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Pittsburgh, PA, United States

The University of Pittsburgh is a state-related research university located in Pittsburgh, Pennsylvania. It was founded on the edge of the American frontier as the Pittsburgh Academy in 1787, and evolved into the Western University of Pennsylvania by alteration of its charter in 1819. After surviving two devastating fires and various relocations within the area, the school moved to its current location in the Oakland neighborhood of the city and was renamed to the University of Pittsburgh in 1908. For most of its history Pitt was a private institution, until it became part of the Commonwealth System of Higher Education in 1966.The university is composed of 17 undergraduate and graduate schools and colleges located at its urban Pittsburgh campus, home to the university's central administration and 28,766 undergraduate, graduate, and professional students. The university also includes four additional undergraduate schools located at campuses within Western Pennsylvania: Bradford, Greensburg, Johnstown, and Titusville. The 132-acre Pittsburgh campus comprises multiple historic buildings of the Schenley Farms Historic District, most notably its 42-story gothic revival centerpiece, the Cathedral of Learning. The campus is situated adjacent to the flagship medical facilities of its closely affiliated University of Pittsburgh Medical Center , as well as the Carnegie Museums of Pittsburgh, Schenley Park, and Carnegie Mellon University.The university has an annual operating budget of approximately $2 billion that includes nearly $900 million in research and development expenditures. A member of the Association of American Universities, Pitt is the sixth largest recipient of federally sponsored research funding among U.S. universities in 2013 and is a major recipient of research funding from the National Institutes of Health. It is the second largest non-government employer in the Pittsburgh region behind UPMC. Pitt has been placed among the top public universities in the United States in both domestic and international rankings, and has been listed as a "best value" in higher education by multiple publications.Pitt students have access to various arts programs throughout the campus and city, and can participate in approximately 350 student organizations. Pitt's varsity athletic teams, collectively known as the Pittsburgh Panthers, compete in Division I of the NCAA, primarily as members of the Atlantic Coast Conference. Wikipedia.


Fanselow E.,University of Pittsburgh
Surgical Neurology International | Year: 2012

Stimulation of peripheral cranial nerves has been shown to exert anticonvulsant effects in animal models as well as in human patients. Specifically, stimulation of both the trigeminal and vagus nerves has been shown in multiple clinical trials to be anticonvulsant, and stimulation of these nerves at therapeutic levels does not cause pain or negatively affect brain function. However, the neuronal mechanisms by which such stimulation exerts therapeutic effects are not well understood. In this review, the possible locations of action for trigeminal nerve stimulation (TNS) and vagus nerve stimulation (VNS) are explored. Additionally, the multiple time scales on which TNS and VNS function are discussed. Copyright: © 2012 Fanselow E.


Jacobs R.L.,University of Pittsburgh | Montie J.E.,Taubman Center
CA Cancer Journal for Clinicians | Year: 2010

Bladder cancer is the fourth most common cancer and ranks eighth as a cause of death from cancer among men in the United States. Although guidelines assist in treatment, the art of managing bladder cancer, such as the decision to use neoadjuvant chemotherapy and the timing of cystectomy, is still variable. Bladder cancer has a propensity to recur, and with recurrence, a significant number of cases progress, which makes the early detection of high-risk patients imperative. Advances in detection, surveillance, and treatment of bladder cancer are reviewed in this article. © 2010 American Cancer Society, Inc.


Hemophilia A and B are X-linked disorders caused by deficient or defective clotting factor VIII (FVIII) or IX factor (FIX) proteins, and characterized by spontaneous or traumatic bleeding into joints and muscles. Previous use of plasma and plasma-derived clotting factors that lacked appropriate viral inactivation steps in manufacturing led to significant morbidity associated with transfusion-transmitted HIV and hepatitis C virus (HCV). The development of recombinant proteins revolutionized their treatment, and, with no new HIV or HCV infection via clotting proteins for nearly 30 years, greatly improved their lifespan, which now approaches that of the general population, and with the same risks for aging complications. Novel long-acting factor proteins are being licensed to extend FVIII and FIX half-life, thereby reducing infusion frequency and potentially bleed frequency and associated morbidity. Further, novel therapeutics which take advantage of new technologies, including siRNA, monoclonal antibody, and small peptide inhibition technologies, have the potential to simplify treatment and improve outcomes for those with inhibitors. © 2015 Springer International Publishing Switzerland.


Qin J.,Cleveland Clinic | Wu C.,University of Pittsburgh
Current Opinion in Cell Biology | Year: 2012

Integrin-linked kinase (ILK) is a widely expressed and evolutionally conserved component of cell-extracellular matrix (ECM) adhesions. Although initially named as a kinase, ILK contains an unusual pseudoactive site that is incapable of catalyzing phosphorylation. Instead, ILK acts as a central component of a heterotrimer (the PINCH-ILK-parvin complex) at ECM adhesions mediating interactions with a large number of proteins via multiple sites including its pseudoactive site. Through higher level protein-protein interactions, this scaffold links integrins to the actin cytoskeleton and catalytic proteins and thereby regulates focal adhesion assembly, cytoskeleton organization and signaling. This review summarizes recent advances in our understanding of the structure and functions of the PINCH-ILK-parvin complex, and discusses emerging new features of the molecular mechanisms by which it regulates diverse cellular, physiological and pathological processes. © 2012 Elsevier Ltd.


Thomson A.W.,University of Pittsburgh
American Journal of Transplantation | Year: 2010

Although well-recognized for their sentinel role and, when activated, their immunostimulatory function, bone marrow-derived dendritic cells (DC) possess inherent tolerogenic (tol) ability. Under quiescent conditions, these cells maintain central and peripheral self tolerance. When appropriately conditioned, in vitro or in vivo, they inhibit innate and adaptive immunity to foreign antigens, including memory T-cell responses. This suppressive function is mediated by various mechanisms, including the expansion and induction of antigen-specific regulatory T cells. Extensive experience in rodent models and recent work in nonhuman primates, indicate the potential of pharmacologically- modified, tol DC (tolDC) to regulate alloimmunity in vivo and to promote lasting, alloantigen-specific T-cell unresponsiveness and transplant survival. While there are many questions yet to be addressed concerning the functional biology of tolDC in humans, these cells offer considerable potential as natural, safe and antigen-specific regulators for long-term control of the outcome of organ and hematopoietic cell transplantation. This minireview surveys recent findings that enhance understanding of the functional biology and therapeutic application of tolDC, with special reference to transplantation. © 2009 The American Society of Transplantation and the American Society of Transplant Surgeons.


Wright A.G.C.,University of Pittsburgh
IEEE Transactions on Affective Computing | Year: 2014

The past 20 years have seen dramatic advances in personality science, both in theory and methodology. Some of these advances reflect a natural but incremental conceptual evolution in a maturing science, but others can be attributed in part to the ever cheaper, more ubiquitous, powerful, and mobile computing. As a result, personality science in the 21st century is a fast-moving field poised to answer important questions across diverse areas, but it is also facing increasingly complex challenges related to assessing and summarizing the important features of human behavior. Computer science and engineering may hold the key to the next advances in personality science. In what is intended to serve as a complement to Vinciarelli and Mohammadi's Survey on Personality Computing , contemporary thinking and research in personality are summarized, the mounting importance of computing in personality research is highlighted, and an outline for future directions in personality computing is offered. © 2014 IEEE.


Vainchtein A.,University of Pittsburgh
Journal of the Mechanics and Physics of Solids | Year: 2010

We consider a one-dimensional chain of phase-transforming springs with harmonic long-range interactions. The nearest-neighbor interactions are assumed to be trilinear, with a spinodal region separating two material phases. We derive the traveling wave solutions governing the motion of an isolated phase boundary through the chain and obtain the functional relation between the driving force and the velocity of a phase boundary which can be used as the closing kinetic relation for the classical continuum theory. We show that a sufficiently wide spinodal region substantially alters the phase boundary kinetics at low velocities and results in a richer solution structure, with phase boundaries emitting short-length lattice waves in both direction. Numerical simulations suggest that solutions of the Riemann problem for the discrete system converge to the obtained traveling waves near the phase boundary. © 2009 Elsevier Ltd. All rights reserved.


The stress-negative affect model for alcohol use was examined. The mediating roles of different components of negative affect were tested in the context of coping style. Data from 1,057 drinking adults (Mage = 44.45) and 352 drinking college students (Mage = 19.07) collected during 2001-2005 and in 2010, respectively, were examined separately. Participants completed self-administered measures of alcohol use, coping strategies, negative life events, and negative affect. A structural equation modeling framework detected stress-related drinking only in the adult sample. Sadness, anger, and guilt were significant mediators and the significant pathways differed based on coping style. The implications and limitations of the study are discussed.


Seethala R.R.,University of Pittsburgh
Head and Neck Pathology | Year: 2013

Epithelial myoepithelial carcinoma (EMCa) is a rare but well characterized biphasic salivary gland malignancy with several variant morphologies. Oncocytic and apocrine EMCa are uncommon variants that constitute up to 8 % of all EMCa. Both variants invoke an eosinophilic or oncocytic differential diagnosis and challenge the traditional requirement of clear myoepithelial cells for EMCa. Oncocytic EMCa occurs in patients a decade older than conventional EMCa. This variant is often papillary with calcification and associated with sebaceous components and occurs in older individuals. Apocrine EMCa is named for its apocrine ductal component, which may be mistaken for salivary duct carcinoma. In this variant, the epithelial component often shows overgrowth in a cribriform or even solid pattern and is immunophenotypically defined by androgen receptor and gross cystic disease fluid protein 15 positivity. The most important aspect of differentiating both oncocytic and apocrine EMCa from other salivary oncocytic tumors is recognition of the biphasic nature of these variants and confirmation that the abluminal outer layer consists of plump, 'activated' myoepithelial cells, regardless of tinctorial characteristics. Both oncocytic and apocrine EMCa behave very indolently in the limited literature to date. © 2013 Springer Science+Business Media New York.


McGowan I.,University of Pittsburgh
Current Opinion in Infectious Diseases | Year: 2010

PURPOSE OF REVIEW: This review discusses recent developments within the field of microbicide development and considers whether there are grounds to be hopeful that it will be possible to develop a microbicide for the prevention of HIV infection. RECENT FINDINGS: Phase 2B/3 effectiveness studies of surfactant and polyanion vaginal microbicides have demonstrated modest or no effect against HIV infection and in the case of nonoxynol-9 and cellulose sulfate the potential to increase the risk of HIV acquisition. However, newer antiretroviral microbicide candidates, such as tenofovir, have shown good safety and significant efficacy in animal models and human tissue explant systems and are currently being evaluated in human effectiveness studies. New formulation platforms, such as vaginal rings, are being developed to optimize product acceptability and adherence, and far greater scrutiny of candidate microbicides is happening at both the preclinical and early clinical phase of development. SUMMARY: Drug development is an inherently high-risk activity and many promising candidates are discarded due to safety issues or lack of efficacy. Lessons learned over the last two decades have helped to improve the microbicide development pathway and provide hope that it will be possible to develop a safe and effective microbicide for HIV prevention. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Sparacino-Watkins C.,Duquesne University | Sparacino-Watkins C.,University of Pittsburgh | Stolz J.F.,Duquesne University | Basu P.,Duquesne University
Chemical Society Reviews | Year: 2014

The nitrate anion is a simple, abundant and relatively stable species, yet plays a significant role in global cycling of nitrogen, global climate change, and human health. Although it has been known for quite some time that nitrate is an important species environmentally, recent studies have identified potential medical applications. In this respect the nitrate anion remains an enigmatic species that promises to offer exciting science in years to come. Many bacteria readily reduce nitrate to nitrite via nitrate reductases. Classified into three distinct types-periplasmic nitrate reductase (Nap), respiratory nitrate reductase (Nar) and assimilatory nitrate reductase (Nas), they are defined by their cellular location, operon organization and active site structure. Of these, Nap proteins are the focus of this review. Despite similarities in the catalytic and spectroscopic properties Nap from different Proteobacteria are phylogenetically distinct. This review has two major sections: in the first section, nitrate in the nitrogen cycle and human health, taxonomy of nitrate reductases, assimilatory and dissimilatory nitrate reduction, cellular locations of nitrate reductases, structural and redox chemistry are discussed. The second section focuses on the features of periplasmic nitrate reductase where the catalytic subunit of the Nap and its kinetic properties, auxiliary Nap proteins, operon structure and phylogenetic relationships are discussed. © The Royal Society of Chemistry.


Wang M.-T.,University of Pittsburgh | Kenny S.,University of Michigan
Child Development | Year: 2014

This study used cross-lagged modeling to examine reciprocal relations between maternal and paternal harsh verbal discipline and adolescents' conduct problems and depressive symptoms. Data were from a sample of 976 two-parent families and their children (51% males; 54% European American, 40% African American). Mothers' and fathers' harsh verbal discipline at age 13 predicted an increase in adolescent conduct problems and depressive symptoms between ages 13 and 14. A child effect was also present, with adolescent misconduct at age 13 predicting increases in mothers' and fathers' harsh verbal discipline between ages 13 and 14. Furthermore, maternal and paternal warmth did not moderate the longitudinal associations between mothers' and fathers' use of harsh verbal discipline and adolescent conduct problems and depressive symptoms. © 2013 Society for Research in Child Development, Inc.


Collins S.,University of Pittsburgh
American journal of obstetrics and gynecology | Year: 2015

OBJECTIVE: The objective of the study was to evaluate the differences in vaginal culture, microscopy, and Gram stain between postmenopausal women who wear pessaries and those who do not to explain pessary-related, bothersome vaginal discharge.STUDY DESIGN: Postmenopausal women not using exogenous estrogen who had either been wearing a pessary for at least 3 months or who were undergoing their first pessary fittings were approached for enrollment. Symptoms were assessed, and vaginal fluid was collected for culture, microscopy, and Gram stain. A cross-sectional analysis was performed, comparing the new and return pessary wearers. The new pessary users were also sampled at 2 weeks, 3 months, and 6 months after fitting.RESULTS: Women who wore pessaries were more likely to be bothered by discharge (30.0% vs 2.1%, P < .001). They were also more likely to show microscopic evidence of vaginal inflammation and vaginitis. Prospective data showed that these changes developed during the first 2 weeks of pessary use. Aerobic and anaerobic organisms were nearly identical in women with and without bothersome vaginal discharge in the cross-sectional analysis and at all time points in the prospective analysis.CONCLUSION: Pessary-related, bothersome vaginal discharge develops early and may be due to an inflammatory process in the vagina. Copyright © 2015 Elsevier Inc. All rights reserved.


Niedermaier M.,University of Pittsburgh
Nuclear Physics B | Year: 2013

The strong coupling limit of Einstein gravity in d+1 dimensions gives rise to a quantum theory where after factorization of the conformal factor mode SL(d,R)/SO(d) nonlinear sigma-models are spatially coupled by the diffeomorphism constraint. A functional integral representation for the theory?s propagation kernel is derived in completions of the proper time gauge which manifestly invokes only physical gauge invariant degrees of freedom. In the weak field limit it reduces to the propagation kernel of massless and transversal-traceless free fields. For strong fields a covariant normal coordinate expansion is developed which covers the configuration manifold globally. Its leading order approximant resembles a semiclassical propagation kernel but without the need to solve the classical constraints. The results have implications for the ground state structure of quantum gravity. © 2013 Elsevier B.V.


Fuschiotti P.,University of Pittsburgh
Cytokine | Year: 2011

Systemic sclerosis (SSc) has the highest fatality rate among connective tissue diseases and is characterized by vascular damage, inflammation and fibrosis. Currently, no therapy has proven effective in modifying the course of SSc, a reflection of its complex pathogenesis. T cell-derived cytokines have been implicated in the induction of fibrosis. The role of the pro-fibrotic type 2 cytokine IL-13 and its regulation appear to be important in the pathogenesis of SSc and other fibrotic disorders. Recent work has shown that dysregulated production of IL-13 by effector CD8 + T cells is critical for predisposing patients to more severe forms of cutaneous disease and that this dysregulation is associated with defects in the molecular control of IL-13 production, such as increased expression of the transcription factor GATA-3. Silencing of GATA-3 with siRNA significantly reduces IL-13 production by CD8 + T cells from patients. We review these new insights into SSc pathogenesis that will enable establishment of highly relevant biomarkers of immune dysfunction in patients predisposed to develop SSc and open new possibilities for development of more specific diagnosis and treatment. © 2011 Elsevier Ltd.


Wang M.-T.,University of Pittsburgh | Huguley J.P.,Harvard University
Child Development | Year: 2012

This study investigated whether parental racial socialization practices moderated the relation between racial discrimination in school and adolescents' educational outcomes. Using data from a longitudinal study of an economically diverse sample of 630 African American adolescents (mean age=14.5) from a major East Coast metropolis, the results revealed that cultural socialization attenuated the effect of teacher discrimination on grade point average (GPA) and educational aspirations, as well as the effect of peer discrimination on GPA. Also, preparation for bias and cultural socialization interacted to make unique contributions to African American adolescents' educational outcomes. Finally, there was some evidence that teacher discrimination was more detrimental to the academic engagement of African American males than females. Implications for research and practice are discussed. © 2012 The Authors. Child Development © 2012 Society for Research in Child Development, Inc.


Perkins K.A.,University of Pittsburgh
Expert Opinion on Drug Discovery | Year: 2014

Introduction: One obstacle to rapid development of new smoking cessation medications is the inefficient early clinical evaluation of the efficacy of novel drugs, which inform us as to whether or not to proceed with the greater expense and time of more formal clinical trials. The vast majority of novel drugs fail to show efficacy for cessation only after substantial resources have been spent and, thus, are largely wasted.Areas covered: The author reviews the general limitations in the current typical procedures for initial tests of cessation efficacy in novel drugs. Small, randomized clinical trials often have good validity but may have practical limitations in achieving adequate statistical power to test novel versus placebo treatment conditions. Lab tests of acute drug effects on abstinence symptoms, during brief enforced cessation periods, are practical but have limited clinical predictive validity.Expert opinion: Initial efficacy testing may be more efficient if done using innovative crossover designs that evaluate brief 'practice' quit periods for both active and placebo treatments within the same smokers, recruiting those high in quit motivation. Because this approach would require far fewer subjects and a shorter duration of testing, results could be obtained more rapidly and inexpensively to indicate that a novel drug may, or may not, be sufficiently efficacious as to warrant the greater costs and time of formal randomized clinical trials. © Informa UK, Ltd.


Pruhs K.,University of Pittsburgh
Proceedings - Annual IEEE Symposium on Foundations of Computer Science, FOCS | Year: 2011

The converging trends of society's desire/need for more sustainable technologies, exponentially increasing power densities within computing devices, and exponentially more computing devices, have inevitably pushed power and energy management into the forefront of computing design and management for purely economic reasons. Thus we are in the midst of a green computing revolution involving the redesign of information technology hardware and software at all levels of the information technology stack. This revolution has spawned a multitude of technological challenges, many of which are algorithmic in nature. We provide pointers into the literature on the green computing algorithmics. © 2011 IEEE.


Gardella T.J.,Massachusetts General Hospital | Vilardaga J.-P.,University of Pittsburgh
Pharmacological Reviews | Year: 2015

The type-1 parathyroid hormone receptor (PTHR1) is a family B G protein–coupled receptor (GPCR) that mediates the actions of two polypeptide ligands; parathyroid hormone (PTH), an endocrine hormone that regulates the levels of calcium and inorganic phosphate in the blood by acting on bone and kidney, and PTHrelated protein (PTHrP), a paracrine-factor that regulates cell differentiation and proliferation programs in developing bone and other tissues. The type-2 parathyroid hormone receptor (PTHR2) binds a peptide ligand, called tuberoinfundibular peptide-39 (TIP39), and while the biologic role of the PTHR2/TIP39 system is not as defined as that of the PTHR1, it likely plays a role in the central nervous systemaswell as in spermatogenesis.Mechanisms of action at these receptors have been explored through a variety of pharmacological and biochemical approaches, and the data obtained support a basic “two-site” mode of ligand binding now thought to be used by each of the family B peptide hormone GPCRs. Recent crystallographic studies on the family B GPCRs are providing new insights that help to further refine the specifics of the overall receptor architecture and modes of ligand docking. One intriguing pharmacological finding for the PTHR1 is that it can form surprisingly stable complexes with certain PTH/PTHrP ligand analogs and thereby mediate markedly prolonged cell signaling responses that persist even when the bulk of the complexes are found in internalized vesicles. The PTHR1 thus appears to be able to activate the Gas/cAMP pathway not only from the plasma membrane but also from the endosomal domain. The cumulative findings could have an impact on efforts to develop new drug therapies for the PTH receptors. © 2015 by The American Society for Pharmacology and Experimental Therapeutics.


Butterfield L.H.,University of Pittsburgh
BMJ (Online) | Year: 2015

Cancer vaccines are designed to promote tumor specific immune responses, particularly cytotoxic CD8 positive T cells that are specific to tumor antigens. The earliest vaccines, which were developed in 1994-95, tested non-mutated, shared tumor associated antigens that had been shown to be immunogenic and capable of inducing clinical responses in a minority of people with late stage cancer. Technological developments in the past few years have enabled the investigation of vaccines that target mutated antigens that are patient specific. Several platforms for cancer vaccination are being tested, including peptides, proteins, antigen presenting cells, tumor cells, and viral vectors. Standard of care treatments, such as surgery and ablation, chemotherapy, and radiotherapy, can also induce antitumor immunity, thereby having cancer vaccine effects. The monitoring of patients' immune responses at baseline and after standard of care treatment is shedding light on immune biomarkers. Combination therapies are being tested in clinical trials and are likely to be the best approach to improving patient outcomes.


Chelly J.E.,University of Pittsburgh
Anesthesiology Clinics | Year: 2012

Paravertebral blocks have been demonstrated to represent an interesting alternative to epidural, especially for the management of perioperative and trauma pain. Initially performed mostly as single-shot blocks for breast surgery, thoracotomy, and hernia repairs in adults and children, presently these blocks are also used for placement of a paravertebral catheter, either unilateral or bilateral. Although complications associated with the performance of these blocks are infrequent, the use of ultrasound-guided approaches, which allow performing the block under direct vision, is becoming the standard in most groups performing these blocks routinely. © 2012 Elsevier Inc..


McEwen B.S.,Rockefeller University | Gianaros P.J.,University of Pittsburgh
Annual Review of Medicine | Year: 2011

The brain is the key organ of stress processes. It determines what individuals will experience as stressful, it orchestrates how individuals will cope with stressful experiences, and it changes both functionally and structurally as a result of stressful experiences. Within the brain, a distributed, dynamic, and plastic neural circuitry coordinates, monitors, and calibrates behavioral and physiological stress response systems to meet the demands imposed by particular stressors. These allodynamic processes can be adaptive in the short term (allostasis) and maladaptive in the long term (allostatic load). Critically, these processes involve bidirectional signaling between the brain and body. Consequently, allostasis and allostatic load can jointly affect vulnerability to brain-dependent and stress-related mental and physical health conditions. This review focuses on the role of brain plasticity in adaptation to, and pathophysiology resulting from, stressful experiences. It also considers interventions to prevent and treat chronic and prevalent health conditions via allodynamic brain mechanisms. © 2011 by Annual Reviews. All rights reserved.


Bagic A.,University of Pittsburgh
Clinical Neurophysiology | Year: 2016

This review considers accumulating evidence for a new role of MEG/MSI in increasing the diagnostic yield of supposedly negative MRIs, and suggests changes in the use of MEG/MSI in presurgical epilepsy evaluations. Specific alterations in practice protocols for both the MEG practitioner (i.e. physician magnetoencephalographer) and MEG user (i.e. referring physician) are proposed that should further enhance the overall value of MEG/MSI. Although advances in MEG analysis methods will likely become increasingly assisted by computers, interpretive competency and prudent clinical judgment remain irreplaceable. © 2015 International Federation of Clinical Neurophysiology.


Bielefeldt K.,University of Pittsburgh
Alimentary Pharmacology and Therapeutics | Year: 2013

Background Expert consensus defines biliary dyskinesia as a rare disorder of the gall-bladder characterised by pain and impaired gall-bladder function. Aim To determine trends in cholecystectomy rates for biliary dyskinesia in the United States. Methods As biliary dyskinesia does not have a distinct diagnosis code, the narrative diagnoses for patients were reviewed and abstracted for 200 patients treated for the most commonly used diagnosis codes for biliary dyskinesia (validation sample). Time trends in cholecystectomies and hospitalisations for biliary diseases were assessed using the Nationwide Inpatient Sample (Agency for Healthcare Research and Quality) based on codes for cholecystectomy and diagnosis codes for different biliary disorders. Results In the validation sample, biliary dyskinesia accounted for 81% of the patients with ICD-9 code 575.8 (gall-bladder disease not elsewhere specified). Between 1997 and 2010, admissions for acute cholecystitis and complications of gallstone disease decreased slightly, whereas admissions with the primary diagnosis code ICD-9 575.8 tripled. This rise was most pronounced in the paediatric population (700% increase), with biliary dyskinesia accounting for more than 10% of cholecystectomies. Compared with acute biliary diseases, significantly more of the elective hospitalisations were covered by private insurances. Conclusions Practice patterns differ from expert opinion, with biliary dyskinesia accounting for an increasing fraction of cholecystectomies. The rise in these elective interventions is associated with a shift to a younger, low risk and predominantly privately insured population. Considering the benign nature of biliary dyskinesia, it is time to reassess the need for operative interventions, which have never been compared with active conservative therapy. © 2012 Blackwell Publishing Ltd.


Brownell C.A.,University of Pittsburgh
Infancy | Year: 2013

Prosocial behavior first appears in the second year of life. How can prosociality so early in life be explained? One possibility is that infants possess specialized cognitive and/or social capacities that drive its emergence. A second possibility is that prosocial behavior emerges out of infants' shared activities and relationships with others. These possibilities have motivated a number of current explanatory efforts, with a focus on two complementary questions. First, what is evolutionarily prepared in the very young child and how does it give rise to prosocial behavior? Second, how do proximal mechanisms, including social experiences, contribute to the early development of prosociality? The papers in this special issue represent some of the most recent work on these questions. They highlight a diverse array of new methods and bring them to bear on the nature and development of early prosocial understanding and behavior. © International Society on Infant Studies (ISIS).


Stommel M.,Michigan State University | Osier N.,University of Pittsburgh
International Journal of Obesity | Year: 2013

Objectives:To investigate temporal changes in the bias associated with self-reported (as opposed to measured) body mass index (BMI) and explore the relationship of such bias to changing social attitudes towards obesity.Methods:Using data from the National Health and Nutrition Examination Survey covering two time periods, 1988-1994 and 2005-2008, discrepancy scores between self-reported vs measured BMI were generated. Changes in the sensitivity of BMI categories based on self-reports were examined for six weight groups, both for the US adult population as a whole and major demographic groups. Linear regression models were used to examine temporal changes in average bias, as well as attitudes about weight within each weight category and by demographic group.Results:Between 2005-2008 and 1988-1994, the bias towards underestimation of a person's BMI based on interview responses has declined among obese individuals, a trend evident in virtually all demographic subgroups explored. Conversely, most demographic groups showed little change in the extent of bias among underweight and normal-weight individuals. Although the 2005-2008 survey respondents underestimated their measured BMI more than the 1988-1994 respondents, this shift can be entirely explained by the increased prevalence of obesity in more recent years. In fact, obese individuals in 2005-2008 were less likely to overreport their height and underreport their weight than their counterparts in the 1988-1994. Evidence from responses to questions about ideal weight and desire to lose weight point in the direction of a shift in social attitudes, which may make it easier to 'admit' to greater weight in surveys.Conclusion:Over the past 20 years, the bias in self-reported height and weight has declined leading to more accurate BMI categorizations based on self-report. This change is likely to affect efforts to find correction factors to adjust BMI scores based on self-reported height and weight.


Morris S.M.,University of Pittsburgh
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2012

Purpose of review Many physiologic and pathophysiologic processes are modulated by arginine availability, which can be regulated by arginase. An understanding of the conditions that result in elevated arginase activity as well as the consequences of arginine deficiency is essential for design of effective nutritional support for disease. This review will emphasize recent findings regarding effects of plasma arginase and arginine deficiencies in disease. Recent findings Elevations in plasma arginase, derived primarily from hemolysis of red blood cells or liver damage, that are associated with arginine deficiency have been identified in an increasing number of diseases and conditions. Arginine insufficiency not only can activate a stress kinase pathway that impairs function of T lymphocytes but it also can inhibit the mitogen-activated protein kinase signaling pathway required for macrophage production of cytokines in response to bacterial endotoxin/lipopolysaccharide. There are at least two broad categories of arginine deficiency syndromes, involving either T-cell dysfunction or endothelial dysfunction, depending on the disease context in which arginine deficiency occurs. There is limited information regarding the safety and efficacy of supplementation with arginine or its precursor citrulline in ameliorating arginine deficiency in specific diseases, indicating the need for further studies. © 2011 Wolters Kluwer Health.


Howland R.H.,University of Pittsburgh
Drug Safety | Year: 2011

Agomelatine is an antidepressant drug that is a synthetic analogue of the hormone melatonin. It stimulates the activity of melatonin MT 1 and MT 2 receptors and inhibits the activity of serotonin 5HT 2C receptor subtypes.The objective of this article is to critically review and evaluate the benefits and risks of agomelatine for the treatment of major depression. The published literature through April 2011 for articles relating to agomelatine, together with unpublished data on agomelatine available from the European Medicines Agency, the US FDA, US ClinicalTrials.gov and the Novartis Clinical Trial Results Database are reviewed.The antidepressant efficacy of agomelatine has been systematically assessed in ten short-term, placebo-controlled studies and three longer-term, placebo-controlled, relapse prevention studies. Five short-term trials demonstrated clinically modest, but statistically significant, benefits over placebo, although two of these studies reported opposite effects for 25mg versus 50mg doses. The other five short-term trials did not find agomelatine more effective than placebo, but in two of these studies the active control drug was more effective than placebo.A meta-analysis of six European trials demonstrated a small, statistically significant, marginally clinically relevant difference in efficacy favouring agomelatine over placebo. The only placebo-controlled study in elderly patients did not demonstrate a significant benefit for agomelatine. Agomelatine was shown to be more effective than placebo in one of three relapse prevention studies.Agomelatine was generally well tolerated compared with placebo. Its adverse effect profile is different to that of other antidepressant drugs, but its overall tolerability in studies with other antidepressants as active control drugs did not appear to be substantially better than the controls. Agomelatine is contraindicated in patients with impaired liver function and in patients taking drugs that potently inhibit cytochrome P450 1A2 metabolic enzymes. Because elevated liver enzymes are common, and there is a rare risk of more serious liver reactions, routine laboratory monitoring of liver function is recommended periodically throughout treatment. Based on this comprehensive review, agomelatine does not have clinically significant advantages compared with other antidepressant drugs, and it has certain limitations and disadvantages. Because of the unique pharmacology of agomelatine and its reported tolerability profile, it should only be considered as an alternative drug for patients who do not respond to or cannot tolerate other antidepressant drugs. © 2011 Adis Data Information BV. All rights reserved.


Previous studies in late-life depression (LLD) have found that patients have altered intrinsic functional connectivity in the dorsal default mode network (DMN) and executive control network (ECN). We aimed to detect connectivity differences across a treatment trial among LLD patients as a function of remission status. LLD patients (N=37) were enrolled into a 12-week trial of venlafaxine and underwent five functional magnetic resonance imaging resting state scans during treatment. Patients had no history of drug abuse, psychosis, dementia/neurodegenerative diseases or medical conditions with known effects on mood. We investigated whether there were differences in three networks: DMN, ECN and anterior salience network connectivity, as well as a whole brain centrality measure (eigenvector centrality). We found that remitters showed increases in ECN connectivity in the right precentral gyrus and decreases in DMN connectivity in the right inferior frontal gyrus and supramarginal gyrus. The ECN and DMN had regions (middle temporal gyrus and bilateral middle/inferior temporal/fusiform gyrus, respectively) that showed reversed effects (decreased ECN and increased DMN, respectively). Early changes in functional connectivity can occur after initial medication exposure. This study offers new data, indicating that functional connectivity changes differ depending on treatment response and can occur shortly after exposure to antidepressant medication.Molecular Psychiatry advance online publication, 19 April 2016; doi:10.1038/mp.2016.55. © 2016 Macmillan Publishers Limited


Flickinger J.C.,University of Pittsburgh
International Journal of Radiation Oncology Biology Physics | Year: 2011

Purpose: To identify factors significantly affecting recurrence rates after postoperative external beam radiotherapy (XRT) of keloids, and to delineate any radiation dose response and effects of radiation dose per fraction. Methods and Materials: A comprehensive literature review was performed to compile a database of 2,515 resected keloids (36.9% earlobe). Postoperative XRT was 45- to 100-kV X-rays in 27.0% or 120- to 250-kV X-rays in 11.1%, Co-60 in 1.9%, Sr-90 in 4.7%, 1.5- to 9-MeV electrons in 26.5%, and no XRT in 28.8%. In the 1,791 irradiated patients, the median radiation parameters were as follows: total dose, 15 Gy (range, 6-30 Gy); dose per fraction, 5.0 Gy (range, 2-15 Gy); fractions, 3 (range, 1-10); and time, 7 days (range, 0-33 days). Results: Multivariate stepwise logistic regression correlated decreased keloid recurrence with earlobe location (p = 1.98E-10; odds ratio, 0.34), biologically effective dose (p = 1.01E-27), and treatment with electron beam or Co-60 vs. other techniques (p = 0.0014; odds ratio, 0.72). Different radiobiological models calculated values of α/β = 1.12 to 2.86 (mean, 2.08) and time (repopulation) correction factors for biologically effective dose from 0.98 to 2.13 Gy per day (mean, 1.34) starting 10 days after surgery. Different models (with α/β = 2.08) predicted that doses needed for 90% and 95% control with 3 fractions of postoperative electron beam were 16.0 to 16.2 Gy and 18.3 to 19.2 Gy, respectively, in less than 10 days for earlobe keloids and 21.5 to 22.2 Gy and 23.4 to 24.8 Gy, respectively, in less than 10 days for other sites. Conclusions: Postoperative keloid radiotherapy requires moderately high doses and optimal technique to be effective. The relatively low α/β ratio indicates that radiotherapy with a limited number of fractions and high doses per fraction is the best strategy. Copyright © 2011 Elsevier Inc.


Bjork J.M.,Virginia Commonwealth University | Pardini D.A.,University of Pittsburgh
Developmental Cognitive Neuroscience | Year: 2015

Functional magnetic resonance imaging (fMRI) has illuminated the development of human brain function. Some of this work in typically-developing youth has ostensibly captured neural underpinnings of adolescent behavior which is characterized by risk-seeking propensity, according to psychometric questionnaires and a wealth of anecdote. Notably, cross-sectional comparisons have revealed age-dependent differences between adolescents and other age groups in regional brain responsiveness to prospective or experienced rewards (usually greater in adolescents) or penalties (usually diminished in adolescents). These differences have been interpreted as reflecting an imbalance between motivational drive and behavioral control mechanisms, especially in mid-adolescence, thus promoting greater risk-taking. While intriguing, we caution here that researchers should be more circumspect in attributing clinically significant adolescent risky behavior to age-group differences in task-elicited fMRI responses from neurotypical subjects. This is because actual mortality and morbidity from behavioral causes (e.g. substance abuse, violence) by mid-adolescence is heavily concentrated in individuals who are not neurotypical, who rather have shown a lifelong history of behavioral disinhibition that frequently meets criteria for a disruptive behavior disorder, such as conduct disorder, oppositional-defiant disorder, or attention-deficit hyperactivity disorder. These young people are at extreme risk of poor psychosocial outcomes, and should be a focus of future neurodevelopmental research. © 2014 The Authors Published by Elsevier Ltd.


Goetzman E.S.,University of Pittsburgh
Progress in Molecular Biology and Translational Science | Year: 2011

There are at least 17 enzymes involved in mitochondrial fatty acid oxidation encoded by at least 21 genes. For most of these genes, humans with genetic deficiencies have been identified. The mouse possesses a very similar fatty acid oxidation system and has served well as an organism for modeling genetic loss of function. Knockout mice have been created for 12 fatty acid oxidation genes, including all three carnitine palmitoyltransferase-1 genes, four of the acyl-CoA dehydrogenases, both subunits of trifunctional protein, short/medium-chain hydroxyacyl-CoA dehydrogenase, and two enzymes required for oxidation of polyunsaturated fatty acids (enoyl-CoA isomerase and 2,4 dienoyl-CoA reductase). This review covers the knowledge that has been gained from these mouse models in terms of understanding both single-gene fatty acid oxidation disorders and the contribution of the fatty acid oxidation pathway to polygenic diseases such as obesity and type 2 diabetes. Also reviewed are other mouse models displaying phenotypic aspects of a fatty acid oxidation disorder such as knockout mice lacking the carnitine transporter and knockouts of key regulators of the pathway such as peroxisome proliferator-activated receptor-α and sirtuin-3. Finally, nongenetic means of manipulating fatty acid oxidation in the mouse are discussed, in particular the various chemical inhibitors that have been used successfully in vivo. © 2011 Elsevier Inc. All rights reserved.


Devlin B.,University of Pittsburgh | Scherer S.W.,University of Toronto
Current Opinion in Genetics and Development | Year: 2012

Autism spectrum disorder (ASD) is characterized by impairments in reciprocal social interaction and communication, and by restricted and repetitive behaviors. Family studies indicate a significant genetic basis for ASD susceptibility, and genomic scanning is beginning to elucidate the underlying genetic architecture. Some 5-15% of individuals with ASD have an identifiable genetic etiology corresponding to known chromosomal rearrangements or single gene disorders. Rare (<1% frequency) de novo or inherited copy number variations (CNVs) (especially those that affect genes with synaptic function) are observed in 5-10% of idiopathic ASD cases. These findings, coupled with genome sequencing data suggest the existence of hundreds of ASD risk genes. Common variants, yet unidentified, exert only small effects on risk. Identification of ASD risk genes with high penetrance will broaden the targets amenable to genetic testing; while the biological pathways revealed by the deeper list of ASD genes should narrow the targets for therapeutic intervention. © 2012 Elsevier Ltd.


McGeachy M.J.,University of Pittsburgh
Journal of Leukocyte Biology | Year: 2013

The development of immune memory is a double-edged sword, helping to maintain health by preventing repeated infections but also driving chronic inflammation when dysregulated. Th17 cells are now well-known as major drivers of autoimmune disease but also play roles in protective immune responses against pathogens. This mini-review will focus on the recent evidence for long-lived, robust Th17 memory cell populations in mouse models and humans, and their functional roles in mediating host protection and chronic disease state. © Society for Leukocyte Biology.


Chaly Y.,University of Pittsburgh
Arthritis and rheumatism | Year: 2012

FSTL1 is a secreted glycoprotein that exacerbates murine arthritis and is overexpressed in human arthritis. The aim of this study was to determine the mechanism by which FSTL1 promotes arthritis. Collagen-induced arthritis was induced in mice hypomorphic for FSTL1, generated with a gene trap-targeted mutant embryonic stem cell line. Arthritis was assessed by measuring paw swelling and using a qualitative arthritis index. Bone marrow-derived mesenchymal stromal cells from hypomorphic mice, as well as mouse stromal ST2 cells transduced with short hairpin RNA to suppress FSTL1 expression, were stimulated with interleukin-1β (IL-1β), tumor necrosis factor α, and IL-17. The monocyte cell line U937, which does not express FSTL1, was transfected with a plasmid encoding FSTL1 and stimulated with phorbol myristate acetate and lipopolysaccharide. Cell supernatants were assayed for IL-6, IL-8, monocyte chemotactic protein 1 (MCP-1), and FSTL1 by enzyme-linked immunosorbent assay. FSTL1 hypomorphic mice had reduced levels of FSTL1 compared to littermate controls. Following induction of arthritis, a significant correlation was observed between serum FSTL1 levels and both paw swelling and the arthritis index. Similar correlations were observed between the amount of FSTL1 produced by mesenchymal stromal cells, stromal ST2 cells, and monocytes and the secretion of IL-6, IL-8, and MCP-1. These findings demonstrate that FSTL1 up-regulates proinflammatory mediators important in the pathology of arthritis, and that serum levels of FSTL1 correlate with severity of arthritis. The latter supports the possibility that FSTL1 might be a target for treatment of certain forms of arthritis. Copyright © 2012 by the American College of Rheumatology.


Butterworth M.B.,University of Pittsburgh
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2010

The epithelial Na+ channel (ENaC) is a major regulator of salt and water reabsorption in a number of epithelial tissues. Abnormalities in ENaC function have been directly linked to several human disease states including Liddle syndrome, psuedohypoaldosteronism, and cystic fibrosis and may be implicated in salt-sensitive hypertension. ENaC activity in epithelial cells is regulated both by open probability and channel number. This review focuses on the regulation of ENaC in the cells of the kidney cortical collecting duct by trafficking and recycling. The trafficking of ENaC is discussed in the broader context of epithelial cell vesicle trafficking. Well-characterized pathways and protein interactions elucidated using epithelial model cells are discussed, and the known overlap with ENaC regulation is highlighted. In following the life of ENaC in CCD epithelial cells the apical delivery, internalization, recycling, and destruction of the channel will be discussed. While a number of pathways presented still need to be linked to ENaC regulation and many details of the regulation of ENaC trafficking remain to be elucidated, knowledge of these mechanisms may provide further insights into ENaC activity in normal and disease states. © 2010 Elsevier B.V.


Metabolic homeostasis reflects the complex output of endocrine, autonomic, and behavioral control circuits that extend throughout the central nervous system. Brain regions that control food intake and energy expenditure are privy to continuous visceral sensory feedback signals that presumably modulate appetite, satiety, digestion, and metabolism. Sensory signals from the gastrointestinal tract and associated digestive viscera are delivered to the brain primarily by vagal afferents that terminate centrally within the caudal nucleus of the solitary tract (NST), with signals subsequently relayed to higher brain regions by parallel noradrenergic and peptidergic projection pathways arising within the NST. This article begins with an overview of these ascending pathways identified in adult rats using a standard anterograde tracer microinjected into the caudal visceral sensory region of the NST, and also by immunocytochemical localization of glucagon-like peptide-1. NST projection targets identified by these two approaches are compared to the distribution of neurons that become infected after inoculating the ventral stomach wall with a neurotropic virus that transneuronally infects synaptically-linked chains of neurons in the anterograde (i.e., ascending sensory) direction. Although the focus of this article is the anatomical organization of axonal projections from the caudal visceral NST to the hypothalamus and limbic forebrain, discussion is included regarding the hypothesized role of these projections in modulating behavioral arousal and coordinating endocrine and behavioral (i.e., hypophagic) responses to stress. © 2010 Elsevier B.V. All rights reserved.


Zhang M.,University of Pittsburgh
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism | Year: 2013

Ischemic stroke is a devastating condition lacking effective therapies. A promising approach to attenuate ischemic injury is mild hypothermia. Recent studies show that adenosine nucleotides can induce hypothermia in mice. The purpose of the present study was to test the hypothesis that adenosine 5'-triphosphate (ATP) induces mild hypothermia in rats and reduces ischemic brain injury. We found that intraperitoneal injections of ATP decreased core body temperature in a dose-dependent manner; the dose appropriate for mild hypothermia was 2 g/kg. When ATP-induced hypothermia was applied to stroke induced by middle cerebral artery occlusion, however, a neuroprotective effect was not observed. Instead, the infarct volume grew even larger in ATP-treated rats. This was accompanied by an increased rate of seizure events, hemorrhagic transformation, and higher mortality. Continuous monitoring of physiologic parameters revealed that ATP reduced heartbeat rate and blood pressure. ATP also increased blood glucose, accompanied by severe acidosis and hypocalcemia. Western blotting showed that ATP decreased levels of both phospho-Akt and total-Akt in the cortex. Our results reveal that, despite inducing hypothermia, ATP is not appropriate for protecting the brain against stroke. Instead, we show for the first time that ATP treatment is associated with exaggerated ischemic outcomes and dangerous systemic side effects.


Morel P.A.,University of Pittsburgh
Frontiers in Immunology | Year: 2013

Type 1 diabetes (T1D) is a T cell mediated autoimmune disease characterized by immune mediated destruction of the insulin-producing ß cells in the islets of Langerhans. Dendritic cells (DC) have been implicated in the pathogenesis of T1D and are also used as immunotherapeutic agents. Plasmacytoid (p)DC have been shown to have both protective and pathogenic effects and a newly described merocytic DC population has been shown to break tolerance in the mouse model of T1D, the non-obese diabetic (NOD) mouse. We have used DC populations to prevent the onset of T1D in NOD mice and clinical trials of DC therapy in T1D diabetes have been initiated. In this review we will critically examine the recent published literature on the role of DC subsets in the induction and regulation of the autoimmune response in T1D. © 2013 Morel.


Butterfield L.H.,University of Pittsburgh
Frontiers in Immunology | Year: 2013

Dendritic cells (DC) have been tested in cancer immunotherapy clinical trials for two decades. Over this time, the methods of DC culture (or manufacture) have evolved, the approaches for antigen loading have broadened, the maturation signals have varied and different sites of administration have been tested. The post-vaccination immunologic questions asked have also varied between trials and over time. In this review, I will consider multiple aspects of DC-based vaccines tested in cancer patients, including the cell culture, antigen loading, maturation, and delivery, as well as what we have learned from testing immune responses in vaccinated patients who have benefited clinically, and those who have not measurably benefited. © 2013 Butterfield.


Palevsky P.M.,University of Pittsburgh
Advances in Chronic Kidney Disease | Year: 2013

Although the use of renal replacement therapy (RRT) to support critically ill patients with acute kidney injury (AKI) has become routine, many of the fundamental questions regarding optimal management of RRT remain. This review summarizes current evidence regarding the timing of initiation of RRT, the selection of the specific modality of RRT, and prescription of the intensity of therapy. Although absolute indications for initiating RRT-such as hyperkalemia and overt uremic symptoms-are well recognized, the optimal timing of therapy in patients without these indications continues to be a subject of debate. There does not appear to be a difference in either mortality or recovery of kidney function associated with the various modalities of RRT. Finally, providing higher doses of RRT is not associated with improved clinical outcomes. © 2013.


Callaway C.W.,University of Pittsburgh
Current Opinion in Cardiology | Year: 2013

PURPOSE OF REVIEW: Epinephrine is the primary drug administered during cardiopulmonary resuscitation (CPR) to reverse cardiac arrest. Epinephrine increases arterial blood pressure and coronary perfusion during CPR via alpha-1-adrenoceptor agonist effects. However, the dose, timing and indications for epinephrine use are based on limited animal data. Recent studies question whether epinephrine provides any overall benefit for patients. RECENT FINDINGS: A randomized controlled trial indicates that epinephrine for out-of-hospital cardiac arrest increases return of pulses, but does not significantly alter longer-term survival. Very large, well-controlled, observational studies suggest that, despite increases in return of pulses, epinephrine reduces long-term survival and functional recovery after CPR. Detrimental effects were greatest in patients found in ventricular fibrillation. Laboratory data suggest that harmful epinephrine-induced reductions in microvascular blood flow during and after CPR may offset the beneficial epinephrine-induced increase in arterial blood pressure during CPR. SUMMARY: The available clinical data confirm that epinephrine administration during CPR can increase short-term survival (return of pulses), but point towards either no benefit or even harm of this drug for more patient-centred outcomes (long-term survival or functional recovery). Prospective trials are needed to determine the correct dose, timing and patients for epinephrine in cardiac arrest. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Simon M.A.,University of Pittsburgh
Nature Reviews Cardiology | Year: 2013

Right ventricular (RV) failure is a complex problem with poor outcomes. Diagnosis requires a high degree of clinical suspicion, because many of the signs and symptoms of this condition are nonspecific and can be acute or chronic. Identification of the underlying aetiology, which can include pulmonary hypertension, cardiomyopathy, myocardial infarction, congenital or valvular heart disease, and sepsis, is essential. Echocardiography is the technique of choice for first-line assessment, but cardiac MRI is the current gold standard for anatomical and functional assessment of the right ventricle. Therapy for RV failure should be directed at the underlying cause, although management of symptoms is also important. Therapeutic options range from pharmacological treatment to mechanical RV support and heart transplantation. The complex 3D geometry of the right ventricle and its intricate interactions with the left ventricle have left many questions about RV failure unanswered. However, promising new targeted therapies are under development and mechanical support is becoming increasingly feasible. The next decade will be an exciting time for advances in our understanding and management of RV failure.© 2013 Macmillan Publishers Limited. All rights reserved.


Cauley J.A.,University of Pittsburgh
Current Osteoporosis Reports | Year: 2013

The Women's Health Initiative (WHI) was a large and complex study focused on strategies for the prevention and control of common chronic diseases of postmenopausal women. The WHI included 3 randomized controlled trials: the Hormone Therapy (HT) Trials, the Diet Modification Trial, and the Calcium/Vitamin D (CaD) Trial. Conjugated equine estrogen with or without a progestin significantly decreased hip, clinical vertebral, and all fractures. Once the intervention was stopped, the fracture benefit dissipated. However, estrogen plus progestin was associated with more risks than benefits and use of hormone therapy solely for the prevention of osteoporosis is not recommended. The CaD trial found no overall benefit for fracture reduction except in adherent women and women taking supplements for 5 or more years. Overall, the common practice of taking calcium and vitamin D supplementation with possible benefits on hip and positive evidence on bone mineral density and few risks is reasonable. © 2013 Springer Science+Business Media New York.


Pinsky M.R.,University of Pittsburgh
Current Opinion in Critical Care | Year: 2014

Purpose of Review: Functional haemodynamic monitoring is the assessment of the dynamic interactions of haemodynamic variables in response to a defined perturbation. Recent Findings: Fluid responsiveness can be predicted during positive pressure breathing by variations in venous return or left ventricular output using numerous surrogate markers, such as arterial pulse pressure variation (PPV), left ventricular stroke volume variation (SVV), aortic velocity variation, inferior and superior vena cavae diameter changes and pulse oximeter pleth signal variability. Similarly, dynamic changes in cardiac output to a passive leg raising manoeuvre can be used in any patient and measured invasively or noninvasively. However, volume responsiveness, though important, reflects only part of the overall spectrum of functional physiological variables that can be measured to define physiologic state and monitor response to therapy. The ratio of PPV to SVV defines central arterial elastance and can be used to identify those hypotensive patients who will not increase their blood pressure in response to a fluid challenge despite increasing cardiac output. Dynamic tissue O2 saturation (StO2) responses to complete stop flow conditions, as can be created by measuring hand StO2 and occluding flow with a blood pressure cuff, assesses cardiovascular sufficiency and micro-circulatory blood flow distribution. They can be used to identify those ventilator-dependent individuals who will fail a spontaneous breathing trial or trauma patients in need of life-saving interventions. Summary: Functional haemodynamic monitoring approaches are increasing in numbers, conditions in which they are useful and resuscitation protocol applications. This is a rapidly evolving field whose pluripotential is just now being realized. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Saidi W.A.,University of Pittsburgh | Norman P.,Linkoping University
Carbon | Year: 2014

Using state-of-the-art time-dependent density functional theory and employing the complex polarization propagator theory, we compute the UV-vis absorption and resonance Raman (RR) spectra of pristine and H- and F-decorated single-walled carbon nanotubes (SWCNTs).We find that H- and F-functionalization brightens a low energy exciton that couples the SWCNT local-defect chemistry to its extended p network. Surprisingly, the energy of the strongly light absorbing φ- φ* excitation (SS 11) and the Raman shift of the radial breathing mode (RBM) are not very sensitive to the presence of the defects, and to a lesser degree their type. In contrast, the RR intensities of the RBM resonance profile are reduced by two orders of magnitude upon functionalization due to changes in the dynamic polarizabilities. Additionally, the resonance profile shows sensitivity to the defect chemistry where the Hfunctionalized CNTs have a factor ∼4 larger intensities than F-functionalized CNTs in the near resonance region. Despite the differences in the nature of the local defects, our findings are in good agreement with recent experiments on individual SWCNTs with well controlled topological defects. The study shows that photoluminescence is not sensitive to low concentrations of defects, but RR spectroscopy provides a powerful ultra-sensitive tool to identify and categorize CNT defects. © 2013 Elsevier Ltd. All rights reserved.


Yuan J.-M.,University of Pittsburgh
American Journal of Clinical Nutrition | Year: 2013

In contrast to the consistent results of an inhibitory effect of green tea extracts and tea polyphenols on the development and growth of carcinogen-induced tumors in experimental animal models, results from human studies are mixed. Both observational and intervention studies have provided evidence in support of a protective role of green tea intake in the development of oral-digestive tract cancer or an inhibitory role of oral supplementation of green tea extract on a precancerous lesion of oral cavity. Evidence in support of green tea intake against the development of liver cancer risk is limited and inconsistent. An inverse association between green tea intake and lung cancer risk has been observed among never smokers but not among smokers. Although observational studies do not support a beneficial role of tea intake against the development of prostate cancer, several phase 2 clinical trials have shown an inhibitory effect of green tea extract against the progression of prostate premalignant lesions to malignant tumors. Prospective epidemiologic studies so far have not provided evidence for a protective effect of green tea consumption on breast cancer development. Current data neither confirm nor refute a definitive cancer-preventive role of green tea intake. Large randomized intervention trials on the efficacy of green tea polyphenols or extracts are required before a recommendation for green tea consumption for cancer prevention should be made. © 2013 American Society for Nutrition.


Winicour J.,Max Planck Institute for Physics | Winicour J.,University of Pittsburgh
Living Reviews in Relativity | Year: 2012

I review the development of numerical evolution codes for general relativity based upon the characteristic initial-value problem. Progress in characteristic evolution is traced from the early stage of 1D feasibility studies to 2D-axisymmetric codes that accurately simulate the oscillations and gravitational collapse of relativistic stars and to current 3D codes that provide pieces of a binary black-hole space time. Cauchy codes have now been successful at simulating all aspects of the binary black-hole problem inside an artificially constructed outer boundary. A prime application of characteristic evolution is to extend such simulations to null infinity where the waveform from the binary in spiral and merger can be unambiguously computed. This has now been accomplished by Cauchy-characteristic extraction, where data for the characteristic evolution is supplied by Cauchy data on an extraction world tube inside the artificial outer boundary. The ultimate application of characteristic evolution is to eliminate the role of this outer boundary by constructing a global solution via Cauchy-characteristic matching. Progress in this direction is discussed.


Levesque M.C.,University of Pittsburgh
BioDrugs | Year: 2012

Rheumatoid arthritis (RA) affects an estimated 1.3 million Americans and is a complex inflammatory disease associated with synovitis and joint destruction. The development of biologic disease-modifying anti-rheumatic drugs (DMARDs) that target specific mediators of inflammation has led to several highly successful therapies for the treatment of RA. The imperfect efficacy of biologic DMARDs has resulted in the absence of clear guidelines on how biologic DMARDs should be used in the clinic to optimize treatment of RA patients. This makes it imperative that better data be available to physicians and RA patients about the comparative effectiveness of different biologic DMARDs. Prior to 2008, there were no randomized trials comparing biologic DMARDs for the treatment of RA. Since then, there have been published studies that directly compared biologic DMARDs for the treatment of RA, and several studies that estimated the relative efficacy of different biologic DMARDs by comparing published results of studies that included treatment of RA patients with biologic DMARDs who had previously experienced an inadequate response to methotrexate or tumor necrosis factor (TNF) antagonists. There are two recent studies that directly compared biologic DMARDs with optimal combinations of oral DMARDs and these are important because there are significant differences in costs and side effects between oral and biologic DMARDs. Among the studies that directly compared biologic DMARDs, it has been reported that RA patients who fail a TNF antagonist have a higher response rate (based on disease activity score DAS28 measurements) to treatment with rituximab as compared with another TNF antagonist. In addition, in the ATTEST trial, the investigators found that, for RA patients with an inadequate response to methotrexate, treatment with abatacept versus infliximab resulted in response rates that were roughly equal. There are also several head-to-head studies of biologic DMARDs that are currently enrolling or about to enroll RA subjects. Pharmaceutical companies have taken more interest in comparative effectiveness studies, in part due to the emphasis that has been placed on this type of research by the US federal government and associated organizations including the Patient-Centered Outcomes Research Institute (PCORI). Therefore, while there is currently a relative lack of comparative effectiveness research to inform clinical decisions about biologic DMARDs for RA patients, it appears likely that there will be wider availability of such data in the near future. © 2012 Adis Data Information BV. All rights reserved.


Obstacles to morbidity-free long-term survival after liver transplantation (LT) include complications of immunosuppression (IS), recurrence of the original disease and malignancies, and unexplained chronic hepatitis and graft fibrosis. Many programs attempt to minimize chronic exposure to IS by reducing dosages and stopping steroids. A few programs have successfully weaned a highly select group of recipients from all IS without apparent adverse consequences, but long-term follow-up is limited. Patients subjected to adjustments in IS are usually followed by serial liver chemistry tests, which are relatively insensitive methods for detecting allograft damage. Protocol biopsy has largely been abandoned for hepatitis C virus-negative recipients, at least in part because of the inability to integrate routine histopathological findings into a rational clinical management algorithm. Recognizing a need to more precisely categorize and determine the clinical significance of findings in long-term biopsy samples, the Banff Working Group on Liver Allograft Pathology has reviewed the literature, pooled the experience of its members, and proposed working definitions for biopsy changes that (1) are conducive to lowering IS and are compatible with operational tolerance (OT) and (2) raise concern for closer follow-up and perhaps increased IS during or after IS weaning. The establishment of guidelines should help us to standardize analyses of the effects of various treatments and/or weaning protocols and more rigorously categorize patients who are assumed to show OT. Long-term follow-up using standardized criteria will help us to determine the consequences of lowering IS and to define and determine the incidence and robustness of OT in liver allografts. Copyright © 2012 American Association for the Study of Liver Diseases.


Monaco E.A.,University of Pittsburgh
Neurosurgical focus | Year: 2010

OBJECT: The authors performed a retrospective review of prospectively collected data to evaluate the safety and efficacy of stereotactic radiosurgery (SRS) for the treatment of patients harboring symptomatic solitary cavernous malformations (CMs) of the brainstem that bleed repeatedly and are high risk for resection. METHODS: Between 1988 and 2005, 68 patients (34 males and 34 females) with solitary, symptomatic CMs of the brainstem underwent Gamma Knife surgery. The mean patient age was 41.2 years, and all patients had suffered at least 2 symptomatic hemorrhages (range 2-12 events) before radiosurgery. Prior to SRS, 15 patients (22.1%) had undergone attempted resection. The mean volume of the malformation treated was 1.19 ml, and the mean prescribed marginal radiation dose was 16 Gy. RESULTS: The mean follow-up period was 5.2 years (range 0.6-12.4 years). The pre-SRS annual hemorrhage rate was 32.38%, or 125 hemorrhages, excluding the first hemorrhage, over a total of 386 patient-years. Following SRS, 11 hemorrhages were observed within the first 2 years of follow-up (8.22% annual hemorrhage rate) and 3 hemorrhages were observed in the period after the first 2 years of follow-up (1.37% annual hemorrhage rate). A significant reduction (p < 0.0001) in the risk of brainstem CM hemorrhages was observed following radiosurgical treatment, as well as in latency period of 2 years after SRS (p < 0.0447). Eight patients (11.8%) experienced new neurological deficits as a result of adverse radiation effects following SRS. CONCLUSIONS: The results of this study support a role for the use of SRS for symptomatic CMs of the brainstem, as it is relatively safe and appears to reduce rebleeding rates in this high-surgical-risk location.


Perkins K.A.,University of Pittsburgh
Nicotine and Tobacco Research | Year: 2012

Introduction: Acutely increased urge to smoke, or craving, in response to smoking cues (i.e., "cue reactivity") is often believed to identify those less able to later quit smoking. Although absolute craving level can predict smoking behavior, smoking cue reactivity per se may not predict cessation outcome. Methods: All clinical trials of cue reactivity and cessation outcome published before 2007 were identified and supplemented with a web-based search of clinical studies published after 2006, producing one additional trial. Examined were a total of 6 studies that directly related self-reported craving in response to laboratory-presented smoking cues with subsequent ability to quit smoking. Results: Of the 6 studies, only one found that lower cue reactivity predicted greater quitting success (with nicotine but not placebo patch). Another study found the opposite, that higher cue reactivity was related to greater, rather than less, quitting success (in an unaided attempt). The other studies showed no association between cue reactivity and cessation outcome. Conclusions: This limited research does not clearly support self-reported craving in response to smoking cues per se as a predictor of later quitting success. Lack of consistent results may partly be due to variability in methods of smoking cue assessment, type of cessation treatment, and duration of follow-up assessment. If it is to improve our understanding of an individual's ability to quit smoking, research on cue reactivity needs to show significant and reliable associations with subsequent long-term smoking behavior. © The Author 2011. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.


Zuckoff A.,University of Pittsburgh
Surgery for Obesity and Related Diseases | Year: 2012

Limited adherence to healthy habits in adults at risk of lifestyle diseases, some of whom become candidates for bariatric surgery, has been paralleled by high rates of nonadherence to postbariatric surgery behavioral recommendations. This is a specific case of the more general problem of nonadherence to medical treatment of chronic conditions. An adequate understanding of the problem of nonadherence requires an understanding of the motivational factors that influence whether persons implement healthy behavior. Motivational interviewing is an empirically supported counseling style for strengthening a person's own motivation and commitment to change. It offers a model for understanding and intervening with nonadherence to behavioral recommendations that emphasizes the role of clinician communication in both increasing and inadvertently decreasing patient motivation. A conceptual account of patient motivation for healthy change, highlighting the centrality of resolution of patient ambivalence through targeted conversation, is illustrated by thought exercises for the reader and supplemented by references to empirical data. Recommendations for changes in clinical practice to improve patient adherence to behavioral recommendations are also offered. © 2012 American Society for Metabolic and Bariatric Surgery.


Dacie S.,University of Pittsburgh
Archives of Pathology and Laboratory Medicine | Year: 2011

Context.-The development of targeted therapies in the treatment of lung carcinoma is a rapidly growing area that requires a precise histologic classification of lung carcinomas and the implementation into clinical practice of testing for predictive biomarkers of therapy response. Molecular testing has added another layer of complexity in the routine workup of rather limited diagnostic tumor tissue. Objective.-To review the most important lung carcinoma biomarkers predictive of response and to discuss proposed routine molecular testing in clinical practice. Data Sources.-PubMed (US National Library of Medicine)-available review articles, peer-reviewed original articles, and experience of the author. Conclusions.-Histologic profile, clinical characteristics, and mutational profile of lung carcinoma have all been reported as predictive factors of response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and other targeted therapies. Recently published results of large clinical trials indicate that mutational profiling, particularly identification of activating epidermal growth factor receptor (EGFR) mutations, is the best predictor for EGFR-TKI response. Despite all these observations, molecular profiling of lung carcinomas has not been standardized or validated in clinical practice. Rapid development of targeted therapies will probably require molecular testing for a panel of mutations to identify molecular subtypes of non-small cell lung carcinomas that will benefit from new therapeutic approaches in personalized patient care.


Fernstrom J.D.,University of Pittsburgh
Journal of Nutrition | Year: 2012

The daily nutritional requirement for L-tryptophan (Trp) is modest (5 mg/kg). However, many adults choose to consume much more, up to 4-5 g/d (60-70 mg/kg), typically to improve mood or sleep. Ingesting L-Trp raises brain tryptophan levels and stimulates its conversion to serotonin in neurons, which is thought to mediate its actions. Are there side effects from Trp supplementation? Some consider drowsiness a side effect, but not those who use it to improve sleep. Though the literature is thin, occasional side effects, seen mainly at higher doses (70-200 mg/kg), include tremor, nausea, and dizziness, and may occur when Trp is taken alone or with a drug that enhances serotonin function (e.g., antidepressants). In rare cases, the "serotonin syndrome" occurs, the result of too much serotonin stimulation when Trp is combined with serotonin drugs. Symptoms include delirium, myoclonus, hyperthermia, and coma. In 1989 a new syndrome appeared, dubbed eosinophilia myalgia syndrome (EMS), and was quickly linked to supplemental Trp use. Key symptoms included debilitating myalgia (muscle pain) and a high peripheral eosinophil count. The cause was shown not to be Trp but a contaminant in certain production batches. This isnot surprising, because side effects long associated with Trp use were not those associated with the EMS. Over 5 decades, Trp has been taken as a supplement and as an adjunct to medications with occasional modest, short-lived side effects. Still, the database is small and largely anecdotal. A thorough, dose-related assessment of side effects remains to be conducted. © 2012 American Society for Nutrition.


Julian M.M.,University of Pittsburgh
Clinical Child and Family Psychology Review | Year: 2013

One of the major questions of human development is how early experience impacts the course of development years later. Children adopted from institutional care experience varying levels of deprivation in their early life followed by qualitatively better care in an adoptive home, providing a unique opportunity to study the lasting effects of early deprivation and its timing. The effects of age at adoption from institutional care are discussed for multiple domains of social and behavioral development within the context of several prominent developmental hypotheses about the effects of early deprivation (cumulative effects, experience-expectant developmental programming, and experience-adaptive developmental programming). Age at adoption effects are detected in a majority of studies, particularly when children experienced global deprivation and were assessed in adolescence. For most outcomes, institutionalization beyond a certain age is associated with a step-like increase in risk for lasting social and behavioral problems, with the step occurring at an earlier age for children who experienced more severe levels of deprivation. Findings are discussed in terms of their concordance and discordance with our current hypotheses, and speculative explanations for the findings are offered. © 2013 Springer Science+Business Media New York.


Kolls J.K.,University of Pittsburgh
Immunological Reviews | Year: 2013

CD4+ T-helper subsets are lineages of T cells that have effector function in the lung and control critical aspects of lung immunity. Depletion of these cells experimentally or by drugs or human immunodeficiency virus (HIV) infection in humans leads to the development of opportunistic infections as well as increased rates of bacteremia with certain bacterial pneumonias. Recently, it has been proposed that CD4+ T-cell subsets may also be excellent targets for mucosal vaccination to prevent pulmonary infections in susceptible hosts. Here, we review recent findings that increase our understanding of T-cell subsets and their effector cytokines in the context of pulmonary infection. © 2013 John Wiley & Sons A/S.


Austin K.M.,University of Pittsburgh
Seminars in Pediatric Surgery | Year: 2012

Hirschsprung's disease-associated enterocolitis (HAEC) remains the most life-threatening complication in Hirschsprung disease (HD) patients. The pathogenesis of HAEC has not been determined and many hypotheses regarding the etiology of HAEC have been proposed. These include a possible causal relationship between the abnormal enteric nervous system development in HD and the development of enterocolitis. Based on the complex genetic causes of HD that have been discovered and the resultant heterogeneous group of patients that exists, the causes of HAEC are likely multiple. New insights regarding the relationship of the role of the enteric nervous system and its interaction between intestinal barrier function, innate host immunity, and commensal microflora have been discovered, which may shed light on this perplexing problem. This review presents current known risk factors of HAEC and the proposed theories and supporting evidence for the potential etiologies of HAEC. © 2012.


Birmaher B.,University of Pittsburgh
Child and Adolescent Mental Health | Year: 2013

Background: The existence of bipolar disorder (BP) in youth is controversial. Methods: The current evidence regarding the diagnosis of BP in youth was reviewed. Results: BP is a recurrent familial disorder that occurs in 1-3% of youth, particularly in adolescents. Except for subsyndromal BP, the prevalence of BP-I is similar across most countries. Due to the child's immaturity, the presence of comorbid disorders, and divergent interpretations of manic symptomatology, it is difficult to diagnose BP in youth. Youth with subsyndromal mania and family history of BP, are at high risk to develop BP-I and BP-II. Both the full-syndromal BP and subsyndromal BP are associated with significant psychosocial difficulties and increased risk for use of substances, suicidality, legal problems, and services utilization. Conclusion: Bipolar disorder exists in youth, but it is difficult to diagnose. The recurrent nature and psychosocial morbidity associated with this illness during critical developmental stages call for comprehensive longitudinal evaluation and accurate recognition and treatment because delays in treatment are associated with poor outcome. © 2013 Association for Child and Adolescent Mental Health.


Park K.J.,University of Pittsburgh
Neurosurgery | Year: 2012

Trigeminal neuralgia (TN) may recur after treatment by gamma knife stereotactic radiosurgery (GKSR). To evaluate management outcomes in patients who underwent repeat GKSR for TN. The authors reviewed their experience with repeat GKSR in 119 patients with recurrent TN. The median patient age was 74 years (range, 34-96 years). The median interval between procedures was 26 months. The median target dose for repeat GKSR was 70 Gy (range, 50-90 Gy) and the median cumulative dose was 145 Gy (range, 120-170 Gy). The median follow-up was 48 months (range, 6-187 months) after repeat GKSR. After repeat GKSR, 87% of patients achieved initial pain relief (Barrow Neurological Institute pain score I-IIIb). Pain relief was maintained in 87.8% at 1 year, 69.8% at 3 years, and 44.2% at 5 years. Facial sensory dysfunction occurred in 21% of patients within 18 months after GKSR. Longer pain relief was observed in patients who had recurrent pain in a reduced pain distribution of the face compared with the pain distribution at the time of their initial GKSR, and in those who developed additional trigeminal sensory loss after a repeat procedure. A cumulative edge of brainstem dose ≥ 44 Gy was more likely to be associated with the development of sensory loss. Repeat GKSR provides a similar rate of pain relief as the first procedure. The best responses were observed in patients who had good pain control after the first procedure and those who developed new sensory dysfunction in the affected trigeminal distribution.


Delitto A.,University of Pittsburgh
The Journal of orthopaedic and sports physical therapy | Year: 2012

The Orthopaedic Section of the American Physical Therapy Association (APTA) has an ongoing effort to create evidence-based practice guidelines for orthopaedic physical therapy management of patients with musculoskeletal impairments described in the World Health Organization's International Classification of Functioning, Disability, and Health (ICF). The purpose of these low back pain clinical practice guidelines, in particular, is to describe the peer-reviewed literature and make recommendations related to (1) treatment matched to low back pain subgroup responder categories, (2) treatments that have evidence to prevent recurrence of low back pain, and (3) treatments that have evidence to influence the progression from acute to chronic low back pain and disability.


Thase M.E.,University of Pittsburgh
The Journal of clinical psychiatry | Year: 2012

Monoamine oxidase inhibitors (MAOIs) have proven efficacy for treating depression, particularly in patients with atypical depression, high levels of anxiety, anergic bipolar depression, and treatment-resistant depression. However, MAOIs are not supported as first-line treatments due to safety and tolerability concerns and the need for dietary restrictions; instead, current guidelines recommend MAOIs as third-, fourth-, or fifth-line treatments. However, a newer, transdermal MAOI formulation limits the need for dietary restrictions and has fewer sexual and metabolic effects than some of the newer antidepressants. © Copyright 2012 Physicians Postgraduate Press, Inc.


Shvedova A.A.,Pathology and Physiology Research Branch NIOSH CDC | Kagan V.E.,University of Pittsburgh
Journal of Internal Medicine | Year: 2010

Nano-sized materials and nano-scaled processes are widely used in many industries. They are being actively introduced as diagnostic and therapeutic in biomedicine and they are found in numerous consumer products. The small size of nanoparticles, comparable with molecular machinery of cells, may affect normal physiological functions of cells and cause cytotoxicity. Their toxic potential cannot be extrapolated from studies of larger particles due to unique physicochemical properties of nanomaterials. Therefore, the use of nanomaterials may pose unknown risks to human health and the environment. This review discusses several important issues relevant to pulmonary toxicity of nanoparticles, especially single-walled carbon nanotubes (SWCNT), their direct cytotoxic effects, their ability to cause an inflammatory response, and induce oxidative stress upon pharyngeal aspiration or inhalation. Further, recognition and engulfment of nanotubes by macrophages as they relate to phagocytosis and bio-distribution of nanotubes in tissues and circulation are discussed. The immunosuppressive effects of CNT and their significance in increased sensitivity of exposed individuals to microbial infections are summarized. Finally, data on biodegradation of SWCNT by oxidative enzymes of inflammatory cells are presented in lieu of their persistence and distribution in the body. © 2009 Blackwell Publishing Ltd.


McCrimmon R.J.,University of Dundee | Ryan C.M.,University of Pittsburgh | Frier B.M.,Royal Infirmary
The Lancet | Year: 2012

Cognitive dysfunction in type 1 and type 2 diabetes share many similarities, but important differences do exist. A primary distinguishing feature of type 2 diabetes is that people with this disorder often (but not invariably) do poorly on measures of learning and memory, whereas deficits in these domains are rarely seen in people with type 1 diabetes. Chronic hyperglycaemia and microvascular disease contribute to cognitive dysfunction in both type 1 and type 2 diabetes, and both disorders are associated with mental and motor slowing and decrements of similar magnitude on measures of attention and executive functioning. Additionally, both types are characterised by neural slowing, increased cortical atrophy, microstructural abnormalities in white matter tracts, and similar, but not identical, changes in concentrations of brain neurometabolites. Disconcertingly, the rapid rise in obesity and type 2 diabetes in all age groups might result in a substantial increase in prevalence of diabetes-related cognitive dysfunction.


Nawaz H.,University of Pittsburgh
American Journal of Gastroenterology | Year: 2015

Objectives:Hypertriglyceridemia (HTG) represents a major health problem with prevalence exceeding 30% in the U.S. The present study aims to assess the effect of elevated serum triglyceride (TG) levels on the severity of acute pancreatitis (AP).Methods:Prospectively enrolled AP patients were categorized into normal, mild, moderate, and severe/very severe categories based on their TG levels and compared in respect to demographics, comorbidities, and clinical outcomes. Multivariate analysis determined whether elevated TG levels were independently associated with persistent organ failure.Results:Two hundred and one out of 400 AP patients had serum TGs measured within 72 h of presentation, of which 115 had normal TG levels and 86 HTG (20 mild, 41 moderate, and 25 severe/very severe). Patients with HTG were of younger age (44 vs. 52 years), predominantly male (65% vs. 45%), obese (57% vs. 34%), diabetic (38% vs. 17%), and developed more frequently persistent organ failure (40% vs. 17%) compared with those with normal TGs (P<0.02). The rate of persistent organ failure increased proportionally with HTG severity grades (17% when normal TGs, 30% in mild, 39% in moderate, and 48% in severe/very severe HTG, Ptrend<0.001). On multivariate analysis controlling for age, gender, body mass index, diabetes, and alcohol etiology, moderate HTG (odds ratio (OR), 2.6; P=0.04) and severe/very severe HTG (OR, 4.9; P=0.009) were independently associated with persistent organ failure.Conclusions:Elevated serum TGs in AP patients are independently and proportionally correlated with persistent organ failure regardless of etiology. TG-mediated lipotoxicity may be an attractive target to design novel interventions for severe AP.Am J Gastroenterol advance online publication, 1 September 2015; doi:10.1038/ajg.2015.261. © 2015 American College of Gastroenterology


Kanai A.J.,University of Pittsburgh
Handbook of Experimental Pharmacology | Year: 2011

Much of the current research on lower urinary tract dysfunction is focused on afferent mechanisms. The main goals are to define and modulate the signaling pathways by which afferent information is generated and conveyed to the central nervous system. Alterations in bladder afferent mechanisms are a potential source of voiding dysfunction and an emerging source of drug targets. Even some established drug therapies such as muscarinic receptor antagonists, as well as emerging therapies such as botulinum toxin type-A, may act partly through afferent mechanisms. This review presents up-to-date findings on the localization of afferent fiber types within the bladder wall, afferent receptors and transmitters, and how these may communicate with the urothelium, interstitial cells, and detrusor smooth muscle to regulate micturition in normal and pathological bladders. Peripheral and central mechanisms of afferent sensitization and myogenic mechanisms that lead to detrusor overactivity, overactive bladder symptoms, and urgency sensations are also covered as well as new therapeutic approaches and new and established methods of measuring afferent activity. © 2011 Springer-Verlag Berlin Heidelberg.


Darville T.,University of Pittsburgh | Hiltke T.J.,National Institute of Allergy and Infectious Diseases
Journal of Infectious Diseases | Year: 2010

Although the pathologic consequences of C. trachomatis genital infection are well-established, the mechanism(s) that result in chlamydia-induced tissue damage are not fully understood. We reviewed in vitro, animal, and human data related to the pathogenesis of chlamydial disease to better understand how reproductive sequelae result from C. trachomatis infection. Abundant in vitro data suggest that the inflammatory response to chlamydiae is initiated and sustained by actively infected nonimmune host epithelial cells. The mouse model indicates a critical role for chlamydia activation of the innate immune receptor, Toll-like receptor 2, and subsequent inflammatory cell influx and activation, which contributes to the development of chronic genital tract tissue damage. Data from recent vaccine studies in the murine model and from human immunoepidemiologic studies support a role for chlamydia-specific CD4 Th1-interferon-γ-producing cells in protection from infection and disease. However, limited evidence obtained using animal models of repeated infection indicates that, although the adaptive T cell response is a key mechanism involved in controlling or eliminating infection, it may have a double-edged nature and contribute to tissue damage. Important immunologic questions include whether anamnestic CD4 T cell responses drive disease rather than protect against disease and the role of specific immune cells and inflammatory mediators in the induction of tissue damage with primary and repeated infections. Continued study of the complex molecular and cellular interactions between chlamydiae and their host and large-scale prospective immunoepidemiologic and immunopathologic studies are needed to address gaps in our understanding of pathogenesis that thwart development of optimally effective control programs, including vaccine development. © 2010 by the Infectious Diseases Society of America. All rights reserved.


The continuing advances in computed tomographic(CT) technology in the past decades have provided ongoing opportunities to improve CT image quality and clinical practice and discover new clinical CT imaging applications. New CT technology, however, has introduced new challenges in clinical radiology practice. One of the challenges is with intravenous contrast medium administration and scan timing. In this article, contrast medium pharmacokinetics and patient, contrast medium, and CT scanning factors associated with contrast enhancement and scan timing are presented and discussed. Published data from clinical studies of contrast medium and physiology are reviewed and interpreted. Computer simulation data are analyzed to provide an in-depth analysis of various factors associated with contrast enhancement and scan timing. On the basis of basic principles and analysis of the factors, clinical considerations and modifications to protocol design that are necessary to optimize contrast enhancement for common clinical CT applications are proposed. © RSNA, 2010.


Tofovic S.P.,University of Pittsburgh
Journal of Cardiovascular Pharmacology | Year: 2010

Severe pulmonary arterial hypertension (PAH) is characterized by clustered proliferation of endothelial cells (ECs) in the lumina of small size pulmonary arteries resulting in concentric obliteration of the lumina and formation of complex vascular structures known as plexiform lesions. This debilitating disease occurs more frequently in women, yet both animal studies in classical models of PAH and limited clinical data suggest protective effects of estrogens: the estrogen paradox in pulmonary hypertension. Little is known about the role of estrogens in PAH, but one line of evidence strongly suggests that the vascular protective effects of 17β-estradiol (estradiol; E2) are mediated largely by its downstream metabolites. Estradiol is metabolized to 2-hydroxyestradiol (2HE) by CYP1A1/ CYP1B1, and 2HE is converted to 2-methoxyestradiol (2ME) by catechol-O-methyl transferase. 2ME is extensively metabolized to 2-methoxyestrone, a metabolite that lacks biologic activity, but which may be converted back to 2ME. 2ME has no estrogenic activity, and its effects are mediated by estrogen receptors-independent mechanism(s). Notably, in systemic and pulmonary vascular ECs, smooth muscle cells, and fibroblasts, 2ME exerts stronger antimitotic effects than E2 itself. E2 and 2ME, despite having similar effects on other cardiovascular cells, have opposing effects on ECs; that is, in ECs, E2 is promitogenic, proangiogenic, and antiapoptotic, whereas 2ME is antimitogenic, antiangiogenic, and proapoptotic. This may have significant ramifications in severe PAH that involves uncontrolled proliferation of monoclonal apoptosis-resistant ECs. Based on its cellular effects, 2ME should be expected to attenuate the progression of disease and provide protection in severe PAH. In contrast, E2, due to its mitogenic, angiogenic, and antiapoptotic effects (otherwise desirable in normal quiescent ECs), may even adversely affect endothelial remodeling in PAH, and this may be even more significant if the E2's effects on injured endothelium are not opposed by 2ME (eg, in the event of reduced E2 conversion to 2ME due to hypoxia, inflammation, drugs, environmental factors, or genetic polymorphism of metabolizing enzymes). This review focuses on the effects of estrogens and their metabolites on pulmonary vascular pathobiology and the development of experimental PAH and offers potential explanation for the estrogen paradox in PAH. Furthermore, we propose that unbalanced estradiol metabolism may lead to the development of PAH. Recent animal data and studies in patients with PAH support this concept. Copyright © 2010 by Lippincott Williams & Wilkins.


Gerszten P.C.,University of Pittsburgh
Journal of neurosurgery | Year: 2012

There is a growing body of evidence to support the safe and effective use of spine radiosurgery. However, there is much less experience regarding the use of radiosurgery for the treatment of benign as opposed to malignant spine tumors. This study represents an evaluation of, and reporting on, the technical aspects of using a dedicated radiosurgery system for the treatment of benign spine tumors. Forty-five consecutive benign spine tumors were treated using the Elekta Synergy S 6-MV linear accelerator with a beam modulator and cone-beam computed tomography (CBCT) image guidance technology for target localization. The study cohort included 16 men and 29 women, ranging in age from 23 to 88 years (mean age 52 years). There were 14 cervical, 12 thoracic, 14 lumbar, and 5 sacral tumors. Forty-one lesions (91%) were intradural. The most common histological types of tumor were schwannoma, neurofibroma, and meningioma. Indications for radiosurgery included primary treatment in 24 cases (53%) and treatment of recurrent or residual tumor after open resection in 21 cases (47%). No subacute or long-term spinal cord or cauda equina toxicity occurred during the follow-up period (median 32 months). The mean maximum dose received by the gross tumor volume (GTV) was 16 Gy (range 12-24 Gy) delivered in a single fraction in 39 cases. The mean lowest dose received to the GTV was 12 Gy (range 8-16 Gy). The GTV ranged from 0.37 to 94.5 cm(3) (mean 13.7 cm(3), median 5.9 cm(3)). In the majority of cases, a planning target volume expansion of 2 mm was employed (38 cases; 84%). The mean maximum point dose delivered to the spinal cord was 8.7 Gy (range 4-11.5 Gy); the mean volume of the spinal cord that received greater than 8 Gy was 0.9 cm(3) (range 0.0-5.1 cm(3)); and the mean dose delivered to 0.1 cm(3) of the spinal cord was 7.5 Gy (range 3-10.5 Gy). The mean maximum point dose delivered to the cauda equina was 10 Gy (range 0-13 Gy); the mean volume of the cauda equina that received greater than 8 Gy was 1.45 cm(3) (range 0.0-10.6 cm(3)); and the mean dose delivered to 0.1 cm(3) of the cauda equina was 8 Gy (range 0.5-11 Gy). In this study the authors describe the contouring and prescribed dose techniques used in the treatment planning and delivery of radiosurgery for benign neoplasms of the spine using CBCT image guidance. This technique may serve as an important reference for the performance of radiosurgery when one believes it is clinically indicated as a treatment modality for a benign spine tumor that is associated with both a high safety profile and a strong positive clinical outcome.


Petek H.,University of Pittsburgh
ACS Nano | Year: 2014

Through a combination of light and electron probes, it may be possible to record single-molecule dynamics with simultaneous sub-Ångstrom spatial and femtosecond temporal resolution. Single-molecule femtochemistry is becoming a realistic prospect through a melding of laser spectroscopy and electron microscopy techniques. The paper by Lee et al. in this issue of ACS Nano takes a significant step toward chemical imaging at the space-time limit of chemical processes. By imaging electroluminescence spectra of single porphyrin molecules with submolecular resolution, the authors extract the implicit femtosecond dynamics of the coupled electron orbital-molecular skeletal motion triggered by a reduction-oxidation scattering process. © 2014 American Chemical Society.


Hill S.Y.,University of Pittsburgh
International Review of Neurobiology | Year: 2010

Opportunities for advances in the neurobiology of alcohol dependence have been facilitated by the development of sophisticated neurophysiological and neuroimaging techniques that allow us to have a window on developmental changes in brain structure and function. The search for genes that may increase susceptibility to alcohol dependence has been greatly facilitated by the recognition that intermediate phenotypes, sometimes referred to as endophenotypes, may be closer to the genetic variation than is the more complex alcohol dependence phenotype. This chapter will review the evidence that the brain is highly plastic, exhibiting major postnatal changes, especially during adolescence, in neural circuits that appear to influence addiction susceptibility. This chapter will suggest that heritable aspects of brain structure and function that are seen developmentally may be an important endophenotypic characteristic associated with familial risk for developing alcohol dependence. Finally, a review of studies showing associations between brain structural and functional characteristics and specific genes will be offered. © 2010 Elsevier Inc.


Zuckerman D.M.,University of Pittsburgh
Annual Review of Biophysics | Year: 2011

Equilibrium sampling of biomolecules remains an unmet challenge after more than 30 years of atomistic simulation. Efforts to enhance sampling capability, which are reviewed here, range from the development of new algorithms to parallelization to novel uses of hardware. Special focus is placed on classifying algorithms most of which are underpinned by a few key ideasin order to understand their fundamental strengths and limitations. Although algorithms have proliferated, progress resulting from novel hardware use appears to be more clear-cut than from algorithms alone, due partly to the lack of widely used sampling measures. © 2011 by Annual Reviews. All rights reserved.


Pinsky M.R.,University of Pittsburgh
Critical Care Medicine | Year: 2010

Biological systems are innately complex, display nonlinear behavior, and respond to both disease and its treatment in similar complex ways. Complex systems display self-organization and predictive behavior along a range of possible states, often referred to as chaotic behavior, and can be both characterized and quantified in terms of this chaotic behavior, which defined strange attractors (ρ) and variability. In this context, disease can be characterized as a difference in a disease state ρ and a healthy ρ. Furthermore, effectiveness of treatment can be defined as a minimization problem to decrease the phase-state difference between disease and health ρ values, such that effective treatment is defined as the ability to restore the healthy ρ. Importantly, this approach will be effective without anything being known about the physiologic processes that define health or disease. The implication is that this approach is a powerful tool to define the determinants of instability as compared with normal variability, to answer why disease is not healthy, and to identify all potentially effective treatment options independent of known pharmacology and physiology. Copyright © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.


Chakraborty D.P.,University of Pittsburgh
Seminars in Nuclear Medicine | Year: 2011

A common task in medical imaging is assessing whether a new imaging system, or a variant of an existing one, is an improvement over an existing imaging technology. Imaging systems are generally quite complex, consisting of several componentsfor example, image acquisition hardware, image processing and display hardware and software, and image interpretation by radiologists- each of which can affect performance. Although it may appear odd to include the radiologist as a "component" of the imaging chain, because the radiologist's decision determines subsequent patient care, the effect of the human interpretation has to be included. Physical measurements such as modulation transfer function, signal-to-noise ratio, are useful for characterizing the nonhuman parts of the imaging chain under idealized and often unrealistic conditions, such as uniform background phantoms and target objects with sharp edges. Measuring the performance of the entire imaging chain, including the radiologist, and using real clinical images requires different methods that fall under the rubric of observer performance methods or "ROC" analysis, that involve collecting rating data on images. The purpose of this work is to review recent developments in this field, particularly with respect to the free-response method, where location information is also collected. © 2011 Elsevier Inc.


Wu F.,Michigan State University | Wang T.,University of Pittsburgh
Cancer Epidemiology Biomarkers and Prevention | Year: 2013

Background: Aristolochic acid is a toxin found in plants of the genus Aristolochia, to which humans can be exposed either through certain Chinese herbal medicines or through inadvertent commingling with food crops. Our objective was to estimate cumulative exposures of aristolochic acid associated with increased risk of end-stage renal disease (ESRD), and to conduct a systematic review and meta-analysis on aristolochic acidinduced upper tract urothelial carcinoma (UUC). Methods: Using epidemiologic studies on aristolochic acid-related disease from multiple different regions of the world, a systematic review was conducted in which relative risks (RR), HRs, and ORs were derived or extracted directly, and a meta-analysis was conducted. One study was used to estimate a benchmark dose lower confidence limit (BMDL) for aristolochic acid-related ESRD. Results: Mean values for risk ratios, ORs, RRs, or HRs, of UUC caused by aristolochic acid ranged from 1 to 49.Ameta-analysis of these studies resulted in a pooledORof 5.97 [95% confidence interval (CI), 2.78-12.84] for this aristolochic acid-related cancer. The obtained BMDL for aristolochic acid-related ESRD was 0.42 g cumulative aristolochic acid exposure. Conclusions: Aristolochic acid exposure is significantly associated with an increased risk of UUC, and there is a dose-dependent relationship between cumulative aristolochic acid exposure and ESRD risk. Impact: Individuals who use certain Chinese herbal medicines may significantly increase their risk of developing UUC and/or ESRD, as would individuals who are inadvertently exposed to aristolochic acid through commingling of Aristolochia plants with harvested food crops. Cancer Epidemiol Biomarkers Prev; 22(5); 812-20. © 2013 AACR.


Neumann C.S.,University of North Texas | Pardini D.,University of Pittsburgh
Journal of Personality Disorders | Year: 2014

A large sample (N = 425) of young adult males from the Pittsburg Youth Study (PYS; Loeber, Farrington, Stouthamer-Loeber, & Van Kammen, 1998) was used to test the item-level structure of the short-form version of the Self-Report Psychopathy Scale (SRP; Paulhus, Neumann, & Hare, in press) and the standard version of the Youth Psychopathic Traits Inventory (YPI; Andershed, Kerr, Stattin, & Levander, 2002). Also, structural equation modeling analyses examined how the SRP and YPI factors were linked to external correlates involving criminal offenses and Internalizing and externalizing psychopathology. The modeling results indicated acceptable fit for the latent structure of both instruments and the SRP and YPI factor correlations were strong, particularly for conceptually-related scales. Finally, both instruments showed similar patterns in predicting externalizing and internalizing psychopathology, as well as criminal oflenses. Taken together, the results provide evidence of convergent and construct validity across the two instruments. New insights into the link between psychopathy and the external correlates in young adult males are discussed. © 2014 The Guilford Press.


Hirsch H.H.,University of Basel | Randhawa P.,University of Pittsburgh
American Journal of Transplantation | Year: 2013

The human BK polyomavirus (BKV) is the major cause of polyomavirus- associated nephropathy (PyVAN) putting 1-15% of kidney transplant patients at risk of premature allograft failure, but is less common in other solid organ transplants. Because effective antiviral therapies are lacking, screening kidney transplant patients for BKV replication in urine and blood has become the key recommendation to guide the reduction of immunosuppression in patients with BKV viremia. This intervention allows for expanding BKV-specific cellular immune responses, curtailing of BKV replication in the graft, and clearance of BKV viremia in 70-90% patients. Postintervention rejection episodes occur in 8-12%, most of which are corticosteroid responsive. Late diagnosis is faced with irreversible functional decline, poor treatment response, and graft loss. Adjunct therapies such as cidofovir, leflunomide and intravenous immunoglobulins have been used, but the benefit is not documented in trials. Retransplantation after PyVAN is largely successful, but requires close monitoring for recurrent BKV viremia. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.


Minshew N.J.,University of Pittsburgh | Keller T.A.,Carnegie Mellon University
Current Opinion in Neurology | Year: 2010

Purpose of Review: Functional magnetic resonance imaging studies have had a profound impact on the delineation of the neurobiologic basis for autism. Advances in fMRI technology for investigating functional connectivity, resting state connectivity, and a default mode network have provided further detail about disturbances in brain organization and brain-behavior relationships in autism to be reviewed in this article. Recent Findings: Recent fMRI studies have provided evidence of enhanced activation and connectivity of posterior, or parietal-occipital, networks and enhanced reliance on visuospatial abilities for visual and verbal reasoning in high functioning individuals with autism. Evidence also indicates altered activation in frontostriatal networks for cognitive control, particularly involving anterior cingulate cortex, and altered connectivity in the resting state and the default mode network. The findings suggest that the specialization of many cortical networks of the human brain has failed to develop fully in high functioning individuals with autism. Summary: This research provides a growing specification of to the neurobiologic basis for this complex syndrome and for the co-occurrence of the signs and symptoms as a syndrome. With this knowledge has come new neurobiologically based opportunities for intervention. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Duquesnoy R.J.,University of Pittsburgh
Tissue Antigens | Year: 2011

Antibodies against allogeneic human leukocyte antigen (HLA) molecules are important impediments to the success of different clinical procedures including transplantation and platelet transfusion. In these settings, characterization of the repertoire of immunogenic epitopes is important for permissible mismatch determination and the identification of acceptable mismatches for sensitized patients. HLAMatchmaker is a computer algorithm that considers small configurations of polymorphic residues referred to as eplets as essential components of HLA epitopes. This review critically elaborates the concepts underlying the HLAMatchmaker and describes the usefulness of HLAMatchmaker in the clinical setting. Recent developments have increased our understanding of structural basis of HLA antigenicity (i.e. reactivity with specific antibody) and immunogenicity (i.e. its ability to induce an antibody response). © 2011 John Wiley & Sons A/S.


Watchko J.F.,University of Pittsburgh
Seminars in Fetal and Neonatal Medicine | Year: 2010

African American neonates evidence a low incidence of hyperbilirubinemia yet account for more than 25% of the reported kernicterus cases in the USA. Glucose-6-phosphate dehydrogenase (G6PD) deficiency accounts for ∼60%, and late preterm gestation and ABO hemolytic disease ∼40% of these cases. Females heterozygous for G6PD A- harbor a population of G6PD-deficient red blood cells and are at risk for hyperbilirubinemia. Pre-discharge bilirubin measurement coupled with gestational age enhances the identification of neonates at hyperbilirubinemia risk. Parental education at the time of birth hospitalization discharge combined with timely follow-up may help to reduce the risk of developing hazardous hyperbilirubinemia. © 2009 Elsevier Ltd. All rights reserved.


The syndrome of inappropriate antidiudresis (SIAD) and cerebral salt wasting (CSW) are similar conditions with the main difference being the absence or presence of volume depletion. The two conditions may be indistinguishable at presentation, as volume status is difficult to assess, which can lead to under-diagnosis of CSW in patients with central nervous system (CNS) disease. Carefully conducted studies in patients with CNS disease have indicated that CSW may be more common than SIAD. CSW may be differentiated from SIAD based on the persistence of hypouricemia and increased fractional excretion of urate following the correction of hyponatremia. Hyponatremia should be prevented if possible and treated promptly when discovered in patients with CNS disease as even mild hyponatremia could lead to neurological deterioration. Fluid restriction should not be used for the prevention or treatment of hyponatremia in hospitalized patients with CNS disease as it could lead to volume depletion especially if CSW is present. 0.9% sodium chloride may not be sufficiently hypertonic for the prevention of hyponatremia in hospitalized patients with CNS disease and a more hypertonic fluid may be required. The preferred therapy for the treatment of hyponatremia in patients with CNS disease is 3% sodium chloride. © IPNA 2012.


Redner R.L.,University of Pittsburgh
Oncologist | Year: 2010

Imatinib mesylate has transformed the treatment for chronic myeloid leukemia (CML). The vast majority of patients obtain hematologic remission, with a low probability of progression of disease. Yet imatinib rarely cures CML, and current recommendations dictate lifelong treatment with imatinib. In this review we analyze the biology behind the failure of imatinib to fully eradicate CML. We review evidence that indicates that the leukemic stem cell for CML is inherently resistant to imatinib, and that imatinib treatment itself may enhance this resistance. ©AlphaMed Press.


Mcewen B.S.,Rockefeller University | Gianaros P.J.,University of Pittsburgh
Annals of the New York Academy of Sciences | Year: 2010

The brain is the key organ of stress reactivity, coping, and recovery processes. Within the brain, a distributed neural circuitry determines what is threatening and thus stressful to the individual. Instrumental brain systems of this circuitry include the hippocampus, amygdala, and areas of the prefrontal cortex. Together, these systems regulate physiological and behavioral stress processes, which can be adaptive in the short-term and maladaptive in the long-term. Importantly, such stress processes arise from bidirectional patterns of communication between the brain and the autonomic, cardiovascular, and immune systems via neural and endocrine mechanisms underpinning cognition, experience, and behavior. In one respect, these bidirectional stress mechanisms are protective in that they promote short-term adaptation (allostasis). In another respect, however, these stress mechanisms can lead to a long-term dysregulation of allostasis in that they promote maladaptive wear-and-tear on the body and brain under chronically stressful conditions (allostatic load), compromising stress resiliency and health. This review focuses specifically on the links between stress-related processes embedded within the social environment and embodied within the brain, which is viewed as the central mediator and target of allostasis and allostatic load. © 2010 New York Academy of Sciences.


Khillan J.S.,University of Pittsburgh
Nutrients | Year: 2014

Retinol, the alcohol form of vitamin A is a key dietary component that plays a critical role in vertebrate development, cell differentiation, reproduction, vision and immune system. Natural and synthetic analogs of retinol, called retinoids, have generally been associated with the cell differentiation via retinoic acid which is the most potent metabolite of retinol. However, a direct function of retinol has not been fully investigated. New evidence has now emerged that retinol supports the self-renewal of stem cells including embryonic stem cells (ESCs), germ line stem cells (GSCs) and cancer stem cells (CSCs) by activating the endogenous machinery for self-renewal by a retinoic acid independent mechanism. The studies have also revealed that stem cells do not contain enzymes that are responsible for metabolizing retinol into retinoic acid. This new function of retinol may have important implications for stem cell biology which can be exploited for quantitative production of pure population of pluripotent stem cells for regenerative medicine as well as clinical applications for cancer therapeutics. © 2014 by the authors;licensee MDPI, Basel, Switzerland.


Sween L.K.,University of Pittsburgh
American journal of obstetrics and gynecology | Year: 2015

OBJECTIVE: The purpose of this study was to identify differences of early-pregnancy body fat percentage and body mass index (BMI) between obese women that experienced preeclampsia and those who did not.STUDY DESIGN: We performed an analysis of the Prenatal Exposures and Preeclampsia Prevention 3 longitudinal cohort study of preeclampsia mechanisms in obese and overweight women. Women completed questionnaires regarding their health behaviors; had hematocrit level, weight and height, and waist and hip circumferences measured, and had resistance and reactance measured by bioelectric impedance analysis machine during the first, second, and third trimesters. Total body water, fat mass, and percent body fat were calculated with the use of pregnancy-specific formulas. Preeclampsia was assessed with the clinical definition and a research definition (clinical preeclampsia plus hyperuricemia). Logistic regression models were constructed to analyze early-pregnancy BMI and body fat percentage (measured at 10.2 ± 3.0 weeks of gestation) as predictors of preeclampsia outcomes.RESULTS: Three hundred seventy-three women were included in the analysis: 30 women had preeclampsia by clinical definition (8.0%), and 14 women had preeclampsia by the research definition (3.8%). There was no relationship between BMI and preeclampsia risk in obese women; however, body fat percentage was associated significantly with increased risk of both the clinical definition of preeclampsia and the research definition. In 239 obese women, a 1% increase in body fat was associated with approximately 12% increased odds of clinical preeclampsia and 24% increased risk of preeclampsia by the research definition.CONCLUSION: Early-pregnancy body fat appears to be important in the pathophysiologic condition of preeclampsia in obese women. Copyright © 2015. Published by Elsevier Inc.


Delgoffe G.M.,University of Pittsburgh | Powell J.D.,Johns Hopkins University
Current Opinion in Immunology | Year: 2015

T cell activation and differentiation is a complex process that has evolved beyond the two-signal model to a number of varied and opposing inputs that must be interpreted to make a cell fate decision. While stimulation through the TCR, costimulatory, and cytokine receptors is required, metabolic signaling has emerged not only as an activation signal, but also one that can influence and shape differentiation. Recent findings have revealed unappreciated roles for glucose, fatty acids, and salt in the function of many T cell subsets. In this review, we will highlight the latest advances in the burgeoning field of immunometabolism, focusing on how the menu of T cell fuels has expanded. © 2015 Elsevier Ltd.


Parks W.T.,University of Pittsburgh
Seminars in Perinatology | Year: 2015

The placental lesions classically ascribed to placental hypoxia, here denoted maternal malperfusion (MMP), are among the more significant that a placental pathologist may encounter. Yet the appearance of these lesions may be subtle, and the clinical implication of their diagnosis is frequently unclear. The aim of this review is to provide a more nuanced perspective on the clinical utility of placental pathology for the detection of MMP. The review will first detail MMP lesions in the placenta and discuss their associations with pregnancy complications. The review will then delve into the diagnostic and interpretive difficulties of these lesions. Finally, recent research findings that may aid in the development of better diagnostic tools will be briefly discussed. © 2014 Elsevier Inc.


Gabriele Sandrian M.,University of Pittsburgh
The British journal of ophthalmology | Year: 2012

To evaluate the utility of gold nanorods (AuNRs) as a contrast agent for ocular optical coherence tomography (OCT). Mice were intravitreally injected with sterile AuNRs coated with either poly(strenesulfate) (PSS-AuNRs) or anti-CD90.2 antibodies (Ab-AuNRs), and imaged using OCT. After 24 h, eyes were processed for transmission electron microscopy or rendered into single cell suspensions for flow cytometric analysis to determine absolute numbers of CD45(+) leukocytes and subsets (T cells, myeloid cells, macrophages, neutrophils). Generalised estimation equations were used to compare cell counts between groups. PSS-AuNRs and Ab-AuNRs were visualised in the vitreous 30 min and 24 h post-injection with OCT. At 24 h, a statistically significant increase in leukocytes, comprised primarily of neutrophils, was observed in eyes that received either AuNR in comparison to eyes that received saline. The accumulation of leukocytes was equal in eyes given PSS-AuNR or Ab-AuNR. Endotoxin-resistant C3H/HeJ mice also showed ocular inflammation after injection with AuNRs, indicating that the inflammatory response was not due to lipopolysaccharide contamination of AuNRs. Although AuNRs can be visualised in the eye using OCT, they can induce ocular inflammation, which limits their use as a contrast agent.


A major concern for all copy number variation (CNV) detection algorithms is their reliability and repeatability. However, it is difficult to evaluate the reliability of CNV-calling strategies due to the lack of gold-standard data that would tell us which CNVs are real. We propose that if CNVs are called in duplicate samples, or inherited from parent to child, then these can be considered validated CNVs. We used two large family-based genome-wide association study (GWAS) datasets from the GENEVA consortium to look at concordance rates of CNV calls between duplicate samples, parent-child pairs, and unrelated pairs. Our goal was to make recommendations for ways to filter and use CNV calls in GWAS datasets that do not include family data. We used PennCNV as our primary CNV-calling algorithm, and tested CNV calls using different datasets and marker sets, and with various filters on CNVs and samples. Using the Illumina core HumanHap550 single nucleotide polymorphism (SNP) set, we saw duplicate concordance rates of approximately 55% and parent-child transmission rates of approximately 28% in our datasets. GC model adjustment and sample quality filtering had little effect on these reliability measures. Stratification on CNV size and DNA sample type did have some effect. Overall, our results show that it is probably not possible to find a CNV-calling strategy (including filtering and algorithm) that will give us a set of "reliable" CNV calls using current chip technologies. But if we understand the error process, we can still use CNV calls appropriately in genetic association studies. © 2012 Wiley Periodicals, Inc.


Whiteside T.L.,University of Pittsburgh
Expert Opinion on Biological Therapy | Year: 2010

Importance of the field: Immunotherapy of cancer has not improved disease-free or overall patient survival. The lack of concordance between immunological and clinical responses in cancer immunotherapy trials is thought to result from the pervasive presence of tumor-driven immune suppression that allows tumor to escape and that has not been adequately targeted by current therapies. Areas covered in this review: Because multiple mechanisms of tumor induced suppression have been identified and shown to contribute to tumor escape, the opportunity arises to interfere with these mechanisms. A range of known tumor-derived inhibitors can now be blocked or neutralized by biologic or metabolic agents. Used alone or in combination with each other or with conventional cancer therapies, these agents offer novel therapeutic strategies for the control of tumor escape. What the reader will gain: This review deals with currently available inhibitors for counteracting tumor immune escape. The restoration of effective anti-tumor immunity in patients with cancer will require new approaches aiming at: i) protection of immune cells from adverse effects of myeloid-derived suppressor cells, regulatory T cells or inhibitory factors thus enhancing effector functions; and ii) prolonging survival of central memory T cells, thus ensuring long-term protection. Take home message: Inhibitors of mechanisms responsible for tumor escape could restore anti-tumor immune responses in patients with cancer. © 2010 Informa UK Ltd.


Saidi W.A.,University of Pittsburgh
Crystal Growth and Design | Year: 2014

The stability and the electronic structure of layered heterostructures MX2 (M = Mo or W and X = S or Se) and graphene (GA) are systematically investigated using first-principles methods. The calculations cover pristine and defected GA systems with up to 12% nitrogen substitutional defects. It is found that the van der Waals (vdW) epitaxy of MX2 on undoped GA substrate, whether pristine or defected, follows a Volmer-Weber growth-mode resulting in thick MX2 films. On the other hand, nitrogen doping of pristine GA (N-GA) and also of GA with Stone-Wales (SW) defects increases the MX2/GA heterostructure adhesion energy favoring the growth of ultrathin MX2 layers. This growth-mode change in MoS2 due to nitrogen doping is in agreement with recent experiments. Furthermore, our study demonstrates that the yield of ultrathin MX2 films can be increased if the N-GA samples have a larger concentration of SW defects or nitrogen. The underpinnings of the extra stability of these N-GA substrates are due to charge-transfer effects that decrease the Pauli repulsion between the two layered systems. © 2014 American Chemical Society.


Gjoerup O.,University of Pittsburgh
Advances in cancer research | Year: 2010

Over 50 years of polyomavirus research has produced a wealth of insights into not only general biologic processes in mammalian cells, but also, how conditions can be altered and signaling systems tweaked to produce transformation phenotypes. In the past few years three new members (KIV, WUV, and MCV) have joined two previously known (JCV and BKV) human polyomaviruses. In this review, we present updated information on general virologic features of these polyomaviruses in their natural host, concentrating on the association of MCV with human Merkel cell carcinoma. We further present a discussion on advances made in SV40 as the prototypic model, which has and will continue to inform our understanding about viruses and cancer. Copyright 2010 Elsevier Inc. All rights reserved.


Welling P.A.,University of Maryland, Baltimore | Weisz O.A.,University of Pittsburgh
Physiology | Year: 2010

Ion and water transport by the kidney is continually adjusted in response to physiological cues. Selective endocytosis and endosomal trafficking of ion transporters are increasingly appreciated as mechanisms to acutely modulate renal function. Here, we discuss emerging paradigms in this new area of investigation. © 2010 Int. Union Physiol. Sci./Am. Physiol. Soc.


Levine S.J.,U.S. National Institutes of Health | Wenzel S.E.,University of Pittsburgh
Annals of Internal Medicine | Year: 2010

New therapeutic approaches are needed for patients with severe asthma who are refractory to standard therapy comprising high doses of inhaled corticosteroids plus long-acting β2-agonists. Current treatment guidelines for patients with severe asthma from the National Asthma Education and Prevention Program recommend the addition of oral corticosteroids, which are associated with substantial morbidity, and, for those with allergic asthma, anti-IgE. Genetic and translational studies, as well as clinical trials, suggest that in a subgroup of patients, the pathobiology of severe asthma is mediated by immune pathways driven by T-helper 2 (Th2)-type CD4+ T cells, which produce a characteristic repertoire of interleukins (ILs), including IL-4, IL-5, and IL-13. Therefore, biological modifiers of Th2-type ILs, such as monoclonal antibodies, soluble receptors, and receptor antagonists, are a rational strategy for developing new treatment approaches but will need to be targeted to selected patients in whom the appropriate Th2 immune pathway is "active." The benefits of immune-modifier therapies targeting Th2-type cytokines, however, need to be weighed against the toxicities associated with inhibition of key biological pathways, as well as the expense of future medications. Therefore, future clinical trials need to clearly establish the efficacy and safety of biological modifiers of Th2 immune pathways before these approaches can enter routine clinical practice for the treatment of severe asthma.


Schnitzer S.A.,University of Wisconsin - Milwaukee | Schnitzer S.A.,Smithsonian Tropical Research Institute | Carson W.P.,University of Pittsburgh
Ecology Letters | Year: 2010

Treefall gaps are hypothesized to maintain diversity by creating resource-rich, heterogeneous habitats necessary for species coexistence. This hypothesis, however, is not supported empirically for shade-tolerant trees, the dominant plant group in tropical forests. The failure of gaps to maintain shade-tolerant trees remains puzzling, and the hypothesis implicated to date is dispersal limitation. In central Panama, we tested an alternative 'biotic interference' hypothesis: that competition between growth forms (lianas vs. trees) constrains shade-tolerant tree recruitment, survival and diversity in gaps. We experimentally removed lianas from eight gaps and monitored them for 8 years, while also monitoring nine un-manipulated control gaps. Removing lianas increased tree growth, recruitment and richness by 55, 46 and 65%, respectively. Lianas were particularly harmful to shade-tolerant species, but not pioneers. Our findings demonstrate that competition between plant growth forms constrains diversity in a species-rich tropical forest. Because lianas are abundant in many tropical systems, our findings may apply broadly. © 2010 Blackwell Publishing Ltd/CNRS.


Zarbock A.,University of Munster | Kellum J.A.,University of Pittsburgh
Critical Care Medicine | Year: 2016

Acute kidney injury is a common complication in critically ill patients and is associated with increased morbidity and mortality. Sepsis, major surgery, and nephrotoxic drugs are the most common causes of acute kidney injury. There is currently no effective strategy available to prevent or treat acute kidney injury. Therefore, novel treatment regimens are required to decrease acute kidney injury prevalence and to improve clinical outcomes. Remote ischemic preconditioning, triggered by brief episodes of ischemia and reperfusion applied in distant tissues or organs before the injury of the target organ, attempts to invoke adaptive responses that protect against acute kidney injury. We sought to evaluate the clinical evidence for remote ischemic preconditioning as a potential strategy to protect the kidney and to review the underlying mechanisms in light of recent studies. Data Sources: We searched PubMed for studies reporting the effect of remote ischemic preconditioning on kidney function in surgical patients (search terms: "remote ischemic preconditioning," "kidney function," and "surgery"). We also reviewed bibliographies of relevant articles to identify additional citations. Study Selection: Published studies, consisting of randomized controlled trials, are reviewed. Data Extraction: The authors used consensus to summarize the evidence behind the use of remote ischemic preconditioning. Data Synthesis: In addition, the authors suggest patient populations and clinical scenarios in which remote ischemic preconditioning might be best applied. Conclusions: Several experimental and clinical studies have shown tissue-protective effects of remote ischemic preconditioning in various target organs, including the kidneys. Remote ischemic preconditioning may offer a novel, noninvasive, and inexpensive treatment strategy for decreasing acute kidney injury prevalence in high-risk patients. Although many new studies have further advanced our knowledge in this area, the appropriate intensity of remote ischemic preconditioning, its mechanisms of action, and the role of biomarkers for patient selection and monitoring are still unknown. © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.


Maldonado-Carreno C.,University of Los Andes, Colombia | Votruba-Drzal E.,University of Pittsburgh
Child Development | Year: 2011

Despite recent growth in research highlighting the potential of teacher-child relationships to promote children's development during the early years of school, questions remain about the importance of these relationships across elementary school. Using data from the NICHD Study of Early Child Care (N=1,364), this study examines between- and within-child associations between teacher-child relationship quality and children's academic achievement and behavior problems from kindergarten (ages 4-6years) through 5th grade (ages 9-11years). Results suggest that increases in teacher-child relationship quality are associated with improvements in teacher-reported academic skills and reductions in behavior problems consistently throughout elementary school. As children progressed from kindergarten through fifth grade, the importance of teacher-child relationship quality is unchanging. © 2011 The Authors. Child Development © 2011 Society for Research in Child Development, Inc..


Birder L.A.,University of Pittsburgh
Handbook of Experimental Pharmacology | Year: 2011

The urinary bladder "mucosa" or innermost portion of the bladder is composed of transitional epithelium, basement membrane, and the lamina propria. This chapter reviews the specialized anatomy of the bladder epithelium (urothelium) and speculates on possible communication mechanisms from urothelial cells to various cell types within the bladder wall. For example, beyond serving as a simple barrier, there is growing evidence that the urinary bladder urothelium exhibits specialized sensory properties and plays a key role in the detection and transmission of both physiological and nociceptive stimuli. Findings from a number of studies suggest that the urothelium exhibits both "sensor" (expressing receptors/ ion channels capable of responding to thermal, mechanical, and chemical stimuli) and "transducer" (ability to release chemicals) properties. Thus, urothelial cells exhibit the ability to sense changes in their extracellular environment including the ability to respond to chemical, mechanical, and thermal stimuli that may communicate the state of the urothelial environment to the underlying nervous and muscular systems. © 2011 Springer-Verlag Berlin Heidelberg.


Pardini D.,University of Pittsburgh
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2011

Background: Delinquent youth with callous-unemotional (CU) traits may have a unique social-cognitive processing pattern that perpetuates their violent behavior. The current study examined the association between CU traits and the endorsement of deviant social goals during peer conflicts as well as expectancies and values regarding victim suffering following aggression. Methods: Participants included 156 (84 males, 72 females) adjudicated juveniles residing at two gender-specific residential facilities in an urban city within the southeastern United States. The association between CU traits and participants' ratings of their social goals in hypothetic conflict situations and outcome expectancies/values regarding victim suffering were examined after controlling for prior violence, intelligence, and demographic covariates. Results: CU traits were associated with an increased endorsement of social goals associated with revenge, dominance, and forced respect in social conflict situations. Adjudicated youth with CU traits were also less likely to endorse conflict avoidance and friendship building as important social goals when provoked by peers. There was no association between CU traits and expectations for victim suffering following aggression, but CU traits were significantly associated with lower levels of concern about victim suffering. These findings were significant after controlling for participants' prior history of violence, intelligence, and demographic covariates. Conclusions: Adjudicated youth with CU traits tend to emphasize power-oriented goals when provoked by peers and have little interest in rectifying social conflicts to build potential friendships with others. Juveniles with CU traits seem to be aware that their aggressive behavior will cause others to suffer, but they do not care when it does. © 2010 The Author. Journal of Child Psychology and Psychiatry © 2010 Association for Child and Adolescent Mental Health.


Wenzel S.,University of Pittsburgh
Clinical and Experimental Allergy | Year: 2012

Asthma, and severe asthma, in particular, is increasingly recognized as a heterogeneous disease. While traditional views of asthma have centered around a childhood onset disease with an allergic component, several large scale network studies are now confirming that severe asthma can present in multiple different ways, only 30-50% of which meet traditional childhood onset allergic criteria. To understand the different groups better, initial studies have attempted to define phenotypes of severe asthma. A phenotype is defined as the integration of different characteristics that are the product of the interaction of the patient's genes with the environment. Both clinical and statistical approaches have identified at least 3-5 phenotypes of severe asthma. However, these phenotypes, in isolation, do not identify the immunopathology that makes these clinical phenotypes distinct or identifies a target population for a specific approach to therapy. As biological characteristics are identified, phenotypes should continue to evolve towards asthma endotypes. The identification of these endotypes, either by matching biology, genetics and therapeutic responses to therapy with clinically or statistically defined phenotypes or through unbiased genetic and genomic approaches, remains limited. Moving forward, this integration of genetics, biology and clinical characteristics should substantially enhance our ability to effectively treat complex heterogeneous diseases, such as severe asthma. Reviews © 2012 Blackwell Publishing Ltd.


Studer A.,University of Munster | Curran D.P.,University of Pittsburgh
Nature Chemistry | Year: 2014

The electron is an efficient catalyst for conducting various types of radical cascade reaction that proceed by way of radical and radical ion intermediates. But because electrons are omnipresent, catalysis by electrons often passes unnoticed. In this Review, a simple analogy between acid/base catalysis and redox catalysis is presented. Conceptually, the electron is a catalyst in much the same way that a proton is a catalyst. The 'electron is a catalyst' paradigm unifies mechanistically an assortment of synthetic transformations that otherwise have little or no apparent relationship. Diverse radical cascades, including unimolecular radical substitution reactions (S RN 1-type chemistry), base-promoted homolytic aromatic substitutions (BHAS), radical Heck-type reactions, radical cross-dehydrogenative couplings (CDC), direct arene trifluoromethylations and radical alkoxycarbonylations, can all be viewed as electron-catalysed reactions.


Catov J.M.,University of Pittsburgh
Obstetrics and Gynecology | Year: 2011

Objective: To estimate whether women who deliver small babies due to preterm birth or growth restriction have excess risk for cardiovascular disease and diabetes later in life. Methods: Eight years after pregnancy, we estimated the prevalence of metabolic syndrome and its components in a cohort study of women with prior preterm (preterm birth before 37 weeks, n=181) or small for gestational age ([SGA], less than the tenth percentile, n=192) births, compared with women with term births (37 or more weeks, n=306). Women delivered at Magee-Womens Hospital in Pittsburgh, Pennsylvania, and those with preeclampsia or prepregnancy diabetes or hypertension were excluded. Women underwent a structured interview and fasting blood sampling. Results: Women were, on average, 8 years postpartum and 39 years old at evaluation. Women with a prior preterm birth had higher blood pressure, triglycerides, and LDL-cholesterol compared with those in a term control group. Women with prior SGA births were leaner and more likely to smoke compared with those with term births. Women with prior preterm birth had elevated risk of metabolic syndrome, adjusted for demographic, smoking and body size factors (23% preterm compared with 17% control group; odds ratio [OR] 1.76 [1.06, 2.80]). In women with a prior preterm birth, low HDL (11% preterm compared with 5% control group; OR 2.6 [1.2, 5.2]), hypertriglyceridemia (22% compared with 14%; OR 1.9 [1.2, 2.9]), and elevated glucose (24% compared with 19%; OR 1.5 [1.0, 2.3]) accounted for this excess metabolic syndrome. In women with SGA, the only element of metabolic syndrome that was aberrant was glucose metabolism. Conclusion: Eight years after pregnancy, women with prior preterm or SGA births had evidence of metabolic syndrome compared with women with term births. Screening and intervention in these women after pregnancy may delay or prevent disease. © 2011 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins.


Cramer D.W.,Brigham and Womens Hospital | Finn O.J.,University of Pittsburgh
Current Opinion in Immunology | Year: 2011

Common 'themes' in epidemiology related to cancer risk beg a comprehensive mechanistic explanation. As people age, risk for cancer increases. Obesity and smoking increase the risk for many types of cancer. History of febrile childhood diseases lowers the risk for melanomas, leukemias, non-Hodgkin's lymphoma (NHL), and ovarian cancer. Increasing number of ovulatory cycles uninterrupted by pregnancies correlate positively with breast, endometrial, and ovarian cancer risk while pregnancies and breastfeeding lower the risk for these cancers as well as cancers of the colon, lung, pancreas, and NHL. Chronic inflammatory events such as endometriosis or mucosal exposure to talc increase the risk for several types of cancer. Mechanisms so far considered are site specific and do not explain multiple associations. We propose that most of these events affect cancer immunosurveillance by changing the balance between an effective immune response and immune tolerance of an emerging cancer. We review recently published data that suggest that immune mechanisms underlie most of these observed epidemiologic associations with cancer risk. © 2011 Elsevier Ltd.


Perlmutter D.H.,University of Pittsburgh
Cold Spring Harbor perspectives in biology | Year: 2011

In α1-antitrypsin (AT) deficiency, a point mutation renders a hepatic secretory glycoprotein prone to misfolding and polymerization. The mutant protein accumulates in the endoplasmic reticulum of liver cells and causes hepatic fibrosis and hepatocellular carcinoma by a gain-of-function mechanism. Genetic and/or environmental modifiers determine whether an affected homozygote is susceptible to hepatic fibrosis/carcinoma. Two types of proteostasis mechanisms for such modifiers have been postulated: variation in the function of intracellular degradative mechanisms and/or variation in the signal transduction pathways that are activated to protect the cell from protein mislocalization and/or aggregation. In recent studies we found that carbamazepine, a drug that has been used safely as an anticonvulsant and mood stabilizer, reduces the hepatic load of mutant AT and hepatic fibrosis in a mouse model by enhancing autophagic disposal of this mutant protein. These results provide evidence that pharmacological manipulation of endogenous proteostasis mechanisms is an appealing strategy for chemoprophylaxis in disorders involving gain-of-function mechanisms.


Swanson E.S.,University of Pittsburgh
Physical Review E - Statistical, Nonlinear, and Soft Matter Physics | Year: 2011

Collective response of DNA to terahertz electric fields is studied in a simple pair bond model. We confirm, with some caveats, a previous observation of destabilizing DNA breather modes and explore the parameter dependence of these modes. It is shown that breather modes are eliminated under reasonable physical conditions and that thermal effects are significant. © 2011 American Physical Society.


Clark N.L.,Cornell University | Clark N.L.,University of Pittsburgh | Alani E.,Cornell University | Aquadro C.F.,Cornell University
Genome Research | Year: 2012

Evolutionary rate covariation (ERC) is a phylogenetic signature that reflects the covariation of a pair of proteins over evolutionary time. ERC is typically elevated between interacting proteins and so is a promising signature to characterize molecular and functional interactions across the genome. ERC is often assumed to result from compensatory changes at interaction interfaces (i.e., intermolecular coevolution); however, its origin is still unclear and is likely to be complex. Here, we determine the biological factors responsible for ERC in a proteome-wide data set of 4459 proteins in 18 budding yeast species. We show that direct physical interaction is not required to produce ERC, because we observe strong correlations between noninteracting but cofunctional enzymes. We also demonstrate that ERC is uniformly distributed along the protein primary sequence, suggesting that intermolecular coevolution is not generally responsible for ERC between physically interacting proteins. Using multivariate analysis, we show that a pair of proteins is likely to exhibit ERC if they share a biological function or if their expression levels coevolve between species. Thus, ERC indicates shared function and coexpression of protein pairs and not necessarily coevolution between sites, as has been assumed in previous studies. This full interpretation of ERC now provides us with a powerful tool to assign uncharacterized proteins to functional groups and to determine the interconnectedness between entire genetic pathways. © 2012 by Cold Spring Harbor Laboratory Press.


Wechsler L.R.,University of Pittsburgh
Stroke | Year: 2011

Background and Purpose: Imaging is an important aspect of decisions regarding treatment for acute stroke. New imaging techniques using MRI and CT enable estimation of tissue viability. This information may be useful to select patients for acute stroke therapies. Summary of Report: Several clinical trials identified patients with penumbra based on MRI or CT imaging. The results indicate patients with penumbra by imaging improve with reperfusion, but it is not yet clear that thrombolysis is beneficial when patients are selected on this basis. New quantitative techniques for assessing perfusion and diffusion may improve these results. Conclusion: Identifying reversible patterns on MRI or CT perfusion imaging may ultimately yield better results than the mismatch concept that is currently under active investigation. © 2010 American Heart Association, Inc.


Thrane S.,University of Pittsburgh
Journal of Pediatric Oncology Nursing | Year: 2013

Throughout the trajectory of the cancer experience, children and adolescents will likely face pain and anxiety in a variety of circumstances. Integrative therapies may be used either alone or as an adjunct to standard analgesics. Children are often very receptive to integrative therapies such as music, art, guided imagery, massage, therapeutic play, distraction, and other modalities. The effect of integrative modalities on pain and anxiety in children with cancer has not been systematically examined across the entire cancer experience. An in-depth search of PubMed, CINAHL, MedLine, PsychInfo, and Web of Science, integrative medicine journals, and the reference lists of review articles using the search terms pain, anxiety, pediatric, child*, oncology, cancer, neoplasm, complementary, integrative, nonconventional, and unconventional yielded 164 articles. Of these, 25 warranted full-text review. Cohen's d calculations show medium (d = 0.70) to extremely large (8.57) effect sizes indicating that integrative interventions may be very effective for pain and anxiety in children undergoing cancer treatment. Integrative modalities warrant further study with larger sample sizes to better determine their effectiveness in this population. © 2013 by Association of Pediatric Hematology/Oncology Nurses.


Kupfer D.J.,University of Pittsburgh
World Psychiatry | Year: 2013

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) marks the first significant revision of the publication since the DSM-IV in 1994. Changes to the DSM were largely informed by advancements in neuroscience, clinical and public health need, and identified problems with the classification system and criteria put forth in the DSM-IV. Much of the decision-making was also driven by a desire to ensure better alignment with the International Classification of Diseases and its upcoming 11th edition (ICD-11). In this paper, we describe select revisions in the DSM-5, with an emphasis on changes projected to have the greatest clinical impact and those that demonstrate efforts to enhance international compatibility, including integration of cultural context with diagnostic criteria and changes that facilitate DSM-ICD harmonization. It is anticipated that this collaborative spirit between the American Psychiatric Association (APA) and the World Health Organization (WHO) will continue as the DSM-5 is updated further, bringing the field of psychiatry even closer to a singular, cohesive nosology. Copyright © 2013 World Psychiatric Association.


Chelly J.E.,University of Pittsburgh
British journal of anaesthesia | Year: 2010

The indications for continuous nerve blocks for the perioperative pain management in hospitalized and ambulatory patients have extended well beyond orthopaedics. These techniques are not only used to control pain in patients undergoing major upper and lower extremity surgery, but also to provide perioperative analgesia in patients undergoing abdominal, plastic, urological, gynaecological, thoracic, and trauma surgeries. Infusion regimens of local anaesthetics and supplements must take into consideration the condition of the patient before and after surgery, the nature and intensity of the surgical stress associated with the surgery, and the possible need for immediate functional recovery. Continuous nerve blocks have proved safe and effective in reducing opioid consumption and related side-effects, accelerating recovery, and in many patients reducing the length of hospital stay. Continuous nerve blocks provide a safer alternative to epidural analgesia in patients receiving thromboprophylaxis, especially with low molecular-weight heparin.


Lopez O.L.,University of Pittsburgh
The American journal of managed care | Year: 2011

Most dementias in people at least 65 years of age are attributable to Alzheimer's disease (AD). While approximately 5.4 million Americans are now believed to have AD, the AD population is expected to nearly triple over the next 40 years, reaching approximately 14.5 million. Presently, there is no cure for AD, but a 2-year delay in AD onset would reduce the expected prevalence by 1.94 million within 50 years. The most important risk factor for AD is age, followed by presence of the apolipoprotein E-4 allele. Other risk factors for AD include sex (female), history of head trauma, family history of Down syndrome or dementia, and cerebrovascular risk factors. The initial neurodegenerative process that causes AD is unknown. However, it is accepted that the presence of amyloid plaques, neurofibrillary tangles, neuronal loss (and synapses), and cerebral amyloid angiopathy are the central pathogenic events. There is selective vulnerability of the limbic system and heteromodal association areas in AD pathology. The most affected neurotransmitter in AD is acetylcholine, as enzymes that are part of its metabolic pathway are depleted. The clinical presentation of AD is heterogeneous and insidious, and the psychological and financial effects of AD on caregivers and family members are significant.


Quesnelle K.M.,University of Pittsburgh
Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2011

Acquired resistance to cetuximab, a chimeric epidermal growth factor receptor (EGFR)-targeting monoclonal antibody, is a widespread problem in the treatment of solid tumors. The paucity of preclinical models has limited investigations to determine the mechanism of acquired therapeutic resistance, thereby limiting the development of effective treatments. The purpose of this study was to generate cetuximab-resistant tumors in vivo to characterize mechanisms of acquired resistance. We generated cetuximab-resistant clones from a cetuximab-sensitive bladder cancer cell line in vivo by exposing cetuximab-sensitive xenografts to increasing concentrations of cetuximab, followed by validation of the resistant phenotype in vivo and in vitro using invasion assays. A candidate-based approach was used to examine the role of HER2 on mediating cetuximab resistance both in vitro and in vivo. We generated a novel model of cetuximab resistance, and, for the first time in the context of EGFR-inhibitor resistance, we identified increased phosphorylation of a C-terminal fragment of HER2 (611-CTF) in cetuximab-resistant cells. Afatinib (BIBW-2992), an irreversible kinase inhibitor targeting EGFR and HER2, successfully inhibited growth of the cetuximab-resistant cells in vitro. When afatinib was combined with cetuximab in vivo, we observed an additive growth inhibitory effect in cetuximab-resistant xenografts. These data suggest that the use of dual EGFR-HER2 kinase inhibitors can enhance responses to cetuximab, perhaps in part due to downregulation of 611-CTF. This study conducted in a novel in vivo model provides a mechanistic rationale for ongoing phase I clinical trials using this combination treatment modality. ©2011 AACR.


Cauley J.A.,University of Pittsburgh
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2013

Objective. To describe the public health impact of osteoporosis including the magnitude of the problem and important consequences of osteoporotic fractures. Methods. Literature review of key references selected by author. Results. Current demographic trends leading to an increased number of individuals surviving past age 65 will result in an increased number of osteoporotic fractures. Important consequences of osteoporotic fractures include an increased mortality that for hip fractures extends to 10 years after the fracture. Increased mortality risk also extends to major and minor fractures, especially, in those over 75 years. Hip and vertebral fractures have important functional consequences and reductions in quality of life. The economic impact of osteoporotic fractures is large and growing. Significant health care resources are required for all fractures. Conclusions. To alleviate the public and private burden of osteoporosis related fractures, assessment of risk and reduction of individual risk is critical. © 2013 © The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.


Gibbs R.B.,University of Pittsburgh
Endocrine Reviews | Year: 2010

The pros and cons of estrogen therapy for use in postmenopausal women continue to be a major topic of debate in women's health. Much of this debate focuses on the potential benefits vs. harm of estrogen therapy on the brain and the risks for cognitive impairment associated with aging and Alzheimer's disease. Many animal and human studies suggest that estrogens can have significant beneficial effects on brain aging and cognition and reduce the risk of Alzheimer's-related dementia; however, others disagree. Important discoveries have been made, and hypotheses have emerged that may explain some of the inconsistencies. This review focuses on the cholinergic hypothesis, specifically on evidence that beneficial effects of estrogens on brain aging and cognition are related to interactions with cholinergic projections emanating from the basal forebrain. These cholinergic projections play an important role in learning and attentional processes, and their function is known to decline with advanced age and in association with Alzheimer's disease. Evidence suggests that many of the effects of estrogens on neuronal plasticity and function and cognitive performance are related to or rely upon interactions with these cholinergic projections; however, studies also suggest that the effectiveness of estrogen therapy decreases with age and time after loss of ovarian function. We propose a model in which deficits in basal forebrain cholinergic function contribute to age-related changes in the response to estrogen therapy. Based on this model, we propose that cholinergic-enhancing drugs, used in combination with an appropriate estrogen-containing drug regimen, may be a viable therapeutic strategy for use in older postmenopausal women with early evidence of mild cognitive decline. Copyright © 2010 by The Endocrine Society.


Benedek T.G.,University of Pittsburgh
Clinical and Experimental Rheumatology | Year: 2011

The first clinical evidence that an extract of animal adrenocortical tissue could counteract human adrenal failure was demonstrated in 1930. As chemical analyses of cortical extracts proceeded, mainly in the laboratories of Kendall at the Mayo Clinic and Reichstein in Zurich, it became evident that there is not one cortical hormone, but that all are steroids. By 1940 it was understood that there are two categories: those that cause sodium and fluid retention and those that counteract shock and inflammation. Structurally the presence or lack of oxygenation at C 11 on the steroid skeleton was critical. In 1948 the first patient with rheumatoid arthritis was treated with cortisone and soon thereafter other rheumatologic patients received cortisone or, to stimulate native cortisone production, ACTH. Oral and intraarticular administration of cortisone and hydrocortisone began in 1950-51. Several lines of research to produce cortisone semi-synthetically showed some success by 1952. Between 1954 and 1958 six synthetic steroids were introduced for systemic anti-imflammatory therapy. By I960 all of the toxic effects of chronic corticosteroid administration had been described, as well as protocols to withdraw such drugs while minimising symptoms of cortical insufficiency. To enable use of lower corticosteroid dosages, companion use of non-steroidal anti-inflammatory drugs began in the late 1950s, with phenylbutazone the first. In the 1970s the introduction of methotrexate and other anti-metabolites further circumscribed the dosages and indications for corticosteroids in the rheumatic diseases. © CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2011.


To perform a systematic literature review of the potential association among molecular markers of inflammation, alterations in body composition, and insulin resistance (IR), a precursor to type 2 diabetes mellitus (DM), in rheumatoid arthritis (RA) patients. To determine the impact of tumor necrosis factor α (TNFα) as a pivotal proinflammatory cytokine in the pathophysiology of type 2 DM and RA, and the effect of antirheumatic drugs on glycemic control. We performed a search of PubMed to identify articles on IR and body habitus in patients with RA. Patients with RA had characteristics placing them at high risk for IR and type 2 DM. The incidence and prevalence of type 2 DM in RA was not clearly increased compared with the general population; however, studies suggested that patients with RA are likely to have IR and have increased risk of cardiovascular disease (CVD). The prevalence of type 2 DM and IR could be estimated from reports of risk factors for CVD in RA patients. The TNFα antagonists provided rapid and effective control of RA-related inflammation. Evidence indicated that extended use of TNFα antagonists in RA may provide the additional benefit of improving insulin sensitivity. These treatment-related changes may contribute to an overall reduction in the risk of type 2 DM and CVD in RA patients. Controlling inflammation may improve insulin sensitivity and subsequently reduce the risk of developing type 2 DM in RA patients. This may also reduce the risk of CVD in this high-risk group. Future studies are required to elucidate the relationships between inflammation, body composition, IR, TNFα antagonist use, and the risk of developing type 2 DM in RA patients. Copyright © 2011 by the American College of Rheumatology.


Krauze M.T.,University of Pittsburgh
Seminars in immunopathology | Year: 2011

Since the pivotal cooperative group trials in the 1980's-90's,, high-dose interferon (HDI) has been the standard of adjuvant therapy. Despite multiple other trials evaluating potential new therapies in melanoma, HDI remains the only FDA-approved therapy for stage IIB and III melanoma. Initial reports from the more recent phase III international trials of modifications of the original HDI regimen linked the appearance of autoimmunity with improved outcomes of disease. Trials of high-dose interleukin-2, many years earlier, reported anecdotal observations that were consistent with the hypothesis that autoimmunity and clinical benefit of immunotherapies of melanoma are linked with one another. The only prospectively conducted study examining the appearance of clinical and laboratory evidence of autoimmunity during HDI therapy was published by Gogas and colleagues, demonstrating statistically significant impact on relapse-free survival and overall survival. Retrospectively conducted studies of different intermediate dosage regimens of interferon (IFN) have not fully confirmed the linkage of serological evidence of autoimmunity and improved survival outcomes. With the emergence of new immunotherapies in treatment of melanoma, this review highlights the importance of autoimmunity for future applications in melanoma and reviews significant differences of past studies evaluating the appearance of autoimmunity during IFN therapy in high-risk melanoma.


Arora M.,University of Pittsburgh
International immunopharmacology | Year: 2011

In humans, the bacterial product lipopolysaccharide (LPS) has been associated with protection from allergic diseases such us asthma. However, in mouse models of allergic asthma, differential effects of LPS have been noted based on the dose. A low dose of LPS promotes Th2 responses and allergic disease but a high dose has been associated with suppression of allergic airway inflammation. Our recent work has described the ability of LPS to increase the frequency of CD11b+Gr1(int)F4/80+(abbreviated as Gr1(int) cells) cells in the lung tissue of mice in a dose-dependent fashion that is dependent on TLR4 and the TLR adaptor protein, MyD88. Both phenotypically and morphologically, the cells were found to have similarities with mycloid-derived suppressor cells. Adoptive transfer of LPS-induced Gr1(int) cells suppressed allergen-induced airway inflammation suggesting regulatory functions of the cells in allergic asthma. Although the Gr1(int) cells are detectable in the lung tissue of LPS-treated mice, they are barely detectable in the lung-draining lymph nodes (Lns) or in the airway lumen. This causes selective enrichment of these cells over dendritic cells (Dcs) in the tissue which upon LPS stimulation migrate to lung-draining LNs. The Gr1(int) cells were found to blunt the ability of the lung DCs to upregulate GATA-3 or to promote STAT5 activation in primed Th2 cells, both transcription factors having critical roles in TH2 effector function. Thus, a complete understanding of the generation and regulation of the Gr1(int) cells would provide new avenues to either promote or delete these cells for disease-specific immunoregulation. Copyright © 2011 Elsevier B.V. All rights reserved.


Shaw A.D.,Duke University | Kellum J.A.,University of Pittsburgh
Clinical Journal of the American Society of Nephrology | Year: 2013

Intravenous fluids are arguably one of the most commonly administered inpatient therapies and for the most part have been viewed as part of the nephrologist's toolkit in the management of acute kidney disease. Recently, findings have suggested that intravenous fluids may be harmful if given in excess (quantitative toxicity) and that some may be more harmful than others (qualitative toxicity), particularly for patients who already have AKI. Recent clinical trials have investigated hydroxyethyl starch solutions and found worrying results for the renal community. In this brief review, we consider the published literature on the role of hydroxyethyl starch solutions in AKI, with particular emphasis on two large recent randomized clinical trials conducted in Europe and Australia. Copyright © 2013 by the American Society of Nephro.


Meirovitch H.,University of Pittsburgh
Journal of Molecular Recognition | Year: 2010

The commonly used simulation techniques, Metropolis Monte Carlo (MC) and molecular dynamics (MD) are of a dynamical type which enables one to sample system configurations i correctly with the Boltzmann probability, PiB, while the value of Pi is not provided directly; therefore, it is difficult to obtain the absolute entropy, S~-InPiB, and the Helmholtz free energy, F. With a different simulation approach developed in polymer physics, a chain is grown step-by-step with transition probabilities (TPs), and thus their product is the value of the construction probability; therefore, the entropy is known. Because all exact simulation methods are equivalent, i.e. they lead to the same averages and fluctuations of physical properties, one can treat an MC or MD sample as if its members have rather been generated step-by-step. Thus, each configuration i of the sample can be reconstructed (from nothing) by calculating the TPs with which it could have been constructed. This idea applies also to bulk systems such as fluids or magnets. This approach has led earlier to the "local states" (LS) and the "hypothetical scanning" (HS) methods, which are approximate in nature. A recent development is the hypothetical scanning Monte Carlo (HSMC) (or molecular dynamics, HSMD) method which is based on stochastic TPs where all interactions are taken into account. In this respect, HSMC(D) can be viewed as exact and the only approximation involved is due to insufficient MC(MD) sampling for calculating the TPs. The validity of HSMC has been established by applying it first to liquid argon, TIP3P water, self-avoiding walks (SAW), and polyglycine models, where the results for F were found to agree with those obtained by other methods. Subsequently, HSMD was applied to mobile loops of the enzymes porcine pancreatic a-amylase and acetylcholineesterase in explicit water, where the difference in F between the bound and free states of the loop was calculated. Currently, HSMD is being extended for calculating the absolute and relative free energies of ligand-enzyme binding. We describe the whole approach and discuss future directions. © 2009 John Wiley & Sons, Ltd.


Lin A.P.,University of Pittsburgh | Ko M.-C.,University of Michigan
ACS Chemical Neuroscience | Year: 2013

Although mu opioid (MOP) receptor agonists are the most commonly used analgesics for the treatment of moderate to severe pain in the clinic, the side effects of MOP agonists such as abuse liability limit their value as a medication. Research to identify novel analgesics without adverse effects is pivotal to advance the health care of humans. The nociceptin/orphanin FQ peptide (NOP) receptor, the fourth opioid receptor subtype, mediates distinctive actions in nonhuman primates which suggests the possibility that activity at this receptor may result in strong analgesia in the absence of virtually all of the side effects associated with MOP agonists. The present review highlights the recent progress of pharmacological studies of NOP-related ligands in primates. Selective NOP agonists, either peptidic or nonpeptidic, produce full analgesia in various assays in primates, when delivered systemically or intrathecally. Yet small molecule NOP agonists do not serve as reinforcers, indicating a lack of abuse liability. Given that NOP agonists have low abuse liability and that coactivation of NOP and MOP receptors produces synergistic antinociception, it is worth developing bifunctional NOP/MOP ligands. The outcomes of these studies and recent developments provide new perspectives to establish a translational bridge for understanding the biobehavioral functions of NOP receptors in primates and for facilitating the development of NOP-related ligands as a new generation of analgesics without abuse liability in humans. © 2012 American Chemical Society.


St Leger A.J.,University of Pittsburgh
Journal of neurovirology | Year: 2011

A hallmark of herpes viruses is their capacity to cause recurrent disease. Recurrences of herpes simplex virus (HSV)-1 disease do not result from reinfection from external sources, but rather from reactivation of virus that is maintained in a latent state in sensory neurons and periodically reactivates from latency to cause recurrent disease. Recent findings implicate HSV-specific CD8(+) T cells in immune surveillance of HSV-1 latently infected sensory neurons in trigeminal ganglia (TG) and inhibition of HSV-1 reactivation from latency. This review summarizes recent findings regarding the characteristics of the TG-resident CD8(+) T cell population and certain unique obstacles that might complicate the development of therapeutic vaccines.


Cytogenetic alterations underlie the development of head and neck squamous cell carcinoma (HNSCC), whether tobacco and alcohol use, betel nut chewing, snuff or human papillomavirus (HPV) causes the disease. Many of the molecular genetic aberrations in HNSCC result from these cytogenetic alterations. This review presents a brief introduction to the epidemiology of HNSCC, and discusses the role of HPV in the disease, cytogenetic alterations and their frequencies in HNSCC, their molecular genetic and The Cancer Genome Atlas (TCGA) correlates, prognostic implications, and possible therapeutic considerations. The most frequent cytogenetic alterations in HNSCC are gains of 5p14-15, 8q11-12, and 20q12-13, gains or amplifications of 3q26, 7p11, 8q24, and 11q13, and losses of 3p, 4q35, 5q12, 8p23, 9p21-24, 11q14-23, 13q12-14, 18q23, and 21q22. To understand their effects on tumor cell biology and response to therapy, the cytogenetic findings in HNSCC are increasingly being examined in the context of the biochemical pathways they disrupt. The goal is to minimize morbidity and mortality from HNSCC using cytogenetic abnormalities to identify valuable diagnostic biomarkers for HNSCC, prognostic biomarkers of tumor behavior, recurrence risk, and outcome, and predictive biomarkers of therapeutic response to identify the most efficacious treatment for each individual patient's tumor, all based on a detailed understanding of the next generation biology of HNSCC. © 2014 Wiley Periodicals, Inc.


Miriyala B.,University of Pittsburgh
Topics in Current Chemistry | Year: 2012

The non-covalent affinity of a perfluoro chain towards similar has been exploited by many to separate fluorous tagged compounds from non-fluorous compounds by F-SPE or F-LLE. This purification strategy found its application across diverse fields including peptide and oligonucleotide synthesis where even slight inefficient couplings result in deletion sequences that are often difficult to remove from the target sequence. Two commonly employed strategies to address this problem involve end-tagging the target sequence or capping the deletion sequences with fluorous tags. Solution phase syntheses using soluble fluorous supports are easier and quicker. These approaches are reviewed here in detail. © 2011 Springer-Verlag Berlin Heidelberg.


Freitas A.,University of Pittsburgh
Journal of High Energy Physics | Year: 2014

Recently, the calculation of fermionic electroweak two-loop corrections to the total width of the Z boson and hadronic Z-peak cross-section in the Standard Model has been presented, where "fermionic" refers to diagrams with closed fermion loops. Here, these results are complemented by presenting contributions of the same order for the Z-boson partial widths, which are the last missing pieces for a complete description of Z-pole physics at the fermionic two-loop order. The definition of the relevant observables and the calculational techniques are described in detail. Numerical results are presented conveniently in terms of simple parametrization formulae. Finally, the remaining theoretical uncertainties from missing higher-order corrections are analyzed and found to be small compared to the current experimental errors. © 2014 The Author(s).


Griffiths D.J.,University of Pittsburgh | Fowler C.J.,University College London
Acta Physiologica | Year: 2013

Dr DeGroat and Wickens has reviewed the central neural mechanisms controlling the lower urinary tract with a major focus on the brain stem circuitry that mediates the switch-like characteristics of micturition, in particular the periaqueductal grey and the pontine micturition centre (de 2012). The review culminates in a computer model of how the brainstem switch operates in animals in which forebrain influences on micturition have been removed by decerebration. In this complementary paper, we review the mechanisms of forebrain involvement in the voluntary control of human micturition and the maintenance of continence with evidence based heavily on the results of functional brain imaging experiments. © 2012 The Authors Acta Physiologica © 2012 Scandinavian Physiological Society.


Velankar S.S.,University of Pittsburgh
Soft Matter | Year: 2015

The equilibrium structures of ternary oil/water/surfactant systems are often represented within a triangular composition diagram with various regions of the triangle corresponding to different equilibrium states. We transplant this idea to ternary liquid/fluid/particle systems that are far from equilibrium. Liquid/liquid/particle mixtures or liquid/gas/particle mixtures yield a wide diversity of morphologies including Pickering emulsions, bijels, pendular aggregates, spherical agglomerates, capillary suspensions, liquid marbles, powdered liquids, and particle-stabilized foams. This paper argues that such ternary liquid/fluid/particle mixtures can be unified into a non-equilibrium state diagram. What is common among all these systems is that the morphology results from an interplay between the preferential wettability of the particles, capillarity, and viscous forces encountered during mixing. Therefore all such systems share certain universal features, regardless of the details of the particles or fluids used. These features guide the construction of a non-equilibrium state diagram which takes the form of a triangular prism, where each triangular cross-section of the prism corresponds to a different relative affinity of the particles towards the two fluids. We classify the prism into regions in which the various morphologies appear and also emphasize the major difference between systems in which the particles are fully-wetted by one of the fluids vs. partially-wetted by both fluids. We also discuss how the state diagram may change with mixing intensity or with interparticle attractions. © 2015 The Royal Society of Chemistry.


Evolutionary dead-end strategies are characterized by short-term productivity benefits and long-term evolutionary costs. Here, I detail a real-time dead-end strategy associated with the behavioural traits of lineage progenitors in the social spider Anelosimus studiosus. Specifically, colony lineages founded by docile spiders were eight times more likely to suffer extinction, despite their superior reproductive output. However, when inquilines were experimentally removed from progenitor colonies, differences in extinction probability among lineages vanished. Similarly, among lineages founded by purely docile or aggressive individuals, the descendants of lineages with the highest reproductive output suffered the lowest survivorship, whereas lineages founded by a mixture of docile/aggressive lacked such a trade-off. Finally, lineages with shorter progenitor-descendant distances gained more inquilines and their descendants had lower survivorship, relative to more diffuse lineages. Overall, this study demonstrates how the traits of lineage progenitors and species interactions can unite to determine the fates of entire lineages. © 2013 John Wiley & Sons Ltd/CNRS.


Boyanovsky D.,University of Pittsburgh
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2016

We obtain the nonequilibrium effective action of an inflatonlike scalar field - the system - by tracing over sub-Hubble degrees of freedom of "environmental" light scalar fields. The effective action is stochastic leading to effective Langevin equations of motion for the fluctuations of the inflatonlike field, with self-energy corrections and stochastic noise correlators that obey a de Sitter space-time analog of a fluctuation dissipation relation. We solve the Langevin equation implementing a dynamical renormalization group resummation of the leading secular terms and obtain the corrections to the power spectrum of super-Hubble fluctuations of the inflaton field, P(k;η)=P0(k)e-γ(k;η) where P0(k) is the nearly scale invariant power spectrum in absence of coupling. γ(k;η)>0 describes the suppression of the power spectrum; it features Sudakov-type double logarithms and entails violations of scale invariance. We also obtain the effective action for the case of a heavy scalar field of mass M蠑H; this case yields a local "Fermi" limit with a very weak self-interaction of the inflatonlike field and dissipative terms that are suppressed by powers of H/M. We conjecture on the possibility that the large scale anomalies in the cosmic microwave background may originate in dissipative processes from inflaton coupling to sub-Hubble degrees of freedom. © 2016 American Physical Society.


Boyanovsky D.,University of Pittsburgh
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2016

Motivated by apparent persistent large scale anomalies in the cosmic microwave background we study the influence of fermionic degrees of freedom on the dynamics of inflaton fluctuations as a possible source of violations of (nearly) scale invariance on cosmological scales. We obtain the nonequilibrium effective action of an inflaton-like scalar field with Yukawa interactions (YD,M) to light fermionic degrees of freedom both for Dirac and Majorana fields in de Sitter space-time. The effective action leads to Langevin equations of motion for the fluctuations of the inflaton-like field, with self-energy corrections and a stochastic Gaussian noise. We solve the Langevin equation in the super-Hubble limit implementing a dynamical renormalization group resummation. For a nearly massless inflaton its power spectrum of super-Hubble fluctuations is enhanced, P(k;η)=(H2π)2eγt[-kη] with γt[-kη]=16π2[i=1NDYi,D2+2j=1NMYj,M2]{ln2[-kη]-2ln[-kη]ln[-kη0]} for ND Dirac and NM Majorana fermions, and η0 is the renormalization scale at which the inflaton mass vanishes. The full power spectrum is shown to be renormalization group invariant. These corrections to the super-Hubble power spectrum entail a violation of scale invariance as a consequence of the coupling to the fermionic fields. The effective action is argued to be exact in the limit of a large number of fermionic fields. A cancellation between the enhancement from fermionic degrees of freedom and suppression from light scalar degrees of freedom conformally coupled to gravity suggests the possibility of a finely tuned supersymmetry among these fields. © 2016 American Physical Society.


Giannoukakis N.,University of Pittsburgh
Expert Opinion on Drug Metabolism and Toxicology | Year: 2014

Introduction: Pharmacologic maintenance of normoglycemia in diabetes cannot prevent the eventual complications mainly due to protein glycation-induced cell death, dysregulated antioxidant defense and signal transduction in affected tissues. The rate-limiting enzyme of this process, aldose reductase, is therefore a pharmacologic target. To date, nine inhibitors of this enzyme have been developed. Ranirestat has completed two Phase III clinical trials. The objective of this evaluation is to summarize and provide expert opinion on the status of ranirestat with an emphasis on its pharmacokinetics in the context of its potential effects to prevent/treat diabetic complications.Areas covered: A qualitative systematic literature search of PubMed through November 2013 using MeSH terms-Aldose reductase inhibitors, diabetic neuropathy, AS-3201, ranirestat, diabetic complications and pharmacokinetics/pharmacodynamics- identified relevant publications limited to human and rodent (mouse and rat) and English-language studies.Expert opinion: Ranirestat is a well-tolerated front-line inhibitor. It reproducibly exhibits some degree of measurable objective beneficial outcomes in diabetic neuropathy. It is the furthest advanced in clinical trials with some depth of supporting preclinical data. Trials in subjects with newly diagnosed neuropathy along with the identification of objective biomarkers/measurements of efficacy will be critical in identifying the real value and effect of ranirestat.© 2014 Informa UK, Ltd.


Singh N.,University of Pittsburgh
Transplantation | Year: 2012

Cryptococcosis is a significant opportunistic mycoses in organ transplant recipients. Topical developments in the field in the past few years have highlighted important issues and at the same time raised new questions regarding the management of this yeast. These include, for example, management of pretransplant cryptococcosis during transplant candidacy and timing of transplant in these instances; potential for donor transmission of cryptococcosis in light of recent fatal transmissions; and prevention and treatment of Cryptococcus-associated immune reconstitution syndrome. Discussed herein are challenges posed by these issues and evidence-based data to optimize the management of posttransplant cryptococcosis.


Nakatsukasa K.,Nagoya University | Kamura T.,Nagoya University | Brodsky J.L.,University of Pittsburgh
Current Opinion in Cell Biology | Year: 2014

Endoplasmic reticulum-associated degradation (ERAD) is a mechanism during which native and misfolded proteins are recognized and retrotranslocated across the ER membrane to the cytosol for degradation by the ubiquitin-proteasome system. Like other cellular pathways, the factors required for ERAD have been analyzed using both conventional genetic and biochemical approaches. More recently, however, an integrated top-down approach has identified a functional network that underlies the ERAD system. In turn, bottom-up reconstitution has become increasingly sophisticated and elucidated the molecular mechanisms underlying substrate recognition, ubiquitylation, retrotranslocation, and degradation. In addition, a live cell imaging technique and a site-specific in vivo photo-crosslinking approach have further dissected specific steps during ERAD. These technical developments have revealed an unexpected dynamicity of the membrane-associated ERAD complex. In this article, we will discuss how these technical developments have improved our understanding of the ERAD pathway and have led to new questions. © 2014 Elsevier Ltd.


Saidi W.A.,University of Pittsburgh
Journal of Physical Chemistry Letters | Year: 2013

First-principles investigations of the electrocatalytic activity toward the four-electron oxygen reduction-reaction in N-doped graphene quantum dots reveal that pyridinic and graphitic nitrogen are the most active sites with overpotentials of 0.55 and 0.79-0.90 V, respectively. This agrees with experimental findings. Our calculations account for van der Waals interactions, solvent effects, and describe the electrochemistry using standard hydrogen electrode model. The results show correlations between OH, OOH, and O* binding energies that impose a lower limit on the oxygen reduction overpotential. © 2013 American Chemical Society.


Studer A.,University of Munster | Curran D.P.,University of Pittsburgh
Angewandte Chemie - International Edition | Year: 2011

A radical outlook: Recently published "organocatalytic C-H activation reactions" have now been interpreted as base-promoted homolytic substitutions. The addition of an aryl radical to an arene followed by deprotonation (see above) and electron transfer form part of the chain reaction. Although these new results are not conceptual breakthroughs, they could be experimental breakthroughs because they presage new transformations in radical (anion) chemistry. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Zhao Y.,University of Pittsburgh | Natarajan V.,University of Illinois at Chicago
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2013

Lysophosphatidic acid (LPA), a simple bioactive phospholipid, is present in biological fluids such as plasma and bronchoalveolar lavage (BAL). It appears to have both pro- and anti-inflammatory roles in inflammatory lung diseases. Exogenous LPA promotes inflammatory responses by regulating the expression of chemokines, cytokines, and cytokine receptors in lung epithelial cells. In addition to the modulation of inflammatory responses, LPA regulates cytoskeleton rearrangement and confers protection against lung injury by enhancing lung epithelial cell barrier integrity and remodeling. The biological effects of LPA are mediated through its cell surface G-protein coupled LPA1-7 receptors. The roles of LPA receptors in lung fibrosis, asthma, and acute lung injury have been investigated using genetically engineered LPA receptor deficient mice and there appears to be a definitive role for endogenous LPA and its receptors in the pathogenesis of pulmonary inflammatory diseases. This review summarizes recent reports on the role of LPA and its receptors in the regulation of lung epithelial inflammatory responses and remodeling. This article is part of a Special Issue entitled: Advances in Lysophospholipid Research. © 2012 Elsevier B.V.


Veronica A.,University of San Pablo - CEU | Friedman P.A.,University of Pittsburgh
Molecular Endocrinology | Year: 2013

G protein-coupled receptors (GPCRs) are the largest and most diverse superfamily of membrane proteins and mediate most cellular responses to hormones and neurotransmitters. Posttranslational modifications are considered the main regulators of all GPCRs. In addition to phosphorylation, glycosylation, and palmitoylation, increasing evidence as reviewed here reveals that ubiquitination also regulates the magnitude and temporospatial aspects of GPCR signaling. Posttranslational protein modification by ubiquitin is a key molecular mechanism governing proteins degradation. Ubiquitination mediates the covalent conjugation of ubiquitin, a highly conserved polypeptide of 76 amino acids, to protein substrates. This process is catalyzed by 3 enzymes acting in tandem: an E1, ubiquitin-activating enzyme; an E2, ubiquitin-carrying enzyme; and an E3, ubiquitin ligase. Ubiquitination is counteracted by deubiquitinating enzymes that deconjugate ubiquitin-modified proteins and rescue the substrate from proteasomal degradation. Although ubiquitination is known to target many GPCRs for lysosomal or proteasomal degradation, emerging findings define novel roles for the basal status of ubiquitination and for rapid deubiquitination and transubiquitination controlling cell surface expression and cellular responsiveness of some GPCRs. In this review, we highlight the classical and novel roles of ubiquitin in the regulation of GPCR function, signaling, and trafficking. © 2013 by The Endocrine Society.


Schmidt M.C.,University of Pittsburgh
Science Signaling | Year: 2013

In yeast, the mating response pathway is activated when a peptide pheromone binds to a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, which leads to the activation of a mitogen-activated protein kinase signaling cascade and the stimulation of mating behavior. However, when nutrients in the environment are limiting, stimulation of the mating response would be maladaptive. A study indicates that the signaling pathways that respond to nutrient availability dampen the mating response by directly phosphorylating Gpa1, the G protein a subunit that initiates the mating response pathway. Snf1, the yeast homolog of adenosine monophosphate-activated protein kinase, is a highly conserved kinase that maintains energy homeostasis in response to nutrient limitation. The study found that the upstream kinases and phosphatase that control the activity of Snf1 also act on Gpa1 and provide a direct means to coordinate cell behavior and integrate the mating response with nutrient sensing. Copyright © 2008 by the American Association for the Advancement of Science.


Aging and reproduction are two defining features of our life. Historically, research has focused on the well-documented decline in reproductive capacity that accompanies old age, especially with increasing maternal age in humans. However, recent experiments in model organisms such as worms, flies, and mice have shown that a dialogue in the opposite direction may be widely prevalent, and that signals from reproductive tissues have a significant effect on the rate of aging of organisms. This pathway has been described in considerable detail in the nematode Caenorhabditis elegans. Molecular genetic studies suggest that signals from the germline control a network of transcriptional regulators that function in the intestine to influence longevity. This network includes conserved, longevity-promoting Forkhead Box (FOX) family transcription factors such as DAF-16/FOXO and PHA-4/FOXA, nuclear hormone receptors, as well as a transcription elongation factor, TCER-1/TCERG1. Genomic and targeted molecular analyses have revealed that these transcription factors modulate autophagy, lipid metabolism, and possibly other cellular processes to increase the length of the animal's life. This review aims to provide an overview of the current knowledge on the genetic mechanism that underlies the reproductive control of aging with particular focus on the transcriptional regulators that constitute the main molecular players in this longevity pathway. © 2012 Wiley Periodicals, Inc..


Haskett R.F.,University of Pittsburgh
Journal of ECT | Year: 2014

Despite a range of etiological theories since the introduction of electroconvulsive therapy (ECT) more than 75 years ago, its mechanism of action remains poorly understood. The neuroendocrine hypothesis is based on the seizure-related release of hypothalamic hormones into the blood and cerebrospinal fluid and evidence of endocrine dysfunction in many patients with severe mood disorder. The specific effect of ECT was hypothesized to result from the transverse passage of current through the brain with direct stimulation of axial structures including the diencephalon. The prompt release of adrenocorticotropic hormone, cortisol, and prolactin into blood followed ECT with a return to pretreatment baseline levels in several hours. The elevated levels of hormones were absorbed by the cerebrospinal fluid, providing contact with brain cells and central nervous system structures. An apparently specific pattern of ECT-induced hormone changes, limited to prolactin and cortisol, suggested that ECT released a substance with dopaminergic antagonist and antipsychotic properties. As hypothalamic dysfunction is a key finding in endogenomorphic depression and the abnormal endocrine and physiological functions usually normalize with recovery, this led to a search for biological markers that would supplement clinical assessment of diagnosis and treatment response. One of these, the overnight dexamethasone suppression test found that 40% to 50% of melancholic depressed patients had abnormal results, whereas 90% of control patients suppressed normally. This was followed by a period of uncritical overenthusiasm followed by wholesale rejection of the clinical neuroendocrine strategies. Several key methodological issues received inadequate attention, and there have been calls to revisit this topic. Copyright © 2014 by Lippincott Williams & Wilkins.


Schwartz A.B.,University of Pittsburgh
Cell | Year: 2016

Voluntary movement is a result of signals transmitted through a communication channel that links the internal world in our minds to the physical world around us. Intention can be considered the desire to effect change on our environment, and this is contained in the signals from the brain, passed through the nervous system to converge on muscles that generate displacements and forces on our surroundings. The resulting changes in the world act to generate sensations that feed back to the nervous system, closing the control loop. This Perspective discusses the experimental and theoretical underpinnings of current models of movement generation and the way they are modulated by external information. Movement systems embody intentionality and prediction, two factors that are propelling a revolution in engineering. Development of movement models that include the complexities of the external world may allow a better understanding of the neuronal populations regulating these processes, as well as the development of solutions for autonomous vehicles and robots, and neural prostheses for those who are motor impaired. © 2016 Elsevier Inc.


Georgiev D.,University of Pittsburgh
International Journal of Modern Physics B | Year: 2015

Environmental decoherence appears to be the biggest obstacle for successful construction of quantum mind theories. Nevertheless, the quantum physicist Henry Stapp promoted the view that the mind could utilize quantum Zeno effect to influence brain dynamics and that the efficacy of such mental efforts would not be undermined by environmental decoherence of the brain. To address the physical plausibility of Stapp's claim, we modeled the brain using quantum tunneling of an electron in a multiple-well structure such as the voltage sensor in neuronal ion channels and performed Monte Carlo simulations of quantum Zeno effect exerted by the mind upon the brain in the presence or absence of environmental decoherence. The simulations unambiguously showed that the quantum Zeno effect breaks down for timescales greater than the brain decoherence time. To generalize the Monte Carlo simulation results for any n-level quantum system, we further analyzed the change of brain entropy due to the mind probing actions and proved a theorem according to which local projections cannot decrease the von Neumann entropy of the unconditional brain density matrix. The latter theorem establishes that Stapp's model is physically implausible but leaves a door open for future development of quantum mind theories provided the brain has a decoherence-free subspace. © 2015 World Scientific Publishing Company.


Hospitalization for heart failure (HHF) is among the most important problems confronting medicine. Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) robustly identifies intrinsic myocardial damage. LGE may indicate inherent vulnerability to HHF, regardless of etiology, across the spectrum of heart failure stage or left ventricular ejection fraction (LVEF). We enrolled 1068 consecutive patients referred for CMR where 448 (42%) exhibited LGE. After a median of 1.4 years (Q1 to Q3: 0.9 to 2.0 years), 57 HHF events occurred, 15 deaths followed HHF, and 43 deaths occurred without antecedent HHF (58 total deaths). Using multivariable Cox regression adjusting for LVEF, heart failure stage, and other covariates, LGE was associated with first HHF after CMR (HR: 2.70, 95% CI: 1.32 to 5.50), death (HR: 2.13, 95% CI: 1.08 to 4.21), or either death or HHF (HR: 2.52, 95% CI: 1.49 to 4.25). Quantifying LGE extent yielded similar results; more LGE equated higher risks. LGE improved model discrimination (IDI: 0.016, 95% CI: 0.005 to 0.028, P=0.002) and reclassification of individuals at risk (continuous NRI: 0.40, 95% CI: 0.05 to 0.70, P=0.024). Adjustment for competing risks of death that shares common risk factors with HHF strengthened the LGE and HHF association (HR: 4.85, 95% CI: 1.40 to 16.9). The presence and extent of LGE is associated with vulnerability for HHF, including higher risks of HHF across the spectrum of heart failure stage and LVEF. Even when LVEF is severely decreased, those without LGE appear to fare reasonably well. LGE may enhance risk stratification for HHF and may enhance both clinical and research efforts to reduce HHF through targeted treatment.


Popowicz G.M.,Max Planck Institute of Biochemistry | Domling A.,University of Pittsburgh | Holak T.A.,Max Planck Institute of Biochemistry
Angewandte Chemie - International Edition | Year: 2011

The p53 protein is the cell's principal bastion of defense against tumor-associated DNA damage. Commonly referred as a "guardian of the genome", p53 is responsible for determining the fate of the cell when the integrity of its genome is damaged. The development of tumors requires breaching this defense line. All known tumor cells either mutate the p53 gene, or in a similar number of cases, use internal cell p53 modulators, Mdm2 and Mdmx proteins, to disable its function. The release of functional p53 from the inhibition by Mdm2 and Mdmx should in principle provide an efficient, nongenotoxic means of cancer therapy. In recent years substantial progress has been made in developing novel p53-activating molecules thanks to several reported crystal structures of Mdm2/x in complex with p53-mimicking peptides and nonpeptidic drug candidates. Understanding the structural attributes of ligand binding holds the key to developing novel, highly effective, and selective drug candidates. Two low-molecular-weight compounds have just recently progressed into early clinical studies. Targeted nongenotoxic tumor therapy is an emerging and promising field of pharmacology. Understanding the cellular mechanism involved in tumorigenesis enables researchers to regulate the molecular machinery responsible for DNA repair and cell-cycle control. Structural data are crucial for the development of such novel nongenotoxic drug leads, which should help cells in the fight against cancer. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Chu E.,University of Pittsburgh
Clinical Colorectal Cancer | Year: 2012

Over the past 8 to 10 years, significant advances have been made in the treatment of metastatic colorectal cancer (mCRC). In particular, the development of the targeted biologic agents bevacizumab, cetuximab, and panitumumab, and their integration with cytotoxic chemotherapy regimens has led to improvements in clinical efficacy. Despite these gains, the overall impact of current targeted agents in the treatment of mCRC has been relatively modest, and while 2-year survival has improved, no gains have been made, as of yet, in 5-year survival. Intense efforts continue to be focused on developing novel targeted agents with a different spectrum of activity. Presently, five novel targeted molecules are in phase III trials, including the antiangiogenesis agents aflibercept and ramucirumab, two novel receptor tyrosine kinase inhibitors, regorafenib and brivanib, and the Akt inhibitor perifosine. There are an additional 52 phase II trials investigating a wide range of other candidate molecules. The potential list of approved targeted agents in mCRC seems likely to increase over the next 5 to 10 years. To maximize their potential clinical impact, however, it will be critically important to introduce efficient molecular diagnostic methodologies into the drug development process for the identification and validation of predictive biomarkers for chemosensitivity. This article reviews the development of targeted agents for the treatment of mCRC, including the three molecules currently approved by the US Food and Drug Administration (FDA), as well as the main non-FDA-approved therapeutics currently undergoing phase II and III clinical testing. © 2012 Elsevier Inc. All rights reserved.


Price J.C.,University of Pittsburgh
Journal of Cerebral Blood Flow and Metabolism | Year: 2012

Multimodality molecular brain imaging encompasses in vivo visualization, evaluation, and measurement of cellular/molecular processes. Instrumentation and software developments over the past 30 years have fueled advancements in multimodality imaging platforms that enable acquisition of multiple complementary imaging outcomes by either combined sequential or simultaneous acquisition. This article provides a general overview of multimodality neuroimaging in the context of positron emission tomography as a molecular imaging tool and magnetic resonance imaging as a structural and functional imaging tool. Several image examples are provided and general challenges are discussed to exemplify complementary features of the modalities, as well as important strengths and weaknesses of combined assessments. Alzheimer's disease is highlighted, as this clinical area has been strongly impacted by multimodality neuroimaging findings that have improved understanding of the natural history of disease progression, early disease detection, and informed therapy evaluation. © 2012 ISCBFM All rights reserved.


Lampert B.C.,Ohio State University | Teuteberg J.J.,University of Pittsburgh
Journal of Heart and Lung Transplantation | Year: 2015

Most patients with advanced systolic dysfunction who are assessed for a left ventricular assist device (LVAD) also have some degree of right ventricular (RV) dysfunction. Hence, RV failure (RVF) remains a common complication of LVAD placement. Severe RVF after LVAD implantation is associated with increased peri-operative mortality and length of stay and can lead to coagulopathy, altered drug metabolism, worsening nutritional status, diuretic resistance, and poor quality of life. However, current medical and surgical treatment options for RVF are limited and often result in significant impairments in quality of life. There has been continuing interest in developing risk models for RVF before LVAD implantation. This report reviews the anatomy and physiology of the RV and how it changes in the setting of LVAD support. We will discuss proposed mechanisms and describe biochemical, echocardiographic, and hemodynamic predictors of RVF in LVAD patients. We will describe management strategies for reducing and managing RVF. Finally, we will discuss the increasingly recognized and difficult to manage entity of chronic RVF after LVAD placement and describe opportunities for future research. © 2015 International Society for Heart and Lung Transplantation.


Brodsky J.L.,University of Pittsburgh | Skach W.R.,Oregon Health And Science University
Current Opinion in Cell Biology | Year: 2011

The evolution of eukaryotes was accompanied by an increased need for intracellular communication and cellular specialization. Thus, a more complex collection of secreted and membrane proteins had to be synthesized, modified, and folded. The endoplasmic reticulum (ER) thereby became equipped with devoted enzymes and associated factors that both catalyze the production of secreted proteins and remove damaged proteins. A means to modify ER function to accommodate and destroy misfolded proteins also evolved. Not surprisingly, a growing number of human diseases are linked to various facets of ER function. Each of these topics will be discussed in this article, with an emphasis on recent reports in the literature that employed diverse models. © 2011 Elsevier Ltd.


Halder I.,University of Pittsburgh
American journal of epidemiology | Year: 2012

Large epidemiologic studies examining differences in cardiovascular disease (CVD) risk factor profiles between European Americans and African Americans have exclusively used self-identified race (SIR) to classify individuals. Recent genetic epidemiology studies of some CVD risk factors have suggested that biogeographic ancestry (BGA) may be a better predictor of CVD risk than SIR. This hypothesis was investigated in 464 African Americans and 771 European Americans enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) Study in March and April 2010. Individual West African and European BGA were ascertained by means of a panel of 1,595 genetic ancestry informative markers. Individual BGA varied significantly among African Americans and to a lesser extent among European Americans. In the total cohort, BGA was not found to be a better predictor of CVD risk factors than SIR. Both measures predicted differences in the presence of the metabolic syndrome, waist circumference, triglycerides, body mass index, very low density lipoprotein cholesterol, lipoprotein A, and systolic and diastolic blood pressure between European Americans and African Americans. These results suggest that for most nongenetic cardiovascular epidemiology studies, SIR is sufficient for predicting CVD risk factor differences between European Americans and African Americans. However, higher body mass index and diastolic blood pressure were significantly associated with West African BGA among African Americans, suggesting that BGA should be considered in genetic cardiovascular epidemiology studies carried out among African Americans.


MacHery E.,University of Pittsburgh
Behavioral and Brain Sciences | Year: 2010

Although cognitive scientists have learned a lot about concepts, their findings have yet to be organized in a coherent theoretical framework. In addition, after twenty years of controversy, there is little sign that philosophers and psychologists are converging toward an agreement about the very nature of concepts. Doing without Concepts (Machery 2009) attempts to remedy this state of affairs. In this article, I review the main points and arguments developed at greater length in Doing without Concepts. Copyright © Cambridge University Press 2010.


Musculoskeletal injuries are the most common cause of severe long-term pain and physical disability, and affect hundreds of millions of people around the world. One of the most popular methods used to biologically enhance healing in the fields of orthopaedic surgery and sports medicine includes the use of autologous blood products, namely, platelet rich plasma (PRP). PRP is an autologous concentration of human platelets to supra-physiologic levels. At baseline levels, platelets function as a natural reservoir for growth factors including platelet-derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor-beta 1 (TGF-β1), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF), hepatocyte growth factor (HGF), and insulin-like growth factor (IGF-I). PRP is commonly used in orthopaedic practice to augment healing in sports-related injuries of skeletal muscle, tendons, and ligaments. Despite its pervasive use, the clinical efficacy of PrP therapy and varying mechanisms of action have yet to be established. Basic science research has revealed that PRP exerts is effects through many downstream events secondary to release of growth factors and other bioactive factors from its alpha granules. These effects may vary depending on the location of injury and the concentration of important growth factors involved in various soft tissue healing responses. This review focuses on the effects of PrP and its associated bioactive factors as elucidated in basic science research. Current findings in PRP basic science research, which have shed light on its proposed mechanisms of action, have opened doors for future areas of PrP research.


Al-Saidi W.A.,University of Pittsburgh | Feng H.,Pennsylvania State University | Feng H.,South China University of Technology | Fichthorn K.A.,Pennsylvania State University
Nano Letters | Year: 2012

We use density functional theory to resolve the role of polyvinylpyrrolidone (PVP) in the shape-selective synthesis of Ag nanostructures. At the segment level, PVP binds more strongly to Ag(100) than Ag(111) because of a surface-sensitive balance between direct binding and van der Waals attraction. At the chain level, correlated segment binding leads to a strong preference for PVP bind to Ag(100). Our study underscores differences between small-molecule and polymeric structure-directing agents. © 2011 American Chemical Society.


Berg M.T.,Indiana University | Loeber R.,University of Pittsburgh
Journal of Quantitative Criminology | Year: 2011

The persistent link between offending and victimization is one of the most robust empirical findings in criminological research. Despite important efforts to isolate the sources of this phenomenon, it is not fully understood. Much attention has been paid to the role of individual-level factors; however, few studies have systematically integrated neighborhood conditions. Using prospective data from the Pittsburgh Youth Study the current research examines a set of hypotheses regarding the interplay of neighborhood structural conditions and the victim-offender overlap. A multilevel analytical technique is applied to the data which purges time-varying covariates of all time-stable unobserved heterogeneity. Results indicate that the relationship between offending and victimization is pronounced in disadvantaged neighborhoods, while offending is not significantly related to victimization risk in contexts marked by lower levels of disadvantage. The implications of the results for theory are discussed, along with recommendations for future research. © 2011 Springer Science+Business Media, LLC.


Jackson E.K.,University of Pittsburgh
American Journal of Physiology - Renal Physiology | Year: 2011

Our recent studies employing HPLC-tandem mass spectrometry to analyze venous perfusate from isolated, perfused kidneys demonstrate that intact kidneys produce and release into the extracellular compartment 2',3'-cAMP, a positional isomer of the second messenger 3',5'-cAMP. To our knowledge, this represents the first detection of 2',3'-cAMP in any cell/tissue/ organ/organism. Nuclear magnetic resonance experiments with isolated RNases and experiments in isolated, perfused kidneys suggest that 2',3'-cAMP likely arises from RNase-mediated transphosphorylation of mRNA. Both in vitro and in vivo kidney experiments demonstrate that extracellular 2',3'-cAMP is efficiently metabolized to 2'-AMP and 3'-AMP, both of which can be further metabolized to adenosine. This sequence of reactions is called the 2',3'-cAMP-adenosine pathway (2',3'-cAMP→2'-AMP/3'-AMP adenosine). Experiments in rat and mouse kidneys show that metabolic poisons increase extracellular levels of 2',3'-cAMP, 2'-AMP, 3'-AMP, and adenosine; however, little is known regarding the pharmacology of 2',3'-cAMP, 2'-AMP, and 3'-AMP. What is known is that 2',3'-cAMP facilitates activation of mitochondrial permeability transition pores, a process that can lead to apoptosis and necrosis, and inhibits proliferation of vascular smooth muscle cells and glomerular mesangial cells. In summary, there is mounting evidence that at least some types of cellular injury, by triggering mRNA degradation, engage the 2',3'-cAMP-adenosine pathway, and therefore this pathway should be added to the list of biochemical pathways that produce adenosine. Although speculative, it is possible that the 2',3'-cAMP-adenosine pathway may protect against some forms of acute organ injury, for example acute kidney injury, by both removing an intracellular toxin (2',3'-cAMP) and increasing an extracellular renoprotectant (adenosine). © 2011 the American Physiological Society.


Houghton A.M.,University of Pittsburgh
Cell Cycle | Year: 2010

Human cancers are comprised of numerous cell types including neutrophils. Although often ignored, neutrophils are frequently present at sites of tumorigenesis including the kidney, breast, colon and lung. These cells possess substances such as reactive oxygen species and proteinases that are capable of modifying tumor growth and invasiveness. This review addresses recent reports describing both pro-host and pro-tumor roles for neutrophils and neutrophil-derived substances and will examine the alterations in neutrophil behavior that explain this apparent biological discrepancy. Unfortunately, with the exception of investigator driven manipulation of neutrophil function, these cells function overwhelmingly against the host in the setting of cancer. Many cancers are capable of recruiting neutrophils to sites of tumorigenesis where they enhance tumor growth. Identification of the neutrophilderived substances that promote tumor growth may yield novel therapeutic approaches to inhibit cancer progression. Alternatively, strategies designed to generate highly activated and cytotoxic neutrophils within the tumor microenvironment may provide a means to unleash the tumoricidal potential of the host's innate immune response. © 2010 Landes Bioscience.


Polderman K.H.,University of Pittsburgh
Critical Care | Year: 2011

In vitro studies and clinical observations suggest that both accidental and controlled/therapeutic hypothermia have a strong immunosuppressive effect, and that hypothermia increases the risk of infections, especially wound infections and pneumonia. In the previous issue of Critical Care, Kamps and colleagues report that when hypothermia was used for prolonged periods in patients with severe traumatic brain injury in conjunction with selective decontamination of the digestive tract, the risks of infection were the same or lower in patients treated with therapeutic cooling. The risk of infection is widely regarded as the most important danger of therapeutic cooling. The findings of Kamps and colleagues need to be verified in prospective trials and in higher-resistance environments, but raise the possibility of cooling for prolonged periods with greatly reduced risk. We may be able to have our cake and eat it. © 2011 BioMed Central Ltd.


Pinsky M.R.,University of Pittsburgh
Critical Care | Year: 2011

Assessment of vasomotor tone is essential in defining appropriate resuscitation strategies for the hypotensive patient. Although changes in mean arterial pressure to cardiac output define arterial resistance, resistance is only one component of vasomotor tone. Compliance is the other component. The reciprocal of compliance is arterial elastance (Ea). Importantly, dynamic Ea can be estimated by the pulse pressure variation to stroke volume variation relation. Dynamic Ea is only one component of vasomotor tone, however, and increases in pulse pressure may not be proportional to increases in mean arterial pressure. Also, devices that use the arterial pressure pulse to calculate the stroke volume have an inherent bias that is different amongst devices based on their transfer function algorithms. The use of dynamic Ea for clinical decision-making thus needs to be validated separately for different devices and types of patients. © 2011 BioMed Central Ltd.


Zenonos G.,University of Pittsburgh
Neurosurgery | Year: 2012

Despite abundant published support of patch angioplasty during carotid endarterectomy (CEA), primary closure is still widely used. The reasons underlying the persistence of primary closure are not quite evident in the literature. To present our experience with primary closure in CEA, and provide a rationale for its persistent wide use. Medical records of all patients undergoing CEA by the senior author (R.F.) were retrospectively reviewed. Follow-up was supplemented with a telephone interview and completion of a structured questionnaire. A review of the current literature was performed. From 1998 to 2010, the senior author performed 111 CEAs. Average cross-clamp time was 33 ± 11 minutes. Postoperative complications included 1 non-ST-elevation myocardial infarction and 2 strokes. No deaths, cranial-nerve deficits, or acute reocclusions were observed. After a mean follow-up of 64.6 months (7170.6 case-months), there were 3 contralateral strokes and 7 deaths. There were no ipsilateral strokes or restenoses >50%. Follow-up medication compliance was 94.6% for antiplatelet agents and 91.9% for statins. The outcomes of the current study were comparable to those of the available trials comparing patch angioplasty with primary closure. A careful evaluation of the literature revealed a number of reasons potentially explaining the persistent use of patch angioplasty. In conjunction with contemporary medical management, primary closure during CEA may yield results comparable or superior to patch angioplasty. Advantages of primary closure include shorter cross-clamp times and elimination of graft-specific complications.


Rinaman L.,University of Pittsburgh
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2011

Central noradrenergic (NA) signaling is broadly implicated in behavioral and physiological processes related to attention, arousal, motivation, learning and memory, and homeostasis. This review focuses on the A2 cell group of NA neurons, located within the hindbrain dorsal vagal complex (DVC). The intra-DVC location of A2 neurons supports their role in vagal sensory-motor reflex arcs and visceral motor outflow. A2 neurons also are reciprocally connected with multiple brain stem, hypothalamic, and limbic forebrain regions. The extra-DVC connections of A2 neurons provide a route through which emotional and cognitive events can modulate visceral motor outflow and also a route through which interoceptive feedback from the body can impact hypothalamic functions as well as emotional and cognitive processing. This review considers some of the hallmark anatomical and chemical features of A2 neurons, followed by presentation of evidence supporting a role for A2 neurons in modulating food intake, affective behavior, behavioral and physiological stress responses, emotional learning, and drug dependence. Increased knowledge about the organization and function of the A2 cell group and the neural circuits in which A2 neurons participate should contribute to a better understanding of how the brain orchestrates adaptive responses to the various threats and opportunities of life and should further reveal the central underpinnings of stress-related physiological and emotional dysregulation. Copyright © 2011 the American Physiological Society.


Galdi G.P.,University of Pittsburgh
Archive for Rational Mechanics and Analysis | Year: 2013

We show existence, uniqueness and spatial asymptotic behavior of a two-dimensional time-periodic flow around a cylinder that moves orthogonal to its axis, with a time-periodic velocity, v. The result is proved if the size of the data is sufficiently small, and the average of v over a period is not zero. © 2013 Springer-Verlag Berlin Heidelberg.


Klinger J.R.,Brown University | Abman S.H.,Aurora University | Gladwin M.T.,University of Pittsburgh
American Journal of Respiratory and Critical Care Medicine | Year: 2013

Nitric oxide (NO) signaling plays a major role in modulating vascular tone and remodeling in the pulmonary circulation, but its role in the pathogenesis of pulmonary vascular diseases is still not completely understood. Numerous abnormalities of NO synthesis and signaling have been identified in animal models of pulmonary vascular disease and in humans with pulmonary hypertension. Many of these abnormalities have become targets of new therapies for the treatment of pulmonary hypertension. However, it is unclear to what extent alterations in NO signaling contribute to pulmonary hypertensive responses or merely reflect abnormalities induced by the underlying disease. This perspective examines the current understanding of altered NO signaling in pulmonary hypertensive diseases and discusses how these alterations may contribute to the pathogenesis of pulmonary hypertension. The efficacy and limitations of presently available therapies for pulmonary hypertension that target NO signaling are reviewed along with an update on investigational therapies that use this pathway to reverse pulmonary hypertensive changes. Copyright © 2013 by the American Thoracic Society.


Whiteside T.L.,University of Pittsburgh
Expert Opinion on Biological Therapy | Year: 2014

Introduction: Regulatory T cells (Tregs) accumulating in the peripheral circulation and tumor sites of patients contribute to tumor escape from the host immune system. Tregs encompass subsets of immune cells with distinct phenotypic and functional properties. Whereas natural (n) or thymic-derived (t) Tregs regulate responses to self-antigens, inducible (i) or peripheral (p) Tregs generated and expanded in regulatory microenvironments control immune responses to a broad variety of antigens. Areas covered: Tregs accumulating in the tumor microenvironment (TME) are contextually regulated. They acquire phenotypic and functional attributes imposed by the inhibitory molecular pathways operating in situ. Several molecular pathways active in human cancer are reviewed. The pathways may differ from one tumor to another, and environmentally induced Tregs may be functionally distinct. Potential therapeutic strategies for selective silencing of iTregs are considered in the light of the newly acquired understanding of their phenotypic and functional diversity. Expert opinion: Human Tregs accumulating in cancer comprise 'bad' subsets, which inhibit antitumor immunity, and 'good' anti-inflammatory subsets, which maintain tolerance to self and benefit the host. Future therapeutic strategies targeting Tregs will need to discriminate between these Treg subsets and will need to consider reprogramming strategies instead of Treg elimination. Re-establishment of effective antitumor immune responses in cancer patients without disturbing a normal homeostatic T-cell balance will greatly benefit from insights into inhibitory pathways engaged by human tumors. © Informa UK, Ltd.


Balaban C.D.,University of Pittsburgh
Journal of Vestibular Research: Equilibrium and Orientation | Year: 2011

This review develops the hypothesis that co-morbid balance disorders and migraine can be understood as additive effects of processing afferent vestibular and pain information in pre-parabrachial and pre-thalamic pathways, that have consequences on cortical mechanisms influencing perception, interoception and affect. There are remarkable parallel neurochemical phenotypes for inner ear and trigeminal ganglion cells and these afferent channels appear to converge in shared central pathways for vestibular and nociceptive information processing. These pathways share expression of receptors targeted by anti-migraine drugs. New evidence is also presented regarding the distribution of serotonin receptors in the planum semilunatum of the primate cristae ampullaris, which may indicate involvement of inner ear ionic homeostatic mechanisms in audiovestibular symptoms that can accompany migraine. © 2011 - IOS Press and the authors. All rights reserved.


Kato G.J.,University of Pittsburgh
Blood | Year: 2014

In this issue of Blood, Gutsaeva and colleagues demonstrate the role of nitric oxide (NO) to suppress and hypoxia to promote adhesion of sickle erythrocytes to blood vessels in the bone marrow of mice, visualized by intravital microscopy.1 © 2014 by The American Society of Hematology.


Dabbs D.J.,University of Pittsburgh
Diagnostic Immunohistochemistry | Year: 2010

Diagnostic Immunohistochemistry presents the latest information and most reliable guidance on immunohistological diagnoses in surgical pathology. David J. Dabbs, MD and other leading experts bring you state-of-the-art coverage on genomic and theranostic applications, molecular anatomic pathology, immunocytology, Non-Hodgkin's lymphoma, and more. Additional features such as tables discussing antibody specifications, differential diagnosis boxes, ancillary anatomic molecular diagnostics, and full-color histological images ensure user-friendly coverage that makes key information easy to find and apply. The fully searchable text is also available online at expertconsult.com, along with a downloadable image bank and access to Path Consult. This concise and complete resource is today's indispensable guide to the effective use of immunohistochemical diagnosis. Discusses diagnostic pitfalls through immunohistologic differential diagnosis wherever appropriate so you can provide the most accurate diagnoses.Presents chapters arranged by organ system for comprehensive coverage of all relevant information in a convenient and intuitive organization.Provides quick reference graphs for antibodies throughout the text that illustrate the frequency of immunostaining for a variety of antibodies in tumors.Includes Key Diagnostic Points boxes in every chapter for a quick summary of text areas that are of particular importance.Features an expert author for each chapter to ensure coverage of the current state of the art.Includes access to the full text online at expertconsult.com, along with a downloadable image bank and Path Consult.Provides guidance on the role of genomics in identifying genetic and molecular aspects of disease that may affect patient care and therapeutic approaches.Covers theranostic applications to enable you to evaluate therapeutic choices based on immunohistochemical results.Reflects the latest developments in the field through new chapters on molecular anatomic pathology and immunocytology, as well as updated chapters on immunohistology of the prostate, bladder, testis, and kidney and Non-Hodgkin's lymphoma.Discusses antibody specifications with tables that convey information on uses, clones, vendors, sources, antibody titers, and types of antigen retrieval.Presents key differential diagnoses boxes that provide tabular summaries of DDx and algorithms.Features discussions of ancillary anatomic molecular diagnostics as an adjunct to immunohistochemistry for a more well-rounded diagnostic approach.Accurately interpret immunohistochemical results and provide the clinician with the best therapeutic approaches for the patientYour purchase entitles you to access the web site until the next edition is published, or until the current edition is no longer offered for sale by Elsevier, whichever occurs first. Elsevier reserves the right to offer a suitable replacement product (such as a downloadable or CD-ROM-based electronic version) should access to the web site be discontinued. © 2010 Elsevier Inc. All rights reserved.


Duquesnoy R.J.,University of Pittsburgh
Tissue Antigens | Year: 2014

Eplets are small configurations of polymorphic amino acid residues on human leukocyte antigen (HLA) molecules and are considered as essential components of HLA epitopes recognized by antibodies. This report describes a new design of the eplet repertoire in HLA-ABC alleles used in Luminex kits for antibody testing. There were three steps (1): identify all combinations of polymorphic residues with HLA molecular modeling within a 3-Å radius, (2) determine polymorphic residue compositions of 3Å patches from amino acid sequences of HLA alleles in Luminex panels and (3) annotate eplets from one or more patches present on one allele or shared by the same group of alleles. There are now 270 HLA-ABC eplets in the Registry, of which 219 are in antibody-accessible positions on the molecular surface and 51 are defined solely by residue polymorphisms located below the molecular surface. Each eplet has a list of Luminex and non-Luminex alleles for which mismatch acceptability can be determined. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Yadav D.,University of Pittsburgh
Current Gastroenterology Reports | Year: 2011

Clinical observation has defined the medical profile of alcoholic pancreatitis, but its low incidence and prevalence has limited characterizing the disease at a population level, the contribution of environmental exposures, and a clear picture of its natural history. Recent studies have defined the impact of alcohol use and smoking on disease risk, and a threshold for alcohol consumption has been identified. Recurrent attacks of acute pancreatitis have been linked with continued alcohol consumption, and aggressive alcohol intervention has been shown to decrease recurrence. Progression from alcoholic acute pancreatitis to chronic pancreatitis is now believed to occur infrequently, and factors associated with progression have been identified. Alcoholic pancreatitis reduces lifespan in these patients, and the economic impact of pancreatitis is substantial. Efforts are needed to increase awareness of the impact of alcohol consumption and smoking on risk for pancreatitis and the benefits of cessation for primary and secondary prevention. © Springer Science+Business Media, LLC 2011.


Boyanovsky D.,University of Pittsburgh
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2012

During deSitter inflation massless particles of minimally coupled scalar fields acquire a mass and a decay width thereby becoming quasiparticles. For bare massless particles nonperturbative infrared radiative corrections lead to a self-consistent generation of mass, for a quartic self-interaction Mλ14H, and for a cubic self-interaction the mass is induced by the formation of a nonperturbative condensate leading to Mλ13H2/3. These radiatively generated masses restore de Sitter invariance and result in anomalous scaling dimensions of superhorizon fluctuations. We introduce a generalization of the nonperturbative Wigner-Weisskopf method to obtain the time evolution of quantum states that include the self-consistent generation of mass and regulate the infrared behavior. The infrared divergences are manifest as poles in Δ=M2/3H2 in the single particle self-energies, leading to a rearrangement of the perturbative series nonanalytic in the couplings. A set of simple rules that yield the leading order infrared contributions to the decay width are obtained and implemented. The lack of kinematic thresholds entail that all particle states acquire a decay width, dominated by the emission and absorption of superhorizon quanta (λ/H)4 /3[H/k ph(η)]6[H/k ph(η)]6 for cubic and quartic couplings respectively to leading order in M/H. The decay of single particle quantum states hastens as their wave vectors cross the Hubble radius and their width is related to the highly squeezed limit of the bi- or trispectrum of scalar fluctuations respectively. © 2012 American Physical Society.


Castle N.G.,University of Pittsburgh
Journal of Elder Abuse and Neglect | Year: 2012

Information on the scale and scope of resident-to-resident abuse, including verbal, physical, material, psychological, and sexual abuse, is presented. Nursing homes (n = 249) from ten states were used, with a total of 4,451 nurse aides in these facilities returning the questionnaire. Most nursing homes experienced verbal, physical, material, and psychological abuse, but sexual abuse was less common. Our findings clearly show that both the scale and scope of resident-to-resident abuse is high in nursing homes. Resident-to-resident abuse is common enough to be considered an issue of concern impacting the quality of life and safety of many residents. © 2012 Copyright Taylor and Francis Group, LLC.


King W.C.,University of Pittsburgh | Bond D.S.,Brown University
Exercise and Sport Sciences Reviews | Year: 2013

There is increasing evidence that physical activity (PA) can enhance weight loss and other outcomes after bariatric surgery. However, most preoperative patients are insufficiently active and, without support, fail to make substantial increases in their PA postoperatively. This review provides the rationale for PA counseling in bariatric surgery and describes how to appropriately tailor strategies to preoperative and postoperative patients. Copyright © 2012 by the American College of Sports Medicine.


Lachin J.M.,George Washington University | Orchard T.J.,University of Pittsburgh | Nathan D.M.,Harvard University
Diabetes Care | Year: 2014

Objective To describe the beneficial long-term effects of an average of 6.5 years of intensive diabetes therapy (INT) in type 1 diabetes on measures of atherosclerosis, cardiac structure and function, and clinical cardiovascular events observed in the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Research Design And Methods The DCCT was a randomized clinical trial of 1,441 participants assigned to receive INT or conventional therapy (CON). It was conducted between 1983-1993 with an average follow-up of 6.5 years. EDIC (1994-present) is an observational follow-up of the DCCT cohort. Cardiovascular events have been recorded throughout. During EDIC common carotid intima-media thickness (IMT) was measured with ultrasound, coronary artery calcification with computed tomography, and cardiac structure and function with cardiac magnetic resonance imaging. Results DCCT INT and lower levels of HbA1c during DCCT/EDIC were associated with thinner carotid IMT, less coronary calcification, and a lower incidence of clinical cardiovascular events including myocardial infarction, stroke, and cardiac death. While there were no significant differences in cardiac structure and function between the former INT and CON groups, they were significantly associated with higher HbA1c during DCCT/EDIC. Conclusions DCCT INT and the attendant 6.5 years of lower HbA1c had long-term salutary effects on the development and progression of atherosclerosis and cardiovascular disease during the subsequent follow-up during EDIC. © 2014 by the American Diabetes Association.


Laskowski K.L.,Leibniz Institute of Freshwater Ecology and Inland Fisheries | Pruitt J.N.,University of Pittsburgh
Proceedings of the Royal Society B: Biological Sciences | Year: 2014

While there are nowa number of theoretical models predicting howconsistent individual differences in behaviour may be generated and maintained, so far, there are few empirical tests. The social niche specialization hypothesis predicts that repeated social interactions among individuals may generate among-individual differences and reinforce within-individual consistency through positive feedback mechanisms. Here, we test this hypothesis using groups of the social spider Stegodyphus mimosarum that differ in their level of familiarity. In support of the social niche specialization hypothesis, individuals in groups of spiders that were more familiar with each other showed greater repeatable among-individual variation in behaviour. Additionally, individuals that were more familiar with each other exhibited lower withinindividual variation in behaviour, providing one of the first examples of how the social environment can influence behavioural consistency. Our study demonstrates the potential for the social environment to generate and reinforce consistent individual differences in behaviour and provides a potentially general mechanism to explain this type of behavioural variation in animals with stable social groups. © 2014 The Author(s) Published by the Royal Society. All rights reserved.


Long-term hematopoietic stem cells (LT-HSCs) replenish the innate and adaptive immune compartments throughout life. Although significant progress has defined the major transcription factors that regulate lineage specification, the architectural proteins that globally coordinate DNA methylation, histone modification, and changes in gene expression are poorly defined. Provocative new studies establish the chromatin organizer special AT-rich binding protein 1 (Satb1) as one such global regulator in LT-HSCs. Satb1 is a nuclear organizer that partitions chromatin through the formation of cage-like structures. By integrating epigenetic and transcriptional pathways, Satb1 coordinates LT-HSC division, self-renewal, and lymphoid potential. Unexpected among the assortment of genes under Satb1 control in hematopoietic stem cells (HSCs) are cytokines, a finding that takes on additional importance with the provocative finding that short-term HSCs and downstream multipotent progenitors are potent and biologically relevant cytokine secretors during stress-mediated hematopoiesis. Together, these studies reveal a new mechanism of fate regulation and an unforeseen functional capability of HSCs. Copyright © 2014 by The American Association of Immunologists, Inc.


Meyer C.A.,Carnegie Mellon University | Swanson E.S.,University of Pittsburgh
Progress in Particle and Nuclear Physics | Year: 2015

A review of the theoretical and experimental status of hybrid hadrons is presented. The states π1(1400), π1(1600), and π1(2015) are thoroughly reviewed, along with experimental results from GAMS, VES, Obelix, COMPASS, KEK, CLEO, Crystal Barrel, CLAS, and BNL. Theoretical lattice results on the gluelump spectrum, adiabatic potentials, heavy and light hybrids, and transition matrix elements are discussed. These are compared with bag, string, flux tube, and constituent gluon models. Strong and electromagnetic decay models are described and compared to lattice gauge theory results. We conclude that while good evidence for the existence of a light isovector exotic meson exists, its confirmation as a hybrid meson awaits discovery of its iso-partners. We also conclude that lattice gauge theory rules out a number of hybrid models and provides a reference to judge the success of others. © 2015 Elsevier B.V.All rights reserved.


Jung H.S.,Sungkyunkwan University | Lee J.-K.,University of Pittsburgh
Journal of Physical Chemistry Letters | Year: 2013

TiO2 nanoparticle-based dye sensitized solar cells (DSSCs) have attracted a significant level of scientific and technological interest for their potential as economically viable photovoltaic devices. While DSSCs have multiple benefits such as material abundance, a short energy payback period, constant power output, and compatibility with flexible applications, there are still several challenges that hold back large scale commercialization. Critical factors determining the future of DSSCs involve energy conversion efficiency, long-term stability, and production cost. Continuous advancement of their long-term stability suggests that state-of-the-art DSSCs will operate for over 20 years without a significant decrease in performance. Nevertheless, key questions remain in regards to energy conversion efficiency improvements and material cost reduction. In this Perspective, the present state of the field and the ongoing efforts to address the requirements of DSSCs are summarized with views on the future of DSSCs. © 2013 American Chemical Society.


Lewis D.A.,University of Pittsburgh
Current Opinion in Neurobiology | Year: 2014

Schizophrenia is a disorder of cognitive neurodevelopment. At least some of the core cognitive deficits of the illness appear to be the product of impaired gamma frequency oscillations which depend, in part, on the inhibitory actions of a subpopulation of cortical GABA neurons that express the calcium binding protein parvalbumin (PV). Recent studies have revealed new facets of the development of PV neurons in primate neocortex and of the nature of their molecular alterations in individuals with schizophrenia. Other recent studies in model systems provide insight into how these alterations may arise in the course of cortical circuitry development. © 2013 Elsevier Ltd.


Duensing S.,University of Pittsburgh
Advances in Experimental Medicine and Biology | Year: 2010

Cancer cells are frequently characterized by ploidy changes including tetra-, poly- or aneuploidy. At the same time, malignant cells often contain supernumerary centrosomes. Aneuploidy and centrosome alterations are both hallmarks of tumor aggressiveness and increase with malignant progression. It has been proposed that aneuploidy results from a sequence of events in which failed mitoses produce tetra-/polyploid cells that enter a subsequent cell division with an increased number of centrosomes and hence with an increased risk for multipolar spindle formation and chromosome missegregation. Although this model attempts to integrate several common findings in cancer cells, it has been difficult to prove. Findings that centrosome aberrations can arise in diploid cells and the uncertain proliferative potential of polyploid cells suggest that alternative routes to chromosomal instability may exist. We discuss here recent results on centrosome biogenesis and the possible link between ploidy changes, centrosome aberrations and cancer. © 2010 Landes Bioscience and Springer Science+Business Media.


Behavioral and emotional dysregulation in childhood may be understood as prodromal to adult psychopathology. Additionally, there is a critical need to identify biomarkers reflecting underlying neuropathological processes that predict clinical/behavioral outcomes in youth. We aimed to identify such biomarkers in youth with behavioral and emotional dysregulation in the Longitudinal Assessment of Manic Symptoms (LAMS) study. We examined neuroimaging measures of function and white matter in the whole brain using 80 youth aged 14.0 (s.d.=2.0) from three clinical sites. Linear regression using the LASSO (Least Absolute Shrinkage and Selection Operator) method for variable selection was used to predict severity of future behavioral and emotional dysregulation measured by the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M)) at a mean of 14.2 months follow-up after neuroimaging assessment. Neuroimaging measures, together with near-scan PGBI-10M, a score of manic behaviors, depressive behaviors and sex, explained 28% of the variance in follow-up PGBI-10M. Neuroimaging measures alone, after accounting for other identified predictors, explained ~1/3 of the explained variance, in follow-up PGBI-10M. Specifically, greater bilateral cingulum length predicted lower PGBI-10M at follow-up. Greater functional connectivity in parietal-subcortical reward circuitry predicted greater PGBI-10M at follow-up. For the first time, data suggest that multimodal neuroimaging measures of underlying neuropathologic processes account for over a third of the explained variance in clinical outcome in a large sample of behaviorally and emotionally dysregulated youth. This may be an important first step toward identifying neurobiological measures with the potential to act as novel targets for early detection and future therapeutic interventions.Molecular Psychiatry advance online publication, 23 February 2016; doi:10.1038/mp.2016.5. © 2016 Macmillan Publishers Limited


The Paf1 complex was originally identified over fifteen years ago in budding yeast through its physical association with RNA polymerase II. The Paf1 complex is now known to be conserved throughout eukaryotes and is well studied for promoting RNA polymerase II transcription elongation and transcription-coupled histone modifications. Through these critical regulatory functions, the Paf1 complex participates in numerous cellular processes such as gene expression and silencing, RNA maturation, DNA repair, cell cycle progression and prevention of disease states in higher eukaryotes. In this review, we describe the historic and current research involving the eukaryotic Paf1 complex to explain the cellular roles that underlie its conservation and functional importance. This article is part of a Special Issue entitled: RNA polymerase II Transcript Elongation. Copyright © 2012 Elsevier B.V. All rights reserved.


Marazita M.L.,Center for Craniofacial and Dental Genetics | Marazita M.L.,University of Pittsburgh
Annual Review of Genomics and Human Genetics | Year: 2012

Orofacial clefts (OFCs)-primarily cleft lip and cleft palate-are among the most common birth defects in all populations worldwide, and have notable population, ethnicity, and gender differences in birth prevalence. Interest in these birth defects goes back centuries, as does formal scientific interest; scientists often used OFCs as examples or evidence during paradigm shifts in human genetics, and have also used virtually every new method of human genetic analysis to deepen our understanding of OFC. This review traces the evolution of human genetic investigations of OFC, highlights the specific insights gained about OFC through the years, and culminates in a review of recent key OFC genetic findings resulting from the powerful tools of the genomics era. Notably, OFC represents a major success for genome-wide approaches, and the field is poised for further breakthroughs in the near future. © 2012 by Annual Reviews. All rights reserved.


Waters J.H.,University of Pittsburgh
British Journal of Anaesthesia | Year: 2014

The concept of rapid delivery of multiple blood products to the bedside of a massively haemorrhaging patient seems to be a logical approach to the management of the massively bleeding patient. However, controversy exists in the use of fixed blood component ratios. Assessing the extent of the coagulopathy through point-of-care testing might provide patients with product administration as needed, and avoid excessive transfusion and its associated complications. © The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.


Bolliger D.,University of Basel | Tanaka K.A.,University of Pittsburgh
Transfusion Medicine Reviews | Year: 2013

The value of thrombelastography (TEG) and thromboelastometry (ROTEM) to improve perioperative hemostasis is under debate. We aimed to assess the effects of TEG- or ROTEM-guided therapy in patients undergoing cardiac surgery on the use of allogeneic blood products. We analyzed 12 trials including 6835 patients, 749 of them included in 7 randomized controlled trials (RCTs). We collected data on the amount of transfused allogeneic blood products and on the proportion of patients who received allogeneic blood products or coagulation factor concentrates. Including all trials, the odds ratios (ORs) for transfusion of red blood cell (RBC) concentrates, fresh-frozen plasma (FFP), and platelets were 0.62 (95% confidence interval [CI], 0.56-0.69; P < .001), 0.28 (95% CI, 0.24-0.33; P < .001), and 0.55 (95% CI, 0.49-0.62; P < .001), respectively. However, more than 50% of the patients in this analysis were derived from one retrospective study. Including RCTs only, the ORs for transfusion of RBC, FFP, and platelets were 0.54 (95% CI, 0.38-0.77; P < .001), 0.36 (95% CI, 0.25-0.53; P < .001), and 0.57 (95% CI, 0.39-0.81; P = .002), respectively. The use of coagulation factor concentrates was reported in 6 studies, 2 of them were RCTs. The ORs for the infusion of fibrinogen and prothrombin complex concentrate were 1.56 (95% CI, 1.29-1.87; P < .001) and 1.74 (95% CI, 1.40-2.18; P < .001), respectively. However, frequencies and amounts were similar in the intervention and control group in the 2 RCTs. It is presumed that TEG- or ROTEM-guided hemostatic management reduces the proportion of patients undergoing cardiac surgery transfused with RBC, FFP, and platelets. This presumption is strongly supported by similar ORs found in the analysis including RCTs only. Patient blood management based on the transfusion triggers by TEG or ROTEM appears to be more restrictive than the one based on conventional laboratory testing. However, evidence for improved clinical outcome is limited at this time. © 2013 Elsevier Inc.


Goh L.K.,University of Pittsburgh
Cold Spring Harbor perspectives in biology | Year: 2013

Endocytosis is the major regulator of signaling from receptor tyrosine kinases (RTKs). The canonical model of RTK endocytosis involves rapid internalization of an RTK activated by ligand binding at the cell surface and subsequent sorting of internalized ligand-RTK complexes to lysosomes for degradation. Activation of the intrinsic tyrosine kinase activity of RTKs results in autophosphorylation, which is mechanistically coupled to the recruitment of adaptor proteins and conjugation of ubiquitin to RTKs. Ubiquitination serves to mediate interactions of RTKs with sorting machineries both at the cell surface and on endosomes. The pathways and kinetics of RTK endocytic trafficking, molecular mechanisms underlying sorting processes, and examples of deviations from the standard trafficking itinerary in the RTK family are discussed in this work.


Li Z.,University of Pittsburgh
American journal of clinical pathology | Year: 2014

There is increasing emphasis on the subclassification of non-small cell lung carcinomas (NSCLCs) and molecular features to guide treatment. Histologic studies have suggested some morphologic features predominating in tumors. Our aim was to determine if mutated cases had distinct cytomorphology. A retrospective study was designed to retrieve all cytopathology cases of NSCLC that had mutation studies for EGFR or KRAS or fluorescence in situ hybridization studies for ALK between 2007 and 2012. All slides from available mutation-positive cases were reviewed, and cytomorphologic features were correlated to mutation status. Of the cases with molecular testing, 62 (39%) of 160 were positive for mutation, including 39 (31%) positive for KRAS, 20 (14%) for EGFR, and 4 (3%) for ALK (one case positive for both EGFR and ALK). More of ALK+ and KRAS+ cases had a diagnosis of NSCLC-favor adenocarcinoma or NSCLC not otherwise specified than did EGFR+ cases (25; 51% vs 5%). Eosinophilic granular cytoplasm was seen in more ALK and KRAS cases than in EGFR cases (100; 32% vs 6%). Cytologic features of ALK+ and KRAS+ tumors included more nuclear pleomorphism, necrosis, and a less vacuolated cytoplasm than did EGFR+ tumors, which may explain the less definitive subclassification in ALK+ and KRAS+ tumors.


Burke J.D.,University of Pittsburgh
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2012

Background: A dimension of negatively oriented affect within oppositional defiant disorder (ODD) symptoms, which has been described as irritability, has been shown to predict depression and anxiety. Related constructs have been linked to temperament and personality constructs. However, only a few studies have examined the prediction from irritability within ODD to psychopathology or personality outcomes. Further, no studies have investigated whether irritability distinguishes among classes of youth. Methods: Data from a clinic-referred sample of 7-12-year-old boys followed up to age 18 were used. Measures included structured clinical interviews with parents through adolescence, and youth self-report of depression and personality domains at age 18. Results: Variable-oriented analyses found predictive links between irritability and outcomes of depression, anxiety, and Neuroticism. Latent classes of youth were distinguished by the presence or absence of irritability symptoms. Youth classified by irritability symptoms at baseline were significantly more likely to show anxiety and depression through adolescence and depression and Neuroticism at 18. No relationship was observed for the other of the Big Five personality factors. Conclusion: Irritability symptoms within ODD distinguish youth at risk for persisting problems with internalizing disorders and Neuroticism into adulthood. The findings are suggestive of a model in which the early emergence of irritability marks life-course risks for specific types of psychopathology and personality problems. © 2012 Association for Child and Adolescent Mental Health.


Lacomis D.,University of Pittsburgh
Muscle and Nerve | Year: 2013

Introduction: Neuromuscular disorders, predominantly critical illness myopathy (CIM) and critical illness polyneuropathy (CIP) occur in approximately one-third of patients in intensive care units. The aim of this study was to review the important role of electrophysiology in this setting. Results: In CIM, sarcolemmal inexcitability causes low amplitude compound muscle action potentials (CMAPs) that may have prolonged durations. Needle electrode examination usually reveals early recruitment of short duration motor unit potentials, often with fibrillation potentials. In CIP, the findings are usually those of a generalized axonal sensorimotor polyneuropathy. Direct muscle stimulation aids in differentiating CIP and CIM and in identifying mixed disorders along with other electrodiagnostic and histopathologic studies. Identifying evolving reductions in fibular CMAP amplitudes in intensive care unit (ICU) patients predicts development of neuromuscular weakness. Conclusions: Knowledge of the various neuromuscular disorders in critically ill patients, their risk factors, and associated electrodiagnostic findings can lead to development of a rational approach to diagnosis of the cause of neuromuscular weakness in ICU patients. © 2013 Wiley Periodicals, Inc., a Wiley company.


Michalopoulos G.K.,University of Pittsburgh
Comprehensive Physiology | Year: 2013

Liver regeneration is perhaps the most studied example of compensatory growth aimed to replace loss of tissue in an organ. Hepatocytes, the main functional cells of the liver, manage to proliferate to restore mass and to simultaneously deliver all functions hepatic functions necessary to maintain body homeostasis. They are the first cells to respond to regenerative stimuli triggered by mitogenic growth factor receptors MET (the hepatocyte growth factor receptor] and epidermal growth factor receptor and complemented by auxiliary mitogenic signals induced by other cytokines. Termination of liver regeneration is a complex process affected by integrin mediated signaling and it restores the organ to its original mass as determined by the needs of the body (hepatostat function). When hepatocytes cannot proliferate, progenitor cells derived from the biliary epithelium transdifferentiate to restore the hepatocyte compartment. In a reverse situation, hepatocytes can also transdifferentiate to restore the biliary compartment. Several hormones and xenobiotics alter the hepatostat directly and induce an increase in liver to body weight ratio (augmentative hepatomegaly). The complex challenges of the liver toward body homeostasis are thus always preserved by complex but unfailing responses involving orchestrated signaling and affecting growth and differentiation of all hepatic cell types. © 2013 American Physiological Society.


Liu Q.,North Carolina State University | Deiters A.,North Carolina State University | Deiters A.,University of Pittsburgh
Accounts of Chemical Research | Year: 2014

Synthetic oligonucleotides have been extensively applied tocontrol a wide range of biological processes such as gene expression, gene repair, DNA replication, and protein activity. Based on well-established sequence design rules that typically rely on Watson-Crick base pairing interactions researchers can readily program the function of these oligonucleotides. Therefore oligonucleotides provide a flexible platform for targeting a wide range of biological molecules, including DNA, RNA, and proteins. In addition, oligonucleotides are commonly used research tools in cell biology and developmental biology. However, a lack of conditional control methods has hampered the precise spatial and temporal regulation of oligonucleotide activity, which limits the application of these reagents to investigate complex biological questions. Nature controls biological function with a high level of spatial and temporal resolution and in order to elucidate the molecular mechanisms of biological processes, researchers need tools that allow for the perturbation of these processes with Nature's precision.Light represents an excellent external regulatory element since irradiation can be easily controlled spatially and temporally. Thus, researchers have developed several different methods to conditionally control oligonucleotide activity with light. One of the most versatile strategies is optochemical regulation through the installation and removal of photolabile caging groups on oligonucleotides. To produce switches that can control nucleic acid function with light, chemists introduce caging groups into the oligomer backbone or on specific nucleobases to block oligonucleotide function until the caging groups are removed by light exposure.In this Account, we focus on the application of caged nucleobases to the photoregulation of DNA function. Using this approach, we have both activated and deactivated gene expression optochemically at the transcriptional and translational level with spatial and temporal control. Specifically, we have used caged triplex-forming oligomers and DNA decoys to regulate transcription, and we have regulated translation with light-activated antisense agents. Moreover, we also discuss strategies that can trigger DNA enzymatic activity, DNA amplification, and DNA mutagenesis by light illumination. More recently, we have developed light-activated DNA logic operations, an advance that may lay the foundation for the optochemical control of complex DNA calculations. © 2013 American Chemical Society.


Shiffman S.,University of Pittsburgh
Nicotine and Tobacco Research | Year: 2014

Ecological momentary assessment (EMA) methods, which involve collection of real-time data in subjects' real-world environments, are particularly well suited to studying tobacco use. Analyzing EMA datasets can be challenging, as the datasets include a large and varied number of observations per subject and are relatively unstructured. This paper suggests that time is typically a key organizing principle in EMA data and that conceptualizing the data as a timeline of events, behaviors, and experiences can help define analytic approaches. EMA datasets lend themselves to answering a diverse array of research questions, and the research question must drive how data are arranged for analysis and the kinds of statistical models that are applied. This is illustrated with brief examples of diverse analyses applied to answer different questions from an EMA study of tobacco use and relapse. © The Author 2013.


Forbes E.E.,University of Pittsburgh | Dahl R.E.,University of California at Berkeley
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2012

Background: Conceptual models and recent evidence indicate that neural response to reward is altered in depression. Taking a developmental approach to investigating reward function in adolescent depression can elucidate the etiology, pathophysiology and course of depression, a disorder that typically begins during adolescence and has high rates of recurrence. Methods: This conceptual review describes the what, when and how of altered reward function in adolescent depression. With the goal of generating new, testable hypotheses within a developmental affective neuroscience framework, we critically review findings and suggest future directions. Peer-reviewed empirical papers for inclusion in this critical review were obtained by searching PubMed, PsycInfo and ScienceDirect for the years 1990-2010. Results: A pattern of low striatal response and high medial prefrontal response to reward is evident in adolescents and adults with depression. Given the salience of social stimuli for positive affect and depression, reward function might be especially disrupted in response to social rewards. Because of changes in the dopamine system and reward function with aging, altered reward function in depression might be more evident during adolescence than later in life; however, low reward function may also be a stable characteristic of people who experience depression. Mechanisms of altered reward function in depression could include disrupted balance of corticostriatal circuit function, with disruption occurring as aberrant adolescent brain development. Conclusions: Future studies should examine responses to social rewards; employ longitudinal and prospective designs; and investigate patterns of functional connectivity in reward circuits. Understanding altered reward function in depression has potential implications for treatment development. A more rigorous approach to investigating anhedonia, threat-reward interactions and comorbid anxiety will be valuable to future progress in describing the role of reward function in the pathophysiology of depression. © 2011 Association for Child and Adolescent Mental Health.


Carcillo J.A.,University of Pittsburgh
Current Opinion in Critical Care | Year: 2014

PURPOSE OF REVIEW: To review the past year's literature, and selected prior literature relevant to these most recent findings, regarding intravenous fluid choices in the management of critically ill children. RECENT FINDINGS: Twenty-eight publications were identified using the keywords pediatrics and intravenous fluid in the PubMed database. The subjects identified included intravenous fluid choices related to perioperative maintenance fluid management, rehydration for dehydration related to diarrhea losses, rehydration in diabetic ketoacidosis, intravenous fluid needs during mechanical ventilation, use of intravenous fluids as hyperosmolar agents in traumatic brain injury, isotonic fluid bolus resuscitation for sepsis-related capillary leak syndrome-induced hypovolemic shock, maintenance intravenous fluid and blood transfusion for malaria-associated euvolemic severe anemia shock, isotonic fluid and blood boluses for trauma-induced hemorrhagic shock, and isotonic fluid boluses and generous maintenance infusion for burn resuscitation. SUMMARY: Because intravenous fluid can be helpful or harmful, it can only be safely done in critically ill children when using state-of-the-art monitoring of patient volume, electrolyte, osmolarity, pH, and glucose status. © 2014 Lippincott Williams & Wilkins.


Bots M.L.,University Utrecht | Sutton-Tyrrell K.,University of Pittsburgh
Journal of the American College of Cardiology | Year: 2012

Carotid intima-media thickness (CIMT) measurements have been used in cardiovascular research for more than 2 decades. There is a wealth of evidence showing that CIMT can be assessed in a reproducible manner and that increased CIMT relates to unfavorable risk factor levels and atherosclerosis elsewhere in the arterial system and to the risk of vascular events. Change in CIMT over time can be readily assessed, and trials showed that the rate of change is modifiable by treatment. Several issues important for the cardiovascular research community and its application in clinical practice are still outstanding. Promising future areas for CIMT measurements are: 1) application in studies among children and adolescents; 2) use of CIMT trials positioned decisively before the start of a morbidity and mortality trial; and 3) the use of CIMT measurement in risk stratification in those with an intermediate 10-year risk estimate. © 2012 American College of Cardiology Foundation.


Pruitt J.N.,University of Pittsburgh | Ferrari M.C.O.,University of Saskatchewan
Ecology | Year: 2011

Although the study of ecological interactions often takes into account functional variation between species, intraspecific variation is commonly ignored. Here, we investigate the importance of an intraspecific polymorphism in shaping interspecific interactions in a habitat-building species. Colonies of the social spider Anelosimus studiosus provide habitat for dozens of arthropod species, and colony members exhibit markedly polymorphic behavioral temperaments (BT): "aggressive" or "docile." We manipulated the phenotypic compositions of colonies (100% aggressive, 50% aggressive and 50% docile, 100% docile) and measured the nature and magnitude of interactions between A. studiosus and two heterospecific web associates, Larinioides cornutus and Agelenopsis emertoni. We found that BT composition significantly affected the outcome of interspecific interactions, changing the relationship between A. studiosus and its web associates from an ammensalism (where A. studiosus experiences reduced fecundity and survival) to a commensalism or mutualism. Our study successfully illustrates the potential of BTs to impact whole community dynamics, and conversely, for community structure to influence the maintenance of BTs. © 2011 by the Ecological Society of America.


Van Der Wel P.C.A.,University of Pittsburgh
Prion | Year: 2012

For several different proteins an apparent correlation has been observed between the propensity for dimerization by domain-swapping and the ability to aggregate into amyloid-like fibrils. Examples include the disease-related proteins beta2-microglobulin and transthyretin. This has led to proposals that the amyloid-formation pathway may feature extensive domain swapping. One possible consequence of such an aggregation pathway is that the resulting fibrils would incorporate structural elements that resemble the domain-swapped forms of the protein and, thus, reflect certain native-like structures or domain-interactions. In magic angle spinning solid-state NMR-based and other structural studies of such amyloid fibrils, it appears that many of these proteins form fibrils that are not native-like. Several fibrils instead have an in-register, parallel conformation, which is a common amyloid structural motif and is seen, for instance, in various prion fibrils. Such a lack of native structure in the fibrils suggests that the apparent connection between domain-swapping ability and amyloid-formation may be more subtle or complex than may be presumed at first glance. © 2012 Landes Bioscience.


Ishima R.,University of Pittsburgh
Topics in Current Chemistry | Year: 2012

Nuclear Magnetic Resonance (NMR) relaxation is a powerful technique that provides information about internal dynamics associated with configurational energetics in proteins, as well as site-specific information involved in conformational equilibria. In particular, 15N relaxation is a useful probe to characterize overall and internal backbone dynamics of proteins because the relaxation mainly reflects reorientational motion of the N-H bond vector. Over the past 20 years, experiments and protocols for analysis of 15N R 1, R 2, and the heteronuclear 15N-{ 1H} NOE data have been well established. The development of these methods has kept pace with the increase in the available static-magnetic field strength, providing dynamic parameters optimized from data fitting at multiple field strengths. Using these methodological advances, correlation times for global tumbling and order parameters and correlation times for internal motions of many proteins have been determined. More recently, transverse relaxation dispersion experiments have extended the range of NMR relaxation studies to the milli- to microsecond time scale, and have provided quantitative information about functional conformational exchange in proteins. Here, we present an overview of recent advances in 15N relaxation experiments to characterize protein backbone dynamics. © 2011 Springer-Verlag Berlin Heidelberg.


Coleman N.M.,University of Pittsburgh
Journal of Geophysical Research E: Planets | Year: 2013

The Elaver Vallis channels provide a unique opportunity to develop calibrated hydrographs for a Martian flood. Groundwater filled Morella Crater until the enclosed lake overtopped the rim, confirming that the groundwater potentiometric surface exceeded 1771 m. The overtopping flow rapidly breached the crater wall, catastrophically drained the lake, and eroded a broad scabland and two main channels. Laser altimeter data were used to calculate a preflood lake volume of 2.216 × 1012 m3. Dam breach methods were used to develop hydrographs of discharge and lake stage over time. The peak discharge was in the range of 1.94 × 107 to 3.51 × 107 m3 s-1, depending on the underlying breach erosion scenario. Approximately 95% of the drainable lake volume discharged in 6.4 to 7.5 days. The 240 m deep southern channel entirely formed in 1 to 1.7 days, indicating a mean erosion rate of 0.10 to 0.17 m min-1. The volume of material eroded from the channels was 0.45 of the flood volume, but the actual eroded fraction was probably greater because distant channel reaches were obliterated by the postflood growth of Ganges Chasma. For comparison, flow calculations were performed using open-channel methods. Channel energy slopes had to be corrected for a postflood tectonic tilt in the regional surface. Comparing the hydrographs to the open-channel calculations reveals that the northern Elaver Vallis channel as seen today never flowed bank full or even at half its maximum depth because the implied flows would have exceeded the peak discharges. Key points Hydrographs have been developed for a flood from a breached crater lake on MarsPeak discharge was 1.94E7-3.51E7 m3/s, with an erosion rate of 0.10-0.17 m/minThis paper shows that 1 flood could erode a deep channel on Mars in 1-1.7 days ©2012. American Geophysical Union. All Rights Reserved.


Ohayon M.M.,Stanford University | Reynolds III C.F.,University of Pittsburgh
Archives of General Psychiatry | Year: 2012

Context: Excessive sleepiness (ES) is poorly defined in epidemiologic studies, although its adverse implications for safety, health, and optimal social and vocational functioning have been extensively reported. Objective: To determine the importance of ES definition, measurement, and prevalence in the general population, together with its coexisting conditions. Design: Cross-sectional telephone study. Participants: A total of 15 929 individuals representative of the adult general population of 15 states in the United States. Main Outcome Measures: Interviews were carried out using Sleep-EVAL, a knowledge-based expert system for use in epidemiologic studies, focusing on sleep, as well as physical and mental disorders, according to classification in DSM-IV and the second edition of the International Classification of Sleep Disorders. The interviews elicited information on ES, naps, frequency, duration, impairment, and distress associated with ES symptoms. Results: Excessive sleepiness was reported by 27.8% (95% CI, 27.1%-28.5%) of the sample. Excessive sleepiness with associated symptoms was found in 15.6% of the participants (95% CI, 15.0%-16.2%). Adding an ES frequency of at least 3 times per week for at least 3 months despite normal sleep duration dropped the prevalence to 4.7% of the sample (95% CI, 4.4%-5.0%). The proportion of individuals having social or professional impairment and psychological distress increased with the frequency of ES symptoms during the week and within the same day. In multivariate models, the number of ES episodes per day and severity of ES were identified as the best predictors for impairment/distress. Prevalence of hypersomnia disorder was 1.5% of the participants (95% CI, 1.3%- 1.7%). The most common coexisting conditions were mood and substance use disorders. Conclusions: Excessive sleepiness is an important problem in the US population, even when using restrictive criteria to define it. Hypersomnia disorder is more prevalent than previously estimated. Excessive sleepiness has to be recognized and given attention by public health authorities, scientists, and clinicians. ©2012 American Medical Association. All rights reserved.


Molina B.S.G.,University of Pittsburgh | Pelham Jr. W.E.,Florida International University
Annual Review of Clinical Psychology | Year: 2014

Many opportunities to explain attention-deficit/hyperactivity disorder (ADHD)-related risk of substance use disorder (SUD) remain available for study. We detail these opportunities by considering characteristics of children with ADHD and factors affecting their outcomes side by side with overlapping variables in the developmental literature on SUD etiology. Although serious conduct problems are a known contributor to ADHD-related risk of SUD, few studies have considered their emergence developmentally and in relation to other candidate mediators and moderators that could also explain risk and be intervention targets. Common ADHD-related impairments, such as school difficulties, are in need of research. Heterogeneous social impairments have the potential for predisposing, and buffering, luences. Research on neurocognitive domains should move beyond standard executive function batteries to measure deficits in the interface between cognitive control, reward, and motivation. Ultimately, maximizing prediction will depend, as it has in the SUD literature, on simultaneous consideration of multiple risk factors. © 2014 by Annual Reviews.


Hager E.S.,University of Pittsburgh
Journal of vascular surgery : official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter | Year: 2012

To determine if there are any differences in outcomes between infrarenal fixation (IF) and suprarenal fixation (SF) endograft systems for the endovascular treatment (endovascular aneurysm repair [EVAR]) of abdominal aortic aneurysms (AAAs) with short, straight proximal aortic necks (<1.5 cm). A retrospective review of 1379 EVAR procedures was performed between the years of 2002 and 2009 at a single institution. The charts and radiographic images of all patients were reviewed. Patients who underwent EVAR with AAA morphology with short proximal necks were stratified into two groups: IF, Gore Excluder (W. L. Gore, Flagstaff, Ariz) group and SF, Cook Zenith (Cook, Bloomington, Ind) group. The primary end point for the study was the presence of proximal type 1 endoleaks. Secondary end points were graft migration at 1- and 2-year follow-up and aneurysm sac regression. The groups' demographics and comorbidities were also compared. A total of 1379 EVARS were performed during the study period and 84 were identified as having a short proximal aortic neck. Sixty patients were in the IF group and 24 in the SF group. The average follow-up period was 18.6 months (IF) and 18.5 months (SF). There was no difference in the average proximal neck length (1.19 cm IF vs 1.14 cm SF; P = not significant [NS]) or the preoperative AAA size (5.8 cm IF vs 5.9 cm SF; P = NS). There were no significant differences in age (76.6 years IF vs 74.8 years SF; P = .32), gender (IF 66.7% vs SF 21.88% men; P = .053), or length of stay (2.2 days IF vs 1.9 days SF; P = .39). The comorbidities (diabetes, hypertension, and warfarin use) were also similar. There were five type 1a endoleaks in group IF and one in group SF (P = .44) identified at the 1-month follow-up; however, only one patient in the IF group underwent intervention for enlargement of the AAA sac. At 1 year, there was persistence of one type 1a endoleak in both groups, but these were deemed dead-end leaks as they did not fill the sac nor lead to aneurysm growth. There were no migrations (>0.5 cm) noted in either group. Sac regression was observed at an average rate of 0.24 cm/year in the IF group and 0.26 cm/year in the SF group (P = NS). There were no aneurysm ruptures during the study period. There are no significant differences in endograft migration or in the incidence of early and late type 1a endoleaks between endografts that use IF (Gore Excluder) and SF (Cook Zenith) fixation for patients with short aortic necks undergoing EVAR. Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.


Signal transducer and activator of transcription 3 (STAT3) overactivation is a common event in many cancers, including head and neck squamous cell carcinoma (HNSCC), where STAT3 represents a promising therapeutic target. HNSCC is not characterized by frequent kinase mutations, in contrast to some malignancies where mutational activation of kinases upstream of STAT3 is common. Instead, STAT3 may be activated by loss-of-function of negative regulators of STAT3, including by promoter hypermethylation of PTPRT. Here we first analyzed The Cancer Genome Atlas data and determined that the PTPRT promoter is frequently hypermethylated in several cancers, including HNSCC (60.1% of tumors analyzed) in association with downregulation of PTPRT mRNA expression and upregulation of pSTAT3 expression. These findings were confirmed in an independent cohort of HNSCC tumors by methylation-specific PCR and immunohistochemistry. We demonstrate that PTPRT promoter methylation and gene silencing is reversible in HNSCC cells, leading to PTPRT-specific downregulation of pSTAT3 expression. We further show that PTPRT promoter methylation is significantly associated with sensitivity to STAT3 inhibition in HNSCC cells, suggesting that PTPRT promoter methylation may serve as a predictive biomarker for responsiveness to STAT3 inhibitors in clinical development.Oncogene advance online publication, 18 May 2015; doi:10.1038/onc.2015.171. © 2015 Macmillan Publishers Limited


Zapolski T.C.B.,University of Kentucky | Pedersen S.L.,University of Pittsburgh | McCarthy D.M.,University of Missouri | Smith G.T.,University of Kentucky
Psychological Bulletin | Year: 2014

Researchers have found that, compared to European Americans, African Americans report later initiation of drinking, lower rates of use, and lower levels of use across almost all age groups. Nevertheless, African Americans also have higher levels of alcohol problems than European Americans. After reviewing current data regarding these trends, we provide a theory to understand this apparent paradox as well as to understand variability in risk among African Americans. Certain factors appear to operate as both protective factors against heavy use and risk factors for negative consequences from use. For example, African American culture is characterized by norms against heavy alcohol use or intoxication, which protects against heavy use but also provides within-group social disapproval when use does occur. African Americans are more likely to encounter legal problems from drinking than European Americans, even at the same levels of consumption, perhaps thus resulting in reduced consumption but more problems from consumption. There appears to be one particular group of African Americans, low-income African American men, who are at the highest risk for alcoholism and related problems. We theorize that this effect is due to the complex interaction of residential discrimination, racism, age of drinking, and lack of available standard life reinforcers (e.g., stable employment and financial stability). Further empirical research will be needed to test our theories and otherwise move this important field forward. A focus on within-group variation in drinking patterns and problems is necessary. We suggest several new avenues of inquiry. © 2014 American Psychological Association.


Sayette M.A.,University of Pittsburgh
Annual Review of Clinical Psychology | Year: 2016

Craving is a central feature of addiction. Its recent inclusion as a diagnostic criterion for substance use disorders in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders appears at a time when craving research is at an all-time high. Craving is thought to predict relapse and may deter individuals from even trying to quit. Researchers have developed experimental craving-induction paradigms to identify factors contributing to craving and to test interventions to alleviate craving. This review offers a critique of laboratory craving studies, with particular emphasis on cigarette craving. It raises questions concerning several conceptual and methodological assumptions underlying this research, identifies processes that may explain why cravings are linked to drug use and relapse, addresses contextual factors that may influence various experiences of craving, and considers recent interventions targeting craving. The relation between craving and both emotion and coping is discussed, as well as the level of insight that individuals have about their own future cravings. Copyright ©2016 by Annual Reviews. All rights reserved.


Miller M.D.,University of Pittsburgh
Dialogues in Clinical Neuroscience | Year: 2012

Complicated grief (CG) is a syndrome that affects 10% to 20% of grievers regardless of age, although proportionally more will face the death of loved ones in late life. CG is characterized by preoccupying and disabling symptoms that can persist for decades such as an inability to accept the death, intense yearning or avoidance, frequent reveries, deep sadness, crying, somatic distress, social withdrawal, and suicidal ideation. This syndrome is distinct from major depression and post-traumatic stress disorder, but CG may be comorbid with each. This communication will focus on the impact of CG in late life (over age 60) and will include a case vignette for illustrating complicated grief therapy. © 2012 LLS SAS.


Huet A.,University of Pittsburgh
Nature Structural and Molecular Biology | Year: 2016

The herpesvirus capsid is a complex protein assembly that includes hundreds of copies of four major subunits and lesser numbers of several minor proteins, all of which are essential for infectivity. Cryo-electron microscopy is uniquely suited for studying interactions that govern the assembly and function of such large functional complexes. Here we report two high-quality capsid structures, from human herpes simplex virus type 1 (HSV-1) and the animal pseudorabies virus (PRV), imaged inside intact virions at ~7-Å resolution. From these, we developed a complete model of subunit and domain organization and identified extensive networks of subunit contacts that underpin capsid stability and form a pathway that may signal the completion of DNA packaging from the capsid interior to outer surface, thereby initiating nuclear egress. Differences in the folding and orientation of subunit domains between herpesvirus capsids suggest that common elements have been modified for specific functions. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Hatfull G.F.,University of Pittsburgh
Advances in Virus Research | Year: 2012

The study of mycobacteriophages provides insights into viral diversity and evolution, as well as the genetics and physiology of their pathogenic hosts. Genomic characterization of 80 mycobacteriophages reveals a high degree of genetic diversity and an especially rich reservoir of interesting genes. These include a vast number of genes of unknown function that do not match known database entries and many genes whose functions can be predicted but which are not typically found as components of phage genomes. Thus many mysteries surround these genomes, such as why the genes are there, what do they do, how are they expressed and regulated, how do they influence the physiology of the host bacterium, and what forces of evolution directed them to their genomic homes? Although the genetic diversity and novelty of these phages is full of intrigue, it is a godsend for the mycobacterial geneticist, presenting an abundantly rich toolbox that can be exploited to devise new and effective ways for understanding the genetics and physiology of human tuberculosis. As the number of sequenced genomes continues to grow, their mysteries continue to thicken, and the time has come to learn more about the secret lives of mycobacteriophages. © 2012 Elsevier Inc.


Nikiforov Y.E.,University of Pittsburgh
Modern Pathology | Year: 2011

In the recent years, a large number of molecular alterations in thyroid cancer has been discovered and characterized. Some of these markers may have significant diagnostic utility, can be used for tumor prognostication, and serve as potential therapeutic targets. The diagnostic utility of these markers is of particular importance in thyroid fine-needle aspiration samples. Some molecular markers, such as BRAF, offer help in risk stratification and can be potentially used to optimize surgical and postsurgical management of patients with thyroid cancer. This review discusses major molecular alterations known to occur in thyroid cancer, focusing on those markers that have been extensively characterized, carry clinical significance, and are being introduced into pathology practice. © 2011 USCAP, Inc. All rights reserved.


Evans C.H.,Rehabilitation Medicine Research Center | Huard J.,University of Pittsburgh
Nature Reviews Rheumatology | Year: 2015

Injuries to the musculoskeletal system are common, debilitating and expensive. In many cases, healing is imperfect, which leads to chronic impairment. Gene transfer might improve repair and regeneration at sites of injury by enabling the local, sustained and potentially regulated expression of therapeutic gene products; such products include morphogens, growth factors and anti-inflammatory agents. Proteins produced endogenously as a result of gene transfer are nascent molecules that have undergone post-translational modification. In addition, gene transfer offers particular advantages for the delivery of products with an intracellular site of action, such as transcription factors and noncoding RNAs, and proteins that need to be inserted into a cell compartment, such as a membrane. Transgenes can be delivered by viral or nonviral vectors via in vivo or ex vivo protocols using progenitor or differentiated cells. The first gene transfer clinical trials for osteoarthritis and cartilage repair have already been completed. Various bone-healing protocols are at an advanced stage of development, including studies with large animals that could lead to human trials. Other applications in the repair and regeneration of skeletal muscle, intervertebral disc, meniscus, ligament and tendon are in preclinical development. In addition to scientific, medical and safety considerations, clinical translation is constrained by social, financial and logistical issues. © 2015 Macmillan Publishers Limited. All rights reserved.


Sigal I.A.,University of Pittsburgh
Investigative Ophthalmology and Visual Science | Year: 2011

Purpose. The ability to predict the biomechanical response of the optic nerve head (ONH) to intraocular pressure (IOP) elevation holds great promise, yet remains elusive. The objective of this work was to introduce an approach to model ONH biomechanics that combines the ease of use and speed of analytical models with the flexibility and power of numerical models. Methods. Models representing a variety of ONHs were produced, and finite element (FE) techniques used to predict the stresses (forces) and strains (relative deformations) induced on each of the models by IOP elevations (up to 10 mm Hg). Multivariate regression was used to parameterize each biomechanical response as an analytical function. These functions were encoded into a Flash-based applet. Applet utility was demonstrated by investigating hypotheses concerning ONH biomechanics posited in the literature. Results. All responses were parameterized well by polynomials (R 2 values between 0.985 and 0.999), demonstrating the effectiveness of our fitting approach. Previously published univariate results were reproduced with the applet in seconds. A few minutes allowed for multivariate analysis, with which it was predicted that often, but not always, larger eyes experience higher levels of stress and strain than smaller ones, even at the same IOP. Conclusions. An applet has been presented with which it is simple to make rapid estimates of IOP-related ONH biomechanics. The applet represents a step toward bringing the power of FE modeling beyond the specialized laboratory and can thus help develop more refined biomechanics-based hypotheses. The applet is available for use at www.ocularbiomechanics. com. © 2011 The Association for Research in Vision and Ophthalmology, Inc.


Alper G.,University of Pittsburgh
Journal of Child Neurology | Year: 2012

Acute disseminated encephalomyelitis is an immune-mediated inflammatory and demyelinating disorder of the central nervous system, commonly preceded by an infection. It principally involves the white matter tracts of the cerebral hemispheres, brainstem, optic nerves, and spinal cord. Acute disseminated encephalomyelitis mainly affects children. Clinically, patients present with multifocal neurologic abnormalities reflecting the widespread involvement in central nervous system. Cerebrospinal fluid may be normal or may show a mild pleocytosis with or without elevated protein levels. Magnetic resonance image (MRI) shows multiple demyelinating lesions. The diagnosis of acute disseminated encephalomyelitis requires both multifocal involvement and encephalopathy by consensus criteria. Acute disseminated encephalomyelitis typically has a monophasic course with a favorable prognosis. Multiphasic forms have been reported, resulting in diagnostic difficulties in distinguishing these cases from multiple sclerosis. In addition, many inflammatory disorders may have a similar presentation with frequent occurrence of encephalopathy and should be considered in the differential diagnosis of acute disseminated encephalomyelitis. © 2012 The Author(s).


Swamynathan S.K.,University of Pittsburgh
Human genomics | Year: 2010

Krüppel-like factors (KLFs), members of the zinc-finger family of transcription factors capable of binding GC-rich sequences, have emerged as critical regulators of important functions all over the body. They are characterised by a highly conserved C-terminal DNA-binding motif containing three C2H2 zinc-finger domains, with variable N-terminal regulatory domains. Currently, there are 17 KLFs annotated in the human genome. In spite of their structural similarity to one another, the genes encoding different KLFs are scattered all over the genome. By virtue of their ability to activate and/or repress the expression of a large number of genes, KLFs regulate a diverse array of developmental events and cellular processes, such as erythropoiesis, cardiac remodelling, adipogenesis, maintenance of stem cells, epithelial barrier formation, control of cell proliferation and neoplasia, flow-mediated endothelial gene expression, skeletal and smooth muscle development, gluconeogenesis, monocyte activation, intestinal and conjunctival goblet cell development, retinal neuronal regeneration and neonatal lung development. Characteristic features, nomenclature, evolution and functional diversities of the human KLFs are reviewed here.


Chakraborty D.P.,University of Pittsburgh
Academic Radiology | Year: 2013

In the receiver operating characteristic paradigm the observer assigns a single rating to each image and the location of the perceived abnormality, if any, is ignored. In the free-response receiver operating characteristic paradigm the observer is free to mark and rate as many suspicious regions as are considered clinically reportable. Credit for a correct localization is given only if a mark is sufficiently close to an actual lesion; otherwise, the observer's mark is scored as a location-level false positive. Until fairly recently there existed no accepted method for analyzing the resulting relatively unstructured data containing random numbers of mark-rating pairs per image. This report reviews the history of work in this field, which has now spanned more than five decades. It introduces terminology used to describe the paradigm, proposed measures of performance (figures of merit), ways of visualizing the data (operating characteristics), and software for analyzing free-response receiver operating characteristic studies. © 2013 AUR.


Zhang P.,University of Pittsburgh
Current Opinion in Structural Biology | Year: 2013

The biological processes occurring in a cell are complex and dynamic, and to achieve a comprehensive understanding of the molecular mechanisms underlying these processes, both temporal and spatial information is required. While cryo-electron tomography (cryoET) provides three-dimensional (3D) still pictures of near-native state cells and organelles at molecular resolution, fluorescence light microscopy (fLM) offers movies of dynamic cellular processes in living cells. Combining and integrating these two commonly used imaging modalities (termed correlative microscopy) provides a powerful means to not only expand the imaging scale and resolution but also to complement the dynamic information available from optical microscopy with the molecular-level, 3D ultrastructure detail provided by cryoET. As such, a correlative approach performed on a given specimen can provide high resolution snapshots of dynamic cellular events. In this article, I review recent advances in correlative light microscopy and cryoET and discuss major findings made available by applying this method. © 2013 Elsevier Ltd.


Johnston P.A.,University of Pittsburgh
Current Opinion in Chemical Biology | Year: 2011

Redox cycling compounds (RCCs) generate μM concentrations of hydrogen peroxide (H2O2) in the presence of strong reducing agents, common buffer components used to maintain the catalytic activity and/or folding of target proteins for high throughput screening (HTS) assays. H2O2 generated by RCCs can indirectly inhibit the catalytic activity of proteins by oxidizing accessible cysteine, tryptophan, methionine, histidine, or selenocysteine residues, and indeed several important classes of protein targets are susceptible to H2O2-mediated inactivation; protein tyrosine phosphatases, cysteine proteases, and metalloenzymes. The main sources of H2O2 in cells are the Nox enzyme/SOD systems, peroxisome metabolism, and the autoxidation of reactive chemicals by enzyme mediated redox cycling at both the microsomal and mitochondrial sites of electron transport. Given the role of H2O2 as a second messenger involved in the regulation of many signaling pathways it is hardly surprising that compounds that can generate intracellular H2O2 by enzyme mediated redox cycling would have pleiotropic effects. RCCs can therefore have serious negative consequences for the probe and/or lead generation process: primary HTS assay hit rates may be inflated by RCC false positives; crucial resources will be diverted to develop and implement follow up assays to distinguish RCCs from real hits; and screening databases will become annotated with the promiscuous activity of RCCs. In an attempt to mitigate the serious impact of RCCs on probe and lead generation, two groups have independently developed assays to indentify RCCs. © 2010 Elsevier Ltd.


Hurwitz D.J.,University of Pittsburgh
Plastic and Reconstructive Surgery | Year: 2014

Background: Aesthetic refinements in body contouring surgery after massive weight loss are evolving in an effort to improve patient appearance. This is a personal clinical review for the trunk. Methods: There are 10 essential elements to performing body contouring surgery after massive weight loss. Based on this generally accepted baseline, the author presents 16 outstanding aesthetic refinements. These reliable and safe adaptations to improve outcomes were assembled from a personal case review of the past 12 years of over 500 cases. The refinements are the result of lectures attended, literature read, and innovations tried. Gender enhancement is emphasized. Plastic surgeons improve female shape through artful management of adipose deposits. Surgeons enhance male muscularity through an abdominoplasty and a series of large opposing ellipses for skin tightening across the entire torso. Results: These 16 refinements have been applied to the trunk. Four representative cases with preoperative markings and late postoperative results demonstrate the value of these aesthetic refinements. The accompanying video that demonstrates drawing the boomerang pattern correction of gynecomastia with J torsoplasty reveals many of these refinements. Conclusions: These aesthetic refinements are previously published anecdotal evidence that are presented together as part of the author's routine clinical experience. They await confirmatory experience or, better yet, rigorous scientific study. Until then, these are practical adaptations routinely used by the author on the trunk that merit the reader's consideration. Copyright © 2014 by the American Society of Plastic Surgeons.


Sayette M.A.,University of Pittsburgh | Tiffany S.T.,State University of New York at Buffalo
Addiction | Year: 2013

Smoking cue-exposure research has provided a powerful tool for examining cravings in the laboratory. A key attraction of this method is that tightly controlled experimental procedures can model craving experiences that are presumed to relate to addiction. Despite its appeal, key assumptions underlying the clinical relevance of smoking cue-reactivity studies have been questioned recently. For both conceptual and methodological reasons it may be difficult to tease apart cue-based and abstinence-based cravings. Moreover, conventional cue-reactivity procedures typically generate levels of craving with only minimal clinical relevance. We argue here that sometimes it is unfeasible-and in some instances conceptually misguided-to disentangle abstinence-based and cued components of cigarette cravings. In light of the challenges associated with cue-reactivity research, we offer an alternative approach to smoking cue-exposure experimental research focusing on peak provoked craving (PPC) states. The PPC approach uses nicotine-deprived smokers and focuses on urges during smoking cue-exposure without subtracting out urge ratings during control cue or baseline assessments. This design relies on two factors found in many cue-exposure studies-nicotine deprivation and exposure to explicit smoking cues-which, when combined, can create powerful craving states. The PPC approach retains key aspects of the cue-exposure method, and in many circumstances may be a viable design for studies examining robust laboratory-induced cravings. © 2012 Society for the Study of Addiction.


Marsland A.L.,University of Pittsburgh
Psychosomatic Medicine | Year: 2013

It has been suggested that childhood adversity programs an inflammatory phenotype characterized by higher levels of systemic inflammation and increased health risk in later life. If this is the case, one might expect associations of early childhood adversity with elevated levels of circulating inflammatory molecules in adolescence. To date, evidence for this association is mixed. This issue of Psychosomatic Medicine includes two studies by Pietras and Goodman and Low et al. that extend the existing literature and provide initial evidence that coping styles and perceived social standing may buffer against the impact of adversity on inflammation among adolescents. The current commentary considers these interesting findings in the context of the existing literature and discusses a critical need for longitudinal studies examining whether individual risk and resilience factors moderate the long-term health effects of childhood adversity, possibly via early programming of inflammatory pathways. Copyright © 2013 by the American Psychosomatic Society.


Lotrich F.E.,University of Pittsburgh
Psychiatric Clinics of North America | Year: 2011

In older adults, several environmental challenges can potentially trigger the onset of an episode of major depression. Vulnerability to these challenges can be influenced by genetics. There is accumulating evidence for an interaction between stress and a serotonin transporter polymorphism, though there is also heterogeneity among studies. Other relevant genes include those encoding for the neuroendocrine stress axis, growth factors, and other monoaminergic systems. Each of these may interact with either predisposing traumas in early childhood or precipitating events later in life. © 2011 Elsevier Inc.


Germain A.,University of Pittsburgh
American Journal of Psychiatry | Year: 2013

The hypothesis that rapid eye movement (REM) sleep disturbances are the hallmark of posttraumatic stress disorder (PTSD), proposed by Ross and colleagues in 1989, has stimulated a wealth of clinical, preclinical, and animal studies on the role of sleep in the pathophysiology of PTSD. The present review revisits this influential hypothesis in light of clinical and experimental findings that have since accumulated. Polysomnographic studies conducted in adults with PTSD have yieldedmixed findings regarding REM sleep disturbances, and they generally suggest modest and nonspecific sleep disruptions. Prospective and treatment studies have providedmore robust evidence for the relationship between sleep disturbances and psychiatric outcomes and symptoms. Experimental animal and human studies that have probed the relationship between REM sleep and fear responses, as well as studies focused more broadly on sleepdependent affective and memory processes, also provide strong support for the hypothesis that sleep plays an important role in PTSD-relevant processes. Overall, the literature suggests that disturbed REM or non-REM sleep can contribute to maladaptive stress and trauma responses and may constitute a modifiable risk factor for poor psychiatric outcomes. Clinicians need to consider that the chronic sleep disruption associated with nightmares may affect the efficacy of first-line PTSD treatments, but targeted sleep treatments may accelerate recovery from PTSD. The field is ripe for prospective and longitudinal studies in highrisk groups to clarify how changes in sleep physiology and neurobiology contribute to increased risk of poor psychiatric outcomes.


Tarhini A.A.,University of Pittsburgh
Immunotherapy | Year: 2013

Tremelimumab is an investigational, fully human IgG2 monoclonal antibody directed against CTLA-4, a coinhibitory receptor that represses effector T-cell activity in cancer. Tremelimumab has produced promising anticancer responses in early clinical trials. However, a Phase III trial of tremelimumab monotherapy versus chemotherapy in advanced melanoma was stopped early when no statistically significant difference in overall survival was observed between the two interventions. This article describes tremelimumab's putative mechanism of action, its preclinical pharmacology and clinical results to date across a range of cancer settings as monotherapy, as well as in combination with other therapies. The failure of the Phase III trial in melanoma is examined and factors affecting the possible future clinical development of tremelimumab are also explored. © 2013 Future Medicine Ltd.


Whitcomb D.C.,University of Pittsburgh
Gastroenterology | Year: 2013

A combination of genetic, environmental, and metabolic factors contribute to the development and recurrence of acute and chronic pancreatitis; information on all of these is required to manage patients effectively. For example, variants that affect regulation of the protease, serine (PRSS)1-PRSS2, and claudin (CLDN)2 loci, rather than their coding sequences, interact with other genetic and environmental factors to affect disease development. New strategies are needed to use these data and determine their contribution to pathogenesis, because these variants differ from previously studied, rare variants in exons (coding regions) of genes such as PRSS1, SPINK1, cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin (CTR)C, and calcium-sensing receptor (CASR). Learning how various genetic factors affect pancreatic cells and systems could lead to etiology-based therapies rather than treatment of symptoms. © 2013 by the AGA Institute.


Grabowski P.,University of Pittsburgh
Current Opinion in Genetics and Development | Year: 2011

The spatial and temporal control of alternative splicing is a major mechanism used to generate proteomic diversity in the brain. Microarray and Next Generation Sequencing approaches reveal mechanistic insights about networks of tissue-specific RNA binding proteins and micro RNAs that coordinate suites of alternative splicing patterns during neuronal differentiation. In the context of large-scale changes, one alternative splicing switch during embryonic brain development is crucial for neuronal migration and the laminar organization of the cerebral cortex. A major challenge to understand alternative splicing at the systems level is now being approached by the design of integrative modeling approaches that predict the combinatorial control of brain-specific exons. © 2011 Elsevier Ltd.


Alpha-1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children. The primary pathological issue is a point mutation that renders an abundant hepatic secretory glycoprotein prone to altered folding and a tendency to polymerize and aggregate. However, the expression of serious liver damage among homozygotes is dependent on genetic andor environmental modifiers. Several studies have validated the concept that endogenous hepatic pathways for disposal of aggregation-prone proteins, including the proteasomal and autophagic degradative pathways, could play a key role in the variation in hepatic damage and be the target of the modifiers. Exciting recent results have shown that a drug that enhances autophagy can reduce the hepatic load of aggregated protein and reverse fibrosis in a mouse model of this disease. © 2011 by Annual Reviews. All rights reserved.


Klunk W.E.,University of Pittsburgh
Neurobiology of Aging | Year: 2011

Since the introduction of amyloid imaging nearly 10 years ago, this technique has gained widespread use and acceptance. More recently, published reports have begun to appear in which amyloid imaging is used to detect the effects of antiamyloid therapies. This review will consider the issues involved in the use of amyloid imaging in the development and evaluation of drugs for the treatment of Alzheimer's disease. Current evidence regarding the postmortem correlates of in vivo amyloid imaging data are considered. The application of amyloid imaging to screening subjects for trials and use as an outcome measure is discussed in light of longitudinal changes in the in vivo amyloid signal. While the bulk of this review is directed at symptomatic patients with dementia, consideration is given to the use of amyloid imaging in nondemented subjects as well. Similarities and differences of cerebral amyloid assessment by amyloid imaging and cerebrospinal fluid (CSF) measurements are delineated and an agenda for further research to improve the applicability of amyloid positron emission tomography (PET) to clinical trials is proposed. © 2011 Elsevier Inc.


Berg W.A.,University of Pittsburgh | Mendelson E.B.,Northwestern University
Radiology | Year: 2014

Breast density-inform legislation is increasing the need for data on outcomes of tailored screening. Dense parenchyma can mask cancers, and denser tissue is also more likely to develop breast cancer than fatty tissue. Digital mammography is standard for women with dense breasts. Supplemental screening magnetic resonance imaging should be offered to women who meet high-risk criteria. Supplemental screening ultrasonographic (US) imaging may be appropriate in the much larger group of women with dense breasts. Both physician- and technologist-performed screening US imaging increases detection of node-negative invasive breast cancer. To meet anticipated demand in the United States, screening US images will most likely be acquired by trained technologists rather than physicians. While automated US offers standard documentation, there are few data on outcomes. US has been used diagnostically for decades to characterize masses seen by using mammography, but training specific to screening has been lacking. Standard approaches to training and documentation of technologist-performed handheld screening US imaging are needed. This article reviews the current status of technologist-performed handheld screening breast US imaging. © RSNA, 2014.


Smith A.M.,University of Pittsburgh
BMC bioinformatics | Year: 2012

Rule-based modeling (RBM) is a powerful and increasingly popular approach to modeling cell signaling networks. However, novel visual tools are needed in order to make RBM accessible to a broad range of users, to make specification of models less error prone, and to improve workflows. We introduce RuleBender, a novel visualization system for the integrated visualization, modeling and simulation of rule-based intracellular biochemistry. We present the user requirements, visual paradigms, algorithms and design decisions behind RuleBender, with emphasis on visual global/local model exploration and integrated execution of simulations. The support of RBM creation, debugging, and interactive visualization expedites the RBM learning process and reduces model construction time; while built-in model simulation and results with multiple linked views streamline the execution and analysis of newly created models and generated networks. RuleBender has been adopted as both an educational and a research tool and is available as a free open source tool at http://www.rulebender.org. A development cycle that includes close interaction with expert users allows RuleBender to better serve the needs of the systems biology community.


Leptin is secreted primarily by fat cells and acts centrally, particularly in the hypothalamus, to reduce food intake and body weight. Besides the classical JAK2 (Janus kinase-2)-STAT3 (signal transducer and activator of transcription-3) pathway, several non-STAT3 pathways play an important role in mediating leptin signaling in the hypothalamus. We have demonstrated that leptin action in the hypothalamus is mediated by an insulin-like signaling pathway involving stimulation of PI3K (phosphatidylinositol-3 kinase) and PDE3B (phosphodiesterase-3B), and reduction in cAMP levels, and that a PI3K-PDE3B-cAMP pathway interacting with the JAK2-STAT3 pathway constitutes a critical component of leptin signaling in the hypothalamus. It appears that defective regulation of multiple signaling pathways in the hypothalamus causes central leptin resistance, a major cause of obesity. In this regard, we have shown that leptin resistance in hypothalamic neurons following chronic central infusion of this hormone is associated with a defect in the PI3KPDE3B-cAMP, and not due to compromised signaling in the JAK2-STAT3 pathway. Similarly, the PI3K, but not the STAT3, pathway is impaired in the hypothalamus during the development of diet-induced obesity. Additionally, our recent work suggests that suppressor of cytokine signaling-3 negatively regulates the PI3K pathway of leptin signaling in the hypothalamus, a mechanism expected to play a significant role in diet-induced obesity. Together, the PI3K-PDE3B-cAMP pathway appears to emerge as a major mechanism of leptin signaling in the hypothalamus in regulating energy balance. © 2011 S. Karger AG, Basel.


Duquesnoy R.J.,University of Pittsburgh
International Journal of Immunogenetics | Year: 2012

Antibodies to HLA mismatches are specific for epitopes rather than antigens. HLAMatchmaker considers each HLA antigen as a string of eplets that represent key elements of epitopes. Certain antibodies are specific for single eplets, but recent studies have demonstrated that epitopes defined by eplet pairs always involve one nonself-eplet and a self-eplet shared between the immunizing antigen and the antibody producer. This suggests an autoreactive component of the alloantibody response to an HLA mismatch and this report expands this concept. During B-cell development, V H and V L gene rearrangements produce a diversity of Ig receptors that can recognize epitopes on autologous proteins. It is hypothesized that B cells carry low-affinity receptors for self-HLA antigens. Their interactions with self-HLA proteins will not lead to B-cell activation or antibody production. In contrast, exposure to HLA mismatches induces often strong alloantibody responses. The activation of self-HLA-specific B cell by a nonself-eplet may require that the remainder of the structural epitope of the immunizing antigen has considerable structural similarity with one of the antibody producer's alleles. This hypothesis has been tested in molecular modelling studies with six epitopes defined by human monoclonal antibodies. In each case, one allele of the antibody producer had no or few differences with the immunizing allele in antibody-accessible positions defined by a 15Ångstrom radius of the mismatched eplet. The other alleles of the antibody producer showed significantly greater numbers of residue differences with the immunizer (5.8±2.0 versus 1.0±0.6, P<0.0001). These data support the concept that HLA antibodies originate from B cells with self-HLA immunoglobulin receptors that recognize mismatched eplets as nonself entities on immunizing antigens. The nonself-self paradigm provides a new insight of HLA epitope immunogenicity and may explain why sensitized patients have antibodies to a restricted number of mismatched epitopes. © 2011 Blackwell Publishing Ltd.


Bates C.M.,University of Pittsburgh
American Journal of Physiology - Renal Physiology | Year: 2011

Fibroblast growth factor receptors (Fgfrs) consist of four signaling family members and one nonsignaling "decoy" receptor, Fgfr-like 1 (Fgfrl1), all of which are expressed in the developing kidney. Several studies have shown that exogenous fibroblast growth factors (Fgfs) affect growth and maturation of the metanephric mesenchyme (MM) and ureteric bud (UB) in cultured tissues. Transgenic and conditional knockout approaches in whole animals have shown that Fgfr1 and Fgfr2 (predominantly the IIIc isoform) in kidney mesenchyme are critical for early MM and UB formation. Conditional deletion of the ligand, Fgf8, in nephron precursors or global deletion of Fgfrl1 interrupts nephron formation. Fgfr2 (likely the IIIb isoform signaling downstream of Fgf7 and Fgf10) is critical for ureteric morphogenesis. Moreover, Fgfr2 appears to act independently of Frs2α (the major signaling adapter for Fgfrs) in regulating UB branching. Loss of Fgfr2 in the MM leads to many kidney and urinary tract anomalies, including vesicoureteral reflux. Thus Fgfr signaling is critical for patterning of virtually all renal lineages at early and later stages of development. © 2011 the American Physiological Society.


Raje N.,Massachusetts General Hospital | Raje N.,Harvard University | Roodman G.D.,University of Pittsburgh
Clinical Cancer Research | Year: 2011

Osteolytic bone disease is pathognomonic of multiple myeloma (MM) and affects more than 80% of patients. Bone disease results in skeletal-related events (SRE) such as vertebral compression fractures, which may cause cord compression, hypercalcemia, pathologic fractures that require radiation or surgical fixation, and severe pain. All of these not only result in a negative impact on quality of life but also adversely impact overall survival. Osteolytic disease is a consequence of increased osteoclast (OC) activation along with osteoblast (OB) inhibition, resulting in altered bone remodeling. OC number and activity are increased in MM via cytokine deregulation within the bone marrow (BM) milieu, whereas negative regulators of OB differentiation suppress bone formation. Bisphosphonates are a well-established treatment of myeloma-related skeletal disease and are the current standard of care. However, complications arising from their long-term use have prompted studies of schedule optimization and alternate strategies. Several novel agents are currently under investigation for their positive effect on bone remodeling via OC inhibition. The identification of negative regulators of OB differentiation has prompted the use of anabolic agents. In addition to restoring bone remodeling, these drugs may inhibit tumor growth in vivo. Future studies will look to combine or sequence all of these agents with the goal of not only alleviating morbidity from bone disease but also capitalizing on the resultant antitumor activity. ©2011 AACR.


Benedek T.G.,University of Pittsburgh
Clinical and Experimental Rheumatology | Year: 2010

The history of the rheumatologic use of methotrexate until the 1990s will be reviewed, beginning with its pharmacology, with the focus on rheumatoid arthritis (RA). The insufficient availability of cortisone in the 1950s as well as the early recognition of its potential toxicity stimulated searches for alternative anti-inflammatory drugs. Two related derivatives of folic acid, aminopterin and amethopterin (MTX,) were found to give rapid symptomatic relief in cases of psoriasis vulgaris and psoriatic arthritis. For several years MTX was used primarily to treat psoriasis, and the dermatologic treatment protocols came to be used by rheumatologists. Giving MTX weekly rather than daily was found to diminish the risk of toxic effects. MTX became favoured over cyclophosphamide because of its lack of carcinogenicity, and although azathioprine lacked the hepatotoxicity of MTX, its anti-rheumatic effects were considered to be somewhat weaker. Although trials of MTX for the treatment of severe RA began in the 1960s, the first placebo-controlled study of MTX in RA was reported in 1985 and a comparison with Myochrysine in 1987. MTX has replaced gold compounds because it has been found to be more rapidly effective and better tolerated. The mechanisms of its anti-rheumatic effects remain incompletely explained, as are explanations of instances of its failure. Its recent use in combination with anti-TNFα agents appears to be another therapeutic advance. © Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2010.


Redner R.L.,University of Pittsburgh
Clinical Cancer Research | Year: 2013

Addition of retinoic acid to chemotherapy improves survival of patients with acute myeloid leukemia. This effect is more pronounced in leukemias that express high levels of PRAME. PRAME is an inhibitor of retinoic acid signaling, which may prove to be an important marker for retinoic acid response. ©2013 AACR.


Whitcomb D.C.,University of Pittsburgh
Current Opinion in Gastroenterology | Year: 2012

PURPOSE OF REVIEW: To provide an expert review and expert perspective on important advances related to the genetics of acute and chronic pancreatitis. RECENT FINDINGS: Provocative new studies highlight the interplay between genetic, developmental, and environmental factors. Key findings include the relationship between pancreas divisum and CFTR mutations, the role of trypsin in acute and recurrent acute pancreatitis, and the discovery of a pancreatitis modifier gene on the X chromosome that provides new clues to why the vast majority of patients with alcoholic pancreatitis are men. SUMMARY: Pancreatic genetics is complex, linked to the multiplicative and modifying effects of multiple interacting genetic, structural, and environmental factors. Clinical interpretation will require disease modeling and simulation to understand the combined effect of risk factors that alone are neither sufficient nor necessary to cause disease, and to design treatment strategies that prevent the development of advanced chronic pancreatitis - which by definition is irreversible. Copyright © Lippincott Williams & Wilkins.


Sharon I.,University of California at Berkeley | Morowitz M.J.,University of Pittsburgh | Thomas B.C.,University of California at Berkeley | Costello E.K.,Stanford University | And 2 more authors.
Genome Research | Year: 2013

The gastrointestinal microbiome undergoes shifts in species and strain abundances, yet dynamics involving closely related microorganisms remain largely unknown because most methods cannot resolve them. We developed new metagenomic methods and utilized them to track species and strain level variations in microbial communities in 11 fecal samples collected from a premature infant during the first month of life. Ninety six percent of the sequencing reads were assembled into scaffolds of >500 bp in length that could be assigned to organisms at the strain level. Six essentially complete (∼99%) and two near-complete genomes were assembled for bacteria that comprised as little as 1% of the community, as well as nine partial genomes of bacteria representing as little as 0.05%. In addition, three viral genomes were assembled and assigned to their hosts. The relative abundance of three Staphylococcus epidermidis strains, as well as three phages that infect them, changed dramatically over time. Genes possibly related to these shifts include those for resistance to antibiotics, heavy metals, and phage. At the species level, we observed the decline of an early-colonizing Propionibacterium acnes strain similar to SK137 and the proliferation of novel Propionibacterium and Peptoniphilus species late in colonization. The Propionibacterium species differed in their ability to metabolize carbon compounds such as inositol and sialic acid, indicating that shifts in species composition likely impact the metabolic potential of the community. These results highlight the benefit of reconstructing complete genomes from metagenomic data and demonstrate methods for achieving this goal.


Mcgowan I.,University of Pittsburgh
American Journal of Reproductive Immunology | Year: 2014

Despite improvements in access to antiretroviral therapy and the use of simplified dosing regimens, HIV infection is still an important global public health problem. As a consequence, significant research efforts have been focused on the development of strategies to prevent the acquisition of HIV infection. These efforts have begun to produce results. The HPTN-052 study demonstrated the effectiveness of treating infected individuals as a means to prevent onward transmission of HIV infection. In addition, Phase 2B/3 studies have shown that the use of oral and topical antiretroviral pre-exposure prophylaxis (PrEP) can significantly reduce the acquisition of HIV infection in serodiscordant couples, young women in sub-Saharan Africa, men who have sex with men, and intravenous drug users. Despite these successes, challenges remain. Adherence to daily PrEP is variable, and some large studies have failed to demonstrate the effectiveness of PrEP in reducing HIV acquisition. Novel PrEP technologies, including sustained delivery intravaginal rings and long-acting injectable products, are being developed to try and circumvent adherence problems associated with daily PrEP regimens. The purpose of this article is to briefly summarize recent progress in the development of antiretroviral PrEP. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Davis P.L.,University of Pittsburgh
American Journal of Roentgenology | Year: 2015

OBJECTIVE. Anaphylactoidlike reactions occur during the nonvascular administration of iodinated contrast media. Many of these reactions have been severe. These reactions have occurred with many procedures, including gastrointestinal imaging, cystography, sialography, and hysterosalpingography. CONCLUSION. This article reviews reports of these reactions. It also reviews what the literature recommends concerning how to deal with individuals undergoing these procedures who are at a higher risk for anaphylactoidlike reactions. © American Roentgen Ray Society.


Lundberg J.O.,Karolinska Institutet | Gladwin M.T.,University of Pittsburgh | Weitzberg E.,Karolinska Institutet
Nature Reviews Drug Discovery | Year: 2015

Nitric oxide (NO) is a key signalling molecule in the cardiovascular, immune and central nervous systems, and crucial steps in the regulation of NO bioavailability in health and disease are well characterized. Although early approaches to therapeutically modulate NO bioavailability failed in clinical trials, an enhanced understanding of fundamental subcellular signalling has enabled a range of novel therapeutic approaches to be identified. These include the identification of: new pathways for enhancing NO synthase activity; ways to amplify the nitrate-nitrite-NO pathway; novel classes of NO-donating drugs; drugs that limit NO metabolism through effects on reactive oxygen species; and ways to modulate downstream phosphodiesterases and soluble guanylyl cyclases. In this Review, we discuss these latest developments, with a focus on cardiovascular disease. © 2015 Macmillan Publishers Limited. All rights reserved.


Monga S.P.,University of Pittsburgh
Gastroenterology | Year: 2015

β-catenin (encoded by CTNNB1) is a subunit of the cell surface cadherin protein complex that acts as an intracellular signal transducer in the WNT signaling pathway; alterations in its activity have been associated with the development of hepatocellular carcinoma and other liver diseases. Other than WNT, additional signaling pathways also can converge at β-catenin. β-catenin also interacts with transcription factors such as T-cell factor, forkhead box protein O, and hypoxia inducible factor 1α to regulate the expression of target genes. We discuss the role of β-catenin in metabolic zonation of the adult liver. β-catenin also regulates the expression of genes that control metabolism of glucose, nutrients, and xenobiotics; alterations in its activity may contribute to the pathogenesis of nonalcoholic steatohepatitis. Alterations in β-catenin signaling may lead to activation of hepatic stellate cells, which is required for fibrosis. Many hepatic tumors such as hepatocellular adenomas, hepatocellular cancers, and hepatoblastomas have mutations in CTNNB1 that result in constitutive activation of β-catenin, so this molecule could be a therapeutic target. We discuss how alterations in β-catenin activity contribute to liver disease and how these might be used in diagnosis and prognosis, as well as in the development of therapeutics. © 2015 AGA Institute.


Pinsky M.R.,University of Pittsburgh
Critical Care Clinics | Year: 2015

Functional hemodynamic monitoring is the assessment of the dynamic interactions of hemodynamic variables in response to a defined perturbation. Recent interest in functional hemodynamic monitoring for the bedside assessment of cardiovascular insufficiency has heightened with the documentation of its accuracy in predicting volume responsiveness using a wide variety of monitoring devices, both invasive and noninvasive, and across multiple patient groups and clinical conditions. However, volume responsiveness, though important, reflects only part of the overall spectrum of functional physiologic variables that can be measured to define the physiologic state and monitor response to therapy. © 2015 Elsevier Inc.


Kim S.-G.,University of Pittsburgh | Ogawa S.,Tohoku Fukushi University | Ogawa S.,Gachon University
Journal of Cerebral Blood Flow and Metabolism | Year: 2012

After its discovery in 1990, blood oxygenation level-dependent (BOLD) contrast in functional magnetic resonance imaging (fMRI) has been widely used to map brain activation in humans and animals. Since fMRI relies on signal changes induced by neural activity, its signal source can be complex and is also dependent on imaging parameters and techniques. In this review, we identify and describe the origins of BOLD fMRI signals, including the topics of (1) effects of spin density, volume fraction, inflow, perfusion, and susceptibility as potential contributors to BOLD fMRI, (2) intravascular and extravascular contributions to conventional gradient-echo and spin-echo BOLD fMRI, (3) spatial specificity of hemodynamic-based fMRI related to vascular architecture and intrinsic hemodynamic responses, (4) BOLD signal contributions from functional changes in cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of O 2 utilization (CMRO 2), (5) dynamic responses of BOLD, CBF, CMRO 2, and arterial and venous CBV, (6) potential sources of initial BOLD dips, poststimulus BOLD undershoots, and prolonged negative BOLD fMRI signals, (7) dependence of stimulus-evoked BOLD signals on baseline physiology, and (8) basis of resting-state BOLD fluctuations. These discussions are highly relevant to interpreting BOLD fMRI signals as physiological means. © 2012 ISCBFM All rights reserved.


Whitcomb D.C.,University of Pittsburgh
Nature Reviews Gastroenterology and Hepatology | Year: 2012

Personalized medicine is a new framework for medical care that involves modelling and simulation of a disease on the basis of its underlying mechanisms. This strategy must replace the 20 th century paradigm of defining disease by pathology or associated signs and symptoms and conducting outcomes research that is based on the presence or absence of the disease syndrome. New technologies, including next-generation sequencing, the 'omics' and powerful computers provide massive amounts of accurate data. However, attempts to understand complex disorders by applying these new technologies within the 20th century framework have failed to produce the expected medical advances. To help physicians embrace a paradigm shift, the limitations of the old framework and major advantages of the new framework must be demonstrated. Chronic pancreatitis is an ideal complex disorder to study to consider the pros and cons of the two frameworks, because the pancreas is such a simple organ for disease modelling, and the advantages of personalized medicine are so profound. © 2012 Macmillan Publishers Limited. All rights reserved.


Sun W.,University of Pittsburgh
Journal of Hematology and Oncology | Year: 2012

The diverse pathways and molecules involved in angiogenesis, the formation of new blood vessels, have been targeted for the treatment of colorectal and other cancers. Vascular endothelial growth factor (VEGF)-A binding to VEGF receptor (VEGFR)-2 is believed to be the key signaling pathway mediating angiogenesis. Other VEGF pathways involved in angiogenesis include VEGF-A, VEGF-B, and placental growth factor binding to VEGFR-1, and VEGF-C and VEGF-D binding to VEGFR-2 and VEGFR-3. VEGF signaling also intersects with other pathways, including angiopoietin/Tie, Notch, hypoxia-inducible factor, and integrin pathways. The roles of these pathways in tumor angiogenesis and in various human cancers will be explored in this article. In addition, preclinical and clinical data on bevacizumab, aflibercept (known as ziv-aflibercept in the US), and investigational antiangiogenic agents in development for the treatment of colorectal and other cancers will be reviewed. © 2012 Sun; licensee BioMed Central Ltd.


Gremillion K.J.,Ohio State University | Barton L.,University of Pittsburgh | Piperno D.R.,Smithsonian Institution | Piperno D.R.,Smithsonian Tropical Research Institute
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

The introduction of new analytic methods and expansion of research into previously untapped regions have greatly increased the scale and resolution of data relevant to the origins of agriculture (OA). As a result, the recognition of varied historical pathways to agriculture and the continuum of management strategies have complicated the search for general explanations for the transition to food production. In this environment, higher-level theoretical frameworks are sometimes rejected on the grounds that they force conclusions that are incompatible with real-world variability. Some of those who take this position argue instead that OA should be explained in terms of local and historically contingent factors. This retreat from theory in favor of particularism is based on the faulty beliefs that complex phenomena such as agricultural origins demand equally complex explanations and that explanation is possible in the absence of theoretically based assumptions. The same scholars who are suspicious of generalization are reluctant to embrace evolutionary approaches to human behavior on the grounds that they are ahistorical, overly simplistic, and dismissive of agency and intent.We argue that these criticisms are misplaced and explain why a coherent theory of human behavior that acknowledges its evolutionary history is essential to advancing understanding of OA. Continued progress depends on the integration of human behavior and culture into the emerging synthesis of evolutionary developmental biology that informs contemporary research into plant and animal domestication.