity. We subsequently demonstrate that greater increases in amygdala reactivity moderate the association between a positive family history for depression and the later manifestation of depressive symptoms. These initial results suggest a specific biological mechanism through which adversity contributes to altered brain function, which in turn moderates the emergence of general liability as individual risk for mental illness. If replicated, this prospective pathway may represent a novel target biomarker for intervention and prevention among high-risk individuals.Molecular Psychiatry advance online publication, 24 May 2016; doi:10.1038/mp.2016.82. © 2016 Macmillan Publishers Limited

Croce J.C.,University Pierre and Marie Curie | McClay D.R.,Duke University
Development | Year: 2010

Endomesoderm is the common progenitor of endoderm and mesoderm early in the development of many animals. In the sea urchin embryo, the Delta/ Notch pathway is necessary for the diversification of this tissue, as are two early transcription factors, Gcm and FoxA, which are expressed in mesoderm and endoderm, respectively. Here, we provide a detailed lineage analysis of the cleavages leading to endomesoderm segregation, and examine the expression patterns and the regulatory relationships of three known regulators of this cell fate dichotomy in the context of the lineages. We observed that endomesoderm segregation first occurs at hatched blastula stage. Prior to this stage, Gcm and FoxA are co-expressed in the same cells, whereas at hatching these genes are detected in two distinct cell populations. Gcm remains expressed in the most vegetal endomesoderm descendant cells, while FoxA is downregulated in those cells and activated in the above neighboring cells. Initially, Delta is expressed exclusively in the micromeres, where it is necessary for the most vegetal endomesoderm cell descendants to express Gcm and become mesoderm. Our experiments show a requirement for a continuous Delta input for more than two cleavages (or about 2.5 hours) before Gcm expression continues in those cells independently of further Delta input. Thus, this study provides new insights into the timing mechanisms and the molecular dynamics of endomesoderm segregation during sea urchin embryogenesis and into the mode of action of the Delta/Notch pathway in mediating mesoderm fate.

Draelos Z.D.,Duke University
Clinics in Plastic Surgery | Year: 2011

The need for cosmeceutical research is ever present. This article has tried to highlight the chemistry of botanic extracts in the current marketplace and review the best research available. In some ways, more questions have been raised than answered; yet, ideas for intellectual discourse have been provided. Herein lies the physician cosmeceutical challenge. © 2011 Elsevier Inc.

Eugene Odum's 1969 paper, The Strategy of Ecosystem Development, marks a watershed moment in approaches to the study of succession, ecosystem change caused by discrete disturbances. He argued that succession is unique from other kinds of change with regard to mechanisms (modification of the physical environment by the community), trajectory (orderly, directional and predictable), and endpoint (a stable climax ecosystem in which "maximum biomass and symbiotic function between organisms are maintained per unit energy flow"). Odum also argued that understanding successional change was central to the management of a great variety of environmental challenges. Given the important role of disturbance in these ecosystems, this is particularly true for management aimed at restoration and conservation of forests. Although there was considerable debate among ecologists regarding successional mechanisms, trajectories and endpoints in the decades preceding his exegesis, the views outlined by Odum generally prevailed. These significantly influenced answers to three central restoration and conservation questions during that era. (1) What should we restore and conserve? Climax ecosystems. (2) How should boundaries be set for restoration and conservation areas? This was not an important matter. (3) How should restoration and conservation be accomplished? Because succession would inexorably lead to the ultimate climax goal, forest ecosystems should be protected from disturbance. Over the past five decades, virtually every aspect of succession theory as presented by Odum (1969) has come into question. We now understand that there is no single unique or unifying mechanism for successional change, that successional trajectories are highly varied and rarely deterministic, and that succession has no specific endpoint. Answers to the three restoration and conservation questions have changed accordingly. (1) Restoration and conservation goals should include the full range of variation in species diversity and composition associated with disturbance and the succession that proceeds from it. (2) Pattern, scale and context influence patterns of both disturbance and succession, and preserve design really does matter. (3) Restoration and conservation practice must be tailored to the unique mechanisms and post-disturbance ecological legacies that determine the trajectory and tempo of successional change in each particular ecosystem. The search for a grand unified theory of succession apart from other kinds of ecosystem change is futile. Nevertheless, the change caused by discrete disturbances remains an important matter for concern for restoration and conservation practitioners. © 2014 Elsevier B.V.

Wang H.,Duke University
Computational Statistics and Data Analysis | Year: 2010

A sparse seemingly unrelated regression (SSUR) model is proposed to generate substantively relevant structures in the high-dimensional distributions of seemingly unrelated regression (SUR) model parameters. The SSUR framework includes prior specifications, posterior computations using Markov chain Monte Carlo methods, evaluations of model uncertainty, and model structure searches. Extensions of the SSUR model to dynamic models embed general structure constraints and model uncertainty in dynamic models. The models represent specific varieties of models recently developed in the growing high-dimensional sparse modelling literature. Two simulated examples illustrate the model and highlight questions regarding model uncertainty, searching, and comparison. The model is then applied to two real-world examples in macroeconomics and finance, according to which its identified structures have practical significance. © 2010 Elsevier B.V. All rights reserved.

Rusche L.N.,Duke University | Rine J.,University of California at Berkeley
Genes and Development | Year: 2010

Programmed DNA rearrangements are critical for the development of many organisms and, intriguingly, can be catalyzed by domesticated mobile genetic elements. In this issue of Genes & Development, Barsoum and colleagues (pp. 33-44) demonstrate that, in the budding yeast Kluyveromyces lactis, a DNA rearrangement associated with mating type switching requires a domesticated transposase and occurs through a mechanism distinct from that in the related yeast, Saccharomyces cerevisiae. Thus, mechanisms for mating type switching have evolved multiple times, indicating the relative ease with which mobile genetic elements can be captured. © 2010 by Cold Spring Harbor Laboratory Press.

Wilcock D.M.,Duke University
CNS and Neurological Disorders - Drug Targets | Year: 2010

Alzheimer's disease is a progressive, neurodegenerative disorder characterized by a devastating cognitive decline. The disease is identified pathologically by amyloid plaques composed of aggregated amyloid- peptide, neurofibrillary tangles composed of aggregated, hyperphosphorylated tau protein and neuron loss. While the disease was first described in 1906, transgenic mouse models for the study of Alzheimer's disease pathologies have only been available to scientists for fifteen years. Despite the generation of many different mouse models that develop amyloid plaques or neurofibrillary tangles, it has only been in recent years that mouse models demonstrating the two pathologies together have been made. Also, neuron loss has been difficult to achieve in many models. Most recently, several transgenic mouse lines have been generated that do demonstrate all three pathological characteristics of Alzheimer's disease: amyloid plaques, neurofibrillary tangles and neuron loss. This review will focus on the advances made in our understanding of Alzheimer's disease pathology using the transgenic mouse models. It will also discuss the limitations associated with studying some of these mice and how transgenic mouse models have contributed to the development of therapeutics for the treatment of Alzheimer's disease. © 2010 Bentham Science Publishers.

Piacentino 3rd. V.,Duke University
The Journal of thoracic and cardiovascular surgery | Year: 2012

Patients referred for implantable continuous-flow left ventricular assist devices (cfLVAD) frequently have preoperative right heart failure and tricuspid regurgitation (TR). The objective of this report is to examine early clinical benefits of concomitant tricuspid surgery for these patients. Sixty-one of 200 consecutive cfLVAD patients at our institution displayed preimplant right heart dysfunction and significant TR. Thirty-three underwent cfLVAD plus a tricuspid valve procedure (TVP), and 28 had cfLVAD alone. Preimplant characteristics and clinical outcomes were retrospectively studied. As previously described, post-LVAD right ventricular failure was defined as need for right ventricular assist device (RVAD) support or greater than 14 days of intravenous inotropic support. Preimplant characteristics were similar between the 2 groups. Cardiopulmonary bypass time was increased for the group that received concomitant TVPs. The most common TVP consisted of an undersizing ring annuloplasty. The cfLVAD-alone group had greater TR after implant relative to the cfLVAD+TVP group. The cfLVAD-alone group experienced greater postprocedure right ventricular failure relative to cfLVAD+TVP (46.4% vs 18.2%; P < .05). Furthermore, prolonged hospitalization was increased for the cfLVAD-alone group versus the cfLVAD+TVP. Survival was similar between the 2 groups. Concomitant TVP appears to reduce postprocedure right ventricular failure for patients with significant TR undergoing cfLVAD implantation. Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Curtis L.H.,Duke University | Brown J.,Harvard University | Platt R.,Harvard University
Health Affairs | Year: 2014

Information in electronic health data that are drawn from large populations of patients is transforming health care, public health practice, and clinical research. This article describes our experience in developing data networks that repurpose electronic health records and administrative data. The four programs we feature are the Food and Drug Administration's Mini-Sentinel program (which focuses on medical product safety), the National Patient-Centered Clinical Research Network (PCORnet, comparative effectiveness research), the National Institutes of Health's Health Care Systems Research Collaboratory Distributed Research Network (biomedical research), and ESPnet (public health surveillance). Challenges to these uses of electronic health data include understanding the factors driving the collection, coding, and preservation of the data; the extensive customization of different systems that collect similar data; the fragmentation of the US health care delivery system and its records; and privacy and proprietary considerations. We view these four programs as examples of the first stage in the development of a shared national big-data resource that leverages the investments of many agencies and organizations for the benefit of multiple networks and users. © 2014 by Project HOPE - The People-to-People Health Foundation.

Yuan X.,Duke University
IEEE Antennas and Wireless Propagation Letters | Year: 2012

This letter shows the closed-form estimation formulas for direction finding and polarization estimation using a collocated quad of orthogonally oriented dipole(s) and loop(s). In total, there are 15 different compositions, and among them, 14 compositions can offer closed-form estimates for the azimuth-elevation direction of arrival and the polarization parameters. © 2011 IEEE.

Watters T.S.,Duke University
Journal of surgical orthopaedic advances | Year: 2011

Recently, patient-specific approaches to total knee arthroplasty (TKA) have been introduced that utilize preoperative magnetic resonance imaging data to manufacture custom cutting jigs specific to a patient's bony anatomy. These approaches intend to provide the benefits of accurate implant alignment while overcoming some of the proposed disadvantages of current computer navigation systems. In this study, a cost and benefit assessment of implementing the patient-specific approach compared to conventional and computer-navigated TKA was conducted at a large academic medical center. Fixed and time-dependent operating room (OR) costs were determined and compared, as well as the cost for processing operative equipment and additional procedure-related expenditures. Overall, patient-specific TKA was not cost saving in this model on a per-case basis compared to conventional methods, although it was less costly overall to the institution compared to implementing intraoperative navigation. However, the patient-specific approach provides the institution with an additional 28 minutes of available OR time per intervention based on reduction in preparation and operative times compared to conventional methods and an additional 67 minutes compared to computer navigation based on this model. This time savings is likely to provide a greater economic impact to the health care system than implant-related cost savings.

Cook-Deegan R.,Duke University
Science | Year: 2012

Will the Supreme Court rule that DNA sequences found in nature cannot be patented?

Kreuzer K.N.,Duke University
Cold Spring Harbor Perspectives in Biology | Year: 2013

Recent advances in the area of bacterial DNA damage responses are reviewed here. The SOS pathway is still the major paradigm of bacterial DNA damage response, and recent studies have clarified the mechanisms of SOS induction and key physiological roles of SOS including a very major role in genetic exchange and variation. When considering diverse bacteria, it is clear that SOS is not a uniform pathway with one purpose, but rather a platform that has evolved for differing functions in different bacteria. Relating in part to the SOS response, the field has uncovered multiple apparent cell-cycle checkpoints that assist cell survival after DNA damage and remarkable pathways that induce programmed cell death in bacteria. Bacterial DNA damage responses are also much broader than SOS, and several important examples of LexA-independent regulation will be reviewed. Finally, some recent advances that relate to the replication and repair of damaged DNAwill be summarized. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.

Gradison M.,Duke University
American Family Physician | Year: 2012

Pelvic inflammatory disease is a polymicrobial infection of the upper genital tract. It primarily affects young, sexually active women. The diagnosis is made clinically; no single test or study is sensitive or specific enough for a definitive diagnosis. Pelvic inflammatory disease should be suspected in at-risk patients who present with pelvic or lower abdominal pain with no identified etiology, and who have cervical motion, uterine, or adnexal tenderness. Chlamydia trachomatis and Neisseria gonorrhoeae are the most commonly implicated microorganisms; however, other microorganisms may be involved. The spectrum of disease ranges from asymptomatic to life-threatening tubo-ovarian abscess. Patients should be treated empirically, even if they present with few symptoms. Most women can be treated successfully as outpatients with a single dose of a parenteral cephalosporin plus oral doxycycline, with or without oral metronidazole. Delay in treatment may lead to major sequelae, including chronic pelvic pain, ectopic pregnancy, and infertility. Hospitalization and parenteral treatment are recommended if the patient is pregnant, has human immunodeficiency virus infection, does not respond to oral medication, or is severely ill. Strategies for preventing pelvic inflammatory disease include routine screening for chlamydia and patient education. © 2012 American Academy of Family Physicians.

Probability distributions of human displacements have been fit with exponentially truncated Lévy flights or fat tailed Pareto inverse power law probability distributions. Thus, people usually stay within a given location (for example, the city of residence), but with a non-vanishing frequency they visit nearby or far locations too. Herein, we show that an important empirical distribution of human displacements (range: from 1 to 1000 km) can be well fit by three consecutive Pareto distributions with simple integer exponents equal to 1, 2, and (>≈) 3. These three exponents correspond to three displacement range zones of about 1 km ≲δr ≲10 km, 10 km ≲δr ≲300 km, and 300 km ≲δr ≲1000 km, respectively. These three zones can be geographically and physically well determined as displacements within a city, visits to nearby cities that may occur within just one-day trips, and visit to far locations that may require multi-days trips. The incremental integer values of the three exponents can be easily explained with a three-scale mobility cost/benefit model for human displacements based on simple geometrical constrains. Essentially, people would divide the space into three major regions (close, medium, and far distances) and would assume that the travel benefits are randomly/uniformly distributed mostly only within specific urban-like areas. The three displacement distribution zones appear to be characterized by an integer (1, 2, or >≈ 3) inverse power exponent because of the specific number (1, 2, or >≈ 3) of cost mechanisms (each of which is proportional to the displacement length). The distributions in the first two zones would be associated to Pareto distributions with exponent β = 1 and β = 2 because of simple geometrical statistical considerations due to the a priori assumption that most benefits are searched in the urban area of the city of residence or in the urban area of specific nearby cities. We also show, by using independent records of human mobility, that the proposed model predicts the statistical properties of human mobility below 1 km ranges, where people just walk. In the latter case, the threshold between zone 1 and zone 2 may be around 100-200 m and, perhaps, may have been evolutionary determined by the natural human high resolution visual range, which characterizes an area of interest where the benefits are assumed to be randomly and uniformly distributed. This rich and suggestive interpretation of human mobility may characterize other complex random walk phenomena that may also be described by a N-piece fit Pareto distributions with increasing integer exponents. This study also suggests that distribution functions used to fit experimental probability distributions must be carefully chosen for not improperly obscuring the physics underlying a phenomenon. © 2011 American Institute of Physics.

Rivera M.P.,University of North Carolina at Chapel Hill | Mehta A.C.,Cleveland Clinic | Wahidi M.M.,Duke University
Chest | Year: 2013

Background: Lung cancer is usually suspected in individuals who have an abnormal chest radiograph or have symptoms caused by either local or systemic effects of the tumor. The method of diagnosis of lung cancer depends on the type of lung cancer (small cell lung cancer or non-small cell lung cancer [NSCLC]), the size and location of the primary tumor, the presence of metastasis, and the overall clinical status of the patient. The objective of this study was to determine the test performance characteristics of various modalities for the diagnosis of suspected lung cancer. Methods: To update previous recommendations on techniques available for the initial diagnosis of lung cancer, a systematic search of the MEDLINE, Healthstar, and Cochrane Library databases covering material to July 2011 and print bibliographies was performed to identify studies comparing the results of sputum cytology, conventional bronchoscopy, flexible bronchoscopy (FB), electromagnetic navigation (EMN) bronchoscopy, radial endobronchial ultrasound (R-EBUS)-guided lung biopsy, transthoracic needle aspiration (TTNA) or biopsy, pleural fluid cytology, and pleural biopsy with histologic reference standard diagnoses among at least 50 patients with suspected lung cancer. Recommendations were developed by the writing committee, graded by a standardized method (see the article "Methodology for Development of Guidelines for Lung Cancer" in this guideline), and reviewed by all members of the Lung Cancer Guideline Panel prior to approval by the Thoracic Oncology NetWork, the Guidelines Oversight Committee, and the Board of Regents of the American College of Chest Physicians. Results: Sputum cytology is an acceptable method of establishing the diagnosis of lung cancer, with a pooled sensitivity rate of 66% and a specificity rate of 99%. However, the sensitivity of sputum cytology varies according to the location of the lung cancer. For central, endobronchial lesions, the overall sensitivity of FB for diagnosing lung cancer is 88%. The diagnostic yield of bronchoscopy decreases for peripheral lesions. Peripheral lesions < 2 or > 2 cm in diameter showed a sensitivity of 34% and 63%, respectively. R-EBUS and EMN are emerging technologies for the diagnosis of peripheral lung cancer, with diagnostic yields of 73% and 71%, respectively. The pooled sensitivity of TTNA for the diagnosis of lung cancer was 90%. A trend toward lower sensitivity was noted for lesions < 2 cm in diameter. TTNA is associated with a higher rate of pneumothorax compared with bronchoscopic procedures. In a patient with a malignant pleural effusion, pleural fluid cytology is reported to have a mean sensitivity of about 72%. A definitive diagnosis of metastatic disease to the pleural space can be estalished with a pleural biopsy. The diagnostic yield for closed pleural biopsy ranges from 38% to 47% and from 75% to 88% for image-guided closed biopsy. Thoracoscopic biopsy of the pleura carries the highest diagnostic yield, 95% to 97%. The accuracy in differentiating between small cell and non-small cell cytology for the various diagnostic modalities was 98%, with individual studies ranging from 94% to 100%. The average false-positive and false-negative rates were 9% and 2%, respectively. Although the distinction between small cell and NSCLC by cytology appears to be accurate, NSCLCs are clinically, pathologically, and molecularly heterogeneous tumors. In the past decade, clinical trials have shown us that NSCLCs respond to different therapeutic agents based on histologic phenotypes and molecular characteristics. The physician performing diagnostic procedures on a patient suspected of having lung cancer must ensure that adequate tissue is acquired to perform accurate histologic and molecular characterization of NSCLCs. Conclusions: The sensitivity of bronchoscopy is high for endobronchial disease and poor for peripheral lesions < 2 cm in diameter. The sensitivity of TTNA is excellent for malignant disease, but TTNA has a higher rate of pneumothorax than do bronchoscopic modalities. R-EBUS and EMN bronchoscopy show potential for increasing the diagnostic yield of FB for peripheral lung cancers. Thoracoscopic biopsy of the pleura has the highest diagnostic yield for diagnosis of metastatic pleural effusion in a patient with lung cancer. Adequate tissue acquisition for histologic and molecular characterization of NSCLCs is paramount. Copyright © by the American College of Chest Physicians 2013.

Lowry D.B.,Duke University
Biology Letters | Year: 2010

Tremendous advances in genetic and genomic techniques have resulted in the capacity to identify genes involved in adaptive evolution across numerous biological systems. One of the next major steps in evolutionary biology will be to determine how landscape-level geographical and environmental features are involved in the distribution of this functional adaptive genetic variation. Here, I outline how an emerging synthesis of multiple disciplines has and will continue to facilitate a deeper understanding of the ways in which heterogeneity of the natural landscapes mould the genomes of organisms. © 2010 The Royal Society.

Goodenough U.,Washington University in St. Louis | Heitman J.,Duke University
Cold Spring Harbor Perspectives in Biology | Year: 2014

Sexual reproduction is a nearly universal feature of eukaryotic organisms. Given its ubiquity and shared core features, sex is thought to have arisen once in the last common ancestor to all eukaryotes. Using the perspectives of molecular genetics and cell biology, we consider documented and hypothetical scenarios for the instantiation and evolution of meiosis, fertilization, sex determination, uniparental inheritance of organelle genomes, and speciation. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

Hylander W.L.,Duke University
American Journal of Physical Anthropology | Year: 2013

This study tests the hypothesis that decreased canine crown height in catarrhines is linked to (and arguably caused by) decreased jaw gape. Associations are characterized within and between variables such as upper and lower canine height beyond the occlusal plane (canine overlap), maximum jaw gape, and jaw length for 27 adult catarrhine species, including 539 living subjects and 316 museum specimens. The data demonstrate that most adult male catarrhines have relatively larger canine overlap dimensions and gapes than do conspecific females. For example, whereas male baboons open their jaws maximally more than 110% of jaw length, females open about 90%. Humans and hylobatids are the exceptions in that canine overlap is nearly the same in both the sexes and so is relative gape (ca. 65% for humans and 110% for hylobatids). A correlation analysis demonstrates that a large portion of relative gape (maximum gape/projected jaw length) is predicted by relative canine overlap (canine overlap/jaw length). Relative gape is mainly a function of jaw muscle position and/or jaw muscle-fiber length. All things equal, more rostrally positioned jaw muscles and/or shorter muscle fibers decrease gape and increase bite force during the power stroke of mastication, and the net benefit is to increase the mechanical efficiency during chewing. Similarly, more caudally positioned muscles and/or longer muscle fibers increase the amount of gape and decrease bite force. Overall, the data support the hypothesis that canine reduction in early hominins is functionally linked to decreased gape and increased mechanical efficiency of the jaws. Copyright © 2012 Wiley Periodicals, Inc.

Keefe R.S.E.,Duke University | Harvey P.D.,University of Miami
Handbook of Experimental Pharmacology | Year: 2012

Cognitive functioning is moderately to severely impaired in patients with schizophrenia. This impairment is the prime driver of the significant disabilities in occupational, social, and economic functioning in patients with schizophrenia and an important treatment target. The profile of deficits in schizophrenia includes many of the most important aspects of human cognition: attention, memory, reasoning, and processing speed. While various efforts are under way to identify specific aspects of neurocognition that may lie closest to the neurobiological etiology and pathophysiology of the illness, and may provide relevant convergence with animal models of cognition, standard neuropsychological measures continue to demonstrate the greatest sensitivity to functionally relevant cognitive impairment. The effects of antipsychotic medications on cognition in schizophrenia and first-episode psychosis appear to be minimal. Important work on the effects of add-on pharmacologic treatments is ongoing. Very few of the studies completed to date have had sufficient statistical power to generate firm conclusions; recent studies examining novel add-on treatments have produced some encouraging findings. Cognitive remediation programs have generated considerable interest as these methods are far less costly than pharmacologic treatment and are likely to be safer. A growing consensus suggests that these interventions produce modest gains for patients with schizophrenia, but the efficacy of the various methods used has not been empirically investigated. © 2012 Springer-Verlag Berlin Heidelberg.

Hodgkinson C.P.,Duke University
Circulation Research | Year: 2014

RATIONALE:: Cardiac progenitor cells (CPCs) are believed to differentiate into the major cell types of the heart; cardiomyocytes, smooth muscle cells, and endothelial cells. We have recently identified Abi3bp as a protein important for mesenchymal stem cell (MSC) biology. Since CPCs share several characteristics with MSCs we hypothesized that Abi3bp would similarly affect CPC differentiation and proliferation.OBJECTIVE:: To determine whether Abi3bp regulates CPC proliferation and differentiation.METHODS AND RESULTS:: In vivo, genetic ablation of the Abi3bp gene inhibited CPC differentiation whereas CPC number and proliferative capacity was increased. This correlated with adverse recovery following myocardial infarction. In vitro, CPCs, either isolated from Abi3bp knockout mice or expressing an Abi3bp shRNA construct, displayed a higher proliferative capacity and, under differentiating conditions, reduced expression of both early and late cardiomyocyte markers. Abi3bp controlled CPC differentiation via integrin-β1, PKCζ, and Akt.CONCLUSIONS:: We have identified Abi3bp as a protein important for CPC differentiation and proliferation. © 2014 American Heart Association, Inc.

Babbitt C.C.,Duke University
Proceedings. Biological sciences / The Royal Society | Year: 2011

There are numerous anthropological analyses concerning the importance of diet during human evolution. Diet is thought to have had a profound influence on the human phenotype, and dietary differences have been hypothesized to contribute to the dramatic morphological changes seen in modern humans as compared with non-human primates. Here, we attempt to integrate the results of new genomic studies within this well-developed anthropological context. We then review the current evidence for adaptation related to diet, both at the level of sequence changes and gene expression. Finally, we propose some ways in which new technologies can help identify specific genomic adaptations that have resulted in metabolic and morphological differences between humans and non-human primates.

Schrode N.,Sloan Kettering Cancer Center | Saiz N.,Sloan Kettering Cancer Center | Di Talia S.,Duke University | Hadjantonakis A.-K.,Sloan Kettering Cancer Center
Developmental Cell | Year: 2014

Cells of the inner cell mass (ICM) of the mouse blastocyst differentiate into the pluripotent epiblast or the primitive endoderm (PrE), marked by the transcription factors NANOG and GATA6, respectively. To investigate the mechanistic regulation of this process, we applied an unbiased, quantitative, single-cell-resolution image analysis pipeline to analyze embryos lacking or exhibiting reduced levels of GATA6. We find that Gata6 mutants exhibit a complete absence of PrE and demonstrate that GATA6 levels regulate the timing and speed of lineage commitment within the ICM. Furthermore, we show that GATA6 is necessary for PrE specification by FGF signaling and propose a model where interactions between NANOG, GATA6, and the FGF/ERK pathway determine ICM cell fate. This study provides a framework for quantitative analyses of mammalian embryos and establishes GATA6 as a nodal point in the gene regulatory network driving ICM lineage specification. © 2014 Elsevier Inc.

Caspi A.,Duke University
American Journal of Psychiatry | Year: 2010

Objective: Premorbid cognitive deficits in schizophrenia are well documented and have been interpreted as supporting a neurodevelopmental etiological model. The authors investigated the following three unresolved questions about premorbid cognitive deficits: What is their developmental course? Do all premorbid cognitive deficits follow the same course? Are premorbid cognitive deficits specific to schizophrenia or shared by other psychiatric disorders? Methods: Participants were members of a representative cohort of 1,037 males and females born between 1972 and 1973 in Dunedin, New Zealand. Cohort members underwent follow-up evaluations at specific intervals from age 3 to 32 years, with a 96% retention rate. Cognitive development was analyzed and compared in children who later developed schizophrenia or recurrent depression as well as in healthy comparison subjects. Results: Children who developed adult schizophrenia exhibited developmental deficits (i.e., static cognitive impairments that emerge early and remain stable) on tests indexing verbal and visual knowledge acquisition, reasoning, and conceptualization. In addition, these children exhibited developmental lags (i.e., growth that is slower relative to healthy comparison subjects) on tests indexing processing speed, attention, visual-spatial problem solving ability, and working memory. These two premorbid cognitive patterns were not observed in children who later developed recurrent depression. Conclusions: These findings suggest that the origins of schizophrenia include two interrelated developmental processes evident from childhood to early adolescence (ages 7-13 years). Children who will grow up to develop adult schizophrenia enter primary school struggling with verbal reasoning and lag further behind their peers in working memory, attention, and processing speed as they get older.

Bartnikas T.B.,Childrens Hospital | Andrews N.C.,Duke University | Fleming M.D.,Childrens Hospital
Blood | Year: 2011

As a central regulator of iron metabolism, hepcidin inhibits dietary iron absorption and macrophage iron recycling. Its expression is regulated by multiple factors including iron availability and erythropoietic activity. To investigate the role of transferrin (Tf) in the regulation of hepcidin expression by these factors in vivo, we employed the hypotransferrinemic (hpx) mouse. These Tf-deficient mice have severe microcytic anemia, tissue iron overload, and hepcidin deficiency. To determine the relationship of Tf levels and erythropoiesis to hepcidin expression, we subjected hpx mutant and control mice to a number of experimental manipulations. Treatment of hpx mice with Tf injections corrected their anemia and restored hepcidin expression. To investigate the effect of erythropoiesis on hepcidin expression, we suppressed erythropoiesis with blood transfusions or myeloablation with chemotherapeutic drugs. Transfusion of hpx animals with wild-type red blood cells led to increased hepcidin expression, while hepcidin expression in myeloablated hpx mice increased only if Tf was administered postablation. These results suggest that hepcidin expression in hpx mice is regulated both by Tf-restricted erythropoiesis and by Tf through a mechanism independent of its role in erythropoiesis. © 2011 by The American Society of Hematology.

Gersbach C.A.,Duke University
Nature Methods | Year: 2014

A decade of advances in genome engineering technologies has enabled the editing of genome sequences much like one edits computer code; many more applications for precisely manipulating genome structure and function are on the horizon.

Deyle T.,Duke University
IEEE Robotics and Automation Magazine | Year: 2012

The Defense Advanced Research Projects Agency (DARPA), for its part, has multiple programs that involve manipulation and bionic devices. Europe's Framework Program is funding the development of cognitive systems and robots that can assist people in everyday tasks. In Asia, the decade-long funding of health-care robots for older adults has intensified. Typically, robots fall somewhere on a spectrum between direct tele-operation and full autonomy. Unfortunately, tele-operation can be cumbersome and full autonomy is often illusive. Somewhere in the middle lies a compelling tradeoff, where humans and co-robots can collaborate to perform practical tasks. According to the NRI, co-robots must be safe, relatively cheap, easy to use, available everywhere, and able to interact with humans to leverage their relative strengths in the planning and performance of a task.

Frank M.M.,Duke University
Allergy and Asthma Proceedings | Year: 2011

The prophylaxis of patients with hereditary angioedema to prevent attacks has gone through major revision as new agents for prophylaxis have come on the market. Earlier treatments, developed empirically, included the fibinolysis inhibitors epsilon aminocaproic acid and tranexamic acid and attenuated androgens such as danazol. With the development of these agents, many patients had relief of severe symptoms, and drugs in these classes have been the only treatments available in America. Their major disadvantage has been their side effects, which range from minor to severe. In Europe various products containing C1 inhibitor, the serum protein deficient in this disease, were prepared from pooled donor plasma. They were reported to be effective in ending attacks and in prophylaxis, but these products in general were not used in prophylaxis, in part because of the short half life of the plasma protein. One such product, C1 esterase inhibitor, has now been shown in a rigorous double-blind study to be effective in prevention of hereditary angioedema attacks and has been approved by the US Federal Drug Administration for prophylaxis of the disease. Its use has been attended by few side-effects, reflecting the fact that it is the purified naturally circulating product. Copyright © 2011, OceanSide Publications, Inc.

Richesson R.L.,Duke University
Journal of Biomedical Informatics | Year: 2014

Medication exposure is an important variable in virtually all clinical research, yet there is great variation in how the data are collected, coded, and analyzed. Coding and classification systems for medication data are heterogeneous in structure, and there is little guidance for implementing them, especially in large research networks and multi-site trials. Current practices for handling medication data in clinical trials have emerged from the requirements and limitations of paper-based data collection, but there are now many electronic tools to enable the collection and analysis of medication data. This paper reviews approaches to coding medication data in multi-site research contexts, and proposes a framework for the classification, reporting, and analysis of medication data. The framework can be used to develop tools for classifying medications in coded data sets to support context appropriate, explicit, and reproducible data analyses by researchers and secondary users in virtually all clinical research domains. © 2014 Elsevier Inc.

Ortel T.L.,Duke University
Critical Care Medicine | Year: 2010

Acquired thrombotic risk factors include a variety of noninherited clinical conditions that can predispose an individual to an increased risk for venous thromboembolism. For patients in a critical care setting, certain acquired risk factors represent chronic conditions that the patients may have had before the current acute illness (e.g., malignancy, various cardiovascular risk factors, certain medications), whereas others may be directly related to the reason the patient is in an intensive care unit or the patient's management there (e.g., postoperative state, trauma, indwelling vascular access, certain medications). Optimal thromboprophylactic strategies depend on individual patient risk profiles including an assessment of the specific clinical setting. Treatment for patients with acquired thrombotic risk factors includes anticoagulant therapy and, if possible, resolution of the acquired risk factor(s). Heparin-induced thrombocytopenia represents a unique clinical situation in which all sources of heparin must be discontinued and the patient started on an alternative anticoagulant (e.g., a direct thrombin inhibitor) in the acute setting. The duration of anticoagulant therapy would vary depending on the specific clinical setting. Copyright © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

James A.H.,Duke University
Critical Care Medicine | Year: 2010

Pregnancy increases the risk of thrombosis three-fold to four-fold. The main reason for the increased risk is hypercoagulability, which has likely evolved to protect women against the bleeding challenges associated with miscarriage and childbirth. The hypercoagulability of pregnancy is present as early as the first trimester and so is the increased risk of thrombosis. Factors that further increase the risk of thromboembolism in pregnancy include a history of thrombosis, inherited and acquired thrombophilia, certain medical conditions, and complications of pregnancy and childbirth. Candidates for anticoagulation are women with a current thrombosis, a history of thrombosis, thrombophilia, and a history of poor pregnancy outcome, or risk factors for postpartum thrombosis. For fetal reasons, the preferred agents for anticoagulation in pregnancy are heparins. There are no large trials of anticoagulation in pregnancy and recommendations are based on case series and the opinion of experts. Nonetheless, anticoagulation is believed to improve the outcome of pregnancy for women at risk. Copyright © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

Jennings R.B.,Duke University
Circulation Research | Year: 2013

A selective history of the pathophysiological, structural, and metabolic changes found during an episode of severe myocardial ischemia in the canine heart is presented. The changes that cause ischemic injury to become irreversible are discussed in detail because these changes are the target of any successful therapy designed to prevent ischemic cell death. Of these, the disruption of the sarcolemma, an injury the development of which is accelerated in vivo by the contraction of viable tissue elsewhere in the heart traumatizing the ischemic area, plus the changes in high-energy phosphate and the total adenine nucleotide pool are considered to be the critical events leading to the development of irreversibility. The discovery of preconditioning with ischemia is discussed, together with a brief description of postconditioning. Finally, reperfusion injury is discussed in a summary fashion. The evidence for the fact that myocytes are salvaged by reperfusion is presented, as is the evidence that myocytes become unsalvageable by reperfusion as the duration of ischemia increases. The concept that some of the myocytes that die after successful reperfusion with arterial blood actually are killed by changes initiated by reperfusion, so-called lethal reperfusion injury, is attractive in that prevention of this change would lead to greater salvage; however, the prevalence of this phenomenon in clinical practice remains to be determined. © 2013 American Heart Association, Inc.

Burns D.K.,Duke University
Clinical Pharmacology and Therapeutics | Year: 2010

Genetics as a discipline is fundamental for the pharmaceutical industry; it contributes to all therapeutic areas and has an impact throughout the research and development continuum, right up to and including clinical practice. Pharmacogenetics is seen as a significant contributor to increasing the efficiency and effectiveness of pharmaceutical R&D, and it enhances the growing interest in personalized medicine. This article discusses some contemporary issues that influence drug development and examines the potential of pharmacogenetics to reduce the risk and uncertainty that are inherent in the drug development process. © 2010 American Society for clinical Pharmacology and Therapeutics.

James A.H.,Duke University
Haemophilia | Year: 2010

While women are rarely affected by haemophilia, they are equally as likely as men to have other bleeding disorders. Menorrhagia, or heavy menstrual bleeding, is the most common symptom that they experience. Not only is menorrhagia more prevalent among women with bleeding disorders, but bleeding disorders are more prevalent among women with menorrhagia. Although menorrhagia is the most common reproductive tract manifestation of a bleeding disorder, it is not the only manifestation. Women with bleeding disorders appear to be at an increased risk of developing haemorrhagic ovarian cysts and possibly endometriosis. Women suspected of having a bleeding disorder or being a carrier of haemophilia should be offered diagnostic testing before getting pregnant to allow for appropriate preconception counselling and pregnancy management. During pregnancy, women with bleeding disorders may be at an increased risk of bleeding complications. At the time of childbirth, women with bleeding disorders appear to be more likely to experience postpartum haemorrhage, particularly delayed or secondary postpartum haemorrhage. As women with bleeding disorders grow older, they may be more likely to manifest gynaecological conditions which present with bleeding. Women with bleeding disorders are more likely to undergo a hysterectomy and are more likely to have the operation at a younger age. While women with bleeding disorders are at risk for the same obstetrical and gynaecological problems that affect all women, women with bleeding disorders are disproportionately affected by conditions that manifest with bleeding. Optimal management involves the combined expertise of haemostasis experts and obstetrician-gynaecologists. © 2010 The Authors. Journal compilation © 2010 Blackwell Publishing Ltd.

Huang Y.-C.T.,Duke University
Journal of Toxicology and Environmental Health - Part B: Critical Reviews | Year: 2013

Exposure to particulate matter (PM) is consistently associated with increased morbidity and mortality rate. The mechanisms for these adverse health effects have been vigorously investigated for many years, but remain uncertain, in part due to the complex interactions between host and exposure. Over the past decade, the use of global gene expression profiling has increased to investigate molecular changes in an attempt to gain more insight into the complex mechanisms that underlie the adverse health effects induced by PM. These experiments have been performed mostly in cell cultures, in part due to the easy availability and maneuverability of different cell types. Whether or not the results obtained from these in vitro experiments are relevant to human exposure is unclear. In this study, cell culture studies were reviewed that used microarray technology to measure global gene expression in response to PM and the findings discussed in the context of global gene expression results obtained from animal and human exposure studies. Ten in vitro studies were identified from PubMed that reported global gene expression results in response to PM exposure. Despite difference in cell types, microarray platforms, incubation time, and PM sources and doses, these experiments showed commonality in the expression of genes and pathways, especially xenobiotic metabolism, oxidative stress, and inflammation. These gene expression profiles were consistent with results from animal and human controlled exposure experiments. The in vitro experiments also uncovered novel biological mechanisms that may be important in PM-induced health effects reported in epidemiological studies. Data indicate that in vitro microarray experiments complement animal and human exposure studies and allow the PM-associated health research to focus on the "toxic" components in PM and novel mechanisms, and may enhance risk assessment beyond the current mass-based standards. © 2013 Copyright Taylor and Francis Group, LLC.

Nadler J.V.,Duke University
Neurochemical Research | Year: 2011

The Ca2+-dependent release of aspartate from hippocampal preparations was first reported 35 years ago, but the functional significance of this process remains uncertain. Aspartate satisfies all the criteria normally required for identification of a CNS transmitter. It is synthesized in nerve terminals, is accumulated and stored in synaptic vesicles, is released by exocytosis upon nerve terminal depolarization, and activates postsynaptic NMDA receptors. Aspartate may be employed as a neuropeptide-like co-transmitter by pathways that release either glutamate or GABA as their principal transmitter. Aspartate mechanisms include vesicular transport by sialin, vesicular content sensitive to glucose concentration, release mainly outside the presynaptic active zones, and selective activation of extrasynaptic NR1-NR2B NMDA receptors. Possible neurobiological functions of aspartate in immature neurons include activation of cAMP-dependent gene transcription and in mature neurons inhibition of CREB function, reduced BDNF expression, and induction of excitotoxic neuronal death. Recent findings suggest new experimental approaches toward resolving the functional significance of aspartate release. © 2010 Springer Science+Business Media, LLC.

Cassidy F.,Duke University
Suicide and Life-Threatening Behavior | Year: 2011

Suicide rates of bipolar patients are among the highest of any psychiatric disorder, and improved identification of risk factors for attempted and completed suicide translates into improved clinical outcome. Factors that may be predictive of suicidality in an exclusively bipolar population are examined. White race, family suicide history, and history of cocaine abuse were predictive of suicidal histories. Gender, nicotine use, medical comorbidity, and history of alcohol and other drug abuse were not, although a trend was noted for a history of benzodiazepine abuse. Attempts, although less common among African Americans, were equally as violent. Likewise, attempts were as violent among females as males, in distinction to general population studies. © 2011 The American Association of Suicidology.

Buckley R.H.,Duke University
Journal of Allergy and Clinical Immunology | Year: 2012

Early recognition of severe combined immunodeficiency (SCID) is a pediatric emergency because a diagnosis before live vaccines or nonirradiated blood products are given and before development of infections permits lifesaving unfractionated HLA-identical or T cell-depleted haploidentical hematopoietic stem cell transplantation, enzyme replacement therapy, or gene therapy. The need for newborn screening for this condition has been recognized for the past 15 years. However, implementation of screening required development of an assay for T-cell lymphopenia that could be performed on dried bloodspots routinely collected from newborn infants for the past 48 years. This was accomplished 6 years ago, and there have already been 7 successful pilot studies. A recommendation to add SCID to the routine newborn-screening panel was approved by the Secretary's Advisory Committee on Heritable Disorders of Newborns and Children in 2010 and was soon after approved by the Secretary of Health and Human Services. It is important for allergists, immunologists, and other health care providers to take an active role in promoting newborn screening for SCID and other T-lymphocyte abnormalities in their states. Even more important will be their roles in establishing accurate diagnoses for infants with positive screen results and in ensuring that they are given the best possible treatment. © 2011 American Academy of Allergy, Asthma & Immunology.

Hastings M.B.,Duke University | Hastings M.B.,University of California at Santa Barbara
Physical Review Letters | Year: 2011

We propose a definition for topological order at nonzero temperature in analogy to the usual zero temperature definition that a state is topologically ordered, or "nontrivial", if it cannot be transformed into a product state (or a state close to a product state) using a local (or approximately local) quantum circuit. We prove that any two-dimensional Hamiltonian which is a sum of commuting local terms is not topologically ordered at T>0. We show that such trivial states cannot be used to store quantum information using certain stringlike operators. This definition is not too restrictive, however, as the four dimensional toric code does have a nontrivial phase at nonzero temperature. © 2011 American Physical Society.

Ciantia M.O.,Polytechnic of Milan | Hueckel T.,Duke University
Geotechnique | Year: 2013

Long portions of the Apulian coast are steep cliffs in carbonate soft rocks. These, especially the calcarenite, are affected by weathering processes that markedly alter their mechanical properties with time, potentially leading to instability of coastal geomorphological structures. Such alterations are mainly due to chemical reactions between the solid and fluid phases, and are driven by chemical variables, which are internal variables and hence uncontrollable. In a search for the variables that drive the process of rock weakening, recourse is made to the micro scale, at which most of the chemical processes are observed and quantified. Observations using scanning electron microsope, thin sections and X-ray computed tomography analyses appear to be crucial for the understanding, interpretation and definition of the degradation mechanisms of the material. A chemo-mechanical coupled model at the meso scale of the chemically reactive stressed porous system is presented and framed in the context of a multi-scale scenario of an array of coupled phenomena. An analogous model at the macro scale is developed in parallel together with upscaling and identification procedures for meso-scale and macro-scale material constants. The main outcome of the study is a tool for predicting the progress of time-dependent weathering phenomena, potentially allowing the stability of geological structures to be assessed as it evolves with a progressing chemical degradation in a specific configuration and under a specific set of loads.

Bellet J.S.,Duke University
Seminars in Perinatology | Year: 2013

This paper focuses on the diagnosis and management of developmental anomalies of the skin that may be seen early in life. Common locations include the head, nose, preauricular area of the face, neck, and spine. Those that occur in or near the midline can be more serious because of possible intracranial connections. Radiologic imaging of the areas of involvement is often important; computed tomography (CT) scans can delineate bony defects; whereas, magnetic resonance imaging (MRI) more clearly defines intracranial connections. Occult spinal dysraphism can be suspected when certain cutaneous signs are present. © 2013 Elsevier Inc.

Riedel R.F.,Duke University
Seminars in Oncology | Year: 2011

A wide variety of cytogenetic abnormalities and molecular pathways have been implicated in the pathogenesis of sarcoma, and significant progress has been made in the past decade toward identifying potential therapeutic targets. However, apart from gastrointestinal stromal tumors (GISTs) and dermatofibrosarcoma protuberans (DFSP), little progress has been made toward translating that knowledge into effective therapeutic strategies. The identification of activating KIT mutations in the majority of GISTs was a defining moment that led to the first effective targeted therapy for sarcoma, and the subsequent use of imatinib mesylate has revolutionized the treatment of GISTs. Beyond imatinib, the most promising agents to dateand the agents most extensively studiedare the multitargeted tyrosine kinase inhibitors. Several other classes of agents have also shown some activity in soft tissue sarcomas, including mammalian target of rapamycin inhibitors, inhibitors of growth factor receptors, histone deacetylase inhibitors, agents that modulate the p53 pathway, inhibitors of molecular chaperone proteins (eg, heat shock protein 90 [Hsp90]), and other signal transduction inhibitors. Despite a large number of completed and ongoing phase II studies, few agents have moved to phase III testing, and much work remains to be done to fully validate the identified targets and determine the optimal treatment strategy. Ongoing studies are exploring a wide range of combination strategies. This review will highlight some of the emerging targeted therapies that appear to hold promise and may eventually contribute to improved systemic therapy for sarcoma. © 2011 Elsevier Inc.

Wernegreen J.J.,Duke University
Current Biology | Year: 2012

The phenomenon of endosymbiosis, or one organism living within another, has deeply impacted the evolution of life and continues to shape the ecology of countless species. Traditionally, biologists have viewed evolution as a largely bifurcating pattern, reflecting mutations and other changes in existing genetic information and the occasional speciation and divergence of lineages. While lineage bifurcation has clearly been important in evolution, the merging of two lineages through endosymbiosis has also made profound contributions to evolutionary novelty. Mitochondria and chloroplasts are relicts of ancient bacterial endosymbionts that ultimately extended the range of acceptable habitats for life by allowing hosts to thrive in the presence of oxygen and to convert light into energy. Today, the sheer abundance of endosymbiotic relationships across diverse host lineages and habitats testifies to their continued significance. © 2012 Elsevier Ltd.

Taylor S.M.,University of North Carolina at Chapel Hill | Taylor S.M.,Duke University | Parobek C.M.,University of North Carolina at Chapel Hill | Fairhurst R.M.,National Institute of Allergy and Infectious Diseases
The Lancet Infectious Diseases | Year: 2012

Background: Haemoglobinopathies can reduce the risk of malaria syndromes. We aimed to quantify the relation between different haemoglobin mutations and malaria protection to strengthen the foundation for translational studies of malaria pathogenesis and immunity. Methods: We systematically searched the Medline and Embase databases for studies that estimated the risk of malaria in patients with and without haemoglobinopathies up to Sept 9, 2011, and identified additional studies from reference lists. We included studies that enrolled mainly children or pregnant women and had the following outcomes: Plasmodium falciparum severe malaria, uncomplicated malaria, asymptomatic parasitaemia, or pregnancy-associated malaria, and Plasmodium vivax malaria. Two reviewers identified studies independently, assessed quality of the studies, and extracted data. We produced odds ratios (ORs; 95% CIs) for case-control studies and incidence rate ratios (IRRs; 95% CIs) for prospective studies. We did the meta-analysis with a random-effects model when equivalent outcomes were reported in more than one study. Findings: Of 62 identified studies, 44 reported data for haemoglobin AS, 19 for haemoglobin AC and CC, and 18 for α-thalassaemia. Meta-analysis of case-control studies showed a decreased risk of severe P falciparum malaria in individuals with haemoglobin AS (OR 0·09, 95% CI 0·06-0·12), haemoglobin CC (0·27, 0·11-0·63), haemoglobin AC (0·83, 0·67-0·96), homozygous α-thalassaemia (0·63, 0·48-0·83), and heterozygous α-thalassaemia (0·83, 0·74-0·92). In meta-analysis of prospective trials only haemoglobin AS was consistently associated with protection from uncomplicated malaria (IRR 0·69, 95% CI 0·61-0·79); no haemoglobinopathies led to consistent protection from asymptomatic parasitaemia. Few clinical studies have investigated β-thalassaemia, haemoglobin E, P vivax malaria, or pregnancy-associated malaria. Interpretation: Haemoglobin AS, CC, and AC genotypes and homozygous and heterozygous α-thalassaemia provide significant protection from severe malaria syndromes, but these haemoglobinopathies differ substantially in the degree of protection provided and confer mild or no protection against uncomplicated malaria and asymptomatic parasitaemia. Through attenuation of severity of malaria, haemoglobinopathies could serve as a model for investigation of the mechanisms of malaria pathogenesis and immunity. Funding: US National Institute of Allergy and Infectious Diseases. © 2012 Elsevier Ltd.

Women with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have fewer children on average than other women. We sought to determine the roles of infertility, pregnancy loss, and personal choice on family size in women with these diseases. A reproductive history questionnaire was completed by women with RA and SLE participating in a longitudinal observational study. Within each disease cohort, participants were divided into 3 groups: those interested in having children at symptom onset who had either fewer children than planned (group A) or the same number as planned (group B), and those no longer interested in having children at diagnosis (group C). Of the 578 RA and 114 SLE women surveyed, >60% were in group C. Of those interested in having children, 55% with RA and 64% with SLE had fewer children than originally planned. Among women with RA, group A had 1 less pregnancy, 1 less live birth, and an infertility rate 1.5 times higher than group B; the miscarriage rate was similar in both groups. Compared to SLE group B, SLE group A had a similar number of pregnancies, but a 3-fold higher rate of miscarriage and 1 less live birth. Concerns about child health and personal welfare were associated with a lower pregnancy rate. In this population, more than one-half of young women with RA or SLE had fewer biologic children than desired. While patient choice plays a role, infertility in RA patients and miscarriage in SLE patients are also important. Copyright © 2012 by the American College of Rheumatology.

Korall P.,Uppsala University | Pryer K.M.,Duke University
Journal of Biogeography | Year: 2014

Aim: Scaly tree ferns, Cyatheaceae, are a well-supported group of mostly tree-forming ferns found throughout the tropics, the subtropics and the south-temperate zone. Fossil evidence shows that the lineage originated in the Late Jurassic period. We reconstructed large-scale historical biogeographical patterns of Cyatheaceae and tested the hypothesis that some of the observed distribution patterns are in fact compatible, in time and space, with a vicariance scenario related to the break-up of Gondwana. Location: Tropics, subtropics and south-temperate areas of the world. Methods: The historical biogeography of Cyatheaceae was analysed in a maximum likelihood framework using Lagrange. The 78 ingroup taxa are representative of the geographical distribution of the entire family. The phylogenies that served as a basis for the analyses were obtained by Bayesian inference analyses of mainly previously published DNA sequence data using MrBayes. Lineage divergence dates were estimated in a Bayesian Markov chain Monte Carlo framework using beast. Results: Cyatheaceae originated in the Late Jurassic in either South America or Australasia. Following a range expansion, the ancestral distribution of the marginate-scaled clade included both these areas, whereas Sphaeropteris is reconstructed as having its origin only in Australasia. Within the marginate-scaled clade, reconstructions of early divergences are hampered by the unresolved relationships among the Alsophila, Cyathea and Gymnosphaera lineages. Nevertheless, it is clear that the occurrence of the Cyathea and Sphaeropteris lineages in South America may be related to vicariance, whereas transoceanic dispersal needs to be inferred for the range shifts seen in Alsophila and Gymnosphaera. Main conclusions: The evolutionary history of Cyatheaceae involves both Gondwanan vicariance scenarios as well as long-distance dispersal events. The number of transoceanic dispersals reconstructed for the family is rather few when compared with other fern lineages. We suggest that a causal relationship between reproductive mode (outcrossing) and dispersal limitations is the most plausible explanation for the pattern observed. © 2013 The Authors Journal of Biogeography Published by John Wiley & Sons Ltd.

This paper describes the EPA's voluntary ENERGY STAR program and the results of the automobile manufacturing industry's efforts to advance energy management as measured by the updated ENERGY STAR Energy Performance Indicator (EPI). A stochastic single-factor input frontier estimation using the gamma error distribution is applied to separately estimate the distribution of the electricity and fossil fuel efficiency of assembly plants using data from 2003 to 2005 and then compared to model results from a prior analysis conducted for the 1997-2000 time period. This comparison provides an assessment of how the industry has changed over time. The frontier analysis shows a modest improvement (reduction) in "best practice" for electricity use and a larger one for fossil fuels. This is accompanied by a large reduction in the variance of fossil fuel efficiency distribution. The results provide evidence of a shift in the frontier, in addition to some "catching up" of poor performing plants over time. © 2013 Elsevier B.V.

Virkud Y.V.,Duke University
Discovery medicine | Year: 2012

Food allergy is a life-threatening allergic disease that is increasing in prevalence with no approved curative therapy. Standard treatment of food allergy is limited to avoidance of the allergen and supportive management of allergic symptoms and anaphylaxis. Current research, however, has been focused on developing therapy that can modify the allergic immune response in both allergen-specific and non-specific methods. This review will provide an overview of these methods including oral immunotherapy, sublingual immunotherapy, epicutaneous immunotherapy, modified food protein vaccines, anti-IgE monoclonal antibody adjuvant therapy, Chinese herbs, and helminth therapy.

Boland D.F.,Duke University
The American journal of managed care | Year: 2012

Parkinson's disease (PD) imposes a significant economic burden on the healthcare system. As the population continues to age and shifts to include a larger proportion of persons 65 years and older, the economic burden related to PD will continue to escalate. Clinicians should be mindful of striving for efficiency, making prudent choices, and allocating resources appropriately. The majority of treatment costs in PD are associated with advancing disease; specifically, the costs related to increasing need for care. Early identification of motor and non-motor signs and symptoms of disease allows for earlier treatment. Through early treatment strategies, symptom control is improved and patients will likely have less need for care. This leads to improvements in quality of life (QoL) and functional independence and reduced caregiver burden and thus results in decreased costs. In addition, although research thus far has not clearly demonstrated the ability of an agent to provide disease modification, as new, potentially neuroprotective therapeutic interventions are developed and become available as treatment options, the recognition of early disease will be more important. If earlier treatment with neuroprotective agents leads to slowing of disease progression, the result may be less need for care and decreased costs for patients with PD. This may have a measurable impact by improving QoL measures for both the patient and caregivers.

Aronson S.,Duke University
Current Hypertension Reports | Year: 2014

The concept of "perioperative hypertensive emergency" must be defined differently from that of ambulatory hypertensive emergency in view of its unique clinical considerations in an atypical setting. It should be noted that moderately high normal blood pressure (BP) values in the perioperative setting often trigger situations requiring immediate treatment in what would otherwise be a "BP-acceptable" non-surgical condition. Commonly recognized circumstances that may result in a perioperative hypertensive emergency include exacerbation of severe mitral insufficiency, hypertension resulting in acute decompensated heart failure, hypertension caused by acute catecholamine excess, rebound hypertension after withdrawal of antihypertensive medications, hypertension resulting in bleeding from vascular surgery suture lines, intracerebral hemorrhage, aortic dissection, hypertension associated with preeclampsia, and hypertension associated with autonomic dysreflexia. In addition, perioperative BP lability has been reported to increase the risk for stroke, acute kidney injury, and 30-day mortality in patients undergoing cardiac surgery. © 2014 Springer Science+Business Media.

Kraak V.I.,Virginia Polytechnic Institute and State University | Story M.,Duke University
Obesity Reviews | Year: 2015

Reducing the extent and persuasive power of marketing unhealthy foods to children worldwide are important obesity prevention goals. Research is limited to understand how brand mascots and cartoon media characters influence children's diet. We conducted a systematic review of five electronic databases (2000-2014) to identify experimental studies that measured how food companies' mascots and entertainment companies' media characters influence up to 12 diet-related cognitive, behavioural and health outcomes for children under 12 years. Eleven studies met the inclusion criteria. Studies used 21 unique popular media characters, but no brand mascots. Results suggest that cartoon media character branding can positively increase children's fruit or vegetable intake compared with no character branding. However, familiar media character branding is a more powerful influence on children's food preferences, choices and intake, especially for energy-dense and nutrient-poor foods (e.g. cookies, candy or chocolate) compared with fruits or vegetables. Future research should use a theoretically grounded conceptual model and larger and more diverse samples across settings to produce stronger findings for mediating and moderating factors. Future research can be used to inform the deliberations of policymakers, practitioners and advocates regarding how media character marketing should be used to support healthy food environments for children. © 2014 The Authors.

Chen L.,Duke University
Operations Research | Year: 2010

In most retail environments, when inventory runs out, the unmet demand is lost and not observed. The sales data are effectively censored by the inventory level. Factoring this censored data effect into demand estimation and inventory control decision makes the problem difficult to solve. In this paper, we focus on developing bounds and heuristics for this problem. Specifically, we consider a finite-horizon inventory control problem for a nonperishable product with unobserved lost sales and a demand distribution having an unknown parameter. The parameter is estimated sequentially by the Bayesian updating method. We first derive a set of solution upper bounds that work for all prior and demand distributions. For a fairly general monotone likelihood-ratio distribution family, we derive relaxed but easily computable lower and upper bounds along an arbitrary sample path. We then propose two heuristics. The first heuristic is derived from the solution bound results. Computing this heuristic solution only requires the evaluation of the objective function in the observed lost-sales case. The second heuristic is based on the approximation of the first-order condition. We combine the first-order derivatives of the simpler observed lost-sales and perishable-inventory models to obtain the approximation. For the latter case, we obtain a recursive formula that simplifies the computation. Finally, we conduct an extensive numerical study to evaluate and compare the bounds and heuristics. The numerical results indicate that both heuristics perform very well. They outperform the myopic policies by a wide margin. © 2010 INFORMS.

Bellemare M.F.,Duke University
Land Economics | Year: 2012

Most studies of tenurial insecurity focus on its effects on investment. This paper studies the hitherto unexplored relationship between tenurial insecurity and land tenancy contracts. Based on distinct features of formal law and customary rights in Madagascar, this paper augments the canonical model of sharecropping by making the strength of the landlord's property right increasing in the amount of risk she bears within the contract. Using data on landlords' subjective perceptions in rural Madagascar, empirical tests support the hypothesis that insecure property rights drive contract choice but offer little support in favor of the canonical risk sharing hypothesis. © 2012 by the Board of Regents of the University of Wisconsin System.

Cordes S.,Boston College | Meck W.H.,Duke University
Journal of Experimental Psychology: General | Year: 2014

An emerging corpus of clinical and neuroimaging data suggests that subsecond and suprasecond durations are represented via 2 distinct mechanisms in humans; however, surprisingly, behavioral data to this effect are lacking. In our first experiment, we perform the first systematic exploration of subsecond and suprasecond timing within the same session in nonhuman subjects. Rats were trained to judge the relative duration of 2 sequential stimuli, responding on one lever if the first stimulus was longer or on a second lever if the converse was true. Our data provide strong evidence of an abstract understanding of longer and shorter for durations in the suprasecond range, whereas responding was at chance levels for durations in the subsecond range. Data from a second experiment reveal that this pattern is not due to an inability to time subsecond signals, as rats respond systematically in subsecond and suprasecond bisection tasks. Together, our results provide the first clear behavioral evidence of a discontinuity in the mental time line. These data from rats are discussed in light of similar findings of a discontinuity in the mental number line in human infants. © 2013 American Psychological Association.

Moffitt T.E.,Duke University | Moffitt T.E.,Kings College London
Development and Psychopathology | Year: 2013

Many young people who are mistreated by an adult, victimized by bullies, criminally assaulted, or who witness domestic violence react to this violence exposure by developing behavioral, emotional, or learning problems. What is less well known is that adverse experiences like violence exposure can lead to hidden physical alterations inside a child's body, alterations that may have adverse effects on life-long health. We discuss why this is important for the field of developmental psychopathology and for society, and we recommend that stress-biology research and intervention science join forces to tackle the problem. We examine the evidence base in relation to stress-sensitive measures for the body (inflammatory reactions, telomere erosion, epigenetic methylation, and gene expression) and brain (mental disorders, neuroimaging, and neuropsychological testing). We also review promising interventions for families, couples, and children that have been designed to reduce the effects of childhood violence exposure. We invite intervention scientists and stress-biology researchers to collaborate in adding stress-biology measures to randomized clinical trials of interventions intended to reduce effects of violence exposure and other traumas on young people. © 2013 Cambridge University Press.

Perfect J.R.,Duke University
Current Medical Research and Opinion | Year: 2013

Background: Morbidity and mortality remain high for patients with invasive fungal infections (IFIs) despite an increasing number of antifungals and other treatments. Many studies indicate that delayed or inaccurate diagnosis and treatment are major causes of poor outcomes in patients with IFIs. Objective: The aim of the current paper is to provide a review of traditional and newer approaches to the diagnosis of IFIs, with a particular focus on invasive candidiasis (IC) and aspergillosis (IA). Recent studies from the author's institution are highlighted, along with an advancement in cryptococcal meningitis diagnosis that should improve the care of AIDS and its opportunistic infection in many developing countries. Findings: Currently available tools for the diagnosis of IFIs include traditional methods like histopathology, culture, and radiology, and newer antigen-and PCR-based diagnostic assays. Attempts have also been made to predict IFIs based on colonization or other factors, including genetic polymorphisms impacting IFI susceptibility in high-risk patients. Biopsy with histopathologic analysis is often not possible in patients suspected of pulmonary aspergillosis due to increased bleeding risk, and blood cultures for IC, IA, or other IFIs are hindered by poor sensitivity and slow turnaround time which delays diagnosis. Radiology is often used to predict IFI but suffers from inability to differentiate certain pathogens and does not generally provide certainty of IFI diagnosis. Newer antigen-based diagnostics for early diagnosis include the β-glucan assay for IFIs, galactomannan assay for IA, and a recent variation on the traditional cryptococcal antigen (CRAG) test with a Lateral Flow Assay for invasive cryptococcosis. PCR-based diagnostics represent additional tools with high sensitivity for the rapid diagnosis of IFIs, although better standardization of these methods is still required for their routine clinical use. Conclusion: Better understanding of the strengths and weaknesses of currently available diagnostic tools, and further devising linked strategies to best implement them either alone or in combination, would greatly improve early and accurate diagnosis of IFIs and improve their successful management. © 2013 Informa UK Ltd.

MacAlpine D.M.,Duke University | Almouzni G.,University Pierre and Marie Curie
Cold Spring Harbor Perspectives in Biology | Year: 2013

The size of a eukaryotic genome presents a unique challenge to the cell: package and organize the DNA to fit within the confines of the nucleus while at the same time ensuring sufficient dynamics to allow access to specific sequences and features such as genes and regulatory elements. This is achieved via the dynamic nucleoprotein organization of eukary-otic DNA into chromatin. The basic unit of chromatin, the nucleosome,comprises a core particle with 147 bp of DNA wrapped 1.7 times around an octamer of histones. The nucle-osome is a highly versatile and modular structure, both in its composition, with the existence of various histone variants, and through the addition of a series of posttranslational modifications on the histones. This versatility allows for both short-term regulatory responses to external signaling, as well as the long-term and multigenerational definition of large functional chromosomal domains within the nucleus, such as the centromere. Chromatin organization and its dynamics participate in essentially all DNA-templated processes, including transcription, replication, recombination, and repair. Here we will focus mainly on nucleo-somal organization and describe the pathways and mechanisms that contribute to assembly of this organization and the role of chromatin in regulating the DNA replication program. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.

Dawson G.,Duke University | Bernier R.,University of Washington
Development and Psychopathology | Year: 2013

The last 25 years have witnessed tremendous changes in our ability to detect autism very early in life and provide interventions that can significantly influence children's outcomes. It was once questioned whether autism could be recognized before children had developed language and symbolic play skills; now changes in early behaviors, as well as structural brain changes, have been documented in infants 6-12 months of age who later develop autism. Advances in brain imaging and genetics offer the possibility of detecting autism before the syndrome is fully manifest, thereby reducing or preventing symptoms from developing. Whereas the primary mode of behavioral intervention a few decades ago relied on operant conditioning, recent approaches integrate the methods of applied behavioral analysis within a developmental, relationship-focused intervention model that are implemented by both parents and clinicians. These interventions have been found to have positive effects on children's developmental trajectory, as measured by both behavioral and neurophysiological assessments. Future approaches will likely combine both behavioral and pharmacological treatments for children who have less robust responses to behavioral interventions. There has been a paradigm shift in the way that autism is viewed, evolving from a lifelong condition with a very poor prognosis to one in which significant gains and neuroplasticity is expected, especially when the condition is detected early and appropriate interventions are provided. The grand challenge for the future is to bridge the tremendous gap between research and the implementation of evidence-based practices in the broader community, both in the United States and worldwide. Significant disparities in access to appropriate health care for children with autism exist that urgently require advocacy and more resources. © 2013 Cambridge University Press.

Frush D.P.,Duke University
Pediatric radiology | Year: 2011

Pediatric CT radiation dose and risk assessment are important but challenging, especially given inherent uncertainties. It is still necessary for those involved in medical imaging of children to have an understanding of the extent of existing knowledge for dose assessment and risk, as well as ongoing work at improvements.

Lachiewicz P.F.,Duke University
Journal of the American Academy of Orthopaedic Surgeons | Year: 2011

The gluteus medius and minimus muscle-tendon complex is crucial for gait and stability in the hip joint. There are three clinical presentations of abductor tendon tears. Degenerative or traumatic tears of the hip abductor tendons, so-called rotator cuff tears of the hip, are seen in older patients with intractable lateral hip pain and weakness but without arthritis of the hip joint. The second type of tear may be relatively asymptomatic. It is often seen in patients undergoing arthroplasty for femoral neck fracture or elective total hip arthroplasty (THA) for osteoarthritis. The third type of abductor tendon dysfunction occurs with avulsion or failure of repair following THA performed through the anterolateral approach. Abductor tendon tear should be confirmed on MRI. When nonsurgical management is unsuccessful, open repair of the tendons with transosseous sutures is recommended. Good pain relief has been reported following endoscopic repair. Abductor tendon repair has had inconsistent results in persons with avulsion following THA. Reconstruction with a gluteus maximus muscle flap or Achilles tendon allograft has provided promising short-term results in small series.

Ortel T.L.,Duke University
Blood | Year: 2012

Perioperative management of antithrombotic therapy is a situation that occurs frequently and requires consideration of the patient, the procedure, and an expanding array of anticoagulant and antiplatelet agents. Preoperative assessment must address each patient's risk for thromboembolic events balanced against the risk for perioperative bleeding. Procedures can be separated into those with a low bleeding risk, which generally do not require complete reversal of the antithrombotic therapy, and those associated with an intermediate or high bleeding risk. For patients who are receiving warfarin who need interruption of the anticoagulant, consideration must be given to whether simply withholding the anticoagulant is the optimal approach or whether a perioperative "bridge" with an alternative agent, typically a low-molecular-weight heparin, should be used. The new oral anticoagulants dabigatran and rivaroxaban have shorter effective half-lives, but they introduce other concerns for perioperative management, including prolonged drug effect in patients with renal insufficiency, limited experience with clinical laboratory testing to confirm lack of residual anticoagulant effect, and lack of a reversal agent. Antiplatelet agents must also be considered in the perioperative setting, with particular consideration given to the potential risk for thrombotic complications in patients with coronary artery stents who have antiplatelet therapy withheld. © 2012 by The American Society of Hematology.

Yang C.-J.,Duke University
Energy Policy | Year: 2010

Grid parity-reducing the cost of solar energy to be competitive with conventional grid-supplied electricity-has long been hailed as the tipping point for solar dominance in the energy mix. Such expectations are likely to be overly optimistic. A realistic examination of grid parity suggests that the cost-effectiveness of distributed photovoltaic (PV) systems may be further away than many are hoping for. Furthermore, cost-effectiveness may not guarantee commercial competitiveness. Solar hot water technology is currently far more cost-effective than photovoltaic technology and has already reached grid parity in many places. Nevertheless, the market penetration of solar water heaters remains limited for reasons including unfamiliarity with the technologies and high upfront costs. These same barriers will likely hinder the adoption of distributed solar photovoltaic systems as well. The rapid growth in PV deployment in recent years is largely policy-driven and such rapid growth would not be sustainable unless governments continue to expand financial incentives and policy mandates, as well as address regulatory and market barriers. © 2010 Elsevier Ltd.

Hubbell J.A.,Ecole Polytechnique Federale de Lausanne | Chilkoti A.,Duke University
Science | Year: 2012

Nanometer-scale polymeric materials are increasingly used to surmount the barriers faced by drugs and vaccines on their way to their site of action.

Gan T.J.,Duke University
Current Medical Research and Opinion | Year: 2010

Background: Diclofenac is a proven, commonly prescribed nonsteroidal anti-inflammatory drug (NSAID) that has analgesic, anti-inflammatory, and antipyretic properties, and has been shown to be effective in treating a variety of acute and chronic pain and inflammatory conditions. As with all NSAIDs, diclofenac exerts its action via inhibition of prostaglandin synthesis by inhibiting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) with relative equipotency. However, extensive research shows the pharmacologic activity of diclofenac goes beyond COX inhibition, and includes multimodal and, in some instances, novel mechanisms of action (MOA). Data sources: Literature retrieval was performed through PubMed/MEDLINE (through May 2009) using combinations of the terms diclofenac, NSAID, mechanism of action, COX-1, COX-2, and pharmacology. Reference citations resulting from publications identified in the literature search were reviewed when appropriate. Methods: This article reviews the established, putative, and emerging MOAs of diclofenac; compares the drugs pharmacologic and pharmacodynamic properties with other NSAIDs to delineate its potentially unique qualities; hypothesizes why it has been chosen for further recent formulation enhancement; and evaluates the potential effect of its MOA characteristics on safety. Discussion: Research suggests diclofenac can inhibit the thromboxane-prostanoid receptor, affect arachidonic acid release and uptake, inhibit lipoxygenase enzymes, and activate the nitric oxidecGMP antinociceptive pathway. Other novel MOAs may include the inhibition of substrate P, inhibition of peroxisome proliferator activated receptor gamma (PPARγ), blockage of acid-sensing ion channels, alteration of interleukin-6 production, and inhibition of N-methyl-D-aspartate (NMDA) receptor hyperalgesia. The review was not designed to compare MOAs of diclofenac with other NSAIDs. Additionally, as the highlighted putative and emerging MOAs do not have clinical data to demonstrate that these models are correct, further research is necessary to ascertain if the proposed pathways will translate into clinical benefits. The diversity in diclofenacs MOA may suggest the potential for a relatively more favorable profile compared with other NSAIDs. © 2010 Informa UK Ltd.

Coffman T.M.,Duke University | Coffman T.M.,National University of Singapore
Nature Medicine | Year: 2011

High blood pressure, or hypertension, is a very common disorder with a substantial impact on public health because of its associated complications. Despite the high prevalence of essential hypertension and years of research, the basic causes remain obscure. Here I review recent advances in understanding the pathophysiology of hypertension. I present a general overview of the field and, by necessity, use broad strokes to portray recent progress and place it in context. For this purpose, I use illustrative examples from the large number of important developments in hypertension research over the last five years. The intent of this review is to provide a sense of where the field is progressing, with an emphasis on work that sheds light on pathogenic mechanisms and that is therefore likely to inform new translational advances. © 2011 Nature America, Inc. All rights reserved.

Chen M.,Duke University | Chory J.,Salk Institute for Biological Studies
Trends in Cell Biology | Year: 2011

As they emerge from the ground, seedlings adopt a photosynthetic lifestyle, which is accompanied by dramatic changes in morphology and global alterations in gene expression that optimizes the plant body plan for light capture. Phytochromes are red and far-red photoreceptors that play a major role during photomorphogenesis, a complex developmental program that seedlings initiate when they first encounter light. The earliest phytochrome signaling events after excitation by red light include their rapid translocation from the cytoplasm to subnuclear bodies (photobodies) that contain other proteins involved in photomorphogenesis, including a number of transcription factors and E3 ligases. In the light, phytochromes and negatively acting transcriptional regulators that interact directly with phytochromes are destabilized, whereas positively acting transcriptional regulators are stabilized. Here, we discuss recent advances in our knowledge of the mechanisms linking phytochrome photoactivation in the cytoplasm and transcriptional regulation in the nucleus. © 2011 Elsevier Ltd.

Lantos P.M.,Duke University
Infectious Disease Clinics of North America | Year: 2015

Chronic Lyme disease is a poorly defined diagnosis that is usually given to patients with prolonged, unexplained symptoms or with alternative medical diagnoses. Data do not support the proposition that chronic, treatment-refractory infection with Borrelia burgdorferi is responsible for the many conditions that get labeled as chronic Lyme disease. Prolonged symptoms after successful treatment of Lyme disease are uncommon, but in rare cases may be severe. Prolonged courses of antibiotics neither prevent nor ameliorate these symptoms and are associated with considerable harm. © 2015 Elsevier Inc.

Scruggs J.T.,Duke University
Journal of Intelligent Material Systems and Structures | Year: 2010

This article illustrates that certain relatively well-known results from feedback control theory can be used to determine the maximum-attainable power generation for a vibratory energy harvester excited by a stationary broadband stochastic disturbance. For such applications, control techniques based on impedance matching theory cannot be used to optimize power generation, because the dynamic controller they prescribe is always anticausal. However, an optimal causal controller does exist, and can be derived using H2/LQG theory. Levels of power generation with this controller are compared to those of the anticausal optimal performance, as well as to traditional 'tuning' techniques which match the anticausal impedance only at the resonant frequency. It is demonstrated that tuning techniques can be significantly sub-optimal in broadband applications, especially when electronic conversion is relatively efficient. In addition to being useful in the design of controllers for energy harvesting applications, these results may also be used to ascertain the insurpassable power generation limits associated with a given combination of transducer and electronic hardware. © 2010 The Author(s).

Thompson S.E.,University of California at Berkeley | Katul G.G.,Duke University
Global Change Biology | Year: 2013

Migration of plant populations is a potential survival response to climate change that depends critically on seed dispersal. Biological and physical factors determine dispersal and migration of wind-dispersed species. Recent field and wind tunnel studies demonstrate biological adaptations that bias seed release toward conditions of higher wind velocity, promoting longer dispersal distances and faster migration. However, another suite of international studies also recently highlighted a global decrease in near-surface wind speeds, or 'global stilling'. This study assessed the implications of both factors on potential plant population migration rates, using a mechanistic modeling framework. Nonrandom abscission was investigated using models of three seed release mechanisms: (i) a simple drag model; (ii) a seed deflection model; and (iii) a 'wear and tear' model. The models generated a single functional relationship between the frequency of seed release and statistics of the near-surface wind environment, independent of the abscission mechanism. An Inertial-Particle, Coupled Eulerian-Lagrangian Closure model (IP-CELC) was used to investigate abscission effects on seed dispersal kernels and plant population migration rates under contemporary and potential future wind conditions (based on reported global stilling trends). The results confirm that nonrandom seed abscission increased dispersal distances, particularly for light seeds. The increases were mitigated by two physical feedbacks: (i) although nonrandom abscission increased the initial acceleration of seeds from rest, the sensitivity of the seed dispersal to this initial condition declined as the wind speed increased; and (ii) while nonrandom abscission increased the mean dispersal length, it reduced the kurtosis of seasonal dispersal kernels, and thus the chance of long-distance dispersal. Wind stilling greatly reduced the modeled migration rates under biased seed release conditions. Thus, species that require high wind velocities for seed abscission could experience threshold-like reductions in dispersal and migration potential if near-surface wind speeds continue to decline. © 2013 Blackwell Publishing Ltd.

Terhune C.E.,Duke University
Journal of Human Evolution | Year: 2011

Previous analyses of the masticatory apparatus have demonstrated that the shape of the temporomandibular joint (TMJ) is functionally and adaptively linked to variation in feeding behavior and diet in primates. Building on previous research, this study presents an analysis of the link between diet and TMJ morphology in the context of functional and dietary differences among New World primates. To evaluate this proposed relationship, I used three-dimensional morphometric methods to quantify TMJ shape across a sample of 13 platyrrhine species. A broad interspecific analysis of this sample found strong relationships among TMJ size, TMJ shape, and diet, suggesting that both size and diet are significant factors influencing TMJ morphology in New World primates. However, it is likely that at least some of these differences are related to a division of dietary categories along clade lines. A series of hypotheses related to load resistance capabilities and range of motion in the TMJ were then tested among small groups of closely related taxa with documented dietary differences. These pairwise analyses indicate that some aspects of TMJ morphology can be used to differentiate among closely related species with different diets. However, not all of my predictions were upheld. The anteroposterior dimensions of the TMJ were most strongly consistent with hypothesized differences in ingestive/masticatory behaviors and jaw gape, whereas the predictions generated for variation in entoglenoid and articular tubercle height were not upheld. These results imply that while some features can be reliably associated with increased load resistance and facilitation of wider jaw gapes in the masticatory apparatus, other features are less strongly correlated with masticatory function. © 2011 Elsevier Ltd.

This study examined the usefulness of a surgical approach (retrosigmoid suprafloccular transhorizontal fissure approach) for resection of brainstem cavernous malformations (CMs). An anatomic study concerning the retrosigmoid suprafloccular transhorizontal fissure approach was performed with 3 cadaveric heads. Clinical course was retrospectively reviewed for 10 patients who underwent microsurgical resection of brainstem CMs with this approach. Medical, surgical, and neuroimaging records of these patients were evaluated. In the anatomic study, after standard suboccipital retrosigmoid craniotomy, the horizontal fissure on the petrosal surface of the cerebellum was dissected between the superior semilunar lobule and flocculus. With this approach, the root entry zone of the trigeminal nerve and the middle cerebellar peduncle could be exposed by superior retraction of the superior semilunar lobule. The lateral surface of the pons was then easily visible around the root entry zone. When this approach was used for 10 brainstem CMs, complete resection was achieved in 9 patients (90%). No mortality was encountered in this study. New neurological deficits occurred in the early postoperative period for 4 patients but were transient in 3 patients. Neurological status at final follow-up was improved in 4 patients (40%), unchanged in 5 patients (50%), and worse in 1 patient (10%) compared with preoperative conditions. The retrosigmoid suprafloccular transhorizontal fissure approach is useful for the resection of lateral pontine CMs.

Haglund M.M.,Duke University
Epilepsia | Year: 2012

Precise localization of neocortical epileptic foci is a complex problem that usually requires ictal video-electroencephalography (EEG) recordings; high-resolution magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT) studies; and/or invasive monitoring with implanted grid array electrodes. The exact ictal-onset site must be identified and removed to obtain the best opportunity for a seizure-free outcome. The goal of this study was to determine if high-resolution optical imaging could precisely identify neocortical epileptic foci and what role underlying neuroanatomic pathways played in the seizure propagation. Small acute epileptic foci (0.5 × 0.5 mm 2) were created in the primate visual neocortex and single-unit and surface EEG recordings were combined with optical imaging of voltage-sensitive dye changes. Brief visual stimulation was used to evoke interictal bursts. In addition, different visually evoked epileptiform bursts were analyzed to determine the location of the epileptic focus. Spike-triggered averaging of the optical images associated with the surface EEG interictal bursts were analyzed to determine the exact location of the epileptic focus. Specific orientations of brief visual stimulation evoked different intensity optical changes and precisely localized the epileptic focus. Optical imaging identified individual epileptic foci that were <3 mm apart. The development of individual epileptic focus was monitored with optical imaging, which demonstrated excitatory activity at the focus with a surrounding zone of inhibitory-like activity. Propagation pathways outside of the inhibitory-like surround demonstrated alternating bands of excitation and inhibition with a pattern orthogonal to the ocular dominance columns. This experimental study demonstrates that optical imaging can precisely localize an epileptic focus, and provides excellent spatial resolution of the changes that occur in and around the site of the epileptic focus. © 2012 International League Against Epilepsy.

Wang I.,Duke University
Journal of Applied Mechanics, Transactions ASME | Year: 2011

The half power method is a technique commonly used for calculating the system damping using frequency response curves. Past derivations typically assume a small damping ratio but do not keep track of the order of magnitude when simplifying results and focus mainly on displacement frequency response curves. This paper provides two separate and rigorous derivations of the half power bandwidth for displacement and acceleration frequency response functions. The exact expressions are simplified systematically using binomial expansions to include third order effects. The third order and classical approximations are compared with the exact expressions, and the truncation errors are presented for both displacement and acceleration cases. The high order effects are more apparent and the truncation errors are greater for the acceleration case. The classical method is sufficiently accurate for many practical cases where the damping ratio is less than 0.1 but higher order corrections may be used to reduce truncation error for systems where the damping ratio is higher. © 2011 American Society of Mechanical Engineers.

Draelos Z.D.,Duke University
Dermatologic Clinics | Year: 2013

This article examines hair care in persons with hair loss. The use of shampoos, conditioners, and hair styling products to camouflage hair loss is discussed. Because hair is nonliving, medical treatments are limited to only inducing change in the follicles within the scalp skin and do not improve the hair loss actually witnessed by the patient. There is therefore a need to accompany medical treatment of hair loss with cosmetic hair treatment to optimize patient satisfaction. © 2013 Elsevier Inc.

Colton C.A.,Duke University
Journal of Neuroimmune Pharmacology | Year: 2013

Dendritic cells (DC) are critical to an integrated immune response and serve as the key link between the innate and adaptive arms of the immune system. Under steady state conditions, brain DC's act as sentinels, continually sampling their local environment. They share this function with macrophages derived from the same basic hemopoietic (bone marrow-derived) precursor and with parenchymal microglia that arise from a unique non-hemopoietic origin. While multiple cells may serve as antigen presenting cells (APCs), dendritic cells present both foreign and self-proteins to naïve T cells that, in turn, carry out effector functions that serve to protect or destroy. The resulting activation of the adaptive response is a critical step to resolution of injury or infection and is key to survival. In this review we will explore the critical roles that DCs play in the brain's response to neuroinflammatory disease with emphasis on how the brain's microenvironment impacts these actions. © 2012 Springer Science+Business Media New York.

Dickneite G.,CSL Behring | Hoffman M.,Duke University
Thrombosis and Haemostasis | Year: 2014

Newer oral anticoagulants offer several advantages over traditional agents (e.g. warfarin), but they are still associated with a bleeding risk and currently there is no validated reversal treatment for them. While there is little support for the use of fresh frozen plasma, and limited data available on the effects of activated recombinant factor VII, pre-clinical data suggest that prothrombin complex concentrates (PCCs) may have potential in this setting. PCCs are currently used to successfully reverse warfarin-induced anticoagulation; however, clinical evidence for their use with new oral anticoagulants is lacking, with most of the available data coming from preclinical animal studies. Furthermore, there appears to be variation in the ability of different PCCs to reverse the coagulopathy induced by the new anticoagulants, and a lack of correlation between the reversal of laboratory test results and the reversal of anticoagulant-induced bleeding. Although there have been encouraging results, care must be taken in generalising findings from animal models and nonbleeding human subjects to the situation in bleeding patients. Ultimately, more evidence supporting anticoagu-lation reversal for new anticoagulants is needed, particularly regarding the treatment of bleeding in human patients in a clinical setting. According to the current evidence, use of PCCs may be considered a reasonable approach in dire clinical situations; however, a consensus has not yet been reached regarding PCC use or dosing, due to lack of clinical data. © Schattauer 2014.

Guilak F.,Duke University
Best Practice and Research: Clinical Rheumatology | Year: 2011

Biomechanical factors play an important role in the health of diarthrodial joints. Altered joint loading - associated to obesity, malalignment, trauma or joint instability - is a critical risk factor for joint degeneration, whereas exercise and weight loss have generally been shown to promote beneficial effects for osteoarthritic joints. The mechanisms by which mechanical stress alters the physiology or pathophysiology of articular cartilage or other joint tissues likely involve complex interactions with genetic and molecular influences, particularly local or systemic inflammation secondary to injury or obesity. Chondrocytes perceive physical signals from their environment using a variety of mechanisms, including ion channels, integrin-mediated connections to the extracellular matrix that involve membrane, cytoskeletal and intracellular deformation. An improved understanding of the biophysical and molecular pathways involved in chondrocyte mechanotransduction can provide insight into the development of novel therapeutic approaches for osteoarthritis. © 2011 Elsevier Ltd. All rights reserved.

Mooney R.,Duke University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

Mirror neurons are theorized to serve as a neural substrate for spoken language in humans, but the existence and functions of auditory-vocal mirror neurons in the human brain remain largely matters of speculation. Songbirds resemble humans in their capacity for vocal learning and depend on their learned songs to facilitate courtship and individual recognition. Recent neurophysiological studies have detected putative auditory-vocal mirror neurons in a sensorimotor region of the songbird's brain that plays an important role in expressive and receptive aspects of vocal communication. This review discusses the auditory and motor-related properties of these cells, considers their potential role on song learning and communication in relation to classical studies of birdsong, and points to the circuit and developmental mechanisms that may give rise to auditory-vocal mirroring in the songbird's brain. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Haynes B.F.,Duke University | McElrath M.J.,Fred Hutchinson Cancer Research Center
Current Opinion in HIV and AIDS | Year: 2013

PURPOSE OF REVIEW: In this review, examples of recent progress in HIV-1 vaccine research are discussed. RECENT FINDINGS: New insights from the immune correlates analyses of the RV144 efficacy trial have accelerated vaccine development with leads to follow in nonhuman primate studies and improved vaccine designs. Several new vaccine vector approaches offer promise in the exquisite control of acute infection and in improving the breadth of T-cell responses. New targets of broadly neutralizing antibodies (BnAbs) have been elucidated, and improved understanding of how the human host controls BnAb development have emerged from BnAb knock-in mice and from analyses of BnAb maturation and virus evolution in individuals followed from the time of HIV-1 transmission to BnAb induction. SUMMARY: Based on these observations, it is clear that the development of a successful HIV-1 vaccine will require new vaccine approaches and iterative testing of immunogens in well designed animal and human trials. © 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.

Draelos Z.D.,Duke University
British Journal of Dermatology | Year: 2012

Male skin care needs are heavily influenced by the need to remove facial hair on a regular basis. Facial skin issues associated with poor hair removal approaches are common and include razor burn and irritation. This paper evaluates current research on shaving technology and how careful ingredient selection can contribute to male skin health. The importance of maintaining hair softness during the shave and restoring facial hydration post-shave is discussed. Data are presented on how post-shave moisturizers containing glycerine and emollients can create an environment for improved barrier function which can be further improved by incorporating specific ingredients such as niacinamide. © 2012 The Author.

Fridovich I.,Duke University
Medical Principles and Practice | Year: 2013

The electronic structure of ground state oxygen, which is essential for the life of all aerobic organisms, makes it potentially dangerous for those organisms. Atmospheric oxygen contains two unpaired electrons with parallel spin states, which predisposes it to reduction by a univalent pathway. As a consequence, normal aerobic metabolism generates dangerous reactive intermediates of the reduction of O2. These include superoxide radical (O2 -), hydrogen peroxide (H2O 2), and hydroxyl radical (HO). These reactive oxygen species and others that they can engender can damage all cellular macromolecules and unless opposed by cellular defenses, would make aerobic life impossible. Such defenses include superoxide dismutases, catalases, and peroxidases, enzymes that decrease the concentration of the reactive oxygen species that are their substrates, and others that repair or recycle oxidatively damaged macromolecules. Any factor that stimulates reactive oxygen species production or suppresses the antioxidant systems would inevitably cause cell damage. The role of such oxidative damage in various diseases is well documented. In vivo detection of O2 - and other reactive oxygen species is however hampered by the lack of easy, specific, and sensitive analytical methods. Potential artifacts and limitations of the most common detection methods currently in use are briefly discussed. © 2013 S. Karger AG, Basel.

Yoder A.D.,Duke University
Molecular Phylogenetics and Evolution | Year: 2013

Morris Goodman was a revolutionary. Together with a mere handful of like-minded scientists, Morris established himself as a leader in the molecular phylogenetic revolution of the 1960s. The effects of this revolution are most evident in this journal, which he founded in 1992. Happily for lemur biologists, one of Morris Goodman's primary interests was in reconstructing the phylogeny of the primates, including the tooth-combed Lorisifomes of Africa and Asia, and the Lemuriformes of Madagascar (collectively referred to as the suborder Strepsirrhini). This paper traces the development of molecular phylogenetic and evolutionary genetic trends and methods over the 50-year expanse of Morris Goodman's career, particularly as they apply to our understanding of lemuriform phylogeny, biogeography, and biology. Notably, this perspective reveals that the lemuriform genome is sufficiently rich in phylogenetic signal such that the very earliest molecular phylogenetic studies - many of which were conducted by Goodman himself - have been validated by contemporary studies that have exploited advanced computational methods applied to phylogenomic scale data; studies that were beyond imagining in the earliest days of phylogeny reconstruction. Nonetheless, the frontier still beckons. New technologies for gathering and analyzing genomic data will allow investigators to build upon what can now be considered a nearly-known phylogeny of the Lemuriformes in order to ask innovative questions about the evolutionary mechanisms that generate and maintain the extraordinary breadth and depth of biological diversity within this remarkable clade of primates. © 2012 Elsevier Inc.

Myers K.A.,University of Western Ontario | Mrkobrada M.,University of Western Ontario | Simel D.L.,Duke University
JAMA - Journal of the American Medical Association | Year: 2013

IMPORTANCE: Obstructive sleep apnea is a common disease, responsible for daytime sleepiness. Prior to referring patients for definitive testing, the likelihood of obstructive sleep apnea should be established in the clinical examination. OBJECTIVE: To systematically review the clinical examination accuracy in diagnosing obstructive sleep apnea. DATA SOURCES: MEDLINE and reference lists from articles were searched from 1966 to June 2013. Titles and abstracts (n = 4449) were reviewed for eligibility and appraised for evidence levels. STUDY SELECTION: For inclusion, studies must have used full, attended nocturnal polysomnography for the reference standard (n = 42). MAIN OUTCOMES AND MEASURES: Community and referral-based prevalence of obstructive sleep apnea; accuracy of symptoms and signs for the diagnosis of obstructive sleep apnea. RESULTS: The prevalence of sleep apnea in community-screened patients is 2%to 14% (sample sizes 360-1741) and 21% to 90% (sample sizes 42-2677) for patients referred for sleep evaluation. The prevalence varies based on the apnea-hypopnea index (AHI) threshold used for the evaluation (≥5 events/h, prevalence 14%; ≥15/h, prevalence 6%) and whether the disease definition requires symptoms in addition to an abnormal AHI (≥5/h with symptoms, prevalence 2%-4%). Among patients referred for sleep evaluation, those with sleep apnea weighed more (summary body mass index, 31.4; 95%CI, 30.5-32.2) than those without sleep apnea (summary BMI, 28.3; 95%CI, 27.6-29.0; P < .001 for the comparison). The most useful observation for identifying patients with obstructive sleep apnea was nocturnal choking or gasping (summary likelihood ratio [LR], 3.3; 95%CI, 2.1-4.6) when the diagnosis was established by AHI ≥10/h). Snoring is common in sleep apnea patients but is not useful for establishing the diagnosis (summary LR, 1.1; 95%CI, 1.0-1.1). Patients with mild snoring and body mass index lower than 26 are unlikely to have moderate or severe obstructive sleep apnea (LR, 0.07; 95%CI, 0.03-0.19 at threshold of AHI ≥15/h). CONCLUSIONS AND RELEVANCE: Nocturnal gasping or choking is the most reliable indicator of obstructive sleep apnea, whereas snoring is not very specific. The clinical examination of patients with suspected obstructive sleep apnea is useful for selecting patients for more definitive testing.

Eichhorn C.D.,University of Michigan | Al-Hashimi H.M.,Duke University
RNA | Year: 2014

Many regulatory RNAs contain long single strands (ssRNA) that adjoin secondary structural elements. Here, we use NMR spectroscopy to study the dynamic properties of a 12-nucleotide (nt) ssRNA tail derived from the prequeuosine riboswitch linked to the 3′ end of a 48-nt hairpin. Analysis of chemical shifts, NOE connectivity, 13C spin relaxation, and residual dipolar coupling data suggests that the first two residues (A25 and U26) in the ssRNA tail stack onto the adjacent helix and assume an ordered conformation. The following U26-A27 step marks the beginning of an A 6-tract and forms an acute pivot point for substantial motions within the tail, which increase toward the terminal end. Despite substantial internal motions, the ssRNA tail adopts, on average, an A-form helical conformation that is coaxial with the helix. Our results reveal a surprising degree of structural and dynamic complexity at the ssRNA - helix junction, which involves a fine balance between order and disorder that may facilitate efficient pseudoknot formation on ligand recognition. © 2014 Eichhorn and Al-Hashimi.

Brady C.W.,Duke University
World Journal of Gastroenterology | Year: 2015

There are numerous physiologic and biochemical changes in menopause that can affect the function of the liver and mediate the development of liver disease. Menopause represents a state of growing estrogen deficiency, and this loss of estrogen in the setting of physiologic aging increases the likelihood of mitochondrial dysfunction, cellular senescence, declining immune responses to injury, and disarray in the balance between antioxidant formation and oxidative stress. The sum effect of these changes can contribute to increased susceptibility to development of significant liver pathology, particularly nonalcoholic fatty liver disease and hepatocellular carcinoma, as well as accelerated progression of fibrosis in liver diseases, as has been particularly demonstrated in hepatitis C virus liver disease. Recognition of the unique nature of these mediating factors should raise suspicion for liver disease in perimenopausal and menopausal women and offer an opportunity for implementation of aggressive treatment measures so as to avoid progression of liver disease to cirrhosis, liver cancer and liver failure. © The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.

Petrella J.R.,Duke University
Radiology | Year: 2013

As radiologists, our role in the workup of the dementia patient has long been limited by the sensitivity of our imaging tools and lack of effective treatment options. Over the past 30 years, we have made tremendous strides in understanding the genetic, molecular, and cellular basis of Alzheimer disease (AD). We now know that the pathologic features of AD are present 1 to 2 decades prior to development of symptoms, though currently approved symptomatic therapies are administered much later in the disease course. The search for true disease-modifying therapy continues and many clinical trials are underway. Current outcome measures, based on cognitive tests, are relatively insensitive to pathologic disease progression, requiring long, expensive trials with large numbers of participants. Biomarkers, including neuroimaging, have great potential to increase the power of trials by matching imaging methodology with therapeutic mechanism. One of the most important advances over the past decade has been the development of in vivo imaging probes targeted to amyloid beta protein, and one agent is already available for clinical use. Additional advances include automated volumetric imaging methods to quantitate cerebral volume loss. Use of such techniques in small, early phase trials are expected to significantly increase the number and quality of candidate drugs for testing in larger trials. In addition to a critical role in trials, structural, molecular, and functional imaging techniques can give us a window on the etiology of AD and other neurodegenerative diseases. This combination of developments has potential to bring diagnostic radiology to the forefront in AD research, therapeutic trials, and patient care. © RSNA, 2013.

To examine the characteristics associated with early dyspnoea relief during acute heart failure (HF) hospitalization, and its association with 30-day outcomes. ASCEND-HF was a randomized trial of nesiritide vs. placebo in 7141 patients hospitalized with acute HF in which dyspnoea relief at 6 h was measured on a 7-point Likert scale. Patients were classified as having early dyspnoea relief if they experienced moderate or marked dyspnoea improvement at 6 h. We analysed the clinical characteristics, geographical variation, and outcomes (mortality, mortality/HF hospitalization, and mortality/hospitalization at 30 days) associated with early dyspnoea relief. Early dyspnoea relief occurred in 2984 patients (43%). In multivariable analyses, predictors of dyspnoea relief included older age and oedema on chest radiograph; higher systolic blood pressure, respiratory rate, and natriuretic peptide level; and lower serum blood urea nitrogen (BUN), sodium, and haemoglobin (model mean C index = 0.590). Dyspnoea relief varied markedly across countries, with patients enrolled from Central Europe having the lowest risk-adjusted likelihood of improvement. Early dyspnoea relief was associated with lower risk-adjusted 30-day mortality/HF hospitalization [hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.68-0.96] and mortality/hospitalization (HR 0.85; 95% CI 0.74-0.99), but similar mortality. Clinical characteristics such as respiratory rate, pulmonary oedema, renal function, and natriuretic peptide levels are associated with early dyspnoea relief, and moderate or marked improvement in dyspnoea was associated with a lower risk for 30-day outcomes.

Macintyre N.R.,Duke University
Respiratory Care | Year: 2012

The ventilator discontinuation process is an essential component of overall ventilator management. Undue delay leads to excess stay, iatrogenic lung injury, unnecessary sedation, and even higher mortality. On the other hand, premature withdrawal can lead to muscle fatigue, dangerous gas exchange impairment, loss of airway protection, and also a higher mortality. An evidence-based task force has recommended a daily discontinuation assessment and management process for most ICU patients requiring at least 24 hours of mechanical ventilator support. This process focuses on assessments on the causes for ventilator dependence, assessments for evidence of disease stability/ reversal, use of regular spontaneous breathing trials (SBTs) as the primary assessment tool for ventilator discontinuation potential, use of separate assessments to evaluate the need for an artificial airway in patients tolerating the SBT, and the use of comfortable, interactive ventilator modes (that do not need to be "weaned") in between regular SBTs. More recent developments have focused on the utility of computer decision support to guide these processes and the importance of linking sedation reduction protocols to ventilator discontinuation protocols. These guidelines are standing the test of time, and practice patterns are evolving in accordance with them. Nevertheless, there is still room for improvement and need for further clinical studies, especially in the patient requiring prolonged mechanical ventilation. © 2012 Daedalus Enterprises.

Pasipoularides A.,Duke University
International Journal of Cardiology | Year: 2014

Early modern medical science did not arise ex nihilo, but was the culmination of a long history stretching back through the Renaissance, the Middle Ages, Byzantium and Roman times, into Greek Antiquity. The long interval between Aristotle and Galen and Harvey and Descartes was punctuated by outstanding visionaries, including Leonardo, the ultimate Renaissance man. His attitude and mindset were based on Aristotelian pursuit of empirical fact and rational thought. He declared himself to be a "man without letters" to underscore his disdain for those whose culture was only mnemonics and philosophical inferences from authoritative books. Leonardo read the Book of Nature with the immense curiosity of the pioneering scientist, ushering in the methodology of modern medical science with help from forerunners. He left no publications, but extensive personal Notebooks: on his scientific research, hydrodynamics, physiological anatomy, etc. Apparently, numerous successors availed themselves of his methodologies and insights, albeit without attribution. In his Notebooks, disordered and fragmentary, Leonardo manifests the exactitude of the engineer and scientist, the spontaneous freshness of one speaking of what he has at heart and that he knows well. His style is unrefined, but intensely personal, rich with emotion and, sometimes, poetic. Leonardo, the visionary anatomist, strived consistently not merely to imitate nature by depicting body structures, but to perceive through analysis and simulations the intimate physiologic processes; i.e., the biomechanics underlying the workings of all bodily organs and components, even the mysterious beating heart. It is fitting to regard him as the first modern medical scientist. © 2013 Published by Elsevier Ireland Ltd.

Frush D.P.,Duke University
Radiologic Clinics of North America | Year: 2011

The chest is the most frequently evaluated region of the body in children. The majority of thoracic diagnostic imaging, namely "conventional" radiography (film screen, computed radiography and direct/digital radiography), fluoroscopy and angiography, and computed tomography, depends on ionizing radiation. Since errors, oversights, and inattention to radiation exposure continue to be extremely visible issue for radiology in the public eye it is incumbent on the imaging community to maximize the yield and minimize both the real and potential radiation risks with diagnostic imaging. Technical (e.g. equipment and technique) strategies can reduce exposure risk and improve study quality, but these must be matched with efforts to optimize appropriate utilization for safe and effective healthcare in thoracic imaging in children. To these ends, material in this chapter will review practice patterns, dose measures and modality doses, radiation biology and risks, and radiation risk reduction strategies for thoracic imaging in children. © 2011 Elsevier Inc.

Vollmer R.T.,Duke University
American Journal of Clinical Pathology | Year: 2014

Objectives: Mitotic counts in melanoma are important and have now become part of the staging of this tumor. Yet, this change was largely based on studies that evaluated the mitotic counts in a limited fashion. Because counts of things with a microscope are often distributed as a Poisson random variable, the major goal of this study was to uncover the probabilistic nature of mitotic counts in melanoma. Methods: Specifically, a general double Poisson model was applied to mitotic counts in 53 cutaneous melanomas representing both thin and thick tumors. Results: The general double Poisson probability model fit the data well. A single Poisson function was sufficient for 46 of the S3 study cases, and two Poisson junctions were required for seven cases because of tissue heterogeneity. Furthermore, the success of the model implied that there is a high probability for false-negative mitotic counts, especially in thin melanomas, and that the "hot" spot methodology introduces bias. Conclusions: Mitotic counts in melanomas are a probabilistic phenomenon closely related to the Poisson probability distribution, and this factor needs to be considered when using mitotic counts for staging and prognosis in melanoma. © American Society for Clinical Pathology.

Vanasse J.,Duke University
Physical Review C - Nuclear Physics | Year: 2013

We introduce a new technique to calculate perturbative corrections to neutron-deuteron (nd) scattering that does not require calculation of the full off-shell scattering amplitude. Its relation to the more familiar partial-resummation technique is explained. Also included is a calculation of the SD-mixing term that occurs at next-to-next-to-leading-order (NNLO) in pionless effective field theory (EFT¬π). By using the new technique with the SD-mixing term, a complete strictly perturbative phase-shift analysis of nd scattering is performed up to NNLO including eigenphases and mixing angles. This is compared to potential model calculations and good agreement is found with the eigenphases and some of the mixing angles at low energies. © 2013 American Physical Society.

Kaddurah-Daouk R.,Duke University
Translational psychiatry | Year: 2013

In this study, we characterized early biochemical changes associated with sertraline and placebo administration and changes associated with a reduction in depressive symptoms in patients with major depressive disorder (MDD). MDD patients received sertraline or placebo in a double-blind 4-week trial; baseline, 1 week, and 4 weeks serum samples were profiled using a gas chromatography time of flight mass spectrometry metabolomics platform. Intermediates of TCA and urea cycles, fatty acids and intermediates of lipid biosynthesis, amino acids, sugars and gut-derived metabolites were changed after 1 and 4 weeks of treatment. Some of the changes were common to the sertraline- and placebo-treated groups. Changes after 4 weeks of treatment in both groups were more extensive. Pathway analysis in the sertraline group suggested an effect of drug on ABC and solute transporters, fatty acid receptors and transporters, G signaling molecules and regulation of lipid metabolism. Correlation between biochemical changes and treatment outcomes in the sertraline group suggested a strong association with changes in levels of branched chain amino acids (BCAAs), lower BCAAs levels correlated with better treatment outcomes; pathway analysis in this group revealed that methionine and tyrosine correlated with BCAAs. Lower levels of lactic acid, higher levels of TCA/urea cycle intermediates, and 3-hydroxybutanoic acid correlated with better treatment outcomes in placebo group. Results of this study indicate that biochemical changes induced by drug continue to evolve over 4 weeks of treatment and that might explain partially delayed response. Response to drug and response to placebo share common pathways but some pathways are more affected by drug treatment. BCAAs seem to be implicated in mechanisms of recovery from a depressed state following sertraline treatment.

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

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

Huang Y.-C.T.,Duke University
Journal of Occupational and Environmental Medicine | Year: 2014

Although the air quality in Western countries has continued to improve over the past decades, rapid economic growth in developing countries has left air quality in many cities notoriously poor. The World Health Organization estimates that urban outdoor air pollution is estimated to cause 1.3 million deaths worldwide per year. The primary health concerns of outdoor air pollution come from particulate matter less than 2.5 μm (PM2.5) and ozone (O3). Short-term exposure to PM2.5 increases cardiopulmonary morbidity and mortality. Long-term exposure to PM2.5 has been linked to adverse perinatal outcomes and lung cancer. Excessive O3 exposure is known to increase respiratory morbidity. Patients with chronic cardiopulmonary diseases are more susceptible to the adverse effects of air pollution. Counseling these patients about air pollution and the associated risks should be part of the regular management plans in clinical practice. Copyright © 2014 by American College of Occupational and Environmental Medicine.

Swamy G.K.,Duke University
Seminars in Perinatology | Year: 2012

In 2009, approximately 23% of all pregnant women in the United States underwent induction of labor, which is more than double the incidence of 9.5% in 1990. The ultimate goal of labor induction is to achieve vaginal delivery by stimulating uterine contractions before the spontaneous onset of labor. Labor induction is clearly indicated when the benefits outweigh the maternal and fetal risks of continued gestation, as well as potential risks associated with the procedure. Many women undergoing labor induction require cervical ripening-a method to facilitate softening, thinning, and dilation of an unfavorable cervix-because it reduces the time to delivery and incidence of failed induction. This article summarizes currently available methods for labor induction and cervical ripening, advantages and disadvantages of various methods, and the safety and effectiveness of each method based on well-conducted clinical trials. © 2012 Elsevier Inc.

Muller B.,Duke University
Nuclear Physics A | Year: 2013

This lecture presents a concise review of the current status of hard QCD and electromagnetic processes as probes of the quark-gluon plasma. © 2012 Elsevier B.V.

McGuire A.L.,Baylor College of Medicine | Beskow L.M.,Duke University
Annual Review of Genomics and Human Genetics | Year: 2010

There are several features of genetic and genomic research that challenge established norms of informed consent. In this paper, we discuss these challenges, explore specific elements of informed consent for genetic and genomic research conducted in the United States, and consider alternative consent models that have been proposed. All of these models attempt to balance the obligation to respect and protect research participants with the larger social interest in advancing beneficial research as quickly as possible. © 2010 by Annual Reviews. All rights reserved.

Wernegreen J.J.,Duke University
Current Opinion in Microbiology | Year: 2012

Predicting whether and how organisms will successfully cope with climate change presents critical questions for biologists and environmental scientists. Models require knowing how organisms interact with their abiotic environment, as well understanding biotic interactions that include a network of symbioses in which all species are embedded. Bacterial symbionts of insects offer valuable models to examine how microbes can facilitate and constrain adaptation to a changing environment. While some symbionts confer plasticity that accelerates adaptation, long-term bacterial mutualists of insects are characterized by tight lifestyle constraints, genome deterioration, and vulnerability to thermal stress. These essential bacterial partners are eliminated at high temperatures, analogous to the loss of zooanthellae during coral bleaching. Recent field-based studies suggest that thermal sensitivity of bacterial mutualists constrains insect responses. In this sense, highly dependent mutualisms may be the Achilles' heel of thermal responses in insects. © 2012 Elsevier Ltd.

Cullen B.R.,Duke University
Genes and Development | Year: 2011

Analyses of small RNA expression profiles have revealed that several DNA viruses-including particularly, herpesviruses-express high levels of multiple viral microRNAs (miRNAs) in infected cells. Here, I review our current understanding of how viral miRNAs influence viral replication and pathogenesis and discuss how viruses reshape the pattern of cellular miRNA expression. Indeed, viruses are now known to both activate and repress the expression of specific cellular miRNAs, and disrupting this process can perturb the ability of viruses to replicate normally. In addition, it is now clear that virally encoded miRNAs play a key role in inhibiting antiviral innate immune responses and can also promote cell transformation in culture. While our understanding of how viruses interact with miRNAs remains somewhat rudimentary, it is nevertheless already clear that these interactions can play a critical role in mediating viral pathogenesis and therefore may represent novel and highly specific targets for therapeutic intervention. © 2011 by Cold Spring Harbor Laboratory Press.

P2Y12 antagonist therapy improves outcomes in acute myocardial infarction (MI) patients. Novel agents in this class are now available in the US. We studied the introduction of prasugrel into contemporary MI practice to understand the appropriateness of its use and assess for changes in antiplatelet management practices. Using ACTION Registry-GWTG (Get-with-the-Guidelines), we evaluated patterns of P2Y12 antagonist use within 24 hours of admission in 100 228 ST elevation myocardial infarction (STEMI) and 158 492 Non-ST elevation myocardial infarction (NSTEMI) patients at 548 hospitals between October 2009 and September 2012. Rates of early P2Y12 antagonist use were approximately 90% among STEMI and 57% among NSTEMI patients. From 2009 to 2012, prasugrel use increased significantly from 3% to 18% (5% to 30% in STEMI; 2% to 10% in NSTEMI; P for trend <0.001 for all). During the same period, we observed a decrease in use of early but not discharge P2Y12 antagonist among NSTEMI patients. Although contraindicated, 3.0% of patients with prior stroke received prasugrel. Prasugrel was used in 1.9% of patients ≥75 years and 4.5% of patients with weight <60 kg. In both STEMI and NSTEMI, prasugrel was most frequently used in patients at the lowest predicted risk for bleeding and mortality. Despite lack of supporting evidence, prasugrel was initiated before cardiac catheterization in 18% of NSTEMI patients. With prasugrel as an antiplatelet treatment option, contemporary practice shows low uptake of prasugrel and delays in P2Y12 antagonist initiation among NSTEMI patients. We also note concerning evidence of inappropriate use of prasugrel, and inadequate targeting of this more potent therapy to maximize the benefit/risk ratio.

Telen M.J.,Duke University
Hematology/Oncology Clinics of North America | Year: 2014

The pathophysiology of vasoocclusion is thought to involve a wide variety of adhesive interactions involving erythrocytes, leukocytes, and the endothelium. Selectins are expressed by leukocytes, platelets, and the endothelium, among other tissues. They contribute to a wide variety of physiologically important cell-cell interactions, including adhesion of all types of blood cells to the endothelium. In vitro, in vivo, and early-phase clinical studies suggest that E-selectin and pan-selectin inhibitors may be promising new therapeutic agents for the treatment of vasoocclusion in sickle cell disease. © 2014 Elsevier Inc.

Kowalski R.M.,Clemson University | Giumetti G.W.,Quinnipiac University | Schroeder A.N.,Western Kentucky University | Lattanner M.R.,Duke University
Psychological Bulletin | Year: 2014

Although the Internet has transformed the way our world operates, it has also served as a venue for cyberbullying, a serious form of misbehavior among youth. With many of today's youth experiencing acts of cyberbullying, a growing body of literature has begun to document the prevalence, predictors, and outcomes of this behavior, but the literature is highly fragmented and lacks theoretical focus. Therefore, our purpose in the present article is to provide a critical review of the existing cyberbullying research. The general aggression model is proposed as a useful theoretical framework from which to understand this phenomenon. Additionally, results from a meta-analytic review are presented to highlight the size of the relationships between cyberbullying and traditional bullying, as well as relationships between cyberbullying and other meaningful behavioral and psychological variables. Mixed effects meta-analysis results indicate that among the strongest associations with cyberbullying perpetration were normative beliefs about aggression and moral disengagement, and the strongest associations with cyberbullying victimization were stress and suicidal ideation. Several methodological and sample characteristics served as moderators of these relationships. Limitations of the meta-analysis include issues dealing with causality or directionality of these associations as well as generalizability for those meta-analytic estimates that are based on smaller sets of studies (k 5). Finally, the present results uncover important areas for future research. We provide a relevant agenda, including the need for understanding the incremental impact of cyberbullying (over and above traditional bullying) on key behavioral and psychological outcomes. © 2014 American Psychological Association.

Naggie S.,Duke University
Topics in Antiviral Medicine | Year: 2012

Chronic hepatitis C virus (HCV) infection affects some 170 million people worldwide, including 3 to 4 million in the United States who are largely unaware of their infection status. HCV has 6 genotypes; genotype 1 is the most common in the United States and genotypes 1 and 4 are less responsive to interferon alfa-based therapy than the other genotypes. Treatment with available direct-acting antiviral (DAA) drugs has increased sustained virologic response (SVR) rates in genotype 1 infection and shortened duration of therapy in many patients, but at this time these agents must still be administered with peginterferon alfa and ribavirin to prevent rapid emergence of resistance. Baseline predictors of response to therapy continue to play a role with triple-drug combination therapy including the pharmacogenetic IL28B genotype, which differs in prevalence throughout the world. The stopping/futility rules are different for tripledrug combination therapy, allowing for earlier decision-making. Ultimately, SVR is the goal of HCV treatment because it dramatically reduces likelihood of poor long-term outcome, even among patients with histologically advanced disease. This article summarizes a basic review presented by Susanna Naggie, MD, at the IAS-USA live management of HCV continuing medical education program held in Atlanta in October 2012. © 2012, IAS-USA.

Horigan A.E.,Duke University
Journal of Pain and Symptom Management | Year: 2012

Context: End-stage renal disease is a common chronic illness increasing in incidence and prevalence. Although kidney function is partially replaced through dialysis, patients endure many symptoms of the disease such as fatigue. Many factors have been studied regarding their relationship with fatigue in this population. Objectives: To provide a state of the science review regarding fatigue in hemodialysis patients by examining the experience of fatigue for patients on hemodialysis and correlates of fatigue in patients on hemodialysis. Methods: PubMed, the Cumulative Index to Nursing and Allied Health Literature, PsycINFO, and Sociological Abstracts were searched using the key terms "fatigue," "dialysis," and "hemodialysis." Articles written after 1980 and those with explicit findings related to fatigue were included in this review. Articles that discussed fatigue in peritoneal dialysis patients or renal transplant patients were not included. Results: There is little knowledge regarding the experience of fatigue for patients on hemodialysis and there has been little success identifying demographic, psychosocial, or physiological factors that are consistently related to fatigue. Conclusion: Further work in this area of inquiry would be of benefit and may shed light on the domains of life that are affected by fatigue for hemodialysis patients. It also may help deepen our knowledge regarding correlates that could identify hemodialysis patients who are at increased risk for fatigue. © 2012 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Thomas P.A.,Duke University
The journals of gerontology. Series B, Psychological sciences and social sciences | Year: 2010

OBJECTIVES. This study examines the separate effects of several dimensions of giving and receiving social support on the well-being of older adults, with hypotheses guided by identity theory. METHODS: Data derive from the Social Networks in Adult Life survey, a national probability sample of older adults (N = 689). Ordinary least squares regression was used to examine the impact of total support, size of support network, number of types of support, and types of alter support relationships-both given and received-on well-being. RESULTS: Providing support to others is beneficial to older adults' well-being, as illustrated in the relatively strong, positive associations of total support given, the number of types of support given, and support given to friends and children on well-being. Receiving support was less important to well-being except when received from a spouse or sibling. CONCLUSION: Evidence from this analysis provides support for hypotheses predicted by identity theory, highlights the importance of examining giving and receiving support net of the other, and suggests that it is often better for the well-being of older adults to give than to receive.

Zenn M.R.,Duke University
Plastic and Reconstructive Surgery | Year: 2015

Summary: With the increasing popularity and acceptance of nipple-sparing mastectomy with immediate reconstruction comes an associated higher complication rate of nipple and skin necrosis. Historically, management of this risk has been addressed by predictive technologies or staged surgery with placement of an initial tissue expander. Certain high-risk patients, such as those with large cup size, previous surgery, or previous radiation, may not even be considered for an immediate nipple-sparing mastectomy approach due to even higher rates of complications. This report details a delay technique that allows safe preservation of the nipple-sparing mastectomy tissues, even in high-risk individuals, and facilitates straight-to-implant reconstruction without the need for tissue expansion. The aesthetic benefits, time savings, and acceptable complication profile in this series are presented. © 2015 by the American Society of Plastic Surgeons.

Scovazzi G.,Duke University
Journal of Computational Physics | Year: 2012

In the past, a number of attempts have failed to robustly compute highly transient shock hydrodynamics flows on tetrahedral meshes. To a certain degree, this is not a surprise, as prior attempts emphasized enhancing the structure of shock-capturing operators rather than focusing on issues of stability with respect to small, linear perturbations. In this work, a new method is devised to stabilize computations on piecewise-linear tetrahedral finite elements. Spurious linear modes are prevented by means of the variational multiscale approach. The resulting algorithm can be proven stable in the linearized limit of acoustic wave propagation. Starting from this solid base, the approach is generalized to fully nonlinear shock computations, by augmenting the discrete formulation with discontinuity-capturing artificial viscosities. Extensive tests in the case of Lagrangian shock dynamics of ideas gases on triangular and tetrahedral grids confirm the stability and accuracy properties of the method. Incidentally, the same tests also reveal the lack of stability of current compatible/mimetic/staggered discretizations: This is due to the presence of specific unstable modes which are theoretically analyzed and verified in computations. © 2012 .

Despite Food and Drug Administration (FDA) approval of hydroxyurea to reduce the frequency of vaso-occlusive episodes, sickle cell disease (SCD) has continued to be treated primarily with analgesics for pain relief. However, elucidation of the multiple pathophysiologic mechanisms leading to vaso-occlusion and tissue injury in SCD has now resulted in a burgeoning effort to identify new treatment modalities to prevent or ameliorate the consequences of the disease. Development of new drugs as well as investigationof drugs previously used in other settings have targeted cell adhesion, inflammatory pathways, upregulation of hemoglobin F, hemoglobin polymerization and sickling, coagulation, and platelet activation. Although these efforts have not yet yielded drugs ready for FDA approval, several early studies have been extremely encouraging. Moreover, the marked increase in clinical pharmaceutical research addressingSCDand the newandold drugs in the pipelinemake it reasonable to expect that we will soon have new treatments for SCD. © 2016 by The American Society of Hematology.

Summers S.A.,National University of Singapore | Summers S.A.,Duke University
Current Opinion in Lipidology | Year: 2010

Purpose of review: Inhibition of sphingolipid synthesis increases insulin sensitivity, resolves hepatic steatosis, and prevents the onset of diabetes in obese rodents. I herein review these interventional studies, aiming to summarize the five Ws - the 'Who, What, Where, When, and Why' questions that need to be addressed to understand roles of sphingolipids in the pathogenesis of diabetes. Recent findings: Who: ceramides and glucosylceramides are likely to be independent antagonists of insulin action. Where: recent data suggest that ceramides may inhibit insulin action in skeletal muscle, whereas glucosylceramides may be more efficacious in adipose tissue. In contrast, sphingolipid accumulation in the liver appears to be insufficient to induce insulin resistance. What: ceramides and glucosylceramides inhibit different insulin signaling events, but it is unclear whether these actions account for the broad spectrum of therapeutic benefits resulting from sphingolipid depletion. When: recent data suggest that obesity-induced inflammation is important for the induction of sphingolipid synthesis. Why: sphingolipids have an evolutionarily conserved role to starve cells of nutrients, and the inhibition of insulin action is possibly a component of this broader action. Summary: Despite considerable attention to the question of how sphingolipids induce metabolic disease, there exist enormous gaps in knowledge. Further elucidation of these molecular details will be essential for the development of new therapeutic strategies for inhibiting sphingolipid action and ameliorating metabolic diseases. © 2010 Wolters Kluwer Health-Lippincott Williams & Wilkins.

Growing evidence that female ornaments and armaments may be important for female reproductive success suggests that a reevaluation of the costs of these potentially sexually selected traits is also necessary. Here, I examine whether intrasexual aggression, a trait favored during direct female-female competition for nesting sites in tree swallows (Tachycineta bicolor), is costly in terms of the quantity or quality of offspring. I compared measures of female aggressiveness to clutch size, and I also cross-fostered offspring just after hatching to explore a possible causal link between female aggression and nestling mass, an established proxy for offspring quality. High levels of aggression in females were not associated with the quantity of offspring, but instead more aggressive females had offspring of lower quality. While several causal factors appear to influence offspring quality, the mechanism most consistent with this cost of aggression is a trade-off between female aggression and aspects of maternal care. Site differences may create variation in how selection shapes female aggression, but the finding that more aggressive females had lower-quality control offspring indicates that this cost may work counter to selection favoring aggressive behavior in the context of competition over nestboxes. © 2011 Blackwell Verlag GmbH.

Vaupel J.W.,Max Planck Institute for Demographic Research | Vaupel J.W.,University of Southern Denmark | Vaupel J.W.,Duke University
Nature | Year: 2010

Human senescence has been delayed by a decade. This finding, documented in 1994 and bolstered since, is a fundamental discovery about the biology of human ageing, and one with profound implications for individuals, society and the economy. Remarkably, the rate of deterioration with age seems to be constant across individuals and over time: it seems that death is being delayed because people are reaching old age in better health. Research by demographers, epidemiologists and other biomedical researchers suggests that further progress is likely to be made in advancing the frontier of survival and healthy survival to even greater ages. © 2010 Macmillan Publishers Limited. All rights reserved.

Research suggests that spirituality is important to a large percentage of the older adult population and serves as a promoter of healthy aging. In this qualitative research I conducted and analyzed multiple interviews with 6 women aged 80 and older. Using multiple in-depth interviews I explored the interplay between spirituality and resilience over the life course. A grounded theory analysis of the 30 interviews was performed. The major finding is that participants used their spirituality as a tool to promote and maintain resilience in later life. I present the results as an interpretation of the participants' perceptions of their spirituality, and indicate their reliance on spirituality to overcome hardship over the life course. In addition, I discuss the connections between spirituality and resilience. The roles these two constructs play in the lives of older adults are considered. © The Author(s) 2012.

Signaling to the mechanistic target of rapamycin (mTOR) regulates diverse cellular processes, including protein translation, cellular proliferation, metabolism, and autophagy. Most models place Akt upstream of the mTOR complex, mTORC1; however, in T cells, Akt may not be necessary for mTORC1 activation. We found that the adaptor protein Carma1 [caspase recruitment domain (CARD)-containing membrane-associated protein 1] and at least one of its associated proteins, the paracaspase MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1), were required for optimal activation of mTOR in T cells in response to stimulation of the T cell receptor (TCR) and the co-receptor CD28. However, Bcl10, which binds to Carma1 and MALT1 to form a complex that mediates signals from the TCR to the transcription factor NF-κB (nuclear factor κB), was not required. The catalytic activity of MALT1 was required for the proliferation of stimulated CD4+ T cells, but not for early TCR-dependent activation events. Consistent with an effect on mTOR, MALT1 activity was required for the increased metabolic flux in activated CD4+ T cells. Together, our data suggest that Carma1 and MALT1 play previously unappreciated roles in the activation of mTOR signaling in T cells after engagement of the TCR. Copyright © 2014, American Association for the Advancement of Science.

Lyman G.H.,Duke University
Oncologist | Year: 2013

Although randomized controlled trials represent the gold standard for comparative effective research (CER), a number of additional methods are available when randomized controlled trials are lacking or inconclusive because of the limitations of such trials. In addition to more relevant, efficient, and generalizable trials, there is a need for additional approaches utilizing rigorous methodology while fully recognizing their inherent limitations. CER is an important construct for defining and summarizing evidence on effectiveness and safety and comparing the value of competing strategies so that patients, providers, and policymakers can be offered appropriate recommendations for optimal patient care. Nevertheless, methodological as well as political and social challenges for CER remain. CER requires constant and sophisticated methodological oversight of study design and analysis similar to that required for randomized trials to reduce the potential for bias. At the same time, if appropriately conducted, CER offers an opportunity to identify the most effective and safe approach to patient care. Despite rising and unsustainable increases in health care costs, an even greater challenge to the implementation of CER arises from the social and political environment questioning the very motives and goals of CER. Oncologists and oncology professional societies are uniquely positioned to provide informed clinical and methodological expertise to steer the appropriate application of CER toward critical discussions related to health care costs, cost-effectiveness, and the comparative value of the available options for appropriate care of patients with cancer. © AlphaMed Press 2013.

Farese Jr. R.V.,University of California at San Francisco | Zechner R.,University of Graz | Newgard C.B.,Duke University | Walther T.C.,Yale University
Cell Metabolism | Year: 2012

Excessive deposition of fat in the liver (hepatic steatosis) is frequently accompanied by hepatic insulin resistance. Whether this correlation is due to a causal relationship between the conditions has been the subject of considerable debate, and the literature abounds with conflicting data and theories. Here we provide a perspective by defining the problem and its challenges, analyzing the possible causative relationships, and drawing some conclusions. © 2012 Elsevier Inc.

Pisetsky D.S.,Medical Research Service | Pisetsky D.S.,Duke University
Clinical Immunology | Year: 2012

DNA is a polymeric macromolecule whose biological activities depend on location as well as binding to associated molecules. Inside the cell, DNA is the source of genetic information and binds histones to form nucleosomes. DNA can exit the cell, however, to enter the extracellular space primarily during cell death, either apoptosis or necrosis, as well as NETosis. While bacterial DNA is a potent immune stimulant by virtue of its CpG motifs, mammalian DNA, which is ordinarily inactive, can acquire activity by associating with nuclear, cytoplasmic and serum proteins which promote its uptake into cells to stimulate internal DNA sensors, including Toll-like receptor 9. Among these proteins, anti-DNA autoantibodies can form immune complexes with DNA to stimulate plasmacytoid dendritic cells to produce type 1 interferon. Together, these findings suggest that the immune properties of DNA are mutable and diverse, reflecting its context and the array of attached molecules. © 2012 Elsevier Inc.

Hobson-Webb L.D.,Duke University
Muscle and Nerve | Year: 2013

Current standards for diagnosing polyneuropathies (PN) and motor neuron disease (MND) sometimes lack early sensitivity and result in delayed diagnosis and treatment. Neuromuscular ultrasound (NMUS), already established in the diagnosis of entrapment neuropathies, may offer another means of diagnosis and monitoring response to therapy. This review of current evidence discusses diffuse nerve hypertrophy in hereditary demyelinating neuropathies, multifocal nerve enlargement in acquired demyelinating PN and the lack of readily apparent structural change in axonal neuropathies. NMUS detection of fasciculations and muscular change in MND is also reviewed, along with the need for further research to better define the role of nerve imaging in patients with PN. © 2013 Wiley Periodicals, Inc.

It is widely appreciated that larvae of the nematode Caenorhabditis elegans arrest development by forming dauer larvae in response to multiple unfavorable environmental conditions. C. elegans larvae can also reversibly arrest development earlier, during the first larval stage (L1), in response to starvation. "L1 arrest" (also known as "L1 diapause") occurs without morphological modification but is accompanied by increased stress resistance. Caloric restriction and periodic fasting can extend adult lifespan, and developmental models are critical to understanding how the animal is buffered from fluctuations in nutrient availability, impacting lifespan. L1 arrest provides an opportunity to study nutritional control of development. Given its relevance to aging, diabetes, obesity and cancer, interest in L1 arrest is increasing, and signaling pathways and gene regulatory mechanisms controlling arrest and recovery have been char-acterized. Insulin-like signaling is a critical regulator, and it is modified by and acts through microRNAs. DAF-18/PTEN, AMP-activated kinase and fatty acid biosynthesis are also involved. The nervous system, epidermis, and intestine contribute systemically to regulation of arrest, but cell-autonomous signaling likely contributes to regulation in the germline. A relatively small number of genes affecting starvation survival during L1 arrest are known, and many of them also affect adult lifespan, reflecting a common genetic basis ripe for exploration. mRNA expression is well characterized during arrest, recovery, and normal L1 development, providing a metazoan model for nutritional control of gene expression. In particular, post-recruitment regulation of RNA polymerase II is under nutritional control, potentially contributing to a rapid and coordinated response to feeding. The phenomenology of L1 arrest will be reviewed, as well as regulation of developmental arrest and starvation survival by various signaling pathways and gene regulatory mechanisms. © 2013 by the Genetics Society of America.

Treatments that modulate the size of the extracellular space (ECS) also block epileptiform activity in adult brain tissue. This includes the loop diuretics furosemide and bumetanide, and alterations of the osmolarity of the ECS. These treatments block epileptiform activity in a variety of laboratory adult seizure models regardless of the underlying synaptic and physiologic mechanisms generating the seizure activity. Optical imaging studies on adult hippocampal slices show that the blockade of epileptiform activity by these treatments is concomitant with their blockade of activity-driven changes of the ECS. Here we develop and analyze the hypothesis that activity-driven changes in the size of the ECS are necessary for the maintenance of hypersynchronous epileptiform activity. In support of this hypothesis is an accumulation of data from a number of studies suggesting that furosemide and bumetanide mediate antiepileptic effects through their blockade of cell swelling, dependent on their antagonism of the glial Na+-K-2Cl cotransporter (NKCC1). © 2012 International League Against Epilepsy.

Vajzovic L.,Duke University
American journal of ophthalmology | Year: 2012

To correlate human foveal development visualized by spectral-domain optical coherence tomography (SDOCT) with histologic specimens. Retrospective, observational case series. Morphology and layer thickness of retinal SDOCT images from 1 eye each of 22 premature infants, 30 term infants, 16 children, and 1 adult without macular disease were compared to light microscopic histology from comparable ages. SDOCT images correlate with major histologic findings at all time points. With both methods, preterm infants demonstrate a shallow foveal pit indenting inner retinal layers (IRL) and short, undeveloped foveal photoreceptors. At term, further IRL displacement forms the pit and peripheral photoreceptors lengthen; the elongation of inner and outer segments (IS and OS, histology) separates the IS band from retinal pigment epithelium. Foveal IS and OS are shorter than peripheral for weeks after birth (both methods). By 13 months, foveal cone cell bodies stack >6 deep, Henle fiber layer (HFL) thickens, and IS/OS length equals peripheral; on SDOCT, foveal outer nuclear layer (which includes HFL) and IS/OS thickens. At 13 to 16 years, the fovea is fully developed with a full complement of SDOCT bands; cone cell bodies >10 deep have thin, elongated, and tightly packed IS/OS. We define anatomic correlates to SDOCT images from normal prenatal and postnatal human fovea. OCT bands typical of photoreceptors of the adult fovea are absent near birth because of the immaturity of foveal cones, develop by 24 months, and mature into childhood. This validates the source of SDOCT signal and provides a framework to assess foveal development and disease. Copyright © 2012 Elsevier Inc. All rights reserved.

Krystal A.D.,Duke University
The Journal of clinical psychiatry | Year: 2015

Research into the sleep-wake cycle has provided new treatment targets for patients with insomnia as well as a better understanding of how medications affect sleep processes. Current insomnia medications, including benzodiazepines and nonbenzodiazepines, focus on enhancing sleep-promoting systems through broad antagonism of GABA. Other medications that promote sleep by blocking wake-promoting systems include antidepressants, antipsychotics, and antihistamines, but adverse effects and nonspecific therapeutic effects limit their use. New and emerging insomnia medications are focusing on blocking wake-promoting systems via more selective antagonism of orexin, serotonin, and norepinephrine. These medications may offer improved efficacy with fewer adverse effects. © Copyright 2015 Physicians Postgraduate Press, Inc.

Samei E.,Duke University
Physics in medicine and biology | Year: 2013

A method was developed to assess the multi-directional modulation transfer function (MTF) of breast tomosynthesis imaging systems using a sphere phantom. The method was initially developed based on a simulation dataset. Projections were simulated for a uniform voxelized breast phantom with sphere inserts using a fluence modeled from a 28 kVp beam incident upon an indirect flat-panel detector. Based on cascaded systems modeling, characteristic noise and blurring were added to each projection. The projections were reconstructed using a standard filtered backprojection technique, producing a 3D volume with an isotropic voxel size of 200 μm. ROIs that completely encompassed single spheres were extracted and conical regions were prescribed along the three major axes extending from the centroids. Pixels within the cones were used to form edge spread functions (ESFs), from which the directional MTFs were calculated. Binning size and conical range were adjusted to maximize the accuracy and to minimize the noise of the MTF. A method was further devised to remove out-of-plane artifacts from the ESF in the x-y plane. Finally, the method was applied to experimentally assess the directional MTF of a prototype tomosynthesis system. Comparisons of the sphere-based MTF along the different axes and the theoretical MTF yielded good agreement. A 30° angular cone and a 20 μm sampling were found to provide an ideal trade-off between the noise and accuracy of the measurement. The removal of artifacts in ESF yielded 'modified' MTFs that enabled a resolution-only characterization of the in-slice resolution of tomosynthesis. Drop-off frequencies in the x- and y-directional MTFs were 1.6 cycles mm(-1) and 1.5 cycles mm(-1), respectively. The presented method of separating the effective resolution and artifacts from the measured ESF was found experimentally implementable and is expected to facilitate the interpretation of MTF measurements in tomosynthesis.

Heye T.,Duke University
AJR. American journal of roentgenology | Year: 2012

OBJECTIVE: The purpose of this article is to give a brief overview of the technical background of dual-energy CT (DECT) imaging and to review various DECT applications in the abdomen that are currently available for clinical practice. In a review of the recent literature, specific DECT applications available for abdominal organs, liver, pancreas, kidneys including renal stones, and adrenal glands, will be discussed in light of reliability and clinical usefulness in replacing true unenhanced imaging, increased lesion conspicuity, iodine extraction, and improved tissue/material characterization (e.g., renal stone composition). Radiation dose considerations will be addressed in comparison with standard abdominal imaging protocols. CONCLUSION: Modern DECT applications for the abdomen expand the use of CT and enable advanced quantitative methods in the clinical routine on the basis of differences in material attenuation observed by imaging at two different distinct photon energies.

This article uses the Chinese Longitudinal Healthy Longevity Survey to examine the dynamics of living arrangements among the elderly in China. First, the author explores what factors are related to living arrangement preference. In addition, the author looks at a relatively unexplored measure--"living arrangement concordance--"having a match between preferred and actual living arrangements. This article also examines the relationship between concordance, self-rated health, and activities of daily living disability. Living arrangement concordance is high among community-residing elderly, but older Chinese and minority ethnicity are more likely to prefer coresidence with children, while people with higher socioeconomic status and greater family care resources are more likely to prefer living independently. This study gives evidence for person-environment fit theory--older adults with independent living concordance are more likely to have good self-rated health. Older adults who coreside with children, however, are more likely to be disabled, regardless of concordance status. © 2011 The Author(s).

Ortel T.L.,Duke University
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

Perioperative management of antithrombotic therapy is a situation that occurs frequently and requires consideration of the patient, the procedure, and an expanding array of anticoagulant and antiplatelet agents. Preoperative assessment must address each patient's risk for thromboembolic events balanced against the risk for perioperative bleeding. Procedures can be separated into those with a low bleeding risk, which generally do not require complete reversal of the antithrombotic therapy, and those associated with an intermediate or high bleeding risk. For patients who are receiving warfarin who need interruption of the anticoagulant, consideration must be given to whether simply withholding the anticoagulant is the optimal approach or whether a perioperative "bridge" with an alternative agent, typically a low-molecular-weight heparin, should be used. The new oral anticoagulants dabigatran and rivaroxaban have shorter effective half-lives, but they introduce other concerns for perioperative management, including prolonged drug effect in patients with renal insufficiency, limited experience with clinical laboratory testing to confirm lack of residual anticoagulant effect, and lack of a reversal agent. Antiplatelet agents must also be considered in the perioperative setting, with particular consideration given to the potential risk for thrombotic complications in patients with coronary artery stents who have antiplatelet therapy withheld.

Flanagan O.,Duke University
Frontiers in Psychiatry | Year: 2013

Addiction is a person-level phenomenon that involves twin normative failures. A failure of normal rational effective agency or self-control with respect to the substance; and shame at both this failure, and the failure to live up to the standards for a good life that the addict himself acknowledges and aspires to. Feeling shame for addiction is not a mistake. It is part of the shape of addiction, part of the normal phenomenology of addiction, and often a source of motivation for the addict to heal. Like other recent attempts in the addiction literature to return normative concepts such as "choice" and "responsibility" to their rightful place in understanding and treating addiction, the twin normative failure model is fully compatible with investigation of genetic and neuroscientific causes of addiction. Furthermore, the model does not re-moralize addiction. There can be shame without blame. "Dear friends, be men; let shame be in your hearts.. Among men who feel shame, more are saved than die." Ajax to his troops in Homer's Illiad. © 2013 Flanagan.

Sinsabaugh R.L.,University of New Mexico | Manzoni S.,Duke University | Moorhead D.L.,University of Toledo | Richter A.,University of Vienna
Ecology Letters | Year: 2013

Carbon use efficiency (CUE) is a fundamental parameter for ecological models based on the physiology of microorganisms. CUE determines energy and material flows to higher trophic levels, conversion of plant-produced carbon into microbial products and rates of ecosystem carbon storage. Thermodynamic calculations support a maximum CUE value of ~ 0.60 (CUE max). Kinetic and stoichiometric constraints on microbial growth suggest that CUE in multi-resource limited natural systems should approach ~ 0.3 (CUE max/2). However, the mean CUE values reported for aquatic and terrestrial ecosystems differ by twofold (~ 0.26 vs. ~ 0.55) because the methods used to estimate CUE in aquatic and terrestrial systems generally differ and soil estimates are less likely to capture the full maintenance costs of community metabolism given the difficulty of measurements in water-limited environments. Moreover, many simulation models lack adequate representation of energy spilling pathways and stoichiometric constraints on metabolism, which can also lead to overestimates of CUE. We recommend that broad-scale models use a CUE value of 0.30, unless there is evidence for lower values as a result of pervasive nutrient limitations. Ecosystem models operating at finer scales should consider resource composition, stoichiometric constraints and biomass composition, as well as environmental drivers, to predict the CUE of microbial communities. © 2013 John Wiley & Sons Ltd/CNRS.

Sudan D.,Duke University
American Journal of Transplantation | Year: 2014

Intestine transplantation is the least common form of organ transplantation in the United States and often deemed one of the most difficult. Patient and graft survival have historically trailed well behind other organ transplants. Over the past 5-10 years registry reports and single center series have demonstrated improvements to patient survival after intestinal transplantation that now match patient survival for those without life-threatening complications on parenteral nutrition. For various reasons including improvements in medical care of patients with intestinal failure and difficulty accessing transplant care, the actual number of intestine transplants has declined by 25% over the past 6 years. In light of the small numbers of intestine transplants, many physicians and the lay public are often unaware that this is a therapeutic option. The aim of this review is to describe the current indications, outcomes and advances in the field of intestine transplantation and to explore concerns over future access to this important and life-saving therapy. The author reviews the current indications and outcomes for intestine transplantation, including alternative therapies and current research priorities. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.

Muir A.J.,Duke University
American Journal of Gastroenterology | Year: 2014

Hepatitis C virus (HCV) treatment took a major step forward at the end of 2013 with the approvals of the second-generation protease inhibitor simeprevir (Olysio) and the nucleotide polymerase inhibitor sofosbuvir (Sovaldi). The interferon-free regimen of sofosbuvir and ribavirin is now available for genotype 2 and 3 patients. This regimen for 12 weeks is highly effective for genotype 2, whereas genotype 3 has proven to be more challenging and requires 24 weeks of therapy. Genotype 1 patients have reduced exposure to peginterferon-α with a 12-week regimen with sofosbuvir and a 24-week regimen with simeprevir. Genotype 4, 5, and 6 patients also respond well to the regimen of sofosbuvir, peginterferon-α, and ribavirin. In another landmark event, the initial approval of sofosbuvir included HCV/HIV-1 coinfected patients. Simeprevir and sofosbuvir also provide a window to the future with sustained virologic response (SVR) rates of >90% for genotype 1 when these agents are combined. Interferon-free regimens for genotype 1 patients have anticipated approvals in late 2014 or early 2015. Clinicians and patients will have the opportunity to discuss and select from current treatment options or await upcoming regimens. These potent new agents provide the tools to cure HCV for many patients. © 2014 by the American College of Gastroenterology.

Dodd R.D.,Duke University
Oncogene | Year: 2015

Approximately 30% of patients with soft-tissue sarcoma die from pulmonary metastases. The mechanisms that drive sarcoma metastasis are not well understood. Recently, we identified miR-182 as a driver of sarcoma metastasis in a primary mouse model of soft-tissue sarcoma. We also observed elevated miR-182 in a subset of primary human sarcomas that metastasized to the lungs. Here, we show that myogenic differentiation factors regulate miR-182 levels to contribute to metastasis in mouse models. We find that MyoD directly binds the miR-182 promoter to increase miR-182 expression. Furthermore, mechanistic studies revealed that Pax7 can promote sarcoma metastasis in vivo through MyoD-dependent regulation of pro-metastatic miR-182. Taken together, these results suggest that sarcoma metastasis can be partially controlled through Pax7/MyoD-dependent activation of miR-182 and provide insight into the role that myogenic transcription factors have in sarcoma progression.Oncogene advance online publication, 3 August 2015; doi:10.1038/onc.2015.252. © 2015 Macmillan Publishers Limited

Chao N.,Duke University
Blood | Year: 2014

Sinusoidal obstruction syndrome (SOS), previously called veno-occlusive disease (VOD) can be a difficult problem after hematopoietic cell transplantation (HCT). The overall incidence has changed since the early days of allogeneic HCT. Prophylaxis and treatment remain important components of supportive care. As the indication and the comorbidities for HCT continue to change, especially with older and more infirm patients, SOS remains an important area for clinicians. I discuss how SOS could be addressed, from prophylaxis to diagnosis and potential therapy. © 2014 by The American Society of Hematology.

Wang D.,Stanford University | Dong X.,Duke University
Molecular Plant | Year: 2011

Secretion of proteins and other molecules is the primary means by which a cell interacts with its surroundings. The overall organization of the secretory system is remarkably conserved among eukaryotes, and many of the components have been investigated in detail in animal models. Plant cells, because of their sessile lifestyle, are uniquely reliant on the secretory pathway to respond to changes in their environments, either abiotic, such as the absence of nutrients, or biotic, such as the presence of predators or pathogens. In particular, most plant pathogens are extracellular, which demands a robust and efficient host secretory system directed at the site of attack. Here, we present a summary of recent advances in our understanding of the molecular details of the secretory pathway during plant-microbe interactions. Secretion is required not only for the delivery of antimicrobial molecules, but also for the biogenesis of cell surface sensors to detect microbes. The deposition of extracellular material is important in the defense against classical bacterial pathogens as well as in the so-called 'non-host' resistance. Finally, boosting the protein secretion capacity is vital for avoiding infection as well as for achieving symbiosis, even though in the latter case, the microbes are engulfed in intracellular compartments. The emerging evidence indicates that secretion provides an essential interface between plant hosts and their associated microbial partners. © 2011 The Author.

Sun T.-P.,Duke University
Current Biology | Year: 2011

Bioactive gibberellins (GAs) are diterpene phytohormones that modulate growth and development throughout the whole life cycle of the flowering plant. Impressive advances have been made in elucidating the GA pathway with the cloning and characterization of genes encoding most GA biosynthesis and catabolism enzymes, GA receptors (GIBBERELLIN INSENSITIVE DWARF1, GID1) and early GA signaling components. Recent biochemical, genetic and structural analyses demonstrate that GA de-represses its signaling pathway by GID1-induced degradation of DELLA proteins, which are master growth repressors, via a ubiquitin-proteasome pathway. Multiple endogenous signals and environmental cues also interact with the GA-GID1-DELLA regulatory module by affecting the expression of GA metabolism genes, and hence GA content and DELLA levels. Importantly, DELLA integrates different signaling activities by direct protein-protein interaction with multiple key regulatory proteins from other pathways. Comparative studies suggest that the functional GA-GID1-DELLA module is highly conserved among vascular plants, but not in the bryophytes. Interestingly, differentiation of the moss Physcomitrella patens is regulated by as yet unidentified ent-kaurene-derived diterpenes, which are distinct from the common active GAs in vascular plants. © 2011 Elsevier Ltd.

Boyer D.M.,Duke University
American journal of physical anthropology | Year: 2013

Questions surrounding the origin and early evolution of primates continue to be the subject of debate. Though anatomy of the skull and inferred dietary shifts are often the focus, detailed studies of postcrania and inferred locomotor capabilities can also provide crucial data that advance understanding of transitions in early primate evolution. In particular, the hand skeleton includes characteristics thought to reflect foraging, locomotion, and posture. Here we review what is known about the early evolution of primate hands from a comparative perspective that incorporates data from the fossil record. Additionally, we provide new comparative data and documentation of skeletal morphology for Paleogene plesiadapiforms, notharctines, cercamoniines, adapines, and omomyiforms. Finally, we discuss implications of these data for understanding locomotor transitions during the origin and early evolutionary history of primates. Known plesiadapiform species cannot be differentiated from extant primates based on either intrinsic hand proportions or hand-to-body size proportions. Nonetheless, the presence of claws and a different carpometacarpal joint form in plesiadapiforms indicate different grasping mechanics. Notharctines and cercamoniines have intrinsic hand proportions with extremely elongated proximal phalanges and digit rays relative to metacarpals, resembling tarsiers and galagos. But their hand-to-body size proportions are typical of many extant primates (unlike those of tarsiers, and possibly Teilhardina, which have extremely large hands). Non-adapine adapiforms and omomyids exhibit additional carpal features suggesting more limited dorsiflexion, greater ulnar deviation, and a more habitually divergent pollex than observed plesiadapiforms. Together, features differentiating adapiforms and omomyiforms from plesiadapiforms indicate increased reliance on vertical prehensile-clinging and grasp-leaping, possibly in combination with predatory behaviors in ancestral euprimates. Copyright © 2013 Wiley Periodicals, Inc.

Siggers T.,Boston University | Gordan R.,Duke University
Nucleic Acids Research | Year: 2014

Binding of proteins to particular DNA sites across the genome is a primary determinant of specificity in genome maintenance and gene regulation. DNA-binding specificity is encoded at multiple levels, from the detailed biophysical interactions between proteins and DNA, to the assembly of multi-protein complexes. At each level, variation in the mechanisms used to achieve specificity has led to difficulties in constructing and applying simple models of DNA binding. We review the complexities in protein-DNA binding found at multiple levels and discuss how they confound the idea of simple recognition codes. We discuss the impact of new highthroughput technologies for the characterization of protein-DNA binding, and how these technologies are uncovering new complexities in protein-DNA recognition. Finally, we review the concept of multi-protein recognition codes in which new DNAbinding specificities are achieved by the assembly of multi-protein complexes. © 2013 The Author(s). Published by Oxford University Press.

Haase S.B.,Duke University | Wittenberg C.,Scripps Research Institute
Genetics | Year: 2014

Nearly 20% of the budding yeast genome is transcribed periodically during the cell division cycle. The precise temporal execution of this large transcriptional program is controlled by a large interacting network of transcriptional regulators, kinases, and ubiquitin ligases. Historically, this network has been viewed as a collection of four coregulated gene clusters that are associated with each phase of the cell cycle. Although the broad outlines of these gene clusters were described nearly 20 years ago, new technologies have enabled major advances in our understanding of the genes comprising those clusters, their regulation, and the complex regulatory interplay between clusters. More recently, advances are being made in understanding the roles of chromatin in the control of the transcriptional program. We are also beginning to discover important regulatory interactions between the cell-cycle transcriptional program and other cell-cycle regulatory mechanisms such as checkpoints and metabolic networks. Here we review recent advances and contemporary models of the transcriptional network and consider these models in the context of eukaryotic cellcycle controls. © 2014 by the Genetics Society of America.

Person A.K.,Duke University
Telemedicine journal and e-health : the official journal of the American Telemedicine Association | Year: 2011

The objective of this study was to assess knowledge, attitudes, and behaviors surrounding healthcare-related mobile phone use and text messaging among persons at risk for or infected with tuberculosis (TB) or the human immunodeficiency virus (HIV). An anonymous survey was conducted in three groups of subjects: (1) HIV-infected persons attending an HIV clinic; (2) persons with latent TB infection at a public health clinic; and (3) persons presenting for TB, HIV, and syphilis screening at a community screening site. Three hundred fifteen (n =315) persons responded to the survey, of whom 241 (76.5%) owned a cell phone. Cell phone owners were younger and more educated than nonowners. Transportation difficulty and forgetting appointments were cited as significant barriers by 34.2% and 39.5% of respondents, respectively. Fifty-six percent of subjects felt it would be acceptable to receive text message appointment reminders, and 33% felt that text message reminders to take medications would be acceptable. Younger age and cell phone ownership were significantly associated with acceptance of text message reminders. Black and Hispanic subjects were more likely to feel that text message reminders for appointments or medications were helpful than White subjects. Further, Black and Hispanic subjects, as well as subjects with lower educational attainment, were more receptive to healthcare-related educational text messages. Cell phones and text messaging were prevalent among our subjects attending HIV and TB clinics, and subjects were generally receptive to text messaging for healthcare-related communication. Interventions that explore the potential for text messaging to improve clinic attendance, medication adherence, and health knowledge should be explored.

Heitman J.,Duke University
Fungal Biology Reviews | Year: 2011

The fungal kingdom is vast, spanning ∼1.5 to as many as 5 million species diverse as unicellular yeasts, filamentous fungi, mushrooms, lichens, and both plant and animal pathogens. The fungi are closely aligned with animals in one of the six to eight supergroups of eukaryotes, the opisthokonts. The animal and fungal kingdoms last shared a common ancestor ∼1 billion years ago, more recently than other groups of eukaryotes. As a consequence of their close evolutionary history and shared cellular machinery with metazoans, fungi are exceptional models for mammalian biology, but prove more difficult to treat in infected animals. The last common ancestor to the fungal/metazoan lineages is thought to have been unicellular, aquatic, and motile with a posterior flagellum, and certain extant species closely resemble this hypothesized ancestor. Species within the fungal kingdom were traditionally assigned to four phyla, including the basal fungi (Chytridiomycota, Zygomycota) and the more recently derived monophyletic lineage, the dikarya (Ascomycota, Basidiomycota). The fungal tree of life project has revealed that the basal lineages are polyphyletic, and thus there are as many as eight to ten fungal phyla. Fungi that infect vertebrates are found in all of the major lineages, and virulence arose multiple times independently. A sobering recent development involves the species Batrachochytrium dendrobatidis from the basal fungal phylum, the Chytridiomycota, which has emerged to cause global amphibian declines and extinctions. Genomics is revolutionizing our view of the fungal kingdom, and genome sequences for zygomycete pathogens (Rhizopus, Mucor), skin-associated fungi (dermatophytes, Malassezia), and the Candida pathogenic species clade promise to provide insights into the origins of virulence. Here we survey the diversity of fungal pathogens and illustrate key principles revealed by genomics involving sexual reproduction and sex determination, loss of conserved pathways in derived fungal lineages that are retained in basal fungi, and shared and divergent virulence strategies of successful human pathogens, including dimorphic and trimorphic transitions in form. The overarching conclusion is that fungal pathogens of animals have arisen repeatedly and independently throughout the fungal tree of life, and while they share general properties, there are also unique features to the virulence strategies of each successful microbial pathogen. © 2011 The British Mycological Society.

Brown J.L.,Duke University | Brown J.L.,City College of New York
Methods in Ecology and Evolution | Year: 2014

Species distribution models (SDMs) are broadly used in ecological and evolutionary studies. Almost all SDM methods require extensive data preparation in a geographic information system (GIS) prior to model building. Often, this step is cumbersome and, if not properly done, can lead to poorly parameterized models or in some cases, if too difficult, prevents the realization of SDMs. Further, for many studies, the creation of SDMs is not the final result and the post-modelling processing can be equally arduous as other steps. SDMtoolbox is designed to facilitate many complicated pre- and post-processing steps commonly required for species distribution modelling and other geospatial analyses. SDMtoolbox consists of 59 Python script-based GIS tools developed and compiled into a single interface. A large set of the tools were created to complement SDMs generated in Maxent or to improve the predictive performance of SDMs created in Maxent. However, SDMtoolbox is not limited to analyses of Maxent models, and many tools are also available for additional analyses or general geospatial processing: for example, assessing landscape connectivity of haplotype networks (using least-cost corridors or least-cost paths); correcting SDM over-prediction; quantifying distributional changes between current and future SDMs; or for calculating several biodiversity metrics, such as corrected weighted endemism. SDMtoolbox is a free comprehensive python-based toolbox for macroecology, landscape genetic and evolutionary studies to be used in ArcGIS 10.1 (or higher) with the Spatial Analyst extension. The toolkit simplifies many GIS analyses required for species distribution modelling and other analyses, alleviating the need for repetitive and time-consuming climate data pre-processing and post-SDM analyses. © 2014 British Ecological Society.

Mazurowski M.A.,Duke University
Journal of the American College of Radiology | Year: 2015

In recent years, a new direction in cancer research has emerged that focuses on the relationship between imaging phenotypes and genomics. This direction is referred to as radiogenomics or imaging genomics. The question that subsequently arises is: What is the practical significance of elucidating this relationship in improving cancer patient outcomes. In this article, I address this question. Although I discuss some limitations of the radiogenomic approach, and describe scenarios in which radiogenomic analysis might not be the best choice, I also argue that radiogenomics will play a significant practical role in cancer research. Specifically, I argue that the significance of radiogenomics is largely related to practical limitations of currently available data that often lack complete characterization of the patients and poor integration of individual datasets. Radiogenomics offers a practical way to leverage limited and incomplete data to generate knowledge that might lead to improved decision making, and as a result, improved patient outcomes. © 2015 American College of Radiology.

Hickey V.,Duke University
Conservation Biology | Year: 2010

Parks are cornerstones of conservation; and non-native invasive species drive extensive changes to biological diversity in parks. Knowing this, national park staff at Lake Mead National Recreation Area in the southwestern United States had a program in place for early detection of the non-native, invasive quagga mussel (Dreissena rostriformis bugensis. ). Upon finding the mussel in January 2007, managers moved quickly to access funding and the best available science to implement a response. Managers considered four options-doing nothing, closing the park, restricting movement on the lakes, and educating and enforcing park visitors-and decided to focus on education and enforcing existing laws. Nonetheless, quagga spread throughout the park and soon began to appear throughout the western United States. I examined why efforts to control the expansion failed and determined the general lessons to be learned from this case. Concentrating human visitation on the lakes through land-use zoning opened a pathway for invasion, reduced management options, and led to the rapid spread of quagga. To reconcile competing mandates to protect nature and provide recreation, zoning in parks has become a common practice worldwide. It reduces stress on some areas of a park by restricting and thus concentrating human activity in particular areas. Concentrating the human activity in one area does three things: cements pathways that repeatedly import and export vectors of non-native invasive species; creates the disturbed area necessary to enable non-native invasive species to gain a foothold; and, establishes a source of invasions that, without appropriate controls, can quickly spread to a park's wilderness areas. ©2010 Society for Conservation Biology.

Shah A.,Duke University
Current Allergy and Asthma Reports | Year: 2012

Hypersensitivity reactions of the immune system have been broadly categorized into the atopic and autoimmune depending on whether the antigen triggering the reaction is endogenous (or self) or exogenous, the types of cellular and humoral components involved, and the clinical symptoms. Research into the pathophysiology of the resultant disease states has focused on a dichotomy between Th1 and Th2 T helper lymphocytes thought to govern autoimmune and atopic disease, respectively. Recent discoveries, however, have served to dispute this paradigm and have provided additional insight into the roles of Th17 cells, Blymphocytes and T regulatory cells as well as the considerable communication and commonalities between the complex signaling pathways. Furthermore, clinical studies have served to challenge the idea that the presence of atopy and autoimmunity are mutually exclusive states. Finally, application of recent approaches to treatment - biologic targeted therapy in autoimmunity and induction of immune tolerance in atopic disease - to both disease states have shown mixed but promising results. © Springer Science+Business Media, LLC 2012.

Marszalek P.E.,Duke University | Dufrene Y.F.,Catholic University of Louvain
Chemical Society Reviews | Year: 2012

The past years have witnessed remarkable advances in our use of atomic force microscopy (AFM) for stretching single biomolecules, thereby contributing to answering many outstanding questions in biophysics and chemical biology. In these single-molecule force spectroscopy (SMFS) experiments, the AFM tip is continuously approached to and retracted from the biological sample, while monitoring the interaction force. The obtained force-extension curves provide key insight into the molecular elasticity and localization of single molecules, either on isolated systems or on cellular surfaces. In this tutorial review, we describe the principle of such SMFS experiments, and we survey remarkable breakthroughs made in manipulating single polysaccharides and proteins, including understanding the conformational properties of sugars and controlling them by force, measuring the molecular elasticity of mechanical proteins, unfolding and refolding individual proteins, probing protein-ligand interactions, and tuning enzymatic reactions by force. In addition, we show how SMFS with AFM tips bearing specific bioligands has enabled researchers to stretch and localize single molecules on live cells, in relation with cellular functions. © The Royal Society of Chemistry 2012.

Smith S.D.,Duke University
New Phytologist | Year: 2010

The development of comparative phylogenetic methods has provided a powerful toolkit for addressing adaptive hypotheses, and researchers have begun to apply these methods to test the role of pollinators in floral evolution and diversification. One approach is to reconstruct the history of both floral traits and pollination systems to determine if floral trait change is spurred by shifts in pollinators. Looking across multiple shifts, it is also possible to test for significant correlations between floral evolution and pollinators using parsimony, likelihood and Bayesian methods for discrete characters or using statistical comparative methods for continuous characters. Evolutionary shifts in pollinators and floral traits may cause changes in diversification rates, and new methods are available for simultaneously studying character evolution and diversification rates. Relatively few studies have yet used formal comparative methods to elucidate how pollinators affect floral evolution across the phylogeny, and fruitful directions for future applications are discussed. © The Author (2010). Journal compilation © New Phytologist (2010).

Gram-positive bacteria pose a serious healthcare threat. The growing antibiotic resistance epidemic creates a dire need for new antibiotic targets. The sortase family of enzymes is a promising target for antimicrobial therapy. This review covers the current knowledge of the mechanism, substrate specificity, and inhibitory studies of the Gram-positive bacter a enzyme sortase. Copyright (c) 2010 Wiley Periodicals, Inc.

Blackman B.K.,Duke University
Molecular Ecology | Year: 2010

From early allozyme work to recent genome-wide scans, many studies have reported associations between molecular markers and latitude. These geographic patterns are tantalizing because they hint at the possibility of identifying specific mutations responsible for climatic adaptation. Unfortunately, few studies have done so because these exciting first glances often prove extremely challenging to follow up. Many difficulties can hinder connecting genetic and phenotypic variation in this context, and without such links, distinguishing the action of spatially varying selection from the other evolutionary processes capable of generating these patterns can be quite thorny. Nevertheless, two papers in this issue report excellent progress in overcoming these obstacles and provide persuasive evidence supporting the involvement of specific natural variants in clinal adaptation of Drosophila melanogaster populations (Fig. 1). In the first paper, Paaby et al. (2010) describe replicated allele frequency clines for a coding polymorphism in the Insulin-like Receptor (InR) gene on two continents, findings that strongly point to selection acting at this locus and that likely reflect life history adaptation. McKechnie et al. (2010) report compelling functional evidence that cis-regulatory variation in the Dca (drosophila cold acclimation) gene contributes to an adaptive cline in wing size. Notably, these papers employ largely alternative and complementary approaches, and together they exemplify how diverse strategies may be interwoven to draw convincing connections between genotype, phenotype, and evolutionary process. © 2010 Blackwell Publishing Ltd.

Grabowski H.G.,Duke University | Guha R.,Cornerstone Research | Salgado M.,Cornerstone Research
Health Affairs | Year: 2014

In March 2010 Congress established an abbreviated Food and Drug Administration approval pathway for biosimilars-drugs that are very similar but not identical to a reference biological product and cost less. Because bringing biosimilars to the market currently requires large investments of money, fewer biosimilars are expected to enter the biologics market than has been the case with generic drugs entering the small-molecule drug market. Additionally, given the high regulatory hurdles to obtaining interchangeability-which would allow pharmacists to substitute a biosimilar for its reference product, subject to evolving state substitution laws-most biosimilars will likely compete as therapeutic alternatives instead of as therapeutic equivalents. In other words, biosimilars will need to compete with their reference product on the basis of quality; price; and manufacturer's reputation with physicians, insurers, and patient groups. Biosimilars also will face dynamic competition from new biologics in the same therapeutic class-including "biobetters," which offer incremental improvements on reference products, such as extended duration of action. The prospects for significant cost savings from the use of biosimilars appear to be limited for the next several years, but their use should increase over time because of both demand-and supply-side factors. © 2014 Project HOPE-The People-to-People Health Foundation, Inc.

Salama A.K.S.,Duke University | Flaherty K.T.,Massachusetts General Hospital
Clinical Cancer Research | Year: 2013

Selective BRAF inhibitors have now been established as a standard of care option for patients diagnosed with metastatic melanoma whose tumors carry a BRAF mutation. Their successful development represents a milestone in the treatment of this disease, and has the potential to impact therapy for other malignancies as well. The use of these agents, however, has introduced a number of critical questions about the optimal use and selection of patients for BRAF inhibitor therapy. This review discusses the current status of BRAF inhibitor clinical development, the clinicopathologic features of BRAF-mutated melanoma, as well as strategies for overcoming resistance. © 2013 American Association for Cancer Research.

Watkins L.L.,Duke University
Journal of the American Heart Association | Year: 2013

Depression has been related to mortality in coronary heart disease (CHD) patients, but few studies have evaluated the role of anxiety or the role of the co-occurrence of depression and anxiety. We examined whether anxiety is associated with increased risk of mortality after accounting for depression in individuals with established CHD. The cohort was composed of 934 men and women with confirmed CHD (mean age, 62±11 years) who completed the Hospital Anxiety and Depression scale (HADS) during hospitalization for coronary angiography. Over the 3-year follow-up period, there were 133 deaths. Elevated scores on the HADS anxiety subscale (HADS-A≥8) were associated with increased risk of mortality after accounting for established risk factors including age, congestive heart failure, left ventricular ejection fraction, 3-vessel disease, and renal disease (hazard ratio [HR], 2.27; 95% CI, 1.55 to 3.33; P<0.001). Elevated scores on the HADS depression subscale (HADS-D≥8) were also associated with increased risk of mortality (HR, 2.18; 95% CI, 1.47 to 3.22; P<0.001). When both psychosocial factors were included in the model, each maintained an association with mortality (anxiety, HR, 1.83; 95% CI, 1.18 to 2.83; P=0.006; depression, HR, 1.66; 95% CI, 1.06 to 2.58; P=0.025). Estimation of the HR for patients with both anxiety and depression versus those with neither revealed a larger HR than for patients with either factor alone (HR, 3.10; 95% CI, 1.95 to 4.94; P<0.001). Anxiety is associated with increased risk of mortality in CHD patients, particularly when comorbid with depression. Future studies should focus on the co-occurrence of these psychosocial factors as markers of increased mortality risk.

The prevalence of atrial fibrillation (AF) continues to increase; however, there are limited data describing the division of care among practitioners in the community and whether care differs depending on provider specialty. Using the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) Registry, we described patient characteristics and AF management strategies in ambulatory clinic practice settings, including electrophysiology (EP), general cardiology, and primary care. A total of 10 097 patients were included; of these, 1544 (15.3%) were cared for by an EP provider, 6584 (65.2%) by a cardiology provider, and 1969 (19.5%) by an internal medicine/primary care provider. Compared with those patients who were cared for by cardiologists or internal medicine/primary care providers, patients cared for by EP providers were younger (median age, 73 years [interquartile range, IQR, 64, 80 years, Q1, Q3] versus 75 years [IQR, 67, 82 years] for cardiology and versus 76 years [IQR, 68, 82 years] for primary care). Compared with cardiology and internal medicine/primary care providers, EP providers used rhythm control (versus rate control) management more often (44.2% versus 29.7% and 28.8%, respectively, P<0.0001; adjusted odds ratio [OR] EP versus cardiology, 1.66 [95% confidence interval, CI, 1.05 to 2.61]; adjusted OR for internal medicine/primary care versus cardiology, 0.91 [95% CI, 0.65 to 1.26]). Use of oral anticoagulant therapy was high across all providers, although it was higher for cardiology and EP providers (overall, 76.1%; P=0.02 for difference between groups). Our data demonstrate important differences between provider specialties, the demographics of the AF patient population treated, and treatment strategies-particularly for rhythm control and anticoagulation therapy.

Scafetta N.,Active Cavity Radiometer Irradiance Monitor ACRIM Laboratory | Scafetta N.,Duke University
Earth-Science Reviews | Year: 2013

Power spectra of global surface temperature (GST) records (available since 1850) reveal major periodicities at about 9.1, 10-11, 19-22 and 59-62years. Equivalent oscillations are found in numerous multisecular paleoclimatic records. The Coupled Model Intercomparison Project 5 (CMIP5) general circulation models (GCMs), to be used in the IPCC Fifth Assessment Report (AR5, 2013), are analyzed and found not able to reconstruct this variability. In particular, from 2000 to 2013.5 a GST plateau is observed while the GCMs predicted a warming rate of about 2°C/century. In contrast, the hypothesis that the climate is regulated by specific natural oscillations more accurately fits the GST records at multiple time scales. For example, a quasi 60-year natural oscillation simultaneously explains the 1850-1880, 1910-1940 and 1970-2000 warming periods, the 1880-1910 and 1940-1970 cooling periods and the post 2000 GST plateau. This hypothesis implies that about 50% of the ~0.5°C global surface warming observed from 1970 to 2000 was due to natural oscillations of the climate system, not to anthropogenic forcing as modeled by the CMIP3 and CMIP5 GCMs. Consequently, the climate sensitivity to CO2 doubling should be reduced by half, for example from the 2.0-4.5°C range (as claimed by the IPCC, 2007) to 1.0-2.3°C with a likely median of ~1.5°C instead of ~3.0°C. Also modern paleoclimatic temperature reconstructions showing a larger preindustrial variability than the hockey-stick shaped temperature reconstructions developed in early 2000 imply a weaker anthropogenic effect and a stronger solar contribution to climatic changes. The observed natural oscillations could be driven by astronomical forcings. The ~9.1year oscillation appears to be a combination of long soli-lunar tidal oscillations, while quasi 10-11, 20 and 60year oscillations are typically found among major solar and heliospheric oscillations driven mostly by Jupiter and Saturn movements. Solar models based on heliospheric oscillations also predict quasi secular (e.g. ~115years) and millennial (e.g. ~983years) solar oscillations, which hindcast observed climatic oscillations during the Holocene. Herein I propose a semi-empirical climate model made of six specific astronomical oscillations as constructors of the natural climate variability spanning from the decadal to the millennial scales plus a 50% attenuated radiative warming component deduced from the GCM mean simulation as a measure of the anthropogenic and volcano contributions to climatic changes. The semi-empirical model reconstructs the 1850-2013 GST patterns significantly better than any CMIP5 GCM simulation. Under the same CMIP5 anthropogenic emission scenarios, the model projects a possible 2000-2100 average warming ranging from about 0.3°C to 1.8°C. This range is significantly below the original CMIP5 GCM ensemble mean projections spanning from about 1°C to 4°C. Future research should investigate space-climate coupling mechanisms in order to develop more advanced analytical and semi-empirical climate models. The HadCRUT3 and HadCRUT4, UAH MSU, RSS MSU, GISS and NCDC GST reconstructions and 162 CMIP5 GCM GST simulations from 48 alternative models are analyzed. © 2013 Elsevier B.V.

Clark J.S.,Duke University
Trends in Ecology and Evolution | Year: 2012

The Unified Neutral Theory of Biodiversity (UNTB), proposed as an alternative to niche theory, has been viewed as a theory that species coexist without niche differences, without fitness differences, or with equal probability of success. Support is claimed when models lacking species differences predict highly aggregated metrics, such as species abundance distributions (SADs) or species area distributions (SARs). Here, I summarize why UNTB generates confusion, and is not actually relevant to niche theory (i.e. an explanation for why and how many species coexist). Equal probability is not a theory, but lack of one; it does not include or exclude any process relevant to coexistence of competitors. Models lacking explicit species can make useful predictions, but this does not support neutral theory. I provide s suggestions that could help reduce confusion generated by the debate. © 2012 Elsevier Ltd.

Foster M.W.,Duke University
Biochimica et Biophysica Acta - General Subjects | Year: 2012