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The University of Pennsylvania is a private, Ivy League, research university located in Philadelphia. Incorporated as The Trustees of the University of Pennsylvania, Penn is one of 14 founding members of the Association of American Universities and one of the nine original Colonial Colleges.Benjamin Franklin, , Penn's founder, advocated an educational program that focused as much on practical education for commerce and public service as on the classics and theology. The university coat of arms features a dolphin on the red chief, adopted directly from the Franklin family's own coat of arms. Penn was one of the first academic institutions to follow a multidisciplinary model pioneered by several European universities, concentrating multiple "faculties" into one institution. It was also home to many other educational innovations. The first school of medicine in North America , the first collegiate business school and the first "student union" building and organization, were all born at Penn.Penn offers a broad range of academic departments, an extensive research enterprise and a number of community outreach and public service programs. It is particularly well known for its medical school, dental school, design school, school of business, law school, engineering school, communications school, nursing school, veterinary school, its social science and humanities programs, as well as its biomedical teaching and research capabilities. Its undergraduate program is also among the most selective in the country, with an acceptance rate of under 10 percent. One of Penn's most well known academic qualities is its emphasis on interdisciplinary education, which it promotes through numerous joint degree programs, research centers and professorships, a unified campus, and the ability for students to take classes from any of Penn's schools .All of Penn's schools exhibit very high research activity. Penn is consistently ranked among the top research universities in the world, for both quality and quantity of research. In fiscal year 2011, Penn topped the Ivy League in academic research spending with an $814 million budget, involving some 4,000 faculty, 1,100 postdoctoral fellows and 5,400 support staff/graduate assistants. As one of the most active and prolific research institutions, Penn is associated with several important innovations and discoveries in many fields of science and the humanities. Among them are the first general purpose electronic computer , the rubella and hepatitis B vaccines, Retin-A, cognitive therapy, conjoint analysis and others.Penn's academic and research programs are led by a large and highly productive faculty. Nine Penn faculty members or graduates have won a Nobel Prize in the last ten years. Over its long history the university has also produced many distinguished alumni. These include twelve heads of state , three United States Supreme Court justices, and supreme court justices of other states, founders of technology companies, international law firms and global financial institutions, and university presidents. According to a 2014 study, the University of Pennsylvania has produced the most billionaires of any university at the undergraduate level. Wikipedia.

Kofke W.A.,University of Pennsylvania
Current Opinion in Anaesthesiology | Year: 2010

Purpose of review: Epilepsy is a clinical disorder of paroxysmal recurring seizures, the diagnosis excluding alcohol or drug withdrawal seizures or such recurring exogenous events as repeated insulin-induced hypoglycemia. Epilepsy has a profound impact on each individual diagnosed with this disease. Recent findings: New antiepileptic drugs (AEDs) have been a major change in the approach to management of patients with epilepsy. These drugs tend to have fewer significant drug interactions and less severe side effects. Nonetheless, first-generation AEDs are still widely used. Propofol and desflurane have reliable anticonvulsant effects, whereas remifentanil in larger doses and sevoflurane appear to support epileptiform activity, although the clinical significance of these observations is unclear. Summary: The primary concerns for providing anesthesia to the patient with epilepsy are the capacity of anesthetics to modulate or potentiate seizure activity and the interaction of anesthetic drugs with AEDs. Proconvulsant and anticonvulsant properties have been reported for virtually every anesthetic such that these properties become elements of the anesthetic plan in the patient with epilepsy. Moreover, AEDs have many physiologic and pharmacologic effects that can have an impact on an anesthetic. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Pignolo R.J.,University of Pennsylvania
Pediatric endocrinology reviews : PER | Year: 2013

Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition characterized by congenital malformations of the great toes and progressive heterotopic endochondral ossification (HEO) which is the most catastrophic of HEO disorders in humans. Flare-ups of FOP are episodic; immobility is cumulative. Heterozygous activating mutations in activin receptor IA/activin-like kinase-2 (ACVRI/ ALK2), a bone morphogenetic protein (BMP) type I receptor, exist in all sporadic and familial cases of FOP. The discovery of the FOP gene established a critical milestone in our understanding of FOP, and revealed a highly conserved therapeutic target in the BMP signaling pathway. This discovery has advanced efforts to develop novel therapies for this disabling disorder of tissue metamorphosis. While effective treatment of FOP will likely be based on interventions that modulate overactive ACVR1/ALK2 signaling, or that specifically block postnatal HEO, current management is focused on early diagnosis, assiduous avoidance of injury or iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function.

Teff K.L.,University of Pennsylvania
Physiology and Behavior | Year: 2010

The hormone, pancreatic polypeptide (PP) is postulated to be involved in body weight regulation. PP release is dependent on vagal activation and is a marker of vagal efferent activity. Because vagal activity plays a role in glucose homeostasis, elucidating the conditions of activation has important implications for nutrient metabolism. In humans, modified sham-feeding is known to elicit vagally-mediated hormonal responses. We present results of 3 studies in which healthy human subjects tasted various stimuli including sweet and salty liquids, unflavored and flavored gum and mixed nutrient foods flavored with either sweet or salt and rendered palatable or unpalatable. We examined the effects of these stimuli on PP levels relative to fasting. We found that liquids flavored with either glucose or salt, did not elicit an increase in PP levels greater than fasting. Similarly, chewing gum, whether unflavored or flavored with a non-nutritive sweetener or the sweetener paired with a mint flavor, did not significantly increase PP levels. In contrast, when subjects tasted mixed nutrient foods, these reliably elicited increases in PP levels at 4 min post-stimulus (sweet palatable, p < 0.002; sweet unpalatable, p < 0.001; salty, palatable, p < 0.05, salty unpalatable, p < 0.05). The magnitude of release was influenced by the flavor, i.e. a sweet palatable stimulus (320.1 ± 93.7 pg/ml/30 min) elicited the greatest increase in PP compared with a salty palatable stimulus (142.4 ± 88.7 pg/ml/30 min; p < 0.05). These data suggest that liquids and chewing gum do not provide adequate stimulation for vagal efferent activation in humans and that mixed nutrient foods are the optimal stimuli. © 2009 Elsevier Inc. All rights reserved.

Ribeiro A.,University of Pennsylvania
IEEE Transactions on Signal Processing | Year: 2010

Ergodic stochastic optimization (ESO) algorithms are proposed to solve resource allocation problems that involve a random state and where optimality criteria are expressed in terms of long term averages. A policy that observes the state and decides on a resource allocation is proposed and shown to almost surely satisfy problem constraints and optimality criteria. Salient features of ESO algorithms are that they do not require access to the state's probability distribution, that they can handle nonconvex constraints in the resource allocation variables, and that convergence to optimal operating points holds almost surely. The proposed algorithm is applied to determine operating points of an orthogonal frequency division multiplexing broadcast channel that maximize a given rate utility. © 2010 IEEE.

Accountable care organizations are intended to improve the quality and lower the cost of health care through several mechanisms, such as disease management programs, care coordination, and aligning financial incentives for hospitals and physicians. Providers employed several of these mechanisms in forming the integrated delivery networks of the 1990s. The networks failed, however, because of heavy financial losses stemming from hospitals' purchase of physician practices and their inability to align incentives, garner capitated contracts, and develop the infrastructure to manage risk. Although the current mechanisms underlying accountable care organizations continue to evolve, whether and how they will have an impact on quality and costs remains open to question. Care coordination and information technology are proving more complicated and expensive to implement than anticipated, providers may lack the ability to implement these mechanisms, and primary care providers are in short supply. As in the 1990s, success depends on targeting specific populations, such as people with multiple chronic conditions who need and may benefit from coordinated care. © 2012 Project HOPE-The People-to-People Health Foundation, Inc.

Karuthu S.,University of Pennsylvania
Clinical journal of the American Society of Nephrology : CJASN | Year: 2012

Infections are a major cause of morbidity and mortality in kidney transplant recipients. To some extent, these may be preventable. Careful pretransplant screening, immunization, and post-transplant prophylactic antimicrobials may all reduce the risk for post-transplant infection. However, because transplant recipients may not manifest typical signs and symptoms of infection, diagnoses may be confounded. Furthermore, treatment regimens may be complicated by drug interactions and the need to maintain immunosuppression to avoid allograft rejection. This article reviews common post-transplant infections, including prophylactic, diagnostic, and treatment strategies, providing guidance regarding care of kidney transplant patients with infection.

Wilson E.H.,University of California at Riverside | Weninger W.,Centenary Institute for Cancer Medicine and Cell Biology | Hunter C.A.,University of Pennsylvania
Journal of Clinical Investigation | Year: 2010

The CNS is an immune-privileged environment, yet the local control of multiple pathogens is dependent on the ability of immune cells to access and operate within this site. However, inflammation of the distinct anatomical sites (i.e., meninges, cerebrospinal fluid, and parenchyma) associated with the CNS can also be deleterious. Therefore, control of lymphocyte entry and migration within the brain is vital to regulate protective and pathological responses. In this review, several recent advances are highlighted that provide new insights into the processes that regulate leukocyte access to, and movement within, the brain.

Paiardini M.,University of Pennsylvania
Current Opinion in HIV and AIDS | Year: 2010

Purpose of review: To summarize our current understanding of the regulation of Th17 cells in pathogenic and nonpathogenic lentiviral infections. Recent findings: It has been shown that Th17 cells, a recently identified T helper-cell subset deemed critical for antimicrobial mucosal immunity, are preferentially depleted in the gastrointestinal tracts of human immunodeficiency virus (HIV)-infected humans and simian immunodeficiency virus (SIV)-infected rhesus and pigtailed (PTMs) macaques. In contrast, Th17 cells are preserved at healthy levels in monkey species that are natural hosts for SIV, such as sooty mangabeys or African green monkeys (AGMs), which maintain mucosal immunity and remain AIDS free. These findings suggest that preservation of Th17 cells (or lack thereof) may be central in determining the pathogenic or nonpathogenic outcome of HIV/SIV infection. Summary: A preferential depletion of mucosal Th17 cells is a feature that distinguishes pathogenic HIV infection of humans from nonprogressive SIV infection of sooty mangabeys and AGMs. The exact mechanism accounting for this different phenotype is still unclear. To understand how natural hosts for SIV preserve Th17 cells and mucosal immunity might be central to the development of therapeutic interventions aimed at improving mucosal immunity in HIV-infected individuals. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Schmidt H.,University of Pennsylvania
American Journal of Public Health | Year: 2012

Wellness incentives are an increasingly popular means of encouraging participation in prevention programs, but they may not benefit all groups equally. To assist those planning, conducting, and evaluating incentive programs, I describe the impact of incentives on 5 groups: the "lucky ones," the "yes-I-can" group, the "I'lldo- it-tomorrow" group, the "unlucky ones," and the "leave-me-alone" group. The 5 groups problem concerns the question of when disparities in the capacity to use incentive programs constitute unfairness and how policymakers ought to respond. I outline 4 policy options: to continue to offer incentives universally, to offer them universally but with modifications, to offer targeted rather than universal programs, and to abandon incentive programs altogether.

Dormans J.P.,University of Pennsylvania
Spine | Year: 2010

STUDY DESIGN.: Literature review. Objective.: This article presents a critical examination of standard of care (SOC) related to intraoperative neurophysiologic monitoring during spine surgery. Definition of SOC and its applications in the surgical setting is accompanied by discussions on SOC for neuromonitoring, credentialing of neuromonitoring personnel, off-site remote monitoring, and unattended surgeon-controlled neuromonitoring devices. Methods.: A literature review of neuromonitoring and SOC over the past 10 years was performed. This information, in conjunction with the author s experience and evidence-based medicine, was used to formulate a framework for critique and discussion. Conclusion.: An appropriate SOC as it relates to neuromonitoring is difficult to devise because of national variance with regard to qualifications of neurophysiologic technical and professional personnel, different levels of training and certification, and anesthesia protocols. A unified group of surgeons working in collaboration with a multidisciplinary group of experienced doctoral level nonphysician and physician professional surgical neurophysiologists is needed to define a protocol for providing and interpreting such data. In addition to ensuring that only the most qualified and experienced personnel are delivering and/or interpreting neuromonitoring services, surgeons, hospital administrators, and insurance company medical directors need to understand the different service delivery models and their respective strengths and limitations with particular attention to the qualifications and competencies of all respective parties. Only then can a well-defined SOC be established, thus improving the treatment of surgical patients for whom neuromonitoring is required. © 2010, Lippincott Williams & Wilkins.

Abella B.S.,University of Pennsylvania
Current Opinion in Critical Care | Year: 2013

Purpose of Review: Cardiopulmonary resuscitation (CPR) is a fundamental component of initial care for the victim of cardiac arrest. In the past few years, increasing quantitative evidence has demonstrated that survival from cardiac arrest is dependent on the quality of delivered CPR. This review will focus on this body of evidence and on a range of practical approaches to improving CPR performance. Recent Findings: A number of strategies to improve CPR quality have been evaluated recently, during both prehospital and in-hospital cardiac arrest care. These strategies have included the use of real-time CPR sensing and feedback, the employment of physiologic monitoring such as end-tidal CO2 measurement and the use of metronome prompting. The use of mechanical CPR devices to avoid the challenges of manual CPR performance has also represented a topic of great current interest. Additional approaches have focused on both prearrest training (e.g. high-fidelity simulation education and CPR refreshers) and postarrest training (e.g. debriefing). Summary: A number of strategies have been evaluated to improve CPR performance. While many questions remain surrounding the relative value of each approach, it is likely that combinations of these methods may be useful in a variety of care settings to improve care for cardiac arrest victims. Copyright © 2013 Wolters Kluwer Health.

Kamath A.F.,University of Pennsylvania
The bone & joint journal | Year: 2013

Patient safety is a critical issue in elective total joint replacement surgery. Identifying risk factors that might predict complications and intensive care unit (ICU) admission proves instrumental in reducing morbidity and mortality. The institution's experience with risk stratification and pre-operative ICU triage has resulted in a reduction in unplanned ICU admissions and post-operative complications after total hip replacement. The application of the prediction tools to total knee replacement has proven less robust so far. This work also reviews areas for future research in patient safety and cost containment.

Bonasio R.,University of Pennsylvania
Journal of Experimental Biology | Year: 2015

Epigenetics studies the emergence of different phenotypes from a single genotype. Although these processes are essential to cellular differentiation and transcriptional memory, they are also widely used in all branches of the tree of life by organisms that require plastic but stable adaptation to their physical and social environment. Because of the inherent flexibility of epigenetic regulation, a variety of biological phenomena can be traced back to evolutionary adaptations of few conserved molecular pathways that converge on chromatin. For these reasons chromatin biology and epigenetic research have a rich history of chasing discoveries in a variety of model organisms, including yeast, flies, plants and humans. Many more fascinating examples of epigenetic plasticity lie outside the realm of model organisms and have so far been only sporadically investigated at a molecular level; however, recent progress on sequencing technology and genome editing tools have begun to blur the lines between model and non-model organisms, opening numerous new avenues for investigation. Here, I review examples of epigenetic phenomena in non-model organisms that have emerged as potential experimental systems, including social insects, fish and flatworms, and are becoming accessible to molecular approaches. © 2015. Published by The Company of Biologists Ltd | The Journal of Experimental Biology.

Kim S.F.,University of Pennsylvania
Neuroscience | Year: 2012

Feeding is a fundamental process for basic survival and is influenced by genetics and environmental stressors. Recent advances in our understanding of behavioral genetics have provided a profound insight on several components regulating eating patterns. However, our understanding of eating disorders, such as anorexia nervosa, bulimia nervosa, and binge eating, is still poor. The animal model is an essential tool in the investigation of eating behaviors and their pathological forms, yet development of an appropriate animal model for eating disorders still remains challenging due to our limited knowledge and some of the more ambiguous clinical diagnostic measures. Therefore, this review will serve to focus on the basic clinical features of eating disorders and the current advances in animal models of eating disorders.This article is part of a Special Issue entitled: Neuroscience Disease Models. © 2012 IBRO.

Cuker A.,University of Pennsylvania
Seminars in Hematology | Year: 2010

The thrombopoietic growth factors (TGFs) are a novel class of compounds for the treatment of chronic immune thrombocytopenia (ITP). The first of these agents to receive regulatory approval, romiplostim and eltrombopag, have demonstrated impressive efficacy and tolerability in randomized controlled trials and open-label extension studies of several years duration and stand poised to revolutionize the management of ITP. Nonetheless, critical questions regarding the safety of these agents, particularly after long-term administration, remain partially unanswered. The objective of this review is to describe the reported and potential toxicities of the TGFs, including bone marrow fibrosis, thrombosis, rebound thrombocytopenia, hematologic malignancy, neutralizing antibody formation, hepatotoxicity, cataract formation, and common adverse events. The incidence and clinical implications of these toxicities as well as strategies for patient safety monitoring are examined. © 2010 Elsevier Inc.

Hajishengallis G.,University of Pennsylvania | Chavakis T.,TU Dresden
Trends in Immunology | Year: 2013

Leukocyte recruitment is a central immune process. Multiple factors have been described to promote leukocyte infiltration into inflamed tissues, but only recently has evidence for endogenous negative modulators of this inflammatory process emerged. The discovery of several locally produced modulators has emerged into a new field of endogenous inhibitors of leukocyte extravasation. Recent findings from several inflammatory disease models show that tissues can self-regulate the recruitment of inflammatory cells, suggesting that local tissues may have a greater 'regulatory say' over the immune response than previously appreciated. Here, we propose that locally produced modulators of leukocyte recruitment may represent local homeostatic mechanisms that tissues and organs may have evolved for protection against the destructive potential of the immune system. © 2012 Elsevier Ltd.

Cuker A.,University of Pennsylvania
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2010

Immune thrombocytopenia (ITP) comprises a heterogeneous group of disorders characterized by autoimmune-mediated platelet destruction and impairment of thrombopoiesis. ITP may occur in the absence of an evident predisposing etiology (primary ITP) or secondary to a growing list of associated conditions (secondary ITP), and must be differentiated from other causes of thrombocytopenia. This review focuses on primary ITP in adults. The traditional goal of therapy in this population is to achieve a hemostatic platelet count of 30×10(9)/L or above for most patients while minimizing treatment-related morbidity. This approach has been called into question by the recent advent of well-tolerated and effective agents for the management of ITP, including pulse-dose dexamethasone, rituximab, and the thrombopoietin receptor agonists. Recent studies suggest the potential for aggressive therapy at the time of diagnosis to alter the natural history of ITP and point to the importance of quality-of-life considerations in therapeutic decision making.

Seale P.,University of Pennsylvania
Diabetes | Year: 2015

Brown and beige adipose tissue is specialized for heat production and can be activated to reduce obesity and metabolic dysfunction in animals. Recent studies also have indicated that human brown fat activity levels correlate with leanness. This has revitalized interest in brown fat biology and has driven the discovery of many new regulators of brown fat development and function. This review summarizes recent advances in our understanding of the transcriptional mechanisms that control brown and beige fat cell development. © 2015 by the American Diabetes Association.

Plotkin S.,University of Pennsylvania
Medical Microbiology and Immunology | Year: 2015

Cytomegalovirus vaccine development started in the 1970s with attenuated strains. In the 1980s, one of the strains was shown to be safe and effective in renal transplant patients. Then, attention switched to glycoprotein gB, which was shown to give moderate but transient protection against acquisition of the virus by women. The identification of the pp65 tegument protein as the principal target of cellular immune responses resulted in new approaches, particularly DNA, plasmids to protect hematogenous stem cell recipients. The subsequent discovery of the pentameric protein complex that generates most neutralizing antibodies led to efforts to incorporate that complex into vaccines. At this point, there are many candidate CMV vaccines, including live recombinants, replication-defective virus, DNA plasmids, soluble pentameric proteins, peptides, virus-like particles and vectored envelope proteins. © 2015, Springer-Verlag Berlin Heidelberg.

Dang C.V.,University of Pennsylvania
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2015

The frequency of cancer is postulated to be proportional to the number of cells an animal possesses, as each cell is similarly exposed to mutagens with every cell division. Larger animals result from more cell divisions with more mutagenic exposure, and hence are expected to have higher frequencies of cancer. Yet, as stipulated by Peto’s paradox, larger animals do not have the higher rates of cancers seen in smaller animals despite the significant differences in cell numbers and a longer lifetime that would expose larger animals to more mutagens. The rates of cancer appear to be inversely proportional to animal body size, which scales inversely with specific metabolic rates of mammals. Studies over the past 20 years have linked oncogenes and tumour suppressors to alterations in cancer metabolism, and conversely, mutations in metabolic genes have been documented to trigger tumorigenesis. The by-products and intermediates of metabolism, such as reactive oxygen species, oxoglutarate, citrate and acetate, all have the potential to mutate and alter the genome or epigenome. On the basis of these general observations, it is proposed that metabolic rates correlate with mutagenic rates, which are higher in small animals and give the mechanistic basis for Peto’s paradox. The observations discussed in this overview collectively indicate that specific metabolic rate varies inversely with body size, which seems to support the hypothesis that metabolism drives tumorigenesis and accounts for Peto’s paradox. 2015 The Author(s) Published by the Royal Society. All rights reserved.

Pollack Jr. C.V.,University of Pennsylvania
Annals of Emergency Medicine | Year: 2011

Recent attention to the increasing incidence of venous thromboembolism has included a call to action from the surgeon general and new guidelines from various specialty organizations. The standard of care for treatment of deep venous thrombosis in the emergency department (ED), supported by the 2008 American College of Chest Physicians (ACCP) guidelines, involves initiation of anticoagulation with low-molecular-weight heparin, pentasaccharide, or unfractionated heparin. For selected appropriate patients with extensive acute proximal deep venous thrombosis, the ACCP guidelines now recommend thrombolysis in addition to anticoagulation to reduce not only the risk of pulmonary embolism but also the risk of subsequent postthrombotic syndrome and recurrent deep venous thrombosis. Postthrombotic syndrome is a potentially debilitating chronic cluster of lower-extremity symptoms occurring in 20% to 50% of deep venous thrombosis patients subsequent to the acute insult, sometimes not until years later. A strategy of early thrombus burden reduction or frank removal might reduce the incidence of postthrombotic syndrome, as per natural history studies, venous thrombectomy data, observations after systemic and catheter-directed thrombolysis, and the still-limited number of randomized trials of catheter-directed thrombolysis (with anticoagulation) versus anticoagulation alone. Contemporary invasive (endovascular) treatments mitigate the drawbacks historically associated with thrombolytic approaches by means of intrathrombus delivery of drugs with greater fibrin specificity and lower allergenicity, followed by mechanical dispersion to accelerate lysis and then aspiration of remaining drug and clot debris. With a 2016 target completion date, the National Heart, Lung, and Blood Institutesponsored Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis trial is comparing the safety and efficacy, in terms of both deep venous thrombosis and postthrombotic syndrome parameters, of the most evolved pharmacomechanical catheter-directed thrombolysis devices versus standard anticoagulation therapy alone. This article reviews the grounds for use of adjunctive thrombolysis in patients with acute proximal deep venous thrombosis and begins to identify types of deep venous thrombosis patients encountered in the ED who might benefit most from multidisciplinary consideration of early referral for possible endovascular therapy. © 2010 American College of Emergency Physicians.

The evolutionary origins of Ig-producing B cells appear to be linked to the emergence of fish in this planet. There are three major classes of living fish species, which from most primitive to modern they are referred to as agnathan (e.g., lampreys), Chondrichthyes (e.g., sharks), and teleost fish (e.g., rainbow trout). Agnathans do not have immunoglobulin- producing B cells, however these fish contain a subset of lymphocytes-like cells producing type B variable lymphocyte receptors (VLRBs) that appear to act as functional analogs of immunoglobulins. Chondrichthyes fish represent the most primitive living species containing bona-fide immunoglobulin-producing B cells. Their B cells are known to secrete three types of antibodies, IgM, IgW and IgNAR. Teleost fish are also called bony fish since they represent the most ancient living species containing true bones. Teleost B cells produce three different immunoglobulin isotypes, IgM, IgD and the recently described IgT. While teleost IgM is the principal player in systemic immunity, IgT appears to be a teleost immunoglobulin class specialized in mucosal immune responses. Thus far, three major B cell lineages have been described in teleost, those expressing either IgT or IgD, and the most common lineage which co-expresses IgD and IgM. A few years ago, the study of teleost fish B cells revealed for the first time in vertebrates the existence of B cell subsets with phagocytic and intracellular bactericidal capacities. This finding represented a paradigm shift as professional phagocytosis was believed to be exclusively performed by some cells of the myeloid lineage (i.e., macrophages, monocytes, neutrophils). This phagocytic capacity was also found in amphibians and reptiles, suggesting that this innate capacity was evolutionarily conserved in certain B cell subsets of vertebrates. Recently, the existence of subsets of B cells with phagocytic and bactericidal abilities have also been confirmed in mammals. Moreover, it has been shown that phagocytic B-1 B cells have a potent ability to present particulate antigen to CD4 +T cells. Thus, studies carried out originally on fish B cells have lead to the discovery of new innate and adaptive roles of B cells in mammals. This review will concentrate on the evolutionary and functional relationships of fish and mammalian B cells, focusing mainly on the newly discovered roles of these cells in phagocytosis, intracellular killing and presentation of particulate antigen. © 2012 Bentham Science Publishers.

Atchison M.L.,University of Pennsylvania
Frontiers in Immunology | Year: 2014

During B cell development, long-distance DNA interactions are needed for V(D)J somatic rearrangement of the immunoglobulin (Ig) loci to produce functional Ig genes, and for class switch recombination (CSR) needed for antibody maturation. The tissue-specificity and developmental timing of these mechanisms is a subject of active investigation. A small number of factors are implicated in controlling Ig locus long-distance interactions including Pax5, Yin Yang 1 (YY1), EZH2, IKAROS, CTCF, cohesin, and condensin proteins. Here we will focus on the role of YY1 in controlling these mechanisms. YY1 is a multifunctional transcription factor involved in transcriptional activation and repression, X chromosome inactivation, Polycomb Group (PcG) protein DNA recruitment, and recruitment of proteins required for epigenetic modifications (acetylation, deacetylation, methylation, ubiquitination, sumoylation, etc.). YY1 conditional knock-out indicated that YY1 is required for B cell development, at least in part, by controlling long-distance DNA interactions at the immunoglobulin heavy chain and Ig? loci. Our recent data show that YY1 is also required for CSR. The mechanisms implicated in YY1 control of long-distance DNA interactions include controlling non-coding antisense RNA transcripts, recruitment of PcG proteins to DNA, and interaction with complexes involved in long-distance DNA interactions including the cohesin and condensin complexes. Though common rearrangement mechanisms operate at all Ig loci, their distinct temporal activation along with the ubiquitous nature of YY1 poses challenges for determining the specific mechanisms of YY1 function in these processes, and their regulation at the tissue-specific and B cell stage-specific level. The large numbers of post-translational modifications that control YY1 functions are possible candidates for regulation. © 2014 Atchison.

Feldman E.A.,University of Pennsylvania
Journal of General Internal Medicine | Year: 2012

Survey data suggest that many people fear genetic discrimination by health insurers or employers. In fact, such discrimination has not yet been a significant problem. This article examines the fear and reality of genetic discrimination in the United States, describes how Congress sought to prohibit such discrimination by passing the Genetic Information Nondiscrimination Act of 2008 (GINA), and explores the implications of GINA for general internists and their institutions. It concludes that medical providers and health care institutions must be familiar with the general intent and specific terms of GINA, and should continue to collect genetic information that can contribute to the high quality provision of medical treatment. Not doing so violates their medical mission and diminishes the quality of care patients deserve. © 2011 Society of General Internal Medicine.

Fishbein L.,University of Pennsylvania
Hematology/Oncology Clinics of North America | Year: 2016

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare but unique neuroendocrine tumors. The hypersecretion of catecholamines from the tumors can be associated with high morbidity and mortality, even when tumors are benign. Up to 40% of PCCs/PGLs are associated with germline mutations in susceptibility genes. About one-quarter are malignant, defined by the presence of distant metastases. Treatment options for unresectable metastatic disease, including chemotherapy, 131I-MIBG, and radiation, can offer limited tumor and hormone control, although none are curative. This article reviews the inherited genetics, diagnosis, and treatment of PCCs and PGLs. © 2016 Elsevier Inc.

Voight B.F.,University of Pennsylvania | Cotsapas C.,Yale University
Current Opinion in Immunology | Year: 2012

In genetic studies of autoimmune and inflammatory diseases, one clear finding that has emerged from genome-wide association studies is that a substantial fraction of variation modifying risk in one disease also contributes mediate risk to multiple, additional autoimmune and inflammatory diseases. The unexpected magnitude of this overlap presents the unique opportunity to dissect the pathogenic mechanisms underlying multiple disease states in the expectation that this may lead to both more sensitive diagnostics and novel therapies. Here, we review the current evidence for this shared genetic architecture and, based on these data, outline models for shared pathways, the underlying hypotheses for them, how these models can be tested and validated. © 2012 Elsevier Ltd.

Langer C.J.,University of Pennsylvania
Critical Reviews in Oncology/Hematology | Year: 2012

Non-small cell lung cancer is the leading cause of cancer death in the United States. Efforts to improve outcomes have led to a greater understanding of the predictive and prognostic value of histologic and molecular characteristics of individual tumors. In standard practice, biopsy specimens are examined first on a histologic level, then on a molecular level with the recognition that both histologic subtype and gene expression profile can guide treatment decisions and have a profound effect on clinical outcomes. Epidermal growth factor activation mutations were among the first biomarkers shown to have therapeutic implications, and levels of gene expression for an array of other biomarkers are being evaluated in clinical trials. Ongoing studies underscore the need to implement molecular and histologic screening as part of routine clinical practice. To achieve an integration of clinical, histologic, and molecular parameters when making treatment decisions, collaboration between oncologists and pathologists is essential. © 2012.

Pyeritz R.E.,University of Pennsylvania
Genetics in Medicine | Year: 2012

The family history has its origins in genealogy and over the past century has become embedded in clinical practice. Its importance in specialized circumstances is unquestioned but largely untested. Moreover, the relevance of the family history to common diseases, especially in an era of genomic markers that convey risk and the emphasis on "personalized medicine", must be given careful scrutiny. Given the time and expertise needed to obtain and interpret the family history, without a clearer sense of clinical validity and utility, its role will likely diminish. The time to perform the requisite investigations is now. © 2012 American College of Medical Genetics.

Alu A.,University of Texas at Austin | Engheta N.,University of Pennsylvania
Physical Review Letters | Year: 2010

Near-field imaging is a well-established technique in biomedical measurements, since closer to the detail of interest it is possible to resolve subwavelength details otherwise unresolved by regular lenses. A near-field scanning optical microscope (NSOM) tip may indeed overcome the resolution limits of far-field optics, but its proximity inherently perturbs the measurement. Here, we apply the recent concept of a "cloaked sensor" to an NSOM device in collection mode, showing theoretically how a proper plasmonic cover applied to an NSOM tip may drastically improve its overall measurement capabilities. © 2010 The American Physical Society.

Bernstein J.,University of Pennsylvania
Journal of Bone and Joint Surgery - Series A | Year: 2011

Background: A recent randomized controlled trial compared early anterior cruciate ligament reconstruction with a program of initial rehabilitation, with delayed anterior cruciate ligament reconstruction if needed. The authors reported that the improvement in Knee Injury and Osteoarthritis Outcome Scores was nearly identical in both groups and concluded that in young, active adults with acute ACL (anterior cruciate ligament) tears, a strategy of rehabilitation plus early ACL reconstruction was not superior to a strategy of rehabilitation plus optional delayed ACL reconstruction. Yet, in making that assessment, the authors did not account for the fact that there were more meniscal injuries in the group with delayed anterior cruciate ligament surgery. Establishing the true superiority of one strategy requires consideration of meniscal injury, as well as a further determination if the apparent protective effect regarding meniscal tears found in the cohort of patients with early anterior cruciate ligament reconstruction is offset by the costs of additional reconstructive surgery. That analysis of offsetting utility, omitted in the randomized controlled trial noted above, is provided in the present study. Methods: A decision analysis model considering the options and probabilities described in the randomized controlled trial was constructed: the functional outcome of all groups was assumed to be equal, the likelihood of a patient eventually needing surgery despite initially choosing a program of rehabilitation was 37%, and the likelihood of needing a meniscectomy was 23% for the early surgery group and 35% for the rehabilitation and deferred anterior cruciate ligament reconstruction group. Results: The early surgery option is the preferable therapeutic approach as long as the costs of a potential meniscal tear are at least 5.25 times the costs of reconstructive surgery. Conclusions: Early surgery for anterior cruciate ligament tears may be the preferred approach for some patients, on the basis of the utility values they assign to the possible treatment outcomes. The reported randomized controlled trial did not establish a dominant strategy. Indeed, early surgery may be the more effective approach overall. Copyright © 2011 by The Journal of Bone and Joint Surgery, Incorporated.

Mack J.W.,Dana-Farber Cancer Institute | Joffe S.,University of Pennsylvania
Pediatrics | Year: 2014

Clinicians are sometimes reluctant to discuss prognosis with parents of children with life-threatening illness, usually because they worry about the emotional impact of this information. However, parents often want this prognostic information because it underpins informed decision-making, especially near the end of life. In addition, despite understandable clinician concerns about its emotional impact, prognostic disclosure can actually support hope and peace of mind among parents struggling to live with a child's illness. Children, too, may need to understand what is ahead to manage uncertainty and make plans for the ways their remaining life will be lived. In this article, we describe the ethical issues involved in disclosure of prognostic information to parents and children with life-threatening illness and offer practical guidance for these conversations. Copyright © 2014 by the American Academy of Pediatrics.

Holzbaur E.,University of Pennsylvania
Current Biology | Year: 2010

A screen for axonal cargo mislocalization in Caenorhabditis elegans neurons implicates the cyclin-dependent kinases CDK-5 and PCT-1 and the cyclin CCY-1 in the regulation of the microtubule motor cytoplasmic dynein. © 2010 Elsevier Ltd All rights reserved.

Sbitany H.,University of Pennsylvania
Aesthetic surgery journal / the American Society for Aesthetic Plastic surgery | Year: 2011

The use of acellular dermal matrix (ADM) in many plastic surgery procedures, including breast reconstruction, has increased dramatically in recent years. While expander/implant reconstruction can be performed successfully with standard techniques, the introduction of ADM has added a new tool with which to achieve lasting, predictable results. This article is a summary of existing literature on ADM for primary implant reconstruction, to provide a more thorough understanding of the benefits of ADM in single- and to two-stage breast reconstruction and to identify the areas where further investigation is needed.

Harris A.B.,University of Pennsylvania
Physical Review B - Condensed Matter and Materials Physics | Year: 2012

The list of possible commensurate phases obtained from the parent tetragonal phase of Ruddlesden-Popper (RP) systems, A n+1B nC 3n+1 for general n due to a single phase transition involving the reorienting of octahedra of C (oxygen) ions is reexamined using a Landau expansion. This expansion allows for the nonlinearity of the octahedral rotations and the rotation-strain coupling. It is found that most structures allowed by symmetry are inconsistent with the constraint of rigid octahedra, which dictates the form of the quartic terms in the Landau free energy. For A 2BC 4 our analysis allows only 10 of the 41 structures which satisfy the general symmetry arguments of Hatch. The symmetry of rotations for RP systems with n>2 is clarified. Our list of possible structures for general n excludes many structures allowed in previous studies. © 2012 American Physical Society.

Joffe M.,University of Pennsylvania
International Journal of Biostatistics | Year: 2011

Pearl's article provides a useful springboard for discussing further the benefits and drawbacks of principal stratification and the associated discomfort with attributing effects to post-treatment variables. The basic insights of the approach are important: pay close attention to modification of treatment effects by variables not observable before treatment decisions are made, and be careful in attributing effects to variables when counterfactuals are ill-defined. These insights have often been taken too far in many areas of application of the approach, including instrumental variables, censoring by death, and surrogate outcomes. A novel finding is that the usual principal stratification estimand in the setting of censoring by death is by itself of little practical value in estimating intervention effects. © 2011 Berkeley Electronic Press. All rights reserved.

Mao X.,University of Pennsylvania | Mao X.,University of Michigan | Chen Q.,Urbana University | Granick S.,Urbana University
Nature Materials | Year: 2013

Burgeoning experimental and simulation activity seeks to understand the existence of self-assembled colloidal structures that are not close-packed. Here we describe an analytical theory based on lattice dynamics and supported by experiments that reveals the fundamental role entropy can play in stabilizing open lattices. The entropy we consider is associated with the rotational and vibrational modes unique to colloids interacting through extended attractive patches. The theory makes predictions of the implied temperature, pressure and patch-size dependence of the phase diagram of open and close-packed structures. More generally, it provides guidance for the conditions at which targeted patchy colloidal assemblies in two and three dimensions are stable, thus overcoming the difficulty in exploring by experiment or simulation the full range of conceivable parameters. © 2013 Macmillan Publishers Limited. All rights reserved.

Magland J.F.,University of Pennsylvania
PloS one | Year: 2012

Image-based mechanical modeling of the complex micro-structure of human bone has shown promise as a non-invasive method for characterizing bone strength and fracture risk in vivo. In particular, elastic moduli obtained from image-derived micro-finite element (μFE) simulations have been shown to correlate well with results obtained by mechanical testing of cadaveric bone. However, most existing large-scale finite-element simulation programs require significant computing resources, which hamper their use in common laboratory and clinical environments. In this work, we theoretically derive and computationally evaluate the resources needed to perform such simulations (in terms of computer memory and computation time), which are dependent on the number of finite elements in the image-derived bone model. A detailed description of our approach is provided, which is specifically optimized for μFE modeling of the complex three-dimensional architecture of trabecular bone. Our implementation includes domain decomposition for parallel computing, a novel stopping criterion, and a system for speeding up convergence by pre-iterating on coarser grids. The performance of the system is demonstrated on a dual quad-core Xeon 3.16 GHz CPUs equipped with 40 GB of RAM. Models of distal tibia derived from 3D in-vivo MR images in a patient comprising 200,000 elements required less than 30 seconds to converge (and 40 MB RAM). To illustrate the system's potential for large-scale μFE simulations, axial stiffness was estimated from high-resolution micro-CT images of a voxel array of 90 million elements comprising the human proximal femur in seven hours CPU time. In conclusion, the system described should enable image-based finite-element bone simulations in practical computation times on high-end desktop computers with applications to laboratory studies and clinical imaging.

Boullata J.I.,University of Pennsylvania
Journal of Parenteral and Enteral Nutrition | Year: 2012

Parenteral nutrition (PN) is a high-alert medication that contains dozens of active pharmaceutical ingredients. This complex prescription drug preparation is used in a wide variety of clinical settings for patients across the age spectrum. Despite the existence of a number of guidance documents, the drug-use process for PN suffers from lack of standardization for order prescription, order verification and review, PN compounding, labeling, and dispensing. As a result, PN-associated medication errors would not be unexpected but are documented infrequently. Copyright © 2012 American Society.

Cricco-Lizza R.,University of Pennsylvania
Qualitative Health Research | Year: 2014

In this 14-month ethnographic study, I examined the emotional labor and coping strategies of 114, level-4, neonatal intensive care unit (NICU) nurses. Emotional labor was an underrecognized component in the care of vulnerable infants and families. The nature of this labor was contextualized within complex personal, professional, and organizational layers of demand on the emotions of NICU nurses. Coping strategies included talking with the sisterhood of nurses, being a super nurse, using social talk and humor, taking breaks, offering flexible aid, withdrawing from emotional pain, transferring out of the NICU, attending memorial services, and reframing loss to find meaning in work. The organization had strong staffing, but emotional labor was not recognized, supported, or rewarded. The findings can contribute to the development of interventions to nurse the nurse, and to ultimately facilitate NICU nurses' nurturance of stressed families. These have implications for staff retention, job satisfaction, and delivery of care. © The Author(s) 2014.

Alu A.,University of Texas at Austin | Engheta N.,University of Pennsylvania
Physical Review Letters | Year: 2010

Optical waveguide interconnects are a major component of chip-scale data processing and computational systems. Here, we propose an alternative mechanism based on optical wireless broadcasting links using nanoantennas, which may overcome some of the limitations of nanoscale waveguide interconnects. By properly loading and matching nanoantenna pairs with optical nanocircuits, we theoretically demonstrate a complete optical wireless link that, in spite of some radiation loss and mismatch factors, may exhibit much less absorption loss, largely outperforming regular plasmonic waveguide links. © 2010 The American Physical Society.

In recent years, the Not-In-My-Back-Yard (NIMBY) phenomenon has become increasingly prevalent with regard to harm reduction sites, addiction treatment facilities and their clients. Drawing from a case study of community conflict generated by the relocation of a methadone clinic into a rapidly gentrifying neighbourhood in downtown Toronto, Canada, this article offers a unique analysis of oppositional strategies regarding the perceived (socio-spatial) 'disorder of drugs'. Based on interviews with local residents and business owners this article suggests the existence of three interrelated oppositional strategies, shifting from a recourse to urban planning policy, to a critique of methadone maintenance treatment (MMT) practice, to explicit forms of socio-spatial stigmatization that posited the body of the (methadone) 'addict' as abject agent of infection and the clinic as a site of contagion. Exploring the dialectical, socio-spatial interplay between the body of the addict and the social body of the city, this article demonstrates the unique aspects of opposition to the physically, ideologically and discursively contested space of addiction treatment. Representations of the methadone clinic, its clients and the larger space of the neighbourhood, this paper suggests, served to situate addiction as a 'pathology (out) of place' and recast the city itself as a site of safe/supervised consumption. © 2009 Elsevier Ltd.

Harris A.B.,University of Pennsylvania
Physical Review B - Condensed Matter and Materials Physics | Year: 2012

A phenomenological explanation of the magnetoelectric behavior of Co 3TeO 6 is developed. We explain the second harmonic generation data and the magnetic field induced spontaneous electric polarization in the magnetically ordered phase below 20 K. © 2012 American Physical Society.

Frank M.G.,University of Pennsylvania | Cantera R.,University of Stockholm
Trends in neurosciences | Year: 2014

Sleep is widely believed to play an essential role in synaptic plasticity. However, the precise mechanisms governing this presumptive function are largely unknown. There is also evidence for independent circadian oscillations in synaptic strength and morphology. Therefore, synaptic changes observed after sleep reflect interactions between state-dependent (e.g., wake versus sleep) and state-independent (circadian) processes. In this review we consider how sleep and biological clocks influence synaptic plasticity. We discuss these findings in the context of current plasticity-based theories of sleep function and propose a new model that integrates circadian and brain-state influences on synaptic plasticity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Shahane A.,University of Pennsylvania
Rheumatology International | Year: 2013

The focus of this review is to increase awareness of pulmonary arterial hypertension (PAH) in patients with rheumatic diseases. Epidemiology and pathogenesis of PAH in rheumatic diseases is reviewed, with recommendations for early screening and diagnosis and suggestion of possible role of immunosuppressive therapy in treatment for PAH in rheumatic diseases. A MEDLINE search for articles published between January 1970 and June 2012 was conducted using the following keywords: pulmonary hypertension, scleroderma, systemic sclerosis, pulmonary arterial hypertension, connective tissues disease, systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis, Sjogren's syndrome, vasculitis, sarcoidosis, inflammatory myopathies, dermatomyositis, ankylosing spondylitis, spondyloarthropathies, diagnosis and treatment. Pathogenesis and disease burden of PAH in rheumatic diseases was highlighted, with emphasis on early consideration and workup of PAH. Screening recommendations and treatment were touched upon. PAH is most commonly seen in systemic sclerosis and may be seen in isolation or in association with interstitial lung disease. Several pathophysiologic processes have been identified including an obliterative vasculopathy, veno-occlusive disease, formation of microthrombi and pulmonary fibrosis. PAH in systemic lupus erythematosus is associated with higher prevalence of antiphospholipid and anticardiolipin antibodies and the presence of Raynaud's phenomenon. Endothelial proliferation with vascular remodeling, abnormal coagulation with thrombus formation and immune-mediated vasculopathy are the postulated mechanisms. Improvement with immunosuppressive medications has been reported. Pulmonary fibrosis, extrinsic compression of pulmonary arteries and granulomatous vasculitis have been reported in patients with sarcoidosis. Intimal and medial hyperplasia with luminal narrowing has been observed in Sjogren's syndrome, mixed connective tissue disease and inflammatory myopathies. Pulmonary arterial hypertension (PAH) associated with rheumatic diseases carries a particularly grim prognosis with faster progression of disease and poor response to therapy. Though largely associated with systemic sclerosis, it is being increasingly recognized in other rheumatic diseases. An underlying inflammatory component may explain the poor response to therapy in patients with rheumatic diseases and is a rationale for consideration of immunosuppressive therapy in conjunction with vasodilator therapy in treatment for PAH. Further studies identifying pathogenetic pathways and possible targets of therapy, especially the role of immunomodulatory medications, are warranted. © 2013 Springer-Verlag Berlin Heidelberg.

Quam C.,University of Arizona | Swingley D.,University of Pennsylvania
Child Development | Year: 2012

Young infants respond to positive and negative speech prosody (A. Fernald, 1993), yet 4-year-olds rely on lexical information when it conflicts with paralinguistic cues to approval or disapproval (M. Friend, 2003). This article explores this surprising phenomenon, testing one hundred eighteen 2- to 5-year-olds' use of isolated pitch cues to emotions in interactive tasks. Only 4- to 5-year-olds consistently interpreted exaggerated, stereotypically happy or sad pitch contours as evidence that a puppet had succeeded or failed to find his toy (Experiment 1) or was happy or sad (Experiments 2, 3). Two- and 3-year-olds exploited facial and body-language cues in the same task. The authors discuss the implications of this late-developing use of pitch cues to emotions, relating them to other functions of pitch. © 2011 The Authors. Child Development © 2011 Society for Research in Child Development, Inc.

Gaiser R.R.,University of Pennsylvania
Current Opinion in Anaesthesiology | Year: 2013

PURPOSE OF REVIEW: To identify newly identified risk factors for the development of a postdural puncture headache (PDPH) as well as to outline the key points in the management of unintentional dural puncture and of PDPH. RECENT FINDINGS: The lack of experience of the proceduralist and a vaginal delivery are two risk factors that increase the risk of the patient developing a PDPH. The use of intrathecal catheters for the prevention of a headache is not of value, although an intrathecal catheter may prove to be the best method for providing analgesia for the patient. When performing an epidural blood patch, the optimal amount of blood is 20 ml, as long as the patient does not develop the symptoms of back pain or leg pain during the injection. SUMMARY: Many practitioners do not practice an evidence-based approach to the management of unintentional dural puncture and PDPH. Written institutional protocols are important to insure that patients receive the optimal care. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Bernstein G.M.,University of Pennsylvania
Monthly Notices of the Royal Astronomical Society | Year: 2010

Precision weak gravitational lensing experiments require measurements of galaxy shapes accurate to <1 part in 1000. We investigate measurement biases, noted by Voigt & Bridle and Melchior et al., that are common to shape measurement methodologies that rely upon fitting elliptical-isophote galaxy models to observed data. The first bias arises when the true galaxy shapes do not match the models being fit. We show that this 'underfitting bias' is due, at root, to these methods' attempts to use information at high spatial frequencies that have been destroyed by the convolution with the point spread function (PSF) and/or by sampling. We propose a new shape-measurement technique that is explicitly confined to observable regions of k-space. A second bias arises for galaxies whose ellipticity varies with radius. For most shape-measurement methods, such galaxies are subject to 'ellipticity gradient bias'. We show how to reduce such biases by factors of 20-100 within the new shape-measurement method. The resulting shear estimator has multiplicative errors <1 part in 10 3 for high signal-to-noise ratio images, even for highly asymmetric galaxies. Without any training or recalibration, the new method obtains Q = 3000 in the GREAT08 Challenge of blind shear reconstruction on low-noise galaxies, several times better than any previous method. © 2010 The Author. Journal compilation © 2010 RAS.

Burdick J.A.,University of Pennsylvania | Prestwich G.D.,University of Utah
Advanced Materials | Year: 2011

Hyaluronic acid (HA), an immunoneutral polysaccharide that is ubiquitous in the human body, is crucial for many cellular and tissue functions and has been in clinical use for over thirty years. When chemically modified, HA can be transformed into many physical forms-viscoelastic solutions, soft or stiff hydrogels, electrospun fibers, non-woven meshes, macroporous and fibrillar sponges, flexible sheets, and nanoparticulate fluids-for use in a range of preclinical and clinical settings. Many of these forms are derived from the chemical crosslinking of pendant reactive groups by addition/condensation chemistry or by radical polymerization. Clinical products for cell therapy and regenerative medicine require crosslinking chemistry that is compatible with the encapsulation of cells and injection into tissues. Moreover, an injectable clinical biomaterial must meet marketing, regulatory, and financial constraints to provide affordable products that can be approved, deployed to the clinic, and used by physicians. Many HA-derived hydrogels meet these criteria, and can deliver cells and therapeutic agents for tissue repair and regeneration. This progress report covers both basic concepts and recent advances in the development of HA-based hydrogels for biomedical applications. Hydrogel biomaterials based on hyaluronic acid are formed with a wide range of diverse chemistry and processing techniques. This versatility in material design has led to application of these materials in fields of tissue regeneration and drug delivery with structures of gels, fibers, and porous substrates. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Rosenbaum P.R.,University of Pennsylvania
Biometrika | Year: 2010

Some experiments involve more than one random assignment of treatments to units. An analogous situation arises in certain observational studies, although randomization is not used, so each assignment may be biased. If each assignment is suspect, it is natural to ask whether there are separate pieces of information, dependent upon different assumptions, and perhaps whether conclusions about treatment effects are not critically dependent upon one or another suspect assumption. The design of an observational study contains evidence factors if it permits several statistically independent tests of the same null hypothesis about treatment effects, where these tests rely on different assumptions about treatment assignments at several levels of assignment. Two designs and two empirical examples are considered, one example of each design. In the dose-control design, there are matched pairs of a treated subject and an untreated control, and doses of treatment vary between pairs for treated subjects; this yields two evidence factors. In the varied intensity design, there are matched sets with two treated subjects and one or more untreated controls, where the two treated subjects within the same matched set receive different doses of treatment, and in a technically different way, the design yields two evidence factors. © 2010 Biometrika Trust.

Sharp K.,University of Pennsylvania
Journal of Chemical Theory and Computation | Year: 2013

There are two fundamental definitions of entropy, Clausius's thermodynamic definition and the Boltzmann-Gibbs statistical mechanical definition. The Clausius definition, applied here to the calculation of molecular entropies, requires an integration over temperature. Analytical and numerical error analysis shows that this quadrature can be done accurately using a small number of large temperature steps involving the calculation of one average system property, the mean internal energy. This makes the method computationally practical for systems with many degrees of freedom, such as biological molecules. The Clausius definition provides a simple and physically insightful way to decompose a total entropy change into components and is useful for benchmarking statistical mechanical based methods for entropy calculation. A temperature quenching protocol is described whereby the Clausius method can be used with existing force fields to evaluate entropy changes in anharmonic and diffusive systems. © 2012 American Chemical Society.

Seale P.,University of Pennsylvania
International Journal of Obesity | Year: 2010

Brown adipose tissue (BAT) is a specialized endothermic tissue in eutherian mammals that protects against hypothermia. Heat production by BAT may also be stimulated by overfeeding as an apparent counter regulatory mechanism to prevent excessive adipose accumulation. Genetic studies in rodents have overwhelmingly demonstrated an antiobesity effect for BAT. There is thus substantial biomedical interest in developing methods to increase the amount or function of BAT as a means to combat obesity. Furthermore, the recent discovery that adult humans have rather significant amounts of active BAT raises speculation that this tissue may naturally affect body weight in humans. Recent advances in our understanding of the transcriptional regulation of brown adipocyte development and adaptive thermogenesis are reviewed here. © 2010 Macmillan Publishers Limited All rights reserved.

Segade F.,University of Pennsylvania
FEBS Letters | Year: 2010

Arterial Tortuosity Syndrome (ATS) is a heritable disease characterized by twisting and lengthening of the major arteries, hypermobility of the joints, and laxity of skin. ATS is caused by mutations in SLC2A10, encoding Glucose Transporter 10 (GLUT10). The current model of ATS holds that loss of GLUT10 at the nuclear periphery induces a glucose-dependent increase in Transforming Growth Factor-β (TGFβ) that stimulates vessel wall cell proliferation. Instead, we propose that GLUT10 transports ascorbate, a cofactor for collagen and elastin hydroxylases, into the secretory pathway. In ATS, loss of GLUT10 results in defective collagen and/or elastin. TGFβ activation represents a secondary response to a defective extracellular matrix. © 2010 Federation of European Biochemical Societies.

Fogarty P.F.,University of Pennsylvania
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2011

Since the introduction of replacement coagulation factor infusions for the treatment of hemophilia in the 1970s and subsequent improvements in the safety profile of available factor VIII (FVIII) and factor IX (FIX) concentrates, mortality among patients with hemophilia has improved considerably and now parallels that of the noncoagulopathic population in developed countries. Substantial morbidity, however, continues from the development of inhibitory antibodies, a recognized complication of clotting factor replacement; from infections and thrombosis complicating placement of central venous catheters, which are required in children with hemophilia due to frequent prophylactic infusions of coagulation factors with defined half-lives; and from disabling joint disease in individuals without access to costly prophylaxis regimens. In response to the need for long-acting, more potent, less immunogenic, and more easily administered therapies, an impressive array of novel agents is nearly ready for use in the clinical setting. These therapeutics derive from rational bioengineering of recombinant coagulation factors or from the discovery of nonpeptide molecules that have the potential to support hemostasis through alternative pathways. The number of novel agents in clinical trials is increasing, and many of the initial results are promising. In addition to advancing treatment of bleeding episodes or enabling adherence to prophylactic infusions of clotting factor concentrate, newer therapeutics may also lead to improvements in joint health, quality of life, and tolerability of iatrogenic or comorbidity-associated bleeding challenges.

Fu L.,Massachusetts Institute of Technology | Kane C.L.,University of Pennsylvania
Physical Review Letters | Year: 2012

A field theory of the Anderson transition in two-dimensional disordered systems with spin-orbit interactions and time-reversal symmetry is developed, in which the proliferation of vortexlike topological defects is essential for localization. The sign of vortex fugacity determines the Z2 topological class of the localized phase. There are two distinct fixed points with the same critical exponents, corresponding to transitions from a metal to an insulator and a topological insulator, respectively. The critical conductivity and correlation length exponent of these transitions are computed in an N=1-Ïμ expansion in the number of replicas, where for small Ïμ the critical points are perturbatively connected to the Kosterlitz-Thouless critical point. Delocalized states, which arise at the surface of weak topological insulators and topological crystalline insulators, occur because vortex proliferation is forbidden due to the presence of symmetries that are violated by disorder, but are restored by disorder averaging. © 2012 American Physical Society.

Lee F.S.,University of Pennsylvania | Percy M.J.,Belfast City Hospital
Annual Review of Pathology: Mechanisms of Disease | Year: 2011

Because of the central role that red blood cells play in the delivery of oxygen to tissues of the body, red blood cell mass must be controlled at precise levels. The glycoprotein hormone erythropoietin (EPO) regulates red blood cell mass. EPO transcription, in turn, is regulated by a distinctive oxygen-sensing mechanism. In this pathway, prolyl hydroxylase domain protein (PHD) site-specifically hydroxylates the α-subunit of the transcription factor hypoxia-inducible factor α (HIF-α), thereby targeting the latter for degradation by the von Hippel-Lindau tumor-suppressor protein (VHL). Under hypoxic conditions, this posttranslational modification of HIF-α is inhibited, which stabilizes it and promotes the transcriptional activation of genes, including that for EPO. Rare patients with erythrocytosis have mutations in the genes encoding for PHD2, HIF-2α, and VHL, which implicates these proteins as critical to the proper control of red blood cell mass in humans. Copyright © 2011 by Annual Reviews. All rights reserved.

Hsu D.,University of Pennsylvania
Energy Policy | Year: 2014

Many different governments have begun to require disclosure of building energy performance, in order to allow owners and prospective buyers to incorporate this information into their investment decisions. These policies, known as disclosure or information policies, require owners to benchmark their buildings and sometimes conduct engineering audits. However, given substantial variation in the cost to disclose different types of information, it is natural to ask: how much and what kind of information about building energy performance should be disclosed, and for what purposes? To answer this question, this paper assembles and cleans a comprehensive panel dataset of New York City multifamily buildings, and analyzes its predictive power using a Bayesian multilevel regression model. Analysis of variance (ANOVA) reveals that building-level variation is the most important factor in explaining building energy use, and that there are few, if any, relationships of building systems to observed energy use. This indicates that disclosure laws requiring benchmarking data may be relatively more useful than engineering audits in explaining the observed energy performance of existing buildings. These results should inform the further development of information disclosure laws. © 2013 The Author.

Serletti J.M.,University of Pennsylvania
Plastic and Reconstructive Surgery | Year: 2010

BACKGROUND:: Discussions of abdominal donor-site morbidity and risk of flap loss continue to surround free flap breast reconstruction. The authors performed a head-to-head comparison of deep inferior epigastric perforator (DIEP) and muscle-sparing free transverse rectus abdominis musculocutaneous (TRAM) flaps performed by a single senior surgeon at a single institution. METHODS:: The senior author's (J.M.S.) recent experience with DIEP and muscle-sparing free TRAM flaps between July of 2006 and July of 2008 was reviewed retrospectively. The choice of flap was dictated by an intraoperative algorithm based on number, size, and location of perforator vessels. Variables assessed included intraoperative and postoperative complications. Three groups were analyzed: DIEP reconstructions, muscle-sparing free TRAM reconstructions, and bilateral reconstructions in which one of each flap type was performed. RESULTS:: Ninety-one patients underwent 123 muscle-sparing free TRAM flap reconstructions, 53 patients underwent 71 DIEP flap reconstructions, and 31 patients underwent bilateral reconstruction with one DIEP and one muscle-sparing free TRAM flap. There were no significant differences in intraoperative complications or in minor postoperative complications. There was, however, a significant increase in total major postoperative complications in the DIEP study group (DIEP = 3.9 percent, muscle-sparing free TRAM = 0 percent, p = 0.03). No significant difference was noted in hernia formation (DIEP = 0, muscle-sparing free TRAM = 4, p = 0.15). CONCLUSIONS:: This study demonstrates that both of these flaps may be reliably performed with an extremely low risk of complications. The choice of flap should be made intraoperatively, based on anatomic findings on a patient-by-patient basis, so as to optimize flap survivability while minimizing donor-site morbidity to the greatest extent possible. © 2010 by the American Society of Plastic Surgeons.

Datta R.,University of Pennsylvania
Cephalalgia : an international journal of headache | Year: 2013

The objective of this study was to compare the interictal cortical response to a visual stimulus between migraine with aura (MWA), migraine without aura (MwoA), and control subjects. In a prospective case-control study, blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) was used to assess the response to a visual stimulus and arterial spin labeled perfusion MR to determine resting cerebral blood flow. A standardized questionnaire was used to assess interictal visual discomfort. Seventy-five subjects (25 MWA, 25 MwoA, and 25 controls) were studied. BOLD fMRI response to visual stimulation within primary visual cortex was greater in MWA (3.09 ± 0.15%) compared to MwoA (2.36 ± 0.13%, P = 0.0008) and control subjects (2.47 ± 0.11%, P = 0.002); responses were also greater in the lateral geniculate nuclei in MWA. No difference was found between MwoA and control groups. Whole brain analysis showed that increased activation in MWA was confined to the occipital pole. Regional resting cerebral blood flow did not differ between groups. MWA and MwoA subjects had significantly greater levels of interictal visual discomfort compared to controls ( P = 0.008 and P = 0.005, respectively), but this did not correlate with BOLD response. Despite similar interictal symptoms of visual discomfort, only MWA subjects have cortical hyperresponsiveness to visual stimulus, suggesting a direct connection between cortical hyperresponsiveness and aura itself.

Langereis J.D.,University of Pennsylvania
Cell Adhesion and Migration | Year: 2013

During an infection, neutrophils are the first immune cells to arrive armed to clear the invading pathogen. In order to do so, neutrophils need to transmigrate from the peripheral blood through the endothelial layer toward the site of inflammation. This process is in most cases dependent on integrins, adhesion molecules present on all immune cells. These molecules are functionally regulated by "inside-out" signaling, where stimulus-induced signaling pathways act on the intracellular integrin tail to regulate the activity of the receptor on the outside. Both a change in conformation (affinity) and clustering (avidity/ valency) of the receptors occurs and many factors have been linked to regulation of integrins on neutrophils. Control of integrin conformation and clustering is of pivotal importance for proper cell adhesion, migration, and bacterial clearance. Recently, gelsolin was found to be involved in β1-integrin affinity regulation and cell adhesion. Here, I summarize the role of neutrophil integrin regulation in the essential steps to reach the site of inflammation and clearance of bacterial pathogens. © 2013 Landes Bioscience.

Multiple lines of evidence suggest that the adrenergic system can modulate sensitivity to anesthetic-induced immobility and anesthetic-induced hypnosis as well. However, several considerations prevent the conclusion that the endogenous adrenergic ligands norepinephrine and epinephrine alter anesthetic sensitivity. Using dopamine β-hydroxylase knockout (Dbh) mice genetically engineered to lack the adrenergic ligands and their siblings with normal adrenergic levels, we test the contribution of the adrenergic ligands upon volatile anesthetic induction and emergence. Moreover, we investigate the effects of intravenous dexmedetomidine in adrenergic-deficient mice and their siblings using both righting reflex and processed electroencephalographic measures of anesthetic hypnosis. We demonstrate that the loss of norepinephrine and epinephrine and not other neuromodulators co-packaged in adrenergic neurons is sufficient to cause hypersensitivity to induction of volatile anesthesia. However, the most profound effect of adrenergic deficiency is retarding emergence from anesthesia, which takes two to three times as long in Dbh mice for sevoflurane, isoflurane, and halothane. Having shown that Dbh mice are hypersensitive to volatile anesthetics, we further demonstrate that their hypnotic hypersensitivity persists at multiple doses of dexmedetomidine. Dbh mice exhibit up to 67% shorter latencies to loss of righting reflex and up to 545% longer durations of dexmedetomidine-induced general anesthesia. Central rescue of adrenergic signaling restores control-like dexmedetomidine sensitivity. A novel continuous electroencephalographic analysis illustrates that the longer duration of dexmedetomidine-induced hypnosis is not due to a motor confound, but occurs because of impaired anesthetic emergence. Adrenergic signaling is essential for normal emergence from general anesthesia. Dexmedetomidine-induced general anesthesia does not depend on inhibition of adrenergic neurotransmission.

Rader D.J.,University of Pennsylvania
Cell Metabolism | Year: 2016

Dyslipidemia is a risk factor for atherosclerotic cardiovascular disease (ASCVD). Abundant data indicate that low-density lipoproteins (LDL) are causal for ASCVD; a new class of LDL-lowering medicines, the PCSK9 inhibitors, will address much unmet medical need. Human genetics suggest that triglyceride-rich lipoproteins (TRL) are pro-atherogenic and have pointed to a number of protein regulators of lipoprotein lipase activity that are candidates for therapeutic targeting. Finally, high-density lipoprotein (HDL) cholesterol does not appear to be causally associated with protection from ASCVD, reinforced by the failure of three CETP inhibitors in CV outcome trials, but HDL function remains of interest. © 2016 Elsevier Inc.

Noncoding RNAs (ncRNAs) comprise a diverse group of RNAs that function in essential cellular processes such as pre-mRNA splicing and mRNA translation and also regulate various aspects of gene expression in physiology and development. Methods of subcellular and tissue localization of ncRNAs are essential to understand their biological roles and their contribution to disease. We describe a rapid fluorescent (FISH) or chromogenic (CISH) in situ hybridization protocol for localization of ncRNAs (including microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), piwi-associated RNAs (piRNAs) and ribosomal RNAs (rRNAs)) in formalin-fixed, paraffin-embedded (FFPE) tissues and cultured cells, using locked nucleic acid (LNA)-modified oligonucleotides. In this protocol, sections are heated in citrate buffer, which eliminates the need for protease treatment, thus preserving optimal morphology and protein epitopes, and allowing the simultaneous detection of proteins with immunofluorescence staining (IF). LNA-FISH requires 5 h, or between 10 and 36 h when combined with IF; LNA-CISH requires 2 d.

Bigham A.W.,University of Michigan | Lee F.S.,University of Pennsylvania
Genes and Development | Year: 2014

Humans have adapted to the chronic hypoxia of high altitude in several locations, and recent genome-wide studies have indicated a genetic basis. In some populations, genetic signatures have been identified in the hypoxiainducible factor (HIF) pathway, which orchestrates the transcriptional response to hypoxia. In Tibetans, they have been found in the HIF2A (EPAS1) gene, which encodes for HIF-2a, and the prolyl hydroxylase domain protein 2 (PHD2, also known as EGLN1) gene, which encodes for one of its key regulators, PHD2. High-altitude adaptation may be due to multiple genes that act in concert with one another. Unraveling their mechanism of action can offer new therapeutic approaches toward treating common human diseases characterized by chronic hypoxia. © 2014 Bigham and Lee.

Bi E.,University of Pennsylvania | Park H.-O.,Ohio State University
Genetics | Year: 2012

Asymmetric cell division, which includes cell polarization and cytokinesis, is essential for generating cell diversity during development. The budding yeast Saccharomyces cerevisiae reproduces by asymmetric cell division, and has thus served as an attractive model for unraveling the general principles of eukaryotic cell polarization and cytokinesis. Polarity development requires G-protein signaling, cytoskeletal polarization, and exocytosis, whereas cytokinesis requires concerted actions of a contractile actomyosin ring and targeted membrane deposition. In this chapter, we discuss the mechanics and spatial control of polarity development and cytokinesis, emphasizing the key concepts, mechanisms, and emerging questions in the field. © 2012 by the Genetics Society of America.

Tan A.S.L.,University of Pennsylvania | Bigman C.A.,University of Illinois at Urbana - Champaign
American Journal of Preventive Medicine | Year: 2014

Background Electronic cigarettes, or e-cigarettes, are increasingly advertised as replacements for regular cigarettes or cessation aids for smokers. Purpose To describe the prevalence and correlates of e-cigarette awareness and perceived harmfulness among U.S. adults and analyze whether these variables are associated with smokers' past-year quit attempts and intention to quit. Methods Data were obtained from the Health Information National Trends Survey (HINTS 4 Cycle 2), conducted from October 2012 to January 2013. Data analyses were performed from June to August 2013. Results Overall, 77% of respondents were aware of e-cigarettes. Of these, 51% believed e-cigarettes were less harmful than cigarettes. Younger, white (compared with Hispanic), more educated respondents and current or former smokers (compared with non-smokers) were more likely to be aware of e-cigarettes. Among those who were aware of e-cigarettes, younger, more educated respondents and current smokers (compared with former and non-smokers) were more likely to believe that e-cigarettes were less harmful. Awareness and perceived harm were not associated with smokers' past year quit attempts or intention to quit. Conclusions Overall e-cigarette awareness increased whereas the proportion of smokers who perceived less harm of e-cigarettes declined compared with earlier surveys. However, awareness and perceived harm of e-cigarettes did not show evidence of promoting smoking cessation at the population level. © 2014 American Journal of Preventive Medicine.

Chen-Plotkin A.S.,University of Pennsylvania
Neuron | Year: 2014

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia have several important features in common. They are progressive, they affect a relatively inaccessible organ, and we have no disease-modifying therapies for them. For these brain-based diseases, current diagnosis and evaluation of disease severity rely almost entirely on clinical examination, which may be only a rough approximation of disease state. Thus, the development of biomarkers-objective, relatively easily measured, and precise indicators of pathogenic processes-could improve patient care and accelerate therapeutic discovery. Yet existing, rigorously tested neurodegenerative disease biomarkers are few, and even fewer biomarkers have translated into clinical use. To find new biomarkers for these diseases, an unbiased, high-throughput screening approach may be needed. In this review, I will describe the potential utility of such an approach to biomarker discovery, using Parkinson's disease as a case example. © 2014 Elsevier Inc.

Grice E.A.,University of Pennsylvania
Genome Research | Year: 2015

The past two decades have been marked by a surge in research to understand the microbial communities that live in association with the human body, in part stimulated by affordable, high-throughput DNA sequencing technology. In the context of the skin, this Perspective focuses on the current state of genomic- and metagenomic-based host-microbe research and future challenges and opportunities to move the field forward. These include elucidating nonbacterial components of the skin microbiome (i.e., viruses); systematic studies to address common perturbations to the skin microbiome (e.g., antimicrobial drugs, topical cosmetic/hygienic products); improved approaches for identifying potential microbial triggers for skin diseases, including species- and strain-level resolution; and improved, clinically relevant models for studying the functional and mechanistic roles of the skin microbiome. In the next 20 years, we can realistically expect that our knowledge of the skin microbiome will inform the clinical management and treatment of skin disorders through diagnostic tests to stratify patient subsets and predict best treatment modality and outcomes and through treatment strategies such as targeted manipulation or reconstitution of microbial communities. © 2015 Grice.

Mortani Barbosa E.J.,University of Pennsylvania
Academic Radiology | Year: 2015

The National Lung Cancer Screening Trial (NLST) demonstrated a mortality reduction benefit associated with low-dose computed tomography (LDCT) screening for lung cancer. There has been considerable debate regarding the benefits and harms of LDCT lung cancer screening, including the challenges related to its practical implementation. One of the controversies regards overdiagnosis, which conceptually denotes diagnosing a cancer that, either because of its indolent, low-aggressiveness biologic behavior or because of limited life expectancy, is unlikely to result in significant morbidity during the patient's remainder lifetime. In theory, diagnosing and treating these cancers offer no measurable benefit while incurring costs and risks. Therefore, if a screening test detects a substantial number of overdiagnosed cancers, it is less likely to be effective. It has been argued that LDCT screening for lung cancer results in an unacceptably high rate of overdiagnosis. This article aims to defend the opposite stance. Overdiagnosis does exist and to a certain extent is inherent to any cancer-screening test. Nonetheless, the concept is less dualistic and more nuanced than it has been suggested. Furthermore, the average estimates of overdiagnosis in LDCT lung cancer screening based on the totality of published data are likely much lower than the highest published estimates, if a careful definition of a positive screening test reflecting our current understanding of lung cancer biology is utilized. This article presents evidence on why reports of overdiagnosis in lung cancer screening have been exaggerated. © 2015 AUR.

Badylak S.F.,McGowan Institute for Regenerative Medicine | Weiss D.J.,University of Vermont | Caplan A.,University of Pennsylvania
The Lancet | Year: 2012

End-stage organ failure is a key challenge for the medical community because of the ageing population and the severe shortage of suitable donor organs available. Equally, injuries to or congenital absence of complex tissues such as the trachea, oesophagus, or skeletal muscle have few therapeutic options. A new approach to treatment involves the use of three-dimensional biological scaffolds made of allogeneic or xenogeneic extracellular matrix derived from non-autologous sources. These scaffolds can act as an inductive template for functional tissue and organ reconstruction after recellularisation with autologous stem cells or differentiated cells. Such an approach has been used successfully for the repair and reconstruction of several complex tissues such as trachea, oesophagus, and skeletal muscle in animal models and human beings, and, guided by appropriate scientific and ethical oversight, could serve as a platform for the engineering of whole organs and other tissues. © 2012 Elsevier Ltd.

Martucci J.,University of Pennsylvania
Social Studies of Science | Year: 2010

In the US, blood donors face a variety of restrictions that leave many people excluded entirely from the donor pool. This paper explores the specific circumstances and meanings surrounding the donor ban on Men-who-have-Sex-with-Men (MSM). The ban on MSM is one of the few existing donor guidelines to receive considerable criticism on grounds that it effectively prohibits any sexually active gay man from donating blood and thus discriminates against gays. Due in part to these questions of fairness, the Blood Products Advisory Committee (BPAC) of the Food and Drug Administration (FDA) met to reconsider the decades-old policy, first in 1997 and again in 2000. The FDA asked its advisory committee to address the efficacy and utility of the MSM ban in light of technological developments in blood-banking, epidemiological data on the spread of HIV, and mounting pressures from gay rights and blood-banking organizations to update the policy. Through a detailed reading of meeting and conference transcripts that took place between 1997 and 2000, I argue that 'MSM' became a contested definitional category during the FDA's reappraisal of the policy. During and between the Committee's discussions, presenters and experts debated the differences between sexual behavior and sexual identity in relation to HIV and, eventually, HHV-8, a virus known to cause Kaposi's sarcoma in immunosuppressed individuals. I argue that the underlying flexibility in the meanings behind the term 'MSM' allowed Committee members, in the end, to retract their more nuanced discussions of human behavior and HIV and to uphold the contested policy. Finally, I suggest how the debates surrounding the MSM donor ban can help us to better understand the place of sexuality in discussions and claims of biopolitical citizenship in early 21st-century America. © The Author(s), 2010.

Sonnenberg G.F.,University of Pennsylvania
International Immunology | Year: 2014

Innate lymphoid cells (ILCs) are a recently appreciated immune cell population that is constitutively found in the healthy mammalian gastrointestinal (GI) tract and associated lymphoid tissues. Translational studies have revealed that alterations in ILC populations are associated with GI disease in patients, such as inflammatory bowel disease, HIV infection and colon cancer, suggesting a potential role for ILCs in either maintaining intestinal health or promoting intestinal disease. Mouse models identified that ILCs have context-dependent protective and pathologic functions either during the steady state, or following infection, inflammation or tissue damage. This review will discuss the associations of altered intestinal ILCs with human GI diseases, and the functional consequences of targeting ILCs in mouse models. Collectively, our current understanding of ILCs suggests that the development of novel therapeutic strategies to modulate ILC responses will be of significant clinical value to prevent or treat human GI diseases. © The Japanese Society for Immunology. 2014. All rights reserved.

Dominguez R.,University of Pennsylvania | Holmes K.C.,Max Planck Institute for Medical Research
Annual Review of Biophysics | Year: 2011

Actin is the most abundant protein in most eukaryotic cells. It is highly conserved and participates in more protein-protein interactions than any known protein. These properties, along with its ability to transition between monomeric (G-actin) and filamentous (F-actin) states under the control of nucleotide hydrolysis, ions, and a large number of actin-binding proteins, make actin a critical player in many cellular functions, ranging from cell motility and the maintenance of cell shape and polarity to the regulation of transcription. Moreover, the interaction of filamentous actin with myosin forms the basis of muscle contraction. Owing to its central role in the cell, the actin cytoskeleton is also disrupted or taken over by numerous pathogens. Here we review structures of G-actin and F-actin and discuss some of the interactions that control the polymerization and disassembly of actin. © 2011 by Annual Reviews. All rights reserved.

Burke F.M.,University of Pennsylvania
Current Atherosclerosis Reports | Year: 2015

Red yeast rice (RYR) is a Chinese herbal supplement produced by fermenting white rice with the yeast, Monascus purpureus. The Chinese have used RYR to flavor, color, and preserve foods and as a traditional medicine for many years. In the USA, RYR has been used as an alternative to statin therapy in treating patients with mild to moderate hypercholesterolemia. RYR contains a variety of monacolins, which inhibit hydroxymethylglutaryl-coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. Consumption of RYR has increased recently especially among patients who might be intolerant to standardized therapy due to statin-associated myalgia (SAM). Several clinical trials have shown RYR to be safe, effective, and well tolerated; however, the studies are small and of short duration. The US Food and Drug Administration has prohibited the sale of all RYR products containing monacolin K, which is chemically identical to lovastatin, because it is considered an unapproved drug. However, many RYR supplements continue to remain on the market and lack standardization and quality control. © 2015, Springer Science+Business Media New York.

Hore M.J.A.,U.S. National Institute of Standards and Technology | Composto R.J.,University of Pennsylvania
Macromolecules | Year: 2014

Because of their shape anisotropy, nanorods are attractive components for creating functional polymer nanocomposites. In many cases, this anisotropy is the basis of physical properties that are distinct from those obtained from isotropic particles, such as nanospheres. For instance, the shape of gold nanorods makes them ideal candidates for applications involving the manipulation of incident light and sensitive molecular spectroscopy due to enhanced polarizability of the particle. On the other hand, semiconducting nanorods, such as those composed of CdSe, have shown promise in polymer-based photovoltaic devices as sites for electron transport and charge transfer. In this Perspective, we motivate the fabrication of functional polymer nanocomposites based specifically upon the inclusion of nanorods over other nanoparticle shapes and discuss ways in which the anisotropy of the individual nanoparticles enhances assembly in and the properties of polymer nanocomposites in comparison to spherical nanoparticles. We briefly summarize methods to successfully disperse and organize nanorods within polymers and discuss applications of polymer nanocomposites involving sensing, energy harnessing, and mechanical enhancement. Finally, we comment on unresolved issues for fabricating nanorod-based polymer composites and suggest topics warranting future investigation. © 2013 American Chemical Society.

Epstein J.A.,University of Pennsylvania
Developmental Cell | Year: 2012

The Notch pathway is a crucial cell-fate regulator in the developing heart. Attention in the past centered on Notch function in cardiomyocytes. However, recent advances demonstrate that region-specific endocardial Notch activity orchestrates the patterning and morphogenesis of cardiac chambers and valves through regulatory interaction with multiple myocardial and neural crest signals. Notch also regulates cardiomyocyte proliferation and differentiation during ventricular chamber development and is required for coronary vessel specification. Here, we review these data and highlight disease connections, including evidence that Notch-Hey-Bmp2 interplay impacts adult heart valve disease and that Notch contributes to cardiac arrhythmia and pre-excitation syndromes. © 2012 Elsevier Inc.

Fuchs S.Y.,University of Pennsylvania
Journal of Interferon and Cytokine Research | Year: 2013

After several decades of intense clinical research, the great promise of Type I interferons (IFN1) as the anticancer wonder drugs that could cure or, at the very least, curb the progression of various oncological diseases has regrettably failed to deliver. Severe side effects and low efficacy of IFN1-based pharmaceutics greatly limited use of these drugs and further reduced the enthusiasm of clinical oncologists for future optimization of IFN1-based therapeutic modalities. Incredibly, extensive clinical studies to assess the efficacy of IFN1 alone or in combination with other anticancer drugs have not been paralleled by an equal scope in defining the determinants that confer cell sensitivity or refractoriness to IFN1. Given that all effects of IFN1 on malignant and benign cells alike are mediated by its receptor, the mechanisms regulating these receptor cell surface levels should play a paramount role in shaping the magnitude and duration of IFN1-elicited effects. These mechanisms and their role in controlling IFN1 responses, as well as an ability of a growing tumor to commandeer these events, are the focus of our review. We postulate that activation of numerous signaling pathways leading to elimination of IFN1 receptor occurs in cancer cells and benign cells that contribute to tumor tissue. We further hypothesize that activation of these eliminative pathways enables the escape from IFN1-driven suppression of tumorigenesis and elicits the primary refractoriness of tumor to the pharmaceutical IFN1. © Copyright 2013, Mary Ann Liebert, Inc. 2013.

High-prevalence foci of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) exist in Japanese on the Kii Peninsula of Japan and in the Chamorros of Guam. Clinical and neuropathologic similarities suggest that the disease in these 2 populations may be related. Recent findings showed that some of the Kii Peninsula ALS cases had pathogenic C9orf72 repeat expansions, a genotype that causes ALS in Western populations. To perform genotyping among Guam residents to determine if the C9orf72 expanded repeat allele contributes to ALS-PDC in this population and to evaluate LRRK2 for mutations in the same population. Case-control series from neurodegenerative disease research programs on Guam that screened residents for ALS, PDC, and dementia. Study participants included 24 with ALS and 22 with PDC and 43 older control subjects with normal cognition ascertained between 1956 and 2006. All but one participant were Chamorro, the indigenous people of Guam. A single individual of white race/ethnicity with ALS was ascertained on Guam during the study. Participants were screened for C9orf72 hexanucleotide repeat length. Participants with repeat numbers in great excess of 30 were considered to have pathogenic repeat expansions. LRRK2 was screened for point mutations by DNA sequencing. We found a single individual with an expanded pathogenic hexanucleotide repeat. This individual of white race/ethnicity with ALS was living on Guam at the time of ascertainment but had been born in the United States. All Chamorro participants with ALS and PDC and control subjects had normal repeats, ranging from 2 to 17 copies. No pathogenic LRRK2 mutations were found. Unlike participants with ALS from the Kii Peninsula, C9orf72 expansions do not cause ALS-PDC in Chamorros. Likewise, LRRK2 mutations do not cause Guam ALS-PDC.

Dang C.V.,University of Pennsylvania
Genes and Development | Year: 2012

Metabolism generates oxygen radicals, which contribute to oncogenic mutations. Activated oncogenes and loss of tumor suppressors in turn alter metabolism and induce aerobic glycolysis. Aerobic glycolysis or the Warburg effect links the high rate of glucose fermentation to cancer. Together with glutamine, glucose via glycolysis provides the carbon skeletons, NADPH, and ATP to build new cancer cells, which persist in hypoxia that in turn rewires metabolic pathways for cell growth and survival. Excessive caloric intake is associated with an increased risk for cancers, while caloric restriction is protective, perhaps through clearance of mitochondria or mitophagy, thereby reducing oxidative stress. Hence, the links between metabolism and cancer are multifaceted, spanning from the low incidence of cancer in large mammals with low specific metabolic rates to altered cancer cell metabolism resulting from mutated enzymes or cancer genes. © 2012 by Cold Spring Harbor Laboratory Press.

Amagai M.,Keio University | Stanley J.R.,University of Pennsylvania
Journal of Investigative Dermatology | Year: 2012

Much of the original research on desmosomes and their biochemical components was through analysis of skin and mucous membranes. The identification of desmogleins 1 and 3, desmosomal adhesion glycoproteins, as targets in pemphigus, a fatal autoimmune blistering disease of the skin and mucous membranes, provided the first link between desmosomes, desmogleins, and human diseases. The clinical and histological similarities of staphylococcal scalded skin syndrome or bullous impetigo and pemphigus foliaceus led us to identify desmoglein 1 as the proteolytic target of staphylococcal exfoliative toxins. Genetic analysis of striate palmoplantar keratoderma and hypotrichosis identified their responsible genes as desmogleins 1 and 4, respectively. More recently, these fundamental findings in cutaneous biology were extended beyond the skin. Desmoglein 2, which is expressed earliest among the four isoforms of desmoglein in development and found in all desmosome-bearing epithelial cells, was found to be mutated in arrythmogenic right ventricular cardiomyopathy and has also been identified as a receptor for a subset of adenoviruses that cause respiratory and urinary tract infections. The story of desmoglein research illuminates how dermatological research, originally focused on one skin disease, pemphigus, has contributed to understanding the biology and pathophysiology of many seemingly unrelated tissues and diseases. © 2012 The Society for Investigative Dermatology.

Coburn R.F.,University of Pennsylvania
Journal of Applied Physiology | Year: 2012

The measurement of endogenous carbon monoxide production. J Appl Physiol 112: 1949-1955, 2012. First published March 22, 2012; doi:10.1152/japplphysiol. 00174.2012.-Recent findings that heme oxygenase-1 can be induced by oxidative stress and inflammation in many different cellular systems, and that carbon monoxide (CO) produced as a by-product of this enzyme is a signaling molecule, have generated a major research area with hundreds of studies published over the last few years. The measurement of expired CO concentration has been used in humans as a biomarker of induced heme oxygenase resulting from inflammation or oxidative stress, but a precise method of measuring endogenous CO production that can be easily used to study patients is needed. The present study describes such a method. The described method allows calculation of the rate of heme catabolism with a precision of ± μmol/h, ∼ 10% of the mean normal rate in subjects used in this investigation. This method, which is subject-patient friendly, precise, and inexpensive to perform, should be applicable to studies performed on humans with induced heme oxygenase and studies of effects of therapy for inflammatory and hemolytic diseases. © 2012 the American Physiological Society.

Min S.H.,University of Pennsylvania
Blood | Year: 2013

Phosphatidylinositol and its phosphorylated derivatives, phosphoinositides, are minor constituents of phospholipids at the cellular membrane level. Nevertheless, phosphatidylinositol and phosphoinositides represent essential components of intracellular signaling that regulate diverse cellular processes, including platelet plug formation. Accumulating evidence indicates that the metabolism of phosphoinositides is temporally and spatially modulated by the opposing effects of specific phosphoinositide-metabolizing enzymes, including lipid kinases, lipid phosphatases, and phospholipases. Each of these enzymes generates a selective phosphoinositide or second messenger within precise cellular compartments. Intriguingly, phosphoinositide-metabolizing enzymes exist in different isoforms, which all produce the same phosphoinositide products. Recent studies using isoform-specific mouse models and chemical inhibitors have elucidated that the different isoforms of phosphoinositide-metabolizing enzymes have nonredundant functions and provide an additional layer of complexity to the temporo-spatial organization of intracellular signaling events. In this review, we will discuss recent advances in our understanding of phosphoinositide organization during platelet activation.

Schindler K.,University of Pennsylvania
Results and Problems in Cell Differentiation | Year: 2011

Oocytes arrest at prophase of meiosis I (MI) and in vivo do not resume meiosis until they receive ovulatory cues. Meiotic resumption entails two rounds of chromosome segregation without an intervening round of DNA replication and an arrest at metaphase of meiosis II (MII); fertilization triggers exit from MII and entry into interphase. During meiotic resumption, there is a burst of protein phosphorylation and dephosphorylation that dramatically changes during the course of oocyte meiotic maturation. Many of these phosphorylation and dephosphorylation events are key to regulating meiotic cell cycle arrest and/or progression, chromosome dynamics, and meiotic spindle assembly and disassembly. This review, which is subdivided into sections based upon meiotic cell cycle stages, focuses on the major protein kinases and phosphatases that have defined requirements during meiosis in mouse oocytes and, when possible, connects these regulatory pathways. © 2011 Springer-Verlag Berlin Heidelberg.

Jandali S.,University of Pennsylvania
Plastic and Reconstructive Surgery | Year: 2010

Background: Microvascular anastomosis is one of the more critical aspects of free flap surgery. A safe, effective, and expedient method for venous anastomosis minimizes flap ischemia time, is easier on the surgical team, and saves costly operating room time. The authors report on their experience using the Synovis microvascular anastomotic coupling device in 1000 consecutive venous anastomoses in free flap breast reconstruction. Methods: The authors retrospectively reviewed 1000 consecutive venous anastomoses that were performed using the microvascular anastomotic coupler between July of 2002 and July of 2008. Data were obtained on flap type, recipient vessel, coupler size, incidence of venous thrombosis, timing of venous thrombosis, and morbidity as a result of venous thrombosis. Results: All anastomoses were performed in an end-to-end fashion. There were 460 unilateral cases and 270 bilateral cases of breast reconstruction. Flap types included muscle-sparing free transverse rectus abdominis myocutaneous, deep inferior epigastric perforator, superficial inferior epigastric artery, superior gluteal artery perforator, and inferior gluteal artery perforator. The vast majority of the recipient vessels were the internal mammary or thoracodorsal vessels. Most of the couplers that were used were either 3 or 2.5 mm in diameter. Overall, there were six instances of venous thrombosis (rate of 0.6 percent). There were no total flap losses due to venous thrombosis in this series, although two patients had partial flap necrosis. Conclusions: The patency rate for venous anastomoses performed with the microvascular coupler is excellent when compared with standard suture techniques and has the advantage of overall easier application. Copyright © 2010 by the American Society of Plastic Surgeons.

Surti S.,University of Pennsylvania
Seminars in Nuclear Medicine | Year: 2013

Breast cancer mammography is a well-acknowledged technique for patient screening due to its high sensitivity. However, in addition to its low specificity the sensitivity of mammography is limited when imaging patients with dense breasts. Radionuclide imaging techniques, such as coincidence photon-based positron emission tomography and single photon emission computed tomography or scintimammography, can play a role in assisting screening of such patients. Radionuclide techniques can also be useful in assessing treatment response of patients with breast cancer to therapy, and staging of patients to diagnose the disease extent. However, the performance of these imaging modalities is generally limited because of the poor spatial resolution and sensitivity of the commercially available multipurpose imaging systems. Here, we describe some of the dedicated imaging systems (positron emission mammography [PEM] and breast-specific gamma imaging [BSGI]) that have been developed both commercially and in research laboratories for radionuclide imaging of breast cancer. Clinical studies with dedicated PEM scanners show improved sensitivity to detecting cancer in patients when using PEM in conjunction with additional imaging modalities, such as magnetic resonance imaging or mammography or both, as well as improved disease staging that can have an effect on surgical planning. High-resolution BSGI systems are more widely available commercially and several clinical studies have shown very high sensitivity and specificity in detecting cancer in high-risk patients. Further development of dedicated PEM and BSGI systems is ongoing, promising further expansion of radionuclide imaging techniques in the realm of breast cancer detection and treatment. © 2013 Elsevier Inc.

Shore E.M.,University of Pennsylvania
Wiley Interdisciplinary Reviews: Developmental Biology | Year: 2012

Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disease in which de novo osteogenesis-a developmental process occurring during embryonic skeletal formation-is induced aberrantly and progressively beginning during early childhood in soft connective tissues. Episodic initiation of spontaneous bone-forming lesions occurs over time, affecting a generally predictable sequence of body locations following a pattern similar to that of the developing embryonic skeleton. The heterotopic (extraskeletal) bone formation in FOP can also be induced by connective tissue injury. At the tissue level, an initial tissue degradation phase is followed by a tissue formation phase during which soft connective tissues are replaced by bone tissue through endochondral osteogenesis. This extraskeletal bone is physiologically normal and develops through the same series of tissue differentiation events that occur during normal embryonic skeletal development. The underlying genetic mutation in FOP alters the signals that regulate induction of cell differentiation leading to bone formation. In addition to postnatal heterotopic ossification, FOP patients show specific malformations of skeletal elements indicating effects on bone formation during embryonic development as well. Nearly all cases of FOP are caused by the identical mutation in the ACVR1 gene that causes a single amino acid substitution, R206H, in the bone morphogenetic protein (BMP) type I receptor ACVR1 (formerly known as ALK2). This mutation causes mild constitutive activation of the BMP signaling pathway and identifies ACVR1 as a key regulator of cell fate decisions and bone formation, providing opportunities to investigate previously unrecognized functions for this receptor during tissue development and homeostasis. © 2011 Wiley Periodicals, Inc.

Hunter A.,University of Pennsylvania
Investigative ophthalmology & visual science | Year: 2012

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Evidence suggests oxidative stress plays a role in the disease. To assess the potential contribution of epigenetic regulation of antioxidant genes relevant to AMD pathogenesis, we evaluated DNA methylation, a tissue-specific genetic modulation that affects gene expression. Using the Infinium HumanMethylation27 Illumina platform, we performed DNA bisulfite sequencing to compare the methylation status in postmortem retina pigment epithelium (RPE)/choroid between patients with AMD and age-matched controls. Gene expression was assessed with the Affymetrix Exon Array. TaqMan gene expression assays were used for relative quantification (RT-PCR) confirmation of the expression array results: Glutathione S-transferase isoform mu1 (GSTM1) and mu5 (GSTM5) promoter methylation was confirmed by CpG island bisulfite pyrosequencing. To assess protein levels and localization, we used Western analysis, immunohistochemistry, and immunofluorescence with murine and human samples. The mRNA levels of GSTM1 and GSTM5 were significantly reduced in AMD versus age-matched controls in RPE/choroid and neurosensory retina (NSR), which corresponded to hypermethylation of the GSTM1 promoter. mRNA and protein levels were decreased (RPE to a greater extent than NSR) in AMD postmortem samples, irrespective of age. Immunohistochemistry and immunofluorescence confirm the presence of the enzymes in the NSR and RPE. Comparison of DNA methylation, together with mRNA levels, revealed significant differences between AMD versus normal retinas. The evidence presented suggests that GSTM1 and GSTM5 undergo epigenetic repression in AMD RPE/choroid, which may increase susceptibility to oxidative stress in AMD retinas.

Ren D.,University of Pennsylvania
New England Journal of Medicine | Year: 2010

The transition from quiescence of the sperm in the epididymis to capacitation in the female reproductive tract depends on alkalinization of the intracellular milieu. A recent study underscores the role of a particular proton channel in the process of alkalinization. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

Sardesai N.Y.,Inovio Pharmaceuticals, Inc. | Weiner D.B.,University of Pennsylvania
Current Opinion in Immunology | Year: 2011

A number of noteworthy technology advances in DNA vaccines research and development over the past few years have led to the resurgence of this field as a viable vaccine modality. Notably, these include - optimization of DNA constructs; development of new DNA manufacturing processes and formulations; augmentation of immune responses with novel encoded molecular adjuvants; and the improvement in new in vivo delivery strategies including electroporation (EP). Of these, EP mediated delivery has generated considerable enthusiasm and appears to have had a great impact in vaccine immunogenicity and efficacy by increasing antigen delivery upto a 1000 fold over naked DNA delivery alone. This increased delivery has resulted in an improved in vivo immune response magnitude as well as response rates relative to DNA delivery by direct injection alone. Indeed the immune responses and protection from pathogen challenge observed following DNA administration via EP in many cases are comparable or superior to other well studied vaccine platforms including viral vectors and live/attenuated/inactivated virus vaccines. Significantly, the early promise of EP delivery shown in numerous pre-clinical animal models of many different infectious diseases and cancer are now translating into equally enhanced immune responses in human clinical trials making the prospects for this vaccine approach to impact diverse disease targets tangible. © 2011 Elsevier Ltd.

Kulesza A.,University of Michigan | Taskar B.,University of Pennsylvania
Foundations and Trends in Machine Learning | Year: 2012

Determinantal point processes (DPPs) are elegant probabilistic models of repulsion that arise in quantum physics and random matrix theory. In contrast to traditional structured models like Markov random fields, which become intractable and hard to approximate in the presence of negative correlations, DPPs offer efficient and exact algorithms for sampling, marginalization, conditioning, and other inference tasks. We provide a gentle introduction to DPPs, focusing on the intuitions, algorithms, and extensions that are most relevant to the machine learning community, and show how DPPs can be applied to real-world applications like finding diverse sets of high-quality search results, building informative summaries by selecting diverse sentences from documents, modeling nonoverlapping human poses in images or video, and automatically building timelines of important news stories. © 2012 A. Kulesza and B. Taskar.

Huh D.,University of Pennsylvania
Annals of the American Thoracic Society | Year: 2015

Here we describe a microphysiological system that replicates the functional unit of the living human lung. This human "breathing lung-on-a-chip" microdevice provides unique capabilities to reconstitute three-dimensional microarchitecture, dynamic mechanical activity, and integrated physiological function of the alveolar-capillary interface. We demonstrate the potential of this microengineered biomimetic model for screening environmental particulates and modeling complex human disease processes. Copyright © 2015 by the American Thoracic Society.

Sharp K.A.,University of Pennsylvania
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

The aqueous milieu inside cells contains as much as 30-40% dissolved protein and RNA by volume. This large concentration of macromolecules is expected to cause significant deviations from solution ideality. In vivo biochemical reaction rates and equilibria might differ significantly from those measured in the majority of in vitro experiments that are performed at much lower macromolecule concentrations. Consequently crowding, a nonspecific phenomenon believed to arise from the large excluded volume of these macromolecules, has been studied extensively by experimental and theoretical methods. However, the relevant theory has not been applied consistently. When the steric effects of macromolecular crowders and small molecules like water and ions are treated on an equal footing, the effect of the macromolecules is opposite to that commonly believed. Large molecules are less effective at crowding than water and ions. There is also a surprisingly weak dependence on crowder size. Molecules of medium size, ∼5 Å radius, have the same effect as much larger macromolecules like proteins and RNA. These results require a reassessment of observed high-concentration effects and of strategies to mimic in vivo conditions with in vitro experiments. © 2015, National Academy of Sciences. All rights reserved.

Fiester A.,University of Pennsylvania
American Journal of Bioethics | Year: 2015

Clinical ethics consultations (CECs) are sometimes deemed complete at the moment when the consultants make a recommendation. In CECs that involve actual ethical conflict, this view of a consult's endpoint runs the risk of overemphasizing the conflict's resolution at the expense of the consult's process, which can have deleterious effects on the various parties in the conflict. This overly narrow focus on reaching a decision or recommendation in consults that involve profound moral disagreement can result in two types of adverse, lingering sequelae: moral distress or negative moral emotions. The problem, succinctly named, is that such consults have insufficient “closure” for patients, families, and providers. To promote closure, and avoid the ills of moral distress and the moral emotions, I argue that CECs need to prioritize assisted conversation between the different stakeholders in these conflicts, what is often referred to as “bioethics mediation.” © 2015, Copyright © Taylor & Francis Group, LLC.

Ewing A.D.,Johns Hopkins University | Ewing A.D.,University of Pennsylvania | Kazazian Jr. H.H.,Johns Hopkins University
Genome Research | Year: 2011

High-throughput sequencing has recently begun to revolutionize the study of structural variants in the genomes of humans and other species. More recently, this technology and others have been applied to the study of human retrotransposon insertion polymorphisms (RIPs), yielding an unprecedented catalog of common and rare variants due to insertional mutagenesis. At the same time, the 1000 Genomes Project has released an enormous amount of whole-genome sequence data. In this article, we present evidence for 1016 L1 insertions across all studies to date that are not represented in the reference human genome assembly,many of which appear to be specific to populations or groups of populations, particularly Africans. Additionally, a cross-comparison of several studies shows that, on average, 27% of surveyed nonreference insertions is present in only one study, indicating the low frequency of many RIPs. © 2011 by Cold Spring Harbor Laboratory Press.

Apter A.J.,University of Pennsylvania
Journal of Allergy and Clinical Immunology | Year: 2015

In 2014, new biologic therapies are emerging for severe asthma based on identification of relevant phenotypes. The exploration of nutritional supplements to treat asthma has been less successful. © 2014 American Academy of Allergy, Asthma & Immunology.

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

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

Burdick J.A.,University of Pennsylvania | Murphy W.L.,University of Wisconsin - Madison
Nature Communications | Year: 2012

Hydrogels are water-swollen polymer networks that have found a range of applications from biological scaffolds to contact lenses. Historically, their design has consisted primarily of static systems and those that exhibit simple degradation. However, advances in polymer synthesis and processing have led to a new generation of dynamic systems that are capable of responding to artificial triggers and biological signals with spatial precision. These systems will open up new possibilities for the use of hydrogels as model biological structures and in tissue regeneration. © 2012 Macmillan Publishers Limited. All rights reserved.

Green L.V.,The New School | Savin S.,University of Pennsylvania | Lu Y.,The New School
Health Affairs | Year: 2013

Most existing estimates of the shortage of primary care physicians are based on simple ratios, such as one physician for every 2,500 patients. These estimates do not consider the impact of such ratios on patients' ability to get timely access to care. They also do not quantify the impact of changing patient demographics on the demand side and alternative methods of delivering care on the supply side. We used simulation methods to provide estimates of the number of primary care physicians needed, based on a comprehensive analysis considering access, demographics, and changing practice patterns. We show that the implementation of some increasingly popular operational changes in the ways clinicians deliver care-including the use of teams or "pods," better information technology and sharing of data, and the use of nonphysicians-have the potential to offset completely the increase in demand for physician services while improving access to care, thereby averting a primary care physician shortage. © 2013 Project HOPE-The People-to-People Health Foundation, Inc.

Farrar J.T.,University of Pennsylvania
Nature Medicine | Year: 2010

Pain is a ubiquitous phenomenon, but the experience of pain varies considerably from person to person. Advances in understanding of the growing number of pathophysiologic mechanisms that underlie the generation of pain and the influence of the brain on the experience of pain led to the investigation of numerous compounds for treating pain. Improved knowledge of the subjective nature of pain, the variations in the measurement of pain, the mind-body placebo effect and the impact of differences in the conduct of a clinical trial on the outcome have changed approaches to design and implement studies. Careful consideration of how these concepts affect the choice of study population, the randomization and blinding process, the measurement and collection of data, and the analysis and interpretation of results should improve the quality of clinical trials for potential pain therapies. © 2010 Nature America, Inc. All rights reserved.

Goldfine H.,University of Pennsylvania
Progress in Lipid Research | Year: 2010

Plasmalogens, 1-O-alk-1′-enyl 2-acyl glycerol phospholipids and glycolipids, seem to have evolved first in anaerobic bacteria, but they did not persist when facultative and aerobic species appeared after the concentration of oxygen increased in the early earth's history. Later, when aerobic animal cells appeared with their mitochondria and other intracellular organelles, plasmalogen biosynthesis requiring molecular oxygen, reappeared. The possible reasons for the disappearance and reappearance of plasmalogens in the evolution of life on earth are discussed. The sensitivity of plasmalogens to reactive oxygen species may have caused their disappearance when respiration first evolved. Special features of plasmalogen structure and the resulting lipid packing may account for their reappearance. © 2010 Elsevier Ltd. All rights reserved.

You J.,University of Pennsylvania
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2010

High-risk human papillomavirus (HPV) infection is the primary risk factor for cervical cancer. HPVs establish persistent infection by maintaining their genomes as extrachromosomal elements (episomes) that replicate along with host DNA in infected cells. The productive life cycle of HPV is intimately tied to the differentiation program of host squamous epithelium. This review examines the involvement of host chromatin in multiple aspects of the papillomavirus life cycle and the malignant progression of infected host cells. Papillomavirus utilizes host mitotic chromosomes as vehicles for transmitting its genetic materials across the cell cycle. By hitchhiking on host mitotic chromosomes, the virus ensures accurate segregation of the replicated viral episomes to the daughter cells during host cell division. This strategy allows persistent maintenance of the viral episome in the infected cells. In the meantime, the virus subverts the host chromatin-remodeling factors to promote viral transcription and efficient propagation of viral genomes. By associating with the host chromatin, papillomavirus redirects the normal cellular control of chromatin to create a cellular environment conducive to both its own survival and malignant progression of host cells. Comprehensive understanding of HPV-host chromatin interaction will offer new insights into the HPV life cycle as well as chromatin regulation. This virus-host interaction will also provide a paradigm for investigating other episomal DNA tumor viruses that share a similar mechanism for interacting with host chromatin.

Veasey S.C.,University of Pennsylvania | Morgan B.J.,University of Wisconsin - Madison | O'Donnell C.P.,University of Pittsburgh
Physiological Reviews | Year: 2010

Sleep-induced apnea and disordered breathing refers to intermittent, cyclical cessations or reductions of airflow, with or without obstructions of the upper airway (OSA). In the presence of an anatomically compromised, collapsible airway, the sleep-induced loss of compensatory tonic input to the upper airway dilator muscle motor neurons leads to collapse of the pharyngeal airway. In turn, the ability of the sleeping subject to compensate for this airway obstruction will determine the degree of cycling of these events. Several of the classic neurotransmitters and a growing list of neuromodulators have now been identified that contribute to neurochemical regulation of pharyngeal motor neuron activity and airway patency. Limited progress has been made in developing pharmacotherapies with acceptable specificity for the treatment of sleep-induced airway obstruction. We review three types of major long-term sequelae to severe OSA that have been assessed in humans through use of continuous positive airway pressure (CPAP) treatment and in animal models via long-term intermittent hypoxemia (IH): 1) cardiovascular. The evidence is strongest to support daytime systemic hypertension as a consequence of severe OSA, with less conclusive effects on pulmonary hypertension, stroke, coronary artery disease, and cardiac arrhythmias. The underlying mechanisms mediating hypertension include enhanced chemoreceptor sensitivity causing excessive daytime sympathetic vasoconstrictor activity, combined with overproduction of superoxide ion and inflammatory effects on resistance vessels. 2) Insulin sensitivity and homeostasis of glucose regulation are negatively impacted by both intermittent hypoxemia and sleep disruption, but whether these influences of OSA are sufficient, independent of obesity, to contribute significantly to the "metabolic syndrome" remains unsettled. 3) Neurocognitive effects include daytime sleepiness and impaired memory and concentration. These effects reflect hypoxic-induced "neural injury." We discuss future research into understanding the pathophysiology of sleep apnea as a basis for uncovering newer forms of treatment of both the ventilatory disorder and its multiple sequelae. Copyright © 2010 the American Physiological Society.

Carver J.R.,University of Pennsylvania
Progress in Cardiovascular Diseases | Year: 2010

Trastuzumab is the standard of care for the treatment of patients with ERB2-positive breast cancer. In a minority of patients, trastuzumab is associated with an increased incidence of cardiac dysfunction that ranges from asymptomatic decreases in left ventricular ejection fraction to symptomatic heart failure. In trials in the adjuvant setting, the difference in the incidence of cardiac events between the control and trastuzumab-containing arms was less than 4%. The baseline evaluation and oncologic setting (adjuvant versus metastatic disease) drive algorithms for the cardiac monitoring and management of these patients. When a patient develops documented left ventricular dysfunction, standard treatments for the management of heart failure should be prescribed. Trastuzumab cardiac dysfunction is an important clinical entity that can be managed effectively and individualized to maximize the cancer treatment benefit and minimize the risk and consequences of cardiac dysfunction. © 2010 Elsevier Inc.

O'Brien C.,University of Pennsylvania
Addiction | Year: 2011

As preparations for the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM) are under way, this paper focuses upon changes proposed for the substance use disorders section. It briefly outlines the history behind the current nomenclature, and the selection of the term 'dependence' over 'addiction' in earlier versions of the DSM. The term 'dependence', while used in past decades to refer to uncontrolled drug-seeking behavior, has an alternative meaning-the physiological adaptation that occurs when medications acting on the central nervous system are ingested with rebound when the medication is abruptly discontinued. These dual meanings have led to confusion and may have propagated current clinical practices related to under-treatment of pain, as physicians fear creating an 'addiction' by prescribing opioids. In part to address this problem, a change proposed for DSM-V is to alter the chapter name to 'Addiction and Related Disorders', which will include disordered gambling. The specific substance use disorders may be referred to as 'alcohol use' or 'opioid use' disorders. The criteria for the disorders are likely to remain similar, with the exception of removal of the 'committing illegal acts' criterion and addition of a 'craving' criterion. The other major change relates to the elimination of the abuse/dependence dichotomy, given the lack of data supporting an intermediate stage. These changes are anticipated to improve clarification and diagnosis and treatment of substance use and related disorders. © 2010 The Author, Addiction © 2010 Society for the Study of Addiction.

Liu J.,University of Pennsylvania
Aggression and Violent Behavior | Year: 2011

Violence and aggression are public health problems that can benefit from ongoing research into risk reduction and prevention. Current developmental theories of violence and aggression emphasize biological and psychosocial factors, particularly during adolescence. However, there has been less focus on understanding the interactive, multiplicative effects of these processes. Furthermore, little attention has been given to the pre-, peri-, and postnatal periods, where prevention and intervention may yield effective results. Early health risk factors that influence negative behavioral outcomes include prenatal and postnatal nutrition, tobacco use during pregnancy, maternal depression, birth complications, traumatic brain injury, lead exposure, and child abuse. There is an ample literature to suggest that these early health risk factors may increase the likelihood of childhood externalizing behaviors, aggression, juvenile delinquency, adult criminal behavior, and/or violence. This paper proposes an early health risk factors framework for violence prediction, built on existing developmental theories of criminal behavior and supported by empirical findings. This framework addresses gaps in the adolescent psychopathology literature and presents a novel conceptualization of behavioral disturbance that emphasizes the pre-, peri-, and post-natal periods, when a child's development is critical and the opportunity for behavioral and environmental modification is high. Implications for such a framework on violence prevention programs are discussed. © 2010 Elsevier Ltd.

Mele E.J.,University of Pennsylvania
Journal of Physics D: Applied Physics | Year: 2012

This paper reviews progress in the theoretical modelling of the electronic structure of rotationally faulted multilayer graphenes. In these systems the crystallographic axes of neighbouring layers are misaligned so that the layer stacking does not occur in the Bernal structure observed in three-dimensional graphite and frequently found in exfoliated bilayer graphene. Notably, rotationally faulted graphenes are commonly found in other forms of multilayer graphene including epitaxial graphenes thermally grown on SiC (0 0 0 1̄), graphemes grown by chemical vapour deposition, folded mechanically exfoliated graphenes, and graphene flakes deposited on graphite. Rotational faults are experimentally associated with a strong reduction of the energy scale for coherent single particle interlayer motion. The microscopic basis for this reduction and its consequences have attracted significant theoretical attention from several groups that are highlighted in this review. © 2012 IOP Publishing Ltd.

Liu W.,University of Pennsylvania
Cell Death and Differentiation | Year: 2014

Bromodomain-containing protein 4 (BRD4) is an important epigenetic reader implicated in the pathogenesis of a number of different cancers and other diseases. Brd4-null mouse embryos die shortly after implantation and are compromised in their ability to maintain the inner cell mass, which gives rise to embryonic stem cells (ESCs). Here we report that BRD4 regulates expression of the pluripotency factor Nanog in mouse ESCs and preimplantation embryos, as well as in human ESCs and embryonic cancer stem cells. Inhibition of BRD4 function using a chemical inhibitor, small interfering RNAs, or a dominant-negative approach suppresses Nanog expression, and abolishes the self-renewal ability of ESCs. We also find that BRD4 associates with BRG1 (brahma-related gene 1, aka Smarca4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4)), a key regulator of ESC self-renewal and pluripotency, in the Nanog regulatory regions to regulate Nanog expression. Our study identifies Nanog as a novel BRD4 target gene, providing new insights for the biological function of BRD4 in stem cells and mouse embryos. Knowledge gained from these non-cancerous systems will facilitate future investigations of how Brd4 dysfunction leads to cancers.Cell Death and Differentiation advance online publication, 22 August 2014; doi:10.1038/cdd.2014.124.

Hoxie J.A.,University of Pennsylvania
Annual Review of Medicine | Year: 2010

Developing an HIV-1 vaccine that can elicit antibodies to prevent infection has been a formidable challenge. Although no single immunogen has generated antibodies that can neutralize diverse isolates, progress has been made in understanding (a) the structure of the HIV-1 envelope glycoprotein, which is targeted by neutralizing antibodies, (b) how HIV-1 evades antibodies made by an infected host, and (c) how rare monoclonal antibodies can exhibit broadly neutralizing activity. Advances in structural and molecular biology coupled with new approaches to isolate neutralizing antibodies from HIV-1-infected individuals are enhancing our understanding of what humoral immune responses will be required for a vaccine. This review summarizes progress in understanding the host antibody response to HIV-1 and current strategies for applying this information to develop an effective vaccine. © 2010 by Annual Reviews All rights reserved.

Bates S.,University of Pennsylvania
Cellular Physiology and Biochemistry | Year: 2010

Surfactant protein-A (SP-A) plays an important role in the clearance of surfactant from the lung alveolar space and in the regulation of surfactant secretion and uptake by type II pneumocytes in culture. Two pathways are important for the endocytosis of surfactant by type II cells and the intact lung, a receptor-mediated clathrin-dependent pathway and a non-clathrin, actin-mediated pathway. The critical role of the clathrin/receptor-mediated pathway in normal mice is supported by the finding that SP-A gene-targeted mice use the actin-dependent pathway to maintain normal clearance of surfactant. Addition of SP-A to the surfactant of the SP-A null mice "rescued" the phenotype, further emphasizing the essential role of the SP-A/receptor-mediated process in surfactant turnover. This review presents an overview of the structure of SP-A and its function in surfactant turnover. The evidence that the interaction of SP-A with type II cells is a receptor-mediated process is presented. A newly identified receptor for SP-A, P63/CKAP4, is described in detail, with elucidation of the specific structural features of this 63 kDa, nonglycosylated, highly coiled, transmembrane protein. The compelling evidence that P63 functions as a receptor for SP-A on type II cells is summarized. Regulation of P63 receptor density on the surface of pneumocytes may be a novel approach for the regulation of surfactant homeostasis by the lung. Copyright © 2010 S. Karger AG, Basel.

McDonald A.T.,University of Pennsylvania
Cretaceous Research | Year: 2012

Dollodon bampingi was recently named based upon a specimen from the Bernissart Quarry that had previously been referred to Mantellisaurus atherfieldensis. The initial diagnosis of Dollodon did not adequately distinguish it from Mantellisaurus or from other basal iguanodonts, necessitating a reassessment of the material. Firsthand examination of the holotypes of the two taxa and numerous other basal iguanodont specimens, as well as a principal components analysis of basal iguanodont dentaries, did not find any morphological features to justify the distinction of Dollodon from Mantellisaurus. D. bampingi is thus best considered a junior synonym of M. atherfieldensis. Furthermore, the recent referral of the species Iguanodon seelyi to the genus Dollodon is not supported; I. seelyi is indistinguishable from Iguanodon bernissartensis, and is considered a junior synonym of that species. Finally, the recently named taxon Proplanicoxa galtoni, also based upon a specimen formerly attributed to M. atherfieldensis, is considered a nomen dubium and probable junior synonym of M. atherfieldensis. Thus, only two species of large-bodied basal iguanodont should be recognized from the Barremian-Aptian of England and Belgium: M. atherfieldensis and I. bernissartensis. © 2011 Elsevier Ltd.

Paschos G.K.,University of Pennsylvania
Frontiers in Pharmacology | Year: 2015

Metabolic processes exhibit diurnal variation from cyanobacteria to humans. The circadian clock is thought to have evolved as a time keeping system for the cell to optimize the timing of metabolic events according to physiological needs and environmental conditions. Circadian rhythms temporally separate incompatible cellular processes and optimize cellular and organismal fitness. A modern 24 h lifestyle can run at odds with the circadian rhythm dictated by our molecular clocks and create desynchrony between internal and external timing. It has been suggested that this desynchrony compromises metabolic homeostasis and may promote the development of obesity (Morris et al., 2012). Here we review the evidence supporting the association between circadian misalignment and metabolic homeostasis and discuss the role of feeding time. © 2015 Paschos.

Svitkina T.M.,University of Pennsylvania
Current Opinion in Cell Biology | Year: 2013

The actin cytoskeleton is the major force-generating machinery in the cell, which can produce pushing, pulling, and resistance forces. To accomplish these diverse functions, actin filaments, with help of numerous accessory proteins, form higher order ensembles, networks and bundles, adapted to specific tasks. Moreover, dynamic properties of the actin cytoskeleton allow a cell to constantly build, renew, and redesign actin structures according to its changing needs. High resolution architecture of actin filament arrays provides key information for understanding mechanisms of force generation. To generate pushing force, cells use coordinated polymerization of multiple actin filaments organized into branched (dendritic) networks or parallel bundles. This review summarizes our current knowledge of the structural organization of these two actin filament arrays. © 2013 Elsevier Ltd.

Bashaw G.J.,University of Pennsylvania
Cold Spring Harbor perspectives in biology | Year: 2010

Determining how axon guidance receptors transmit signals to allow precise pathfinding decisions is fundamental to our understanding of nervous system development and may suggest new strategies to promote axon regeneration after injury or disease. Signaling mechanisms that act downstream of four prominent families of axon guidance cues--netrins, semaphorins, ephrins, and slits--have been extensively studied in both invertebrate and vertebrate model systems. Although details of these signaling mechanisms are still fragmentary and there appears to be considerable diversity in how different guidance receptors regulate the motility of the axonal growth cone, a number of common themes have emerged. Here, we review recent insights into how specific receptors for each of these guidance cues engage downstream regulators of the growth cone cytoskeleton to control axon guidance.

Ewbank D.,University of Pennsylvania
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2016

Estimates of the speed of evolution between generations depend on the association between individual traits and ameasure of fitness. The twomost frequently used measures of fitness are the net reproduction rate and the 1-year growth factor implied by the fertility and mortality rates. Results based on the two lead to very different results. The reason is that the 1-year growth factor is not a measure of change between generations. Therefore, studies of changes between generations should use the amount of growth over the length of a generation. This is especially important for studies of human populations because of the long length of generation. In addition, estimates based on a single year’s growth are overly sensitive to data on individuals who fail to reproduce. The effects of using a generational measure are demonstrated using data from Kenya and Ukraine. These results demonstrate that using a 1-year growth rate to measure fitness leads to estimates that understate the rate at which evolution changes the characteristics of a human population. © 2016 The Author(s) Published by the Royal Society. All rights reserved.

Kim H.Y.,Indiana University - Purdue University Indianapolis | Walsh P.J.,University of Pennsylvania
Accounts of Chemical Research | Year: 2012

Cyclopropanes occur in a diverse array of natural products, including pheromones, steroids, terpenes, fatty acid metabolites, and amino acids, and compounds that contain cyclopropanes exhibit interesting and important pharmacological properties. These valuable synthetic intermediates can be functionalized, or their rings can be opened, and the synthetic utility and unique biological activity of cyclopropanes have inspired many investigations into their preparation. One of the most powerful methods to generate cyclopropanes is the Simmons-Smith cyclopropanation. Since the original studies in the late 1950s reported that IZnCH2I could transform alkenes into cyclopropanes, researchers have introduced various modifications of the original procedure. Significantly, Furukawa demonstrated that diethylzinc and CH 2I2 react to generate carbenoids, and Shi described more reactive zinc carbenoids that contain electron-withdrawing groups on zinc (XZnCHI2). Despite these advances, the development of catalytic asymmetric Simmons-Smith reactions remains challenging. Although researchers have achieved catalytic asymmetric cyclopropanation of allylic alcohols, these reactions have had limited success. One attractive approach to the synthesis of cyclopropanes involves tandem reactions, where researchers carry out sequential synthetic transformations without the isolation or purification of intermediates. Such a synthetic strategy minimizes difficulties in the handling and purification of reactive intermediates and maximizes yields and the generation of molecular complexity.This Account summarizes our recent effort in the one-pot enantio- and diastereoselective synthesis of cyclopropyl alcohols. In one approach, an asymmetric alkyl addition to α,β-unsaturated aldehydes or asymmetric vinylation of aliphatic or aromatic aldehydes generates allylic zinc alkoxide intermediates. Directed diastereoselective cyclopropanation of the resulting alkoxide intermediates using in situ generated zinc carbenoids provides cyclopropyl or halocyclopropyl alcohols with high enantio-, diastereo-, and chemoselectivity. Other strategies employ bimetallic reagents such as 1-alkenyl-1,1-heterobimetallics or CH2(ZnI) 2 and provide access to di- and trisubstituted cyclopropyl alcohols. These methods enable facile access to skeletally diverse chiral cyclopropyl alcohols in high yields and stereoselectivities without the isolation or purification of the intermediates. © 2012 American Chemical Society.

Huisman E.M.,Leiden University | Lubensky T.C.,University of Pennsylvania
Physical Review Letters | Year: 2011

We numerically investigate deformations and modes of networks of semiflexible biopolymers as a function of crosslink coordination number z and strength of bending and stretching energies. In equilibrium filaments are under internal stress, and the networks exhibit shear rigidity below the Maxwell isostatic point. In contrast to two-dimensional networks, ours exhibit nonaffine bending-dominated response in all rigid states, including those near the maximum of z=4 when bending energies are less than stretching ones. © 2011 American Physical Society.

Koffel E.A.,University of Minnesota | Koffel J.B.,University of Minnesota | Gehrman P.R.,University of Pennsylvania
Sleep Medicine Reviews | Year: 2015

Insomnia is the most common sleep disorder among the general population. Although cognitive behavioral therapy for insomnia (CBT-I) is the psychological treatment of choice, the availability of individual therapy is often not sufficient to meet the demand for treatment. Group treatment can increase the efficiency of delivery, but its efficacy has not been well-established. Randomized controlled trials (RCTs) comparing group CBT-I to a control group in patients with insomnia were identified. A review of 670 unique citations resulted in eight studies that met criteria for analysis. Outcome variables included both qualitative (e.g., sleep quality) and quantitative (e.g., sleep diary) outcomes, as well as depression and pain severity, at both pre- to post-treatment and follow-up (3-12mo post-treatment). Overall, we found medium to large effect sizes for sleep onset latency, sleep efficiency, and wake after sleep onset and small effect sizes for pain outcomes. Effect sizes remained significant at follow-up, suggesting that treatment gains persist over time. Other variables, including total sleep time, sleep quality, and depression, showed significant improvements, but these findings were limited to the within treatment group analyses. It is clear that group CBT-I is an efficacious treatment. Implications for stepped care models for insomnia are discussed. © 2014.

Thom S.R.,University of Pennsylvania
Plastic and Reconstructive Surgery | Year: 2011

Background: This article outlines therapeutic mechanisms of hyperbaric oxygen therapy and reviews data on its efficacy for clinical problems seen by plastic and reconstructive surgeons. Methods: The information in this review was obtained from the peer-reviewed medical literature. Results: Principal mechanisms of hyperbaric oxygen are based on intracellular generation of reactive species of oxygen and nitrogen. Reactive species are recognized to play a central role in cell signal transduction cascades, and the discussion will focus on these pathways. Systematic reviews and randomized clinical trials support clinical use of hyperbaric oxygen for refractory diabetic wound-healing and radiation injuries; treatment of compromised flaps and grafts and ischemia-reperfusion disorders is supported by animal studies and a small number of clinical trials, but further studies are warranted. Conclusions: Clinical and mechanistic data support use of hyperbaric oxygen for a variety of disorders. Further work is needed to clarify clinical utility for some disorders and to hone patient selection criteria to improve cost efficacy. Copyright © 2010 by the American Society of Plastic Surgeons.

Brisson D.,University of Pennsylvania | Drecktrah D.,University of Montana | Eggers C.H.,Quinnipiac University | Samuels D.S.,University of Montana
Annual Review of Genetics | Year: 2012

The spirochetes in the Borrelia burgdorferi sensu lato genospecies group cycle in nature between tick vectors and vertebrate hosts. The current assemblage of B. burgdorferi sensu lato, of which three species cause Lyme disease in humans, originated from a rapid species radiation that occurred near the origin of the clade. All of these species share a unique genome structure that is highly segmented and predominantly composed of linear replicons. One of the circular plasmids is a prophage that exists as several isoforms in each cell and can be transduced to other cells, likely contributing to an otherwise relatively anemic level of horizontal gene transfer, which nevertheless appears to be adequate to permit strong natural selection and adaptation in populations of B. burgdorferi. Although the molecular genetic toolbox is meager, several antibiotic-resistant mutants have been isolated, and the resistance alleles, as well as some exogenous genes, have been fashioned into markers to dissect gene function. Genetic studies have probed the role of the outer membrane lipoprotein OspC, which is maintained in nature by multiple niche polymorphisms and negative frequency-dependent selection. One of the most intriguing genetic systems in B. burgdorferi is vls recombination, which generates antigenic variation during infection of mammalian hosts. © 2012 by Annual Reviews.

Winkelstein B.A.,University of Pennsylvania
Spine | Year: 2011

Study Design. A nonsystematic review of the literature.Objective. The objective was to present general schema for mechanisms of whiplash pain and review the role of animal models in understanding the development of chronic pain from whiplash injury.Summary of Background Data. Extensive biomechanical and clinical studies of whiplash have been performed to understand the injury mechanisms and symptoms of whiplash injury. However, only recently have animal models of this painful disorder been developed based on other pain models in the literature.Methods. A nonsystematic review was performed and findings were integrated to formulate a generalized picture of mechanisms by which chronic whiplash pain develops from mechanical tissue injuries.Results. The development of chronic pain from tissue injuries in the neck due to whiplash involves complex interactions between the injured tissue and spinal neuroimmune circuits. A variety of animal models are beginning to define these mechanisms.Conclusion. Continued work is needed in developing appropriate animal models to investigate chronic pain from whiplash injuries and care must be taken to determine whether such models aim to model the injury event or the pain symptoms. © 2011, Lippincott Williams & Wilkins.

Doty R.L.,University of Pennsylvania
Nature Reviews Neurology | Year: 2012

Olfactory dysfunction is among the earliest nonmotor features of Parkinson disease (PD). Such dysfunction is present in approximately 90% of early-stage PD cases and can precede the onset of motor symptoms by years. The mechanisms responsible for olfactory dysfunction are currently unknown. As equivalent deficits are observed in Alzheimer disease, Down syndrome, and the Parkinson - dementia complex of Guam, a common pathological substrate may be involved. Given that olfactory loss occurs to a lesser extent or is absent in disorders such as multiple system atrophy, corticobasal degeneration, and progressive supranuclear palsy, olfactory testing can be useful in differential diagnosis. The olfactory dysfunction in PD and a number of related diseases with smell loss correlates with decreased numbers of neurons in structures such as the locus coeruleus, the raphe nuclei, and the nucleus basalis of Meynart. These neuroanatomical findings, together with evidence for involvement of the autonomic nervous system in numerous PD-related symptoms, suggest that deficits in cholinergic, noradrenergic and serotonergic function may contribute to the olfactory loss. This Review discusses the current understanding of olfactory dysfunction in PD, including factors that may be related to its cause. © 2012 Macmillan Publishers Limited. All rights reserved.

FitzGerald G.A.,University of Pennsylvania
Science Translational Medicine | Year: 2016

Biomarker tests for molecularly targeted therapies might be the key to unlocking the entry gate to precision medicine. © 2016, American Association for the Advancement of Science. All rights reserved.

Shorter J.,University of Pennsylvania
Molecular BioSystems | Year: 2010

Drug resistance is a refractory barrier in the battle against many fatal diseases caused by rapidly evolving agents, including HIV, apicomplexans and specific cancers. Emerging evidence suggests that drug resistance might extend to lethal prion disorders and related neurodegenerative amyloidoses. Prions are self-replicating protein conformers, usually 'cross-β' amyloid polymers, which are naturally transmitted between individuals and promote phenotypic change. Prion conformers are catalytic templates that specifically convert other copies of the same protein to the prion form. Once in motion, this chain reaction of conformational replication can deplete all non-prion copies of a protein. Typically, prions exist as ensembles of multiple structurally distinct, self-replicating forms or 'strains'. Each strain confers a distinct phenotype and replicates at different rates depending on the environment. As replicators, prions are units of selection. Thus, natural selection inescapably enriches or depletes various prion strains from populations depending on their conformational fitness (ability to self-replicate) in the prevailing environment. The most successful prions confer advantages to their host as with numerous yeast prions. Here, I review recent evidence that drug-like small molecules can antagonize some prion strains but simultaneously select for drug-resistant prions composed of mammalian PrP or the yeast prion protein, Sup35. For Sup35, the drug-resistant strain configures original intermolecular amyloid contacts that are not ordinarily detected. Importantly, a synergistic small-molecule cocktail counters prion diversity by eliminating multiple Sup35 prion strains. Collectively, these advances illuminate the plasticity of prionogenesis and suggest that synergistic combinatorial therapies might circumvent this pathological vicissitude. © The Royal Society of Chemistry 2010.

Hammers C.M.,University of Pennsylvania
Journal of Investigative Dermatology | Year: 2014

Pemphigus vulgaris (PV) is a prototypic tissue-specific autoantibody-mediated disease, in which anti-desmoglein 3 (Dsg3) IgG autoantibodies cause life-threatening blistering. We characterized the autoimmune B-cell response over 14 patient years in two patients with active and relapsing disease, then in one of these patients after long-term remission induced by multiple courses of rituximab (anti-CD20 antibody). Characterization of the anti-Dsg3 IgG+ repertoire by antibody phage display (APD) and PCR indicated that six clonal lines persisted in patient 1 (PV3) over 5.5 years, with only one new clone detected. Six clonal lines persisted in patient 2 (PV1) for 4 years, of which five persisted for another 4.5 years without any new clones detected. However, after long-term clinical and serologic remission, ∼11 years after initial characterization, we could no longer detect any anti-Dsg3 clones in PV1 by APD. Similarly, in another PV patient, ∼4.5 years after a course of rituximab that induced long-term remission, anti-Dsg3 B-cell clones were undetectable. These data suggest that in PV a given set of non-tolerant B-cell lineages causes autoimmune diseases and that new sets do not frequently or continually escape tolerance. Therapy such as rituximab, aimed at eliminating these aberrant sets of lineages, may be effective for disease because new ones are unlikely to develop.Journal of Investigative Dermatology advance online publication, 21 August 2014; doi:10.1038/jid.2014.291.

Summary: This supplement presents the foundational elements for INFORMAS (International Network for Food and Obesity/non-communicable diseases Research, Monitoring and Action Support). As explained in the overview article by Swinburn and colleagues, INFORMAS has a compelling rationale and has set forth clear objectives, outcomes, principles and frameworks for monitoring and benchmarking key aspects of food environments and the policies and actions that influence the healthiness of food environments. This summary highlights the proposed monitoring approaches for the 10 interrelated INFORMAS modules: public and private sector policies and actions; key aspects of food environments (food composition, labelling, promotion, provision, retail, prices, and trade and investment) and population outcomes (diet quality). This ambitious effort should be feasible when approached in a step-wise manner, taking into account existing monitoring efforts, data sources, country contexts and capacity, and when adequately resourced. After protocol development and pilot testing of the modules, INFORMAS aims to be a sustainable, low-cost monitoring framework. Future directions relate to institutionalization, implementation and, ultimately, to leveraging INFORMAS data in ways that will bring key drivers of food environments into alignment with public health goals. © 2013 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of the International Association for the Study of Obesity.

Rosenbaum P.R.,University of Pennsylvania
Biometrika | Year: 2012

In a matched observational study of treatment effects, a sensitivity analysis asks about the magnitude of the departure from random assignment that would need to be present to alter the conclusions of an analysis that assumes that matching for measured covariates removes all bias. The reported degree of sensitivity to unmeasured biases depends on both the process that generated the data and the chosen methods of analysis, so a poor choice of method may lead to an exaggerated report of sensitivity to bias. This suggests the possibility of performing more than one analysis with a correction for multiple inference, say testing one null hypothesis using two or three different tests. In theory and in an example, it is shown that, in large samples, the gains from testing twice will often be large, because testing twice has the larger of the two design sensitivities of the component tests, and the losses due to correcting for two tests will often be small, because two tests of one hypothesis will typically be highly correlated, so a correction for multiple testing that takes this into account will be small. An illustration uses data from the U.S. National Health and Nutrition Examination Survey concerning lead in the blood of cigarette smokers. © 2012 Biometrika Trust.

Aronica E.,University of Amsterdam | Crino P.B.,University of Pennsylvania
Epilepsia | Year: 2011

Over the past decade, an increasing number of observations indicate that activation of inflammatory processes occurs in variety of focal epilepsies. Understanding the feature and consequences of neuroinflammation, including the contribution to development and perpetuation of seizures, as well as to mood or cognitive dysfunction, is a major requisite for delineating its role in epilepsy. The present article discusses the most recent observations supporting the involvement of the inflammatory response in human focal epilepsy. It also evaluates emerging evidence concerning the possibility to identify epilepsy-associated inflammatory biomarkers in cerebrospinal fluid and serum, as well as the potential application of neuroimaging approaches to study the inflammatory reactions in chronic epilepsy patients in vivo, aiming to improve the recognition of appropriate patient populations who might benefit from antiinflammatory or immunomodulatory therapies. © 2011 International League Against Epilepsy.

Minn A.J.,University of Pennsylvania
Trends in Immunology | Year: 2015

Much of our understanding on resistance mechanisms to conventional cancer therapies such as chemotherapy and radiation has focused on cell intrinsic properties that antagonize the detrimental effects of DNA and other cellular damage. However, it is becoming clear that the immune system and/or innate immune signaling pathways can integrate with these intrinsic mechanisms to profoundly influence treatment efficacy. In this context, recent evidence indicates that interferon (IFN) signaling has an important role in this integration by influencing immune and intrinsic/non-immune determinants of therapy response. However, IFN signaling can be both immunostimulatory and immunosuppressive, and the factors determining these outcomes in different disease settings are unclear. Here I discuss the regulation and molecular events in cancer that are associated with these dichotomous functions. © 2015 Elsevier Ltd.

Kaestner K.H.,University of Pennsylvania
Cell Metabolism | Year: 2014

The discovery of a potent mitogen for insulin-producing pancreatic β cells, optimistically termed "betatrophin," excited researchers and laypeople alike, promising a new therapeutic approach to diabetes. A recent "Matters Arising" report by Gusarova and colleagues (2014) places serious doubts on whether "betatrophin" plays any major role in β cell replication. © 2014 Elsevier Inc.

Weitz J.I.,McMaster University | Pollack C.V.,University of Pennsylvania
Thrombosis and Haemostasis | Year: 2015

Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used in the prevention and treatment of venous thromboembolism and in the prevention of stroke in patients with non-valvular atrial fibrillation. In phase III clinical trials and meta-analyses, the NOACs were at least as effective as vitamin K antagonists (VKAs) and were associated with a similar or lower incidence of major bleeding, including consistent and significant decreases in intracranial bleeding, although with an increase in gastrointestinal bleeding for some agents compared with VKAs. Subsequent real-world evidence supports these outcomes. Despite this, physicians have concerns about serious bleeding or emergencies because there are no specific reversal agents for the NOACs. However, in clinical trials, patients receiving NOACs generally had similar or better outcomes after these events than those taking VKAs. As with any bleeding, anticoagulant-related bleeding should first be stratified according to severity and location; risk can be minimised by ongoing assessment. Management protocols for NOAC-related bleeding are similar to those for VKAs but should take into account the pharmacological profile of the specific drug. Because of their short half-lives, NOAC-related mild bleeding can often be controlled by temporarily withholding treatment. More severe bleeding requires standard escalating haemodynamic support measures, and non-specific reversal agents can be considered in lifethreatening situations, based on limited clinical data. Specific and rapid reversal agents are not currently available for any oral anti - coagulant and restoration of coagulation may not necessarily lead to better outcomes. Nevertheless, specific NOAC reversal agents are in development and show promise in healthy volunteers. © Schattauer 2015.

Kandalaft L.E.,University of Pennsylvania
Current topics in microbiology and immunology | Year: 2011

Cancer immunotherapies have yielded promising results in recent years, but new approaches must be utilized if more patients are to experience the benefits of these therapies. Angiogenesis and the tumor endothelium confer unique immune privilege to a growing tumor, with significant effects on diverse immunological processes such as hematopoietic cell maturation, antigen presentation, effector T cell differentiation, cytokine production, adhesion, and T cell homing and extravasation. Here, we review the role of angiogenesis and the tumor endothelium on regulation of the antitumor immune response. We place particular emphasis on the role of vascular endothelial growth factor (VEGF) in the suppression of numerous immunological processes that control tumor progression. Further, we describe the unique crosstalk between the VEGF and endothelin systems, and how their interactions may shape the antitumor immune response. These insights establish new targets for combinatorial approaches to modify existing cancer immunotherapies.

Foa E.B.,University of Pennsylvania
Dialogues in Clinical Neuroscience | Year: 2010

Until the mid-1960s, obsessive-compulsive disorder (OCD) was considered to be treatment-resistant, as both psychodynamic psychotherapy and medication had been unsuccessful in significantly reducing OCD symptoms. The first real breakthrough came in 1966 with the introduction of exposure and ritual prevention. This paper will discuss the cognitive behavioral conceptualizations that influenced the development of cognitive behavioral treatments for OCD. There will be a brief discussion of the use of psychodynamic psychotherapy and early behavioral therapy, neither of which produced successful outcomes with OCD. The main part of the paper will be devoted to current cognitive behavioral therapy (CBT) with an emphasis on variants of exposure and ritual or response prevention (EX/RP) treatments, the therapy that has shown the most empirical evidence of its efficacy. © 2010, LLS SAS. All rights reserved.

Stambolian D.,University of Pennsylvania
Clinical Genetics | Year: 2013

Refractive errors, myopia and hyperopia, are the most common causes of visual impairment worldwide. Recent advances in genetics have been utilized to identify a wealth of genetic loci believed to contain susceptibility genes for refractive error (RE). The current genetic evidence confirms that RE is influenced by both common and rare variants with a significant environmental component. These studies argue that only by combining genetic and environmental knowledge with in vivo measurements of biological states will it be possible to understand the underlying biology of RE that will lead to novel therapeutic targets and accurate genetic predictions. © 2013 John Wiley & Sons A/S.

Brown C.D.,University of Pennsylvania | Mangravite L.M.,Sage Bionetworks | Engelhardt B.E.,Duke University
PLoS Genetics | Year: 2013

Genetic variants in cis-regulatory elements or trans-acting regulators frequently influence the quantity and spatiotemporal distribution of gene transcription. Recent interest in expression quantitative trait locus (eQTL) mapping has paralleled the adoption of genome-wide association studies (GWAS) for the analysis of complex traits and disease in humans. Under the hypothesis that many GWAS associations tag non-coding SNPs with small effects, and that these SNPs exert phenotypic control by modifying gene expression, it has become common to interpret GWAS associations using eQTL data. To fully exploit the mechanistic interpretability of eQTL-GWAS comparisons, an improved understanding of the genetic architecture and causal mechanisms of cell type specificity of eQTLs is required. We address this need by performing an eQTL analysis in three parts: first we identified eQTLs from eleven studies on seven cell types; then we integrated eQTL data with cis-regulatory element (CRE) data from the ENCODE project; finally we built a set of classifiers to predict the cell type specificity of eQTLs. The cell type specificity of eQTLs is associated with eQTL SNP overlap with hundreds of cell type specific CRE classes, including enhancer, promoter, and repressive chromatin marks, regions of open chromatin, and many classes of DNA binding proteins. These associations provide insight into the molecular mechanisms generating the cell type specificity of eQTLs and the mode of regulation of corresponding eQTLs. Using a random forest classifier with cell specific CRE-SNP overlap as features, we demonstrate the feasibility of predicting the cell type specificity of eQTLs. We then demonstrate that CREs from a trait-associated cell type can be used to annotate GWAS associations in the absence of eQTL data for that cell type. We anticipate that such integrative, predictive modeling of cell specificity will improve our ability to understand the mechanistic basis of human complex phenotypic variation. © 2013 Brown et al.

Lee J.T.,Howard Hughes Medical Institute | Lee J.T.,Harvard University | Bartolomei M.S.,University of Pennsylvania
Cell | Year: 2013

X chromosome inactivation and genomic imprinting are classic epigenetic processes that cause disease when not appropriately regulated in mammals. Whereas X chromosome inactivation evolved to solve the problem of gene dosage, the purpose of genomic imprinting remains controversial. Nevertheless, the two phenomena are united by allelic control of large gene clusters, such that only one copy of a gene is expressed in every cell. Allelic regulation poses significant challenges because it requires coordinated long-range control in cis and stable propagation over time. Long noncoding RNAs have emerged as a common theme, and their contributions to diseases of imprinting and the X chromosome have become apparent. Here, we review recent advances in basic biology, the connections to disease, and preview potential therapeutic strategies for future development. © 2013 Elsevier Inc.

Chen X.,University of Pennsylvania
Child Development Perspectives | Year: 2012

This article discusses a contextual-developmental perspective that focuses on peer interaction as an important context that mediates the links between culture and socioemotional development. According to this perspective, cultural norms and values provide a basis for social evaluation processes in peer interaction, which, in turn, serve to regulate individual socioemotional functioning. Children play an active role in their development through their response to peer influence and through their participation in adopting existing cultures and constructing new cultures for social evaluation and other peer activities. Culture may also guide the social processes by specifying the functional and structural characteristics of children's peer relationships such as friendships and group networks in which interaction occurs. © 2011 The Author. Child Development Perspectives © 2011 The Society for Research in Child Development.

Livolsi V.A.,University of Pennsylvania
Modern Pathology | Year: 2011

The past two decades have seen numerous developments in the understanding of the origins and biology of papillary thyroid carcinoma. Advances in molecular biology, clinicopathologic studies of new entities, facility with fine-needle aspiration biopsy, and new radiologic imaging techniques have allowed for earlier diagnosis of these tumors. However, these advances have also caused controversies in cytologic and histopathologic diagnoses as well as therapy decisions. This paper will focus on several pathologic aspects of papillary carcinoma, which impact on its biology and prognosis. © 2011 USCAP, Inc. All rights reserved.

Mahatthananchai J.,ETH Zurich | Zheng P.,University of Pennsylvania | Bode J.W.,ETH Zurich
Angewandte Chemie - International Edition | Year: 2011

Caught in the act: Acyl azoliums have long been thought to be key reactive intermediates in N-heterocyclic carbene catalysis, but they have never been observed under catalytic conditions. Now, this has been successfully achieved by the characterization of α,β-unsaturated acyl azoliums (see scheme) using different spectroscopic techniques. Kinetic studies revealed the origin of their unexpected chemoselectivity in acylation and annulation reactions. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Takeshita J.,University of Pennsylvania
Journal of the American Heart Association | Year: 2014

Psoriasis, especially when severe, is a risk factor for cardiometabolic disease beyond traditional risk factors. The mechanism of atherogenesis in psoriasis remains unknown. Cell membrane vesicles (ie, microparticles), released upon cell activation or apoptosis, have recently been associated with cardiometabolic disease and may play a pathogenic role. Microparticle levels, particularly from endothelial cells and platelets, are elevated in patients with cardiovascular disorders, metabolic syndrome, other inflammatory diseases, autoimmune conditions, and have been shown to be predictive of cardiovascular outcomes. Concentrations of microparticles with positive expression for any of 7 cell surface markers (Annexin V, CD3, CD31, CD41a, CD64, CD105, and CD144) were measured in blood samples from psoriasis patients (n=53) and control subjects without psoriasis (n=41). Platelet-free plasma was separated from whole blood by one-step centrifugation for microparticle analysis. Microparticles were fluorescently labeled and characterized by flow cytometry. Higher concentrations of CD105 (5.5/μL versus 2.5/μL, P<0.001), CD31 (31/μL versus 18/μL, P=0.002), CD41a (50/μL versus 22/μL, P<0.001), and CD64 (5.0/μL versus 4.1/μL, P=0.02) singly positive microparticles corresponding to endothelial cell-, platelet-, and monocyte/macrophage-derived microparticles, respectively, were found in psoriasis patients compared with controls. These differences persisted after adjustment for traditional cardiometabolic risk factors including body mass index. Increased microparticle concentrations, independent of cardiometabolic risk factors, in patients with psoriasis suggest that the presence of increased endothelial cell, platelet, and monocyte/macrophage activation with cell turnover may contribute to the heightened atherogenesis associated with psoriasis.

Pyeritz R.E.,University of Pennsylvania
Current Opinion in Cardiology | Year: 2014

PURPOSE OF REVIEW: Disease of the wall of the thoracic aorta has many causes: inflammation, infection and atherosclerosis are the most common 'acquired' causes, but even these have genetic predispositions. This article deals with aortic disease due to mutations in specific genes. The conditions can affect tissues and organs other than the aorta (syndromic) or be limited to the aorta (nonsyndromic). RECENT FINDINGS: A classification scheme based on the gene is emerging, those that affect primarily the extracellular matrix (e.g., FBN1, COL3A1), TGF-β signaling (e.g., TGFBR1, TGFB2), or vascular smooth muscle cell contractility (e.g., ACTA2, MYH11). SUMMARY: Understanding pathogenesis is driving the development of novel therapies, such as angiotensin receptor blockade, which is in clinical trial. However, recurrent imaging, restriction of exercise, β-adrenergic blockade, and prophylactic surgery remain effective in preventing dissection and sudden death. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

The complement network is increasingly recognized as an important triage system that is able to differentiate between healthy host cells, microbial intruders, cellular debris and immune complexes, and tailor its actions accordingly. At the center of this triage mechanism is the alternative pathway C3 convertase (C3bBb), a potent enzymatic protein complex capable of rapidly converting the inert yet abundant component C3 into powerful effector fragments (C3a and C3b), thereby amplifying the initial response on unprotected surfaces and inducing a variety of effector functions. A fascinating molecular mechanism of convertase assembly and intrinsic regulation, as well as the interplay with a panel of cell surface-bound and soluble inhibitors are essential for directing complement attack to intruders and protecting healthy host cells. While efficiently keeping immune surveillance and homeostasis on track, the reliance on an intricate cascade of interaction and conversion steps also renders the C3 convertase vulnerable to derail. On the one hand, tissue damage, accumulation of debris, or polymorphisms in complement genes may unfavorably shift the balance between activation and regulation, thereby contributing to a variety of clinical conditions. On the other hand, pathogens developed powerful evasion strategies to avoid complement attack by targeting the convertase. Finally, we increasingly challenge our bodies with foreign materials such as biomaterial implants or drug delivery vehicles that may induce adverse effects that are at least partially caused by complement activation and amplification via the alternative pathway. The involvement of the C3 convertase in a range of pathological conditions put this complex into the spotlight of complement-targeted drug discovery efforts. Fortunately, the physiological regulation and microbial evasion approaches provide a rich source of inspiration for the development of powerful treatment options. This review provides insight into the current knowledge about the molecular mechanisms that drive C3 convertase activity, reveals common and divergent strategies of convertase inhibition employed by host and pathogens, and how this inhibitory arsenal can be tapped for developing therapeutic options to treat complement-related diseases. © 2012 Elsevier GmbH.

Milkman K.L.,University of Pennsylvania
Organizational Behavior and Human Decision Processes | Year: 2012

This paper examines the effect of uncertainty about the future on whether individuals select want options (e.g., junk foods, lowbrow films) or instead exert self-control and select should options (e.g., healthy foods, highbrow films). Consistent with the ego-depletion literature, which suggests that self-control resembles an exhaustible muscle, coping with uncertainty about what the future may bring reduces self-control resources and increases individuals' tendency to favor want options over should options. These results persist when real uncertainty is induced, when the salience of naturally-arising uncertainty is heightened and when individuals are able to make choices contingent upon the outcomes of uncertain events. Overall, this work suggests that reducing uncertainty in a decision maker's environment may have important spillover effects, leading to less impulsive choices. © 2012 Elsevier Inc.

Hoxie J.A.,University of Pennsylvania
Cold Spring Harbor perspectives in medicine | Year: 2012

Highly active antiretroviral therapy dramatically improves survival in HIV-infected patients. However, persistence of HIV in reservoirs has necessitated lifelong treatment that can be complicated by cumulative toxicities, incomplete immune restoration, and the emergence of drug-resistant escape mutants. Cell and gene therapies offer the promise of preventing progressive HIV infection by interfering with HIV replication in the absence of chronic antiviral therapy. Individuals homozygous for a deletion in the CCR5 gene (CCR5Δ32) are largely resistant to infection from R5-topic HIV-1 strains, which are most commonly transmitted. A recent report that an HIV-infected patient with relapsed acute myelogenous leukemia was effectively cured from HIV infection after transplantation of hematopoietic stem/progenitor cells (HSC) from a CCR5Δ32 homozygous donor has generated renewed interest in developing treatment strategies that target viral reservoirs and generate HIV resistance in a patient's own cells. Although the development of cell-based and gene transfer therapies has been slow, progress in a number of areas is evident. Advances in the fields of gene-targeting strategies, T-cell-based approaches, and HSCs have been encouraging, and a series of ongoing and planned trials to establish proof of concept for strategies that could lead to successful cell and gene therapies for HIV are under way. The eventual goal of these studies is to eliminate latent viral reservoirs and the need for lifelong antiretroviral therapy.

Penning T.M.,University of Pennsylvania
Chemical Research in Toxicology | Year: 2014

Aldo-keto reductases (AKRs) are promiscuous NAD(P)(H) dependent oxidoreductases implicated in the metabolic activation of polycyclic aromatic hydrocarbons (PAH). These enzymes catalyze the oxidation of non-K-region trans-dihydrodiols to the corresponding o-quinones with the concomitant production of reactive oxygen species (ROS). The PAH o-quinones are Michael acceptors and can form adducts but are also redox-active and enter into futile redox cycles to amplify ROS formation. Evidence exists to support this metabolic pathway in humans. The human recombinant AKR1A1 and AKR1C1-AKR1C4 enzymes all catalyze the oxidation of PAH trans-dihydrodiols to PAH o-quinones. Many human AKRs also catalyze the NADPH-dependent reduction of the o-quinone products to air-sensitive catechols, exacerbating ROS formation. Moreover, this pathway of PAH activation occurs in a panel of human lung cell lines, resulting in the production of ROS and oxidative DNA damage in the form of 8-oxo-2′-deoxyguanosine. Using stable-isotope dilution liquid chromatography tandem mass spectrometry, this pathway of benzo[a]pyrene (B[a]P) metabolism was found to contribute equally with the diol-epoxide pathway to the activation of this human carcinogen in human lung cells. Evaluation of the mutagenicity of anti-B[a]P-diol epoxide with B[a]P-7,8-dione on p53 showed that the o-quinone produced by AKRs was the more potent mutagen, provided that it was permitted to redox cycle, and that the mutations observed were G to T transversions, reminiscent of those observed in human lung cancer. It is concluded that there is sufficient evidence to support the role of human AKRs in the metabolic activation of PAH in human lung cell lines and that they may contribute to the causation of human lung cancer. © 2014 American Chemical Society.

Deriano L.,Institute Pasteur Paris | Roth D.B.,University of Pennsylvania
Annual Review of Genetics | Year: 2013

DNA double-strand breaks (DSBs) are common lesions that continually threaten genomic integrity. Failure to repair a DSB has deleterious consequences, including cell death. Misrepair is also fraught with danger, especially inappropriate end-joining events, which commonly underlie oncogenic transformation and can scramble the genome. Canonically, cells employ two basic mechanisms to repair DSBs: homologous recombination (HR) and the classical nonhomologous end-joining pathway (cNHEJ). More recent experiments identified a highly error-prone NHEJ pathway, termed alternative NHEJ (aNHEJ), which operates in both cNHEJ-proficient and cNHEJ-deficient cells. aNHEJ is now recognized to catalyze many genome rearrangements, some leading to oncogenic transformation. Here, we review the mechanisms of cNHEJ and aNHEJ, their interconnections with the DNA damage response (DDR), and the mechanisms used to determine which of the three DSB repair pathways is used to heal a particular DSB. We briefly review recent clinical applications involving NHEJ and NHEJ inhibitors. © 2013 by Annual Reviews. All rights reserved.

Millar J.S.,University of Pennsylvania
Current Opinion in Lipidology | Year: 2013

Purpose of review This review provides an overview of newly described mechanisms by which peroxisome proliferatoractivated receptors (PPARs) (α, γ, and σ) regulate several factors associated with cardiovascular risk. Recent findings PPAR agonists have known effects on plasma lipoprotein levels, inflammation, and insulin resistance all of which influence the risk of cardiovascular disease. Recent studies provide more detail regarding the mechanisms behind these changes. PPAR-α activation in the enterocyte on HDL and chylomicron formation. PPAR-γ agonists reduce inflammation, in part, through direct effects on adipocytes and regulatory T cells within visceral adipose. PPAR-σ also has a relatively high expression in the macrophage. Incubation of macrophages with PPAR-d agonists was shown to inhibit foam cell formation induced excessive levels of VLDL remnants. Summary Treatments that activate PPAR-α, PPAR-γ, and PPAR-σ alone or in combination have the potential to reduce cardiovascular risk although multiple independent mechanisms. Treatment with PPAR agonists can reduce the burden of atherogenic postprandial lipoproteins and improve vascular function, reduce inflammation and inhibit foam cell formation. All of these would be expected to have favorable effects on cardiovascular risk. The challenge remains to develop compounds that maximize these potential cardiovascular benefits while minimizing undesirable effects of these compounds. © 2013 Wolters Kluwer Health | Lippincott Williams amp; Wilkins.

Leone R.D.,University of Pennsylvania | Amaravadi R.K.,Abramson Cancer Center
Trends in Endocrinology and Metabolism | Year: 2013

Cancer cells display several features of aberrant cellular metabolism. Two consequences of this dysregulated metabolism are rapid depletion of intracellular nutrients and a buildup of aggregated proteins and damaged organelles. Autophagy provides a mechanism for recycling proteins, lipids, and organelles. In cancer cells, oncogenes and conditions of severe stress drive profound upregulation of autophagy. In this setting, autophagy ameliorates the ill effects of dysregulated cellular metabolism, allowing a steady supply of nutrients and removal of damaged organelles. Although therapeutic strategies targeting cancer cell metabolism and autophagy are already entering clinical trials, further study of the precise mechanisms of interplay between oncogenic signaling, cellular metabolism, and autophagy will provide more effective strategies in the future. © 2013 Elsevier Ltd.

Bin-Nun A.Y.,University of Pennsylvania
Classical and Quantum Gravity | Year: 2011

In recent years, there has been increasing recognition of the potential to use the galactic center as a probe of general relativity in the strong field. There is almost certainly a black hole at Sgr A* in the galactic center, and this would allow us to have the opportunity to probe dynamics near the exterior of the black hole. In the last decade, there has been theoretical research into extreme gravitational lensing in the galactic center. Unlike in most applications of gravitational lensing, where the bending angle is of the order of, at most, an arc minute, very large bending angles are possible for light that closely approaches a black hole. Photons may even loop multiple times around a black hole before reaching the observer. There have been many proposals to use light's close approach to the black hole as a probe of the black hole metric. Of particular interest are the properties of images formed from the light of S stars orbiting in the galactic center. This paper will review some of the attempts made to study extreme lensing as well as extend the analysis of S star lensing. In particular, we are interested in the effect of a Reissner-Nordstrom like 1/r2 term in the metric and how this would affect the properties of relativistic images. © 2011 IOP Publishing Ltd.

Sweeney H.L.,University of Pennsylvania | Houdusse A.,University Pierre and Marie Curie
Cell | Year: 2010

Myosin VI is the only type of myosin motor known to move toward the minus ends of actin filaments. This reversal in the direction of its movement is in part a consequence of the repositioning of its lever arm. In addition, myosin VI has a number of other specialized structural and functional adaptations that optimize performance of its unique cellular roles. Given that other classes of myosins may share some of these features, understanding the design principles of myosin VI will help guide the study of the functions of myosins that adopt similar strategies. © 2010 Elsevier Inc.

Nathanson K.L.,University of Pennsylvania
Biochemical Pharmacology | Year: 2010

Individualizing therapeutic selection for patients is a major goal in cancer treatment today. This goal is best facilitated by understanding both an individual's inherited genetic variation and the somatic genetic changes arising during cancer development. Clinical decision making based on inherited genetic variation is done for those patients with cancer susceptibility syndromes and more generally to personalize drug dosing. Personalized medicine based on genetic and genomic changes within tumors is being applied more widely, with increased use of therapies targeted to somatic mutations and amplifications. Somatic mutations associated with resistance also are being used to select against therapies. Somatic point mutation testing being used clinically includes direct sequencing, short sequencing and single nucleotide interrogation. Single amplifications are commonly assessed using FISH or CISH; high throughput assessment of amplifications and deletions is done mainly on a research basis. Melanomas contain complex mutational profiles that allow them to be sub-grouped by their genetic and genomic profile, each of which then can be evaluated pre-clinically to determine their response to targeted therapies. BRAF V600E mutations are the most common found in melanoma; specific inhibitors of mutant BRAF have been developed and are currently in clinical trials. In addition, other melanoma sub-groups have been identified genetically, which respond to other inhibitors. These studies focus on somatic genetic changes in cancer, which can be targeted directly by therapies. However in the future, personalized medicine will use a combination of inherited and somatic genetics to select the optimal tailored therapy for each patient. © 2010 Elsevier Inc.

Hunter C.A.,University of Pennsylvania | Kastelein R.,Merck Palo Alto CA
Immunity | Year: 2012

It has been more than 15 years since the identification of individual interleukin-27 (IL-27) and IL-27 receptor components. The last decade has seen the description of the signaling pathways engaged by IL-27, and an appreciation has emerged that this cytokine can modulate the intensity and duration of many classes of T cell responses. Here we provide an overview of the immunobiology of IL-27 and review advances in understanding the functions of individual IL-27 and IL-27 receptor subunits and the role of IL-27 in dictating the balance between protective and pathological immunity. Additionally, this cytokine has been proposed as a therapy to modify inflammatory conditions or to promote antitumor responses, and situations where experimental and clinical data sets implicate IL-27 in the outcome of disease are highlighted. © 2012 Elsevier Inc.

Lo Re 3rd. V.,University of Pennsylvania
Annals of internal medicine | Year: 2011

Adherence to therapy with pegylated interferon and ribavirin for hepatitis C virus (HCV) infection has been incompletely examined. To evaluate the relationship between adherence to HCV therapy and early and sustained virologic response, assess changes in adherence over time, and examine risk factors for nonadherence. Retrospective cohort study. National Veterans Affairs Hepatitis C Clinical Case Registry. 5706 HCV-infected patients (genotypes 1, 2, 3, or 4) with at least 1 prescription for both pegylated interferon and ribavirin between 2003 and 2006 and HCV RNA results before and after treatment initiation. Adherence was calculated over 12-week intervals by using pharmacy refill data. End points included early virologic response (decrease of ≥2 log(10) HCV RNA at 12 weeks) and sustained virologic response (undetectable HCV RNA 24 weeks after the end of treatment). Early virologic response increased with higher levels of adherence to ribavirin therapy over the initial 12 weeks (patients with HCV genotype 1 or 4, 25 of 68 [37%] with ≤40% adherence vs. 1367 of 2187 [63%] with 91% to 100% adherence [P < 0.001]; patients with HCV genotype 2 or 3, 12 of 18 [67%] with ≤40% adherence vs. 651 of 713 [91%] with 91% to 100% adherence [P < 0.001]). Among patients with HCV genotype 1 or 4, sustained response increased with higher adherence to ribavirin therapy over the second, third, and fourth 12-week intervals. Results were similar for adherence to interferon therapy. Mean adherence to therapy with interferon and ribavirin decreased by 3.4 and 6.6 percentage points per 12-week interval, respectively (P for trend < 0.001 for each drug). Patients who received growth factors or thyroid medications during treatment had higher mean adherence to antiviral therapy. This was an observational study without standardized timing for outcome measurements. Early and sustained virologic responses increased with higher levels of adherence to interferon and ribavirin therapy. Adherence to therapy with both antivirals decreased over time, but more so for ribavirin.

Chatterjee A.,University of Pennsylvania | Vartanian O.,University of Toronto
Trends in Cognitive Sciences | Year: 2014

Neuroaesthetics is an emerging discipline within cognitive neuroscience that is concerned with understanding the biological bases of aesthetic experiences. These experiences involve appraisals of natural objects, artifacts, and environments. Because aesthetic encounters are common in everyday life, exploration of their biological bases can deepen our understanding of human behavior in important domains such as mate selection, consumer behavior, communication, and art. We review recent evidence showing that aesthetic experiences emerge from the interaction between sensory-motor, emotion-valuation, and meaning-knowledge neural systems. Neuroaesthetics draws from and informs traditional areas of cognitive neuroscience including perception, emotion, semantics, attention, and decision-making. The discipline is at a historical inflection point and is poised to enter the mainstream of scientific inquiry. © 2014 Elsevier Ltd.

Bekker A.,University of Manitoba | Holland H.D.,University of Pennsylvania
Earth and Planetary Science Letters | Year: 2012

During the Lomagundi Event, ca. 2.22 to 2.06Ga, marine carbonates recorded the largest and longest uninterrupted positive carbon isotope excursion, the earliest extensive marine sulfate evaporites were deposited, and the average ferric iron to total iron (expressed as Fe 2O 3/∑Fe |Fe2O3|) ratio of shales increased dramatically. At the end of the Lomagundi Event, the first economic sedimentary phosphorites were deposited, and the carbon isotope values of marine carbonates returned to ~0% VPDB. Thereafter marine sulfate evaporites and phosphorites again became scarce, while the average Fe 2O 3/∑Fe |Fe2O3| ratio of shales decreased to values intermediate between those of the Archean and Lomagundi-age shales. We propose that the large isotopic and chemical excursions during the Lomagundi Event were caused by a positive feedback between the rise of atmospheric O 2, the weathering of sulfides in the pre-2.3Ga continental crust, and the flux of phosphate to the oceans (cf. Holland, 2002). The rise in the terrestrial phosphate flux led to an increase in the burial rate of organic carbon and a major transfer of oxygen from the carbon to the sulfur cycle.The end of the Lomagundi Event was probably caused by a decrease in the terrestrial phosphate flux related to the weathering of low-pyrite sediments that were deposited during the Lomagundi Event. The rate of deposition of organic matter and the precipitation of sulfate evaporites decreased, the isotopic and chemical excesses of the Lomagundi Event were eliminated, and the ocean-atmosphere system entered the period frequently called the Boring Billion. © 2011 Elsevier B.V.

Beiting D.P.,University of Pennsylvania
Trends in Parasitology | Year: 2014

Protozoan parasites, such as Plasmodium, Toxoplasma, Cryptosporidium, trypanosomes, and Leishmania, are a major cause of disease in both humans and other animals, highlighting the need to understand the full spectrum of strategies used by the host immune system to sense and respond to parasite infection. Although type II interferon (IFN-γ) has long been recognized as an essential antiparasite immune effector, much less is known about the role of type I interferons (IFN-α and -β) in host defense, particularly in vivo. Recent studies are reviewed which collectively highlight that type I IFN can be induced in response to parasite infection and influence the outcome of infection. © 2014 Elsevier Ltd.

Penning T.M.,University of Pennsylvania
Journal of Steroid Biochemistry and Molecular Biology | Year: 2011

Hydroxysteroid dehydrogenases (HSDs) represent a major class of NAD(P)(H) dependent steroid hormone oxidoreductases involved in the pre-receptor regulation of hormone action. This is achieved by HSDs working in pairs so that they can interconvert ketosteroids with hydroxysteroids resulting in a change in ligand potency for nuclear receptors. HSDs belong to two protein superfamilies the aldo-keto reductases and the short-chain dehydrogenase/reductases. In humans, many of the important enzymes have been thoroughly characterized including the elucidation of their three-dimensional structures. Because these enzymes play fundamental roles in steroid hormone action they can be considered to be drug targets for a variety of steroid driven diseases, e.g. metabolic syndrome and obesity, inflammation, and hormone dependent malignancies of the endometrium, prostate and breast. This article will review how fundamental knowledge of these enzymes can be exploited in the development of isoform specific HSD inhibitors from both protein superfamilies. Article from the Special issue on Targeted Inhibitors. © 2011 Elsevier Ltd. All rights reserved.

Desai R.A.,University of Pennsylvania
Journal of the Royal Society, Interface / the Royal Society | Year: 2013

Contact inhibition of locomotion (CIL) is the process whereby cells collide, cease migrating in the direction of the collision, and repolarize their migration machinery away from the collision. Quantitative analysis of CIL has remained elusive because cell-to-cell collisions are infrequent in traditional cell culture. Moreover, whereas CIL predicts mutual cell repulsion and 'scattering' of cells, the same cells in vivo are observed to undergo CIL at some developmental times and collective cell migration at others. It remains unclear whether CIL is simply absent during collective cell migration, or if the two processes coexist and are perhaps even related. Here, we used micropatterned stripes of extracellular matrix to restrict cell migration to linear paths such that cells polarized in one of two directions and collisions between cells occurred frequently and consistently, permitting quantitative and unbiased analysis of CIL. Observing repolarization events in different contexts, including head-to-head collision, head-to-tail collision, collision with an inert barrier, or no collision, and describing polarization as a two-state transition indicated that CIL occurs probabilistically, and most strongly upon head-to-head collisions. In addition to strong CIL, we also observed 'trains' of cells moving collectively with high persistence that appeared to emerge from single cells. To reconcile these seemingly conflicting observations of CIL and collective cell migration, we constructed an agent-based model to simulate our experiments. Our model quantitatively predicted the emergence of collective migration, and demonstrated the sensitivity of such emergence to the probability of CIL. Thus CIL and collective migration can coexist, and in fact a shift in CIL probabilities may underlie transitions between solitary cell migration and collective cell migration. Taken together, our data demonstrate the emergence of persistently polarized, collective cell movement arising from CIL between colliding cells.

Heller S.B.,University of Pennsylvania | Heller S.B.,University of Chicago
Science | Year: 2014

Every day, acts of violence injure more than 6000 people in the United States. Despite decades of social science arguing that joblessness among disadvantaged youth is a key cause of violent offending, programs to remedy youth unemployment do not consistently reduce delinquency. This study tests whether summer jobs, which shift focus from remediation to prevention, can reduce crime. In a randomized controlled trial among 1634 disadvantaged high school youth in Chicago, assignment to a summer jobs program decreases violence by 43% over 16 months (3.95 fewer violent-crime arrests per 100 youth). The decline occurs largely after the 8-week intervention ends. The results suggest the promise of using low-cost, well-targeted programs to generate meaningful behavioral change, even with a problem as complex as youth violence.

Fortune H.T.,University of Pennsylvania
Physical Review C - Nuclear Physics | Year: 2012

I have examined the B(E2)'s in 12Be connecting the first 2 + state to the first two 0 + states. I find that they can be understood in the simple model that has been successful for a variety of other observables in this nucleus, but only if the 2 + state has an excited-core component. © 2012 American Physical Society.

D'Antonio P.,University of Pennsylvania
American Journal of Public Health | Year: 2013

I examine the history of the East Harlem Nursing and Health Service in New York City from its beginnings as a demonstration project in 1922 to its closing in 1941. I explore the less tangible goals, needs, and ambitions of the many different constituents that paid for, delivered, and received health care services. I place these goals, needs, and ambitions as critically important drivers of ultimate success or failure. The East Harlem Nursing and Health Service gained international fame among public health leaders for its innovative and independent nursing practice and teaching. However, it ultimately failed because its commitment was to a particular disciplinary mission that did not meet the needs of the constituent communities it served. From 1928 to 1941, the service focused more on the educational advancement of public health nursing and less on addressing the real health care needs of those in East Harlem.

Cuker A.,University of Pennsylvania
Seminars in Thrombosis and Hemostasis | Year: 2012

Nearly 100 years after its discovery, unfractionated heparin (UFH) remains a widely used anticoagulant for the treatment of venous thromboembolism (VTE) and several other thrombotic and prothrombotic conditions. Decades of experience and investigation have contributed to our knowledge of this agent, but crucial questions regarding its optimal use in clinical practice remain unanswered. This review will critically examine the evidence for dosing and laboratory monitoring of UFH in the management of VTE, and highlight areas of uncertainty and future research. © 2012 by Thieme Medical Publishers, Inc.

OBJECTIVE: To review the available literature addressing the role of decitabine for the treatment of acute myeloid leukemia (AML). DATA SOURCES: Relevant literature was identified by a PubMed search (January 1970-March 2012) of English-language literature using the terms decitabine, acute myeloid leukemia, and DNA methyltransferase inhibitors. STUDY SELECTION AND DATA EXTRACTION: All published studies and abstracts, as well as relevant consensus guidelines, evaluating the current literature about the role of decitabine for the treatment of AML were included. DATA SYNTHESIS: Decitabine has been evaluated for the treatment of AML in several different settings. In patients with newly diagnosed AML who are not candidates for standard remission induction chemotherapy, a Phase 2 trial of decitabine administered for 5 days per cycle demonstrated a 24% complete remission rate (CR). A subsequent Phase 3 trial comparing decitabine and lowdose cytarabine or best supportive care in a similar patient population showed a greater CR rate (18% vs 8%; p = 0.001) but no overall survival benefit. A Phase 2 trial demonstrated a 47% CR rate with decitabine initially administered for 10 days per cycle, with subsequent doses customized to individual response and toxicity. This novel dosing schedule has yet to be evaluated in a Phase 3 trial. Decitabine is also being investigated for the treatment of relapsed/refractory AML and as bridge therapy to allogeneic hematopoietic stem cell transplantation. CONCLUSIONS: Decitabine offers a promising alternative therapeutic option for patients with AML who are not candidates for standard remission induction chemotherapy. Because of its acceptable safety profile, research is investigating the clinical benefit of decitabine in combination with other antileukemic therapies. The potential roles of decitabine in the treatment of AML continue to be explored in numerous clinical trials.

Context: Two vaccines to prevent Lyme disease (LD) were developed and tested in the 1990s. Despite evidence of their safety and efficacy in clinical trials and initial postmarketing surveillance, one vaccine was withdrawn before the regulatory review and the other after only three years on the market. An investigation of their history can illuminate (1) the challenges faced by many new risk-reducing products and practices and (2) the important role played by their social and psychological, as distinct from their biomedical or scientific, efficacy in how they are used, and their ultimate market success or failure. Methods: This article reviewed medical and popular literature on LD vaccines, analyzed the regulatory hearings, and conducted interviews with key participants. Findings: Even if proved safe and effective, LD vaccines faced regulatory and market challenges because the disease was geographically limited, treatable, and preventable by other means. Pharmaceutical companies nevertheless hoped to appeal to consumers' desire for protection and control and to their widespread fear of the disease. The LD advocacy community initially supported the vaccines but soon became critical opponents. The vaccines' success was seen as threatening their central position that LD was chronic, protean, and difficult to treat. The activists' opposition flipped the vaccines' social and psychological efficacy. Instead of the vaccines restoring control and reducing fear, demand was undermined by beliefs that the vaccines caused an LD-like syndrome. Conclusions: The social and psychological efficacy of many risk-reducing practices and products, such as new "personalized vaccines," is to provide insurance and reduce fear. Yet the actions of self-interested actors can easily undermine this appeal. In addition to evaluating the scientific efficacy and safety of these practices and products, policymakers and others need to understand, anticipate, and perhaps shape the potential social and psychological work they might do. © 2012 Milbank Memorial Fund.

Siegelman E.S.,University of Pennsylvania
Journal of Magnetic Resonance Imaging | Year: 2012

The article reviews current magnetic resonance imaging (MRI) techniques and illustrates the MRI features of the commonly encountered lesions of the adrenal gland. MR may not always be able to characterize an adrenal mass. In these instances, reviewing the patient's clinical history and prior imaging can usually differentiate benign from malignant lesions, even if you cannot establishing an exact tissue diagnosis. The reader is referred to other reviews of adrenal imaging that emphasizes the use of CT and imaging-management algorithms that are beyond the purview of this focused review (1-6). Copyright © 2012 Wiley Periodicals, Inc.

Maclean J.C.,University of Pennsylvania
Journal of Health Economics | Year: 2013

This study investigates the lasting health effects of leaving school in a bad economy. Three empirical patterns motivate this study: Leaving school in a bad economy has persistent and negative career effects, career and health outcomes are correlated, and fluctuations in contemporaneous economic conditions affect health in the short-run. I draw data from the National Longitudinal Survey of Youth 1979 Age 40 Health Supplement. Members of my sample left school between 1976 and 1992. I find that men who left school when the school-leaving state unemployment rate was high have worse health at age 40 than otherwise similar men, while leaving school in a bad economy lowers depressive symptoms at age 40 among women. A 1 percentage point increase in the school-leaving state unemployment rate leads to a 0.5% to 18% reduction in the measured health outcomes among men and a 6% improvement in depressive symptoms among women. © 2013 Elsevier B.V.

Bartolomei M.S.,University of Pennsylvania | Ferguson-Smith A.C.,University of Cambridge
Cold Spring Harbor Perspectives in Biology | Year: 2011

Normal mammalian development requires a maternal and paternal contribution, which is attributed to imprinted genes, or genes that are expressed from a single parental allele. Approximately 100 imprinted genes have been reported in mammals thus far. Imprinted genes are controlled by cis-acting regulatory elements, termed imprinting control regions (ICRs), which have parental-specific epigenetic modifications, including DNA methylation. ICRs are methylated by de novo DNA methyltransferases during germline development; these parental-specific modifications must be maintained following fertilization when the genome is extensively reprogrammed. Many imprinted genes reside in ~1-megabase clusters, with two major mechanisms of imprinting regulation currently recognized, CTCF-dependent insulators and long noncoding RNAs. Unclustered imprinted genes are generally regulated by germline-derived differential promoter methylation. Here, we describe the identification and functions of imprinted genes, cis-acting control sequences, trans-acting factors, and imprinting mechanisms in clusters. Finally, we define questions that require more extensive research. © 2011 Cold Spring Harbor Laboratory Press.

Cuker A.,University of Pennsylvania
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2010

Clinical scenario: An otherwise healthy 25-year-old woman returns to your office for management of chronic primary immune thrombocytopenia. She was diagnosed 6 months earlier and continues to require prednisone 15 mg daily and periodic infusions of intravenous immunoglobulin to maintain a hemostatic platelet count. You discuss second-line treatment options, including splenectomy. The patient asks if there are any means by which to predict likelihood of response to splenectomy. You have heard about the use of indium-labeled autologous platelet scanning for this purpose and wonder what the evidence shows.

Brass L.,University of Pennsylvania
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2010

The contribution of platelets to normal hemostasis and vascular disease is well described. However, recent studies make it clear that much remains to be learned about platelet activation at the single cell and the molecular level, and about the contribution of platelets to inflammation, tumor angiogenesis, and embryonic development. This article is divided into two themes. The first is an overview of current knowledge of the mechanisms that drive platelet function in vivo and a brief summary of some of the emerging ideas that are modifying older views. The second theme is a consideration of the strengths and weaknesses of the tools we have as hematologists to assess platelet function in the clinical setting, identify mechanisms, and evaluate the impact of antiplatelet agents.

Li H.,University of Pennsylvania
Wiley Interdisciplinary Reviews: Systems Biology and Medicine | Year: 2013

Systems biology approaches to epidemiological studies of complex diseases include collection of genetic, genomic, epigenomic, and metagenomic data in large-scale epidemiological studies of complex phenotypes. Designs and analyses of such studies raise many statistical challenges. This article reviews some issues related to integrative analysis of such high dimensional and inter-related datasets and outline some possible solutions. I focus my review on integrative approaches for genome-wide genetic variants and gene expression data, methods for joint analysis of genetic and epigenetic variants, and methods for analysis of microbiome data. Statistical methods such as mediation analysis, high-dimensional instrumental variable regression, sparse signal recovery, and compositional data regression provide potential frameworks for integrative analysis of these high-dimensional genomic data. © 2013 Wiley Periodicals, Inc.

Siderowf A.,University of Pennsylvania | Lang A.E.,University of Toronto
Movement Disorders | Year: 2012

Parkinson's disease (PD) has a prodromal phase during which nonmotor clinical features as well as physiological abnormalities may be present. These premotor markers could be used to screen for PD before motor abnormalities are present. The technology to identify PD before it reaches symptomatic Braak Stage 3 (substantia nigra compacta [SNc] involvement) already exists. The current challenge is to define the appropriate scope of use of predictive testing for PD. Imaging technologies such as dopamine transporter imaging currently offer the highest degree of accuracy for identifying premotor PD, but they are expensive as screening tools, and abnormalities on these studies would only be evident at Braak Stage 3 or higher. Efficiency is greatly enhanced by combining imaging with a prescreening test such as olfactory testing. This 2-step process has the potential to greatly reduce costs while retaining diagnostic accuracy. Alternatively, or in concert with this approach, evaluating high-risk populations (eg, patients with rapid eye movement behavior disorder or LRRK2 mutations) would enrich the sample for cases with underlying PD. Ultimately, the role of preclinical detection of PD will be determined by the ability of emerging therapies to influence clinical outcomes. As such, implementation of large-scale screening strategies awaits the arrival of clearly safe and effective therapies that address the underlying pathogenesis of PD. Future research will establish more definitive biomarkers capable of revealing the presence of disease in advance of SNc involvement with the promise of the potential for introducing disease-modifying therapy even before the development of evidence of dopamine deficiency. © 2012 Movement Disorder Society.

Zetterberg H.,Gothenburg University | Smith D.H.,University of Pennsylvania | Blennow K.,Gothenburg University
Nature Reviews Neurology | Year: 2013

Mild traumatic brain injury (TBI), which is defined as a head trauma resulting in a brief loss of consciousness and/or alteration of mental state, is usually benign, but occasionally causes persistent and sometimes progressive symptoms. Whether a threshold for the amount of brain injury and/or individual vulnerability might contribute to the development of these long-term consequences is unknown. Furthermore, reliable diagnostic methods that can establish whether a blow to the head has affected the brain (and in what way) are lacking. In this Review, we discuss potential biomarkers of injury to different structures and cell types in the CNS that can be detected in body fluids. We present arguments in support of the need for further development and validation of such biomarkers, and for their use in assessing patients with head trauma in whom the brain might have been affected. Specifically, we focus on the need for such biomarkers in the management of sports-related concussion, the most common cause of mild TBI in young individuals, to prevent long-term neurological sequelae due to concussive or subconcussive blows to the head. © 2013 Macmillan Publishers Limited. All rights reserved.

Stokes A.,University of Pennsylvania
Population Health Metrics | Year: 2014

Background: The high prevalence of disease and associated weight loss at older ages limits the validity of prospective cohort studies examining the association between body mass index (BMI) and mortality.Methods: I examined mortality associated with excess weight using maximum BMI-a measure that is robust to confounding by illness-induced weight loss. Analyses were carried out on US never-smoking adults ages 50-84 using data from the National Health and Nutrition Examination Surveys (1988-1994 and 1999-2004) linked to the National Death Index through 2006. Cox models were used to estimate hazard ratios for mortality according to BMI at time of survey and at maximum.Results: Using maximum BMI, hazard ratios for overweight (BMI, 25.0-29.9 kg/m2), obese class 1 (BMI, 30.0-34.9 kg/m2) and obese class 2 (BMI, 35.0 kg/m2 and above) relative to normal weight (BMI, 18.5-24.9 kg/m2) were 1.28 (95% confidence interval [CI], 0.89-1.84), 1.67 (95% CI, 1.15-2.40), and 2.15 (95% CI, 1.47-3.14), respectively. The corresponding hazard ratios using BMI at time of survey were 0.98 (95% CI, 0.77-1.24), 1.18 (95% CI, 0.91-1.54), and 1.31 (95% CI, 0.95-1.81). The percentage of mortality attributable to overweight and obesity among never-smoking adults ages 50-84 was 33% when assessed using maximum BMI. The comparable figure obtained using BMI at time of survey was substantially smaller at 5%. The discrepancy in estimates is explained by the fact that when using BMI at time of survey, the normal category combines low-risk stable-weight individuals with high-risk individuals that have experienced weight loss. In contrast, only the low-risk stable-weight group is categorized as normal weight using maximum BMI.Conclusions: Use of maximum BMI reveals that estimates based on BMI at the time of survey may substantially underestimate the mortality burden associated with excess weight in the US. © 2014 Stokes; licensee BioMed Central Ltd.

Roepke A.M.,University of Pennsylvania
Journal of Consulting and Clinical Psychology | Year: 2015

Objective: People commonly report growth after adversity. Can psychosocial intervention facilitate posttraumatic growth (PTG)? Method: This meta-analysis assesses the relationship between intervention participation and PTG using published and unpublished reports located with the database PsycINFO. Eligible studies included randomized controlled trials (k = 12) that provided a psychosocial intervention to people who had experienced an identifiable hardship or trauma (N = 1,171). None of these interventions were specifically designed to promote PTG as a primary outcome. Results: The overall controlled effect size (Hedges's g) of 0.36 (95% CI [0.23, 0.48]), using a fixed effects model, suggests that current interventions modestly increase PTG. Moderation analyses revealed little about the factors that increase interventions' effect on PTG, indicating only that interventions that administered the posttest soon after treatment tended to show larger effect sizes. Conclusions: Overall, these estimates may be unreliable due to the small number of eligible studies and the varied types of interventions tested, but they suggest that active intervention can help people make the most of adversity. © 2014 American Psychological Association.

Barlow D.P.,Austrian Academy of Sciences | Bartolomei M.S.,University of Pennsylvania
Cold Spring Harbor Perspectives in Biology | Year: 2014

Genomic imprinting affects a subset of genes in mammals and results in a monoallelic, parental-specific expression pattern. Most of these genes are located in clusters that are regulated through the use of insulators or long noncoding RNAs (lncRNAs). To distinguish the parental alleles, imprinted genes are epigenetically marked in gametes at imprinting control elements through the use of DNA methylation at the very least. Imprinted gene expression is subsequently conferred through lncRNAs, histone modifications, insulators, and higher-order chromatin structure. Such imprints are maintained after fertilization through these mechanisms despite extensive reprogramming of the mammalian genome. Genomic imprinting is an excellent model for understanding mammalian epigenetic regulation. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

Wilson D.F.,University of Pennsylvania
Journal of Applied Physiology | Year: 2013

Mitochondrial oxidative phosphorylation is programmed to set and maintain metabolic homeostasis. This is accomplished through an intrinsic program that determines the metabolic [ATP]/[ADP]/[Pi], where [Pi] is the concentration of inorganic phosphate (energy state) and maintains it through a bidirectional sensory/signaling control network that reaches every aspect of cellular metabolism. The program sets the energy state with high precision (to better than one part in 109) and can respond to transient changes in energy demand (ATP use) to more than 100 times the resting rate. Epigenetic and environmental factors are able to "fine tune" the programmed set point over a narrow range to meet the special needs associated with cell differentiation and chronic changes in metabolic requirements. The result is robust, across platform control of metabolism, essential to cellular differentiation and the evolution of complex organisms. Copyright © 2013 the American Physiological Society.

Pierce R.C.,University of Pennsylvania
Cold Spring Harbor perspectives in medicine | Year: 2013

Medium spiny neurons of the nucleus accumbens serve as the interface between corticolimbic regions that elicit and modulate motivated behaviors, including those related to drugs of abuse, and motor regions responsible for their execution. Medium spiny neurons are excited primarily by AMPA-type glutamate receptors, making AMPA receptor transmission in the accumbens a key regulatory point for addictive behaviors. In animal models of cocaine addiction, changes in the strength of AMPA receptor transmission onto accumbens medium spiny neurons have been shown to underlie cocaine-induced behavioral adaptations related to cocaine seeking. Here we review changes in AMPA receptor levels and subunit composition that occur after discontinuing different types of cocaine exposure, as well as changes elicited by cocaine reexposure following abstinence or extinction. Signaling pathways that regulate these cocaine-induced adaptations will also be considered, as they represent potential targets for addiction pharmacotherapies.

Li H.,University of Pennsylvania
Human Genetics | Year: 2012

Many common human diseases are complex and are expected to be highly heterogeneous, with multiple causative loci and multiple rare and common variants at some of the causative loci contributing to the risk of these diseases. Data from the genome-wide association studies (GWAS) and metadata such as known gene functions and pathways provide the possibility of identifying genetic variants, genes and pathways that are associated with complex phenotypes. Single-marker-based tests have been very successful in identifying thousands of genetic variants for hundreds of complex phenotypes. However, these variants only explain very small percentages of the heritabilities. To account for the locus- and allelic-heterogeneity, gene-based and pathway-based tests can be very useful in the next stage of the analysis of GWAS data. U-statistics, which summarize the genomic similarity between pair of individuals and link the genomic similarity to phenotype similarity, have proved to be very useful for testing the associations between a set of single nucleotide polymorphisms and the phenotypes. Compared to single marker analysis, the advantages afforded by the U-statistics-based methods is large when the number of markers involved is large. We review several formulations of U-statistics in genetic association studies and point out the links of these statistics with other similarity-based tests of genetic association. Finally, potential application of U-statistics in analysis of the next-generation sequencing data and rare variants association studies are discussed. © Springer-Verlag 2012.

Heasly B.S.,University of Pennsylvania
Journal of vision | Year: 2014

RenderToolbox3 provides MATLAB utilities and prescribes a workflow that should be useful to researchers who want to employ graphics in the study of vision and perhaps in other endeavors as well. In particular, RenderToolbox3 facilitates rendering scene families in which various scene attributes and renderer behaviors are manipulated parametrically, enables spectral specification of object reflectance and illuminant spectra, enables the use of physically based material specifications, helps validate renderer output, and converts renderer output to physical units of radiance. This paper describes the design and functionality of the toolbox and discusses several examples that demonstrate its use. We have designed RenderToolbox3 to be portable across computer hardware and operating systems and to be free and open source (except for MATLAB itself). RenderToolbox3 is available at https://github.com/DavidBrainard/RenderToolbox3.

Dang C.V.,University of Pennsylvania
Cell | Year: 2012

The MYC oncogene contributes to the genesis of many human cancers. Recent insights into its expression and function have led to therapeutic opportunities. MYC's activation by bromodomain proteins could be inhibited by drug-like molecules, resulting in tumor inhibition in vivo. Tumor growth can also be curbed by pharmacologically uncoupling bioenergetic pathways involving glucose or glutamine metabolism from Myc-induced cellular biomass accumulation. Other approaches to halt Myc on the path to cancer involve targeting Myc-Max dimerization or Myc-induced microRNA expression. Here the richness of our understanding of MYC is reviewed, highlighting new biological insights and opportunities for cancer therapies. © 2012 Elsevier Inc.

Hajishengallis G.,University of Pennsylvania
Molecular Oral Microbiology | Year: 2014

Summary: In periodontitis, dysbiotic microbial communities exhibit synergistic interactions for enhanced protection from host defenses, nutrient acquisition, and persistence in an inflammatory environment. This review discusses evidence that periodontitis-associated communities are 'inflammo-philic' (=loving or attracted to inflammation) in that they have evolved to not only endure inflammation but also to take advantage of it. In this regard, inflammation can drive the selection and enrichment of these pathogenic communities by providing a source of nutrients in the form of tissue breakdown products (e.g. degraded collagen peptides and heme-containing compounds). In contrast, those species that cannot benefit from the altered ecological conditions of the inflammatory environment, or for which host inflammation is detrimental, are likely to be outcompeted. Consistent with the concept that inflammation fosters the growth of dysbiotic microbial communities, the bacterial biomass of human periodontitis-associated biofilms was shown to increase with increasing periodontal inflammation. Conversely, anti-inflammatory treatments in animal models of periodontitis were shown to diminish the periodontal bacterial load, in addition to protecting from bone loss. The selective flourishing of inflammophilic bacteria can perpetuate inflammatory tissue destruction by setting off a 'vicious cycle' for disease progression, in which dysbiosis and inflammation reinforce each other. Therefore, the control of inflammation appears to be central to the treatment of periodontitis, as it is likely to control both dysbiosis and disease progression. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Marks M.S.,University of Pennsylvania | Heijnen H.F.G.,Laboratory of Clinical Chemistry and Haematology | Raposo G.,University Pierre and Marie Curie | Raposo G.,French National Center for Scientific Research
Current Opinion in Cell Biology | Year: 2013

Lysosome-related organelles (LROs) comprise a group of cell type-specific subcellular compartments with unique composition, morphology and structure that share some features with endosomes and lysosomes and that function in varied processes such as pigmentation, hemostasis, lung plasticity and immunity. In recent years, studies of genetic diseases in which LRO functions are compromised have provided new insights into the mechanisms of LRO biogenesis and the regulated secretion of LRO contents. These insights have revealed previously unappreciated specialized endosomal sorting processes in all cell types, and are expanding our views of the plasticity of the endosomal and secretory systems in adapting to cell type-specific needs. © 2013 Elsevier Ltd.

Berns J.S.,University of Pennsylvania
Clinical Journal of the American Society of Nephrology | Year: 2015

The development and widespread use of serum creatinine concentration-based prediction equations to calculate eGFR have been major advances for detection of patients with CKD and the epidemiologic study of CKD and its outcomes. However, these equations as well as those that also incorporate serum cystatin C concentration provide GFR estimates that, although reasonably precise on average, can differ markedly and in clinically important ways from actual GFR. Thus, it is important that clinicians who use these equations for clinical decisionmaking be familiar with their strengths andweaknesses and have an appreciation of their potential for error.More precise knowledge of actual GFR is important in certain clinical circumstances, including, as presented in this Attending Rounds, patients with stage 5 CKD, in whom decisions regarding dialysis initiation are necessary. Nephrologists should have the ability to accurately determine GFR when needed if clinical circumstances suggest inaccuracy of the calculated eGFR reported by the clinical laboratory. © 2015 by the American Society of Nephrology.

Gupta J.,University of Pennsylvania
Clinical journal of the American Society of Nephrology : CJASN | Year: 2012

Increased risk of mortality in patients with CKD has been attributed to inflammation. However, the association between kidney function, albuminuria, and biomarkers of inflammation has not been examined in a large cohort of CKD patients. This study measured the plasma levels of IL-1β, IL-1 receptor antagonist (IL-1RA), IL-6, TNF-α, TGF-β, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and serum albumin in 3939 participants enrolled in the Chronic Renal Insufficiency Cohort study between June 2003 and September 2008. An inflammation score was established based on plasma levels of IL-1β, IL-6, TNF-α, hs-CRP, and fibrinogen. Estimated GFR (eGFR) and serum cystatin C were used as measures of kidney function. Albuminuria was quantitated by urine albumin to creatinine ratio (UACR). Plasma levels of IL-1β, IL-1RA, IL-6, TNF-α, hs-CRP, and fibrinogen were higher among participants with lower levels of eGFR. Inflammation score was higher among those with lower eGFR and higher UACR. In regression analysis adjusted for multiple covariates, eGFR, cystatin C, and UACR were strongly associated with fibrinogen, serum albumin, IL-6, and TNF-α. Each unit increase in eGFR, cystatin C, and UACR was associated with a -1.2% (95% confidence interval, -1.4, -1), 64.9% (56.8, 73.3) and 0.6% (0.4, 0.8) change in IL-6, respectively (P<0.001). Biomarkers of inflammation were inversely associated with measures of kidney function and positively with albuminuria.

Patterson K.C.,University of Pennsylvania | Strek M.E.,University of Chicago
Chest | Year: 2014

Both inherited and acquired immunodeficiency and chronic pulmonary disease predispose to the development of a variety of pulmonary syndromes in response to Aspergillus, a fungus that is ubiquitous in the environment. These syndromes include invasive aspergillosis, which is now recognized to occur in patients with critical illness without neutropenia and in those with mild degrees of immunosuppression, including from corticosteroid use in the setting of COPD. Chronic pulmonary aspergillosis includes simple aspergilloma, which is occasionally complicated by life-threatening hemoptysis, and progressive destructive cavitary disease requiring antifungal therapy. Allergic bronchopulmonary aspergillosis occurs almost exclusively in patients with asthma or cystic fi brosis. Recent advances in each of these syndromes include a greater understanding of the underlying pathophysiology and hosts at risk; improved diagnostic algorithms; and the availability of more eff ective and well-tolerated therapies. Improvement in outcomes for Aspergillus pulmonary syndromes requires that physicians recognize the varied and sometimes subtle presentations, be aware of populations at risk of illness, and institute potentially life-saving therapies early in the disease course. © 2014 American College of Chest Physicians.

Naidoo N.,University of Pennsylvania
NeuroMolecular Medicine | Year: 2012

Sleep disturbances are contributing factors to health risk for several diseases including hypertension, diabetes, obesity, depression, and stroke. On a molecular level, sleep disturbances that incur sleep loss and sleep fragmentation result in cellular stress, inflammation, and an impaired immune system. It has been hypothesized that sleep deprivation or prolonged waking leads to increased energy demand and thus energetic stress. Sleep loss and sleep fragmentation are also known to lead to cellular stress specifically endoplasmic reticulum (ER) stress. This review will summarize the current knowledge of the roles of ER and energetic stress during sleep loss and fragmentation that are characteristics of many sleep disturbances. Sleep research pertinent to these specific pathways will be discussed. © 2012 Springer Science+Business Media, LLC.

Susztak K.,University of Pennsylvania
Journal of the American Society of Nephrology | Year: 2014

The cells in a human body have identical DNA sequences, yet the body has.200 cell types with different phenotypes. The basis for this nongenetic cellular memory, which records developmental and environmental cues, is epigenetics. The epigenome includes covalent modifications of the DNA and its associated proteins and defines DNA accessibility to the transcriptional machinery. Notably, the epigenome has emerged as an important mediator of the long-term programming effect of environmental exposure, and multiple lines of evidence point to the epigenome as an important missing link in our understanding of CKD development. For example, recent studies identified epigenetic differences in the enhancer regions of fibrosis-related genes in diseased human kidney samples. Furthermore, chromatin profiling and epigenome analysis are powerful tools for annotating gene regulatory regions that can be harnessed to interpret disease-causing polymorphisms for complex traits such as CKD. This reviewhighlights the results of studies investigating the renal epigenome and discusses the significance of these findings and future directions in the context of novel diagnostic and treatment strategies for CKD. Copyright © 2014 by the American Society of Nephrology.

Zhang Y.,University of Pennsylvania
Nature Structural and Molecular Biology | Year: 2016

Long noncoding RNAs (lncRNAs) play critical roles during tumorigenesis by functioning as scaffolds that regulate protein-protein, protein-DNA or protein-RNA interactions. Using a clinically guided genetic screening approach, we identified lncRNA in nonhomologous end joining (NHEJ) pathway 1 (LINP1), which is overexpressed in human triple-negative breast cancer. We found that LINP1 enhances repair of DNA double-strand breaks by serving as a scaffold linking Ku80 and DNA-PKcs, thereby coordinating the NHEJ pathway. Importantly, blocking LINP1, which is regulated by p53 and epidermal growth factor receptor (EGFR) signaling, increases the sensitivity of the tumor-cell response to radiotherapy in breast cancer. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Sharp P.M.,University of Edinburgh | Rayner J.C.,Wellcome Trust Sanger Institute | Hahn B.H.,University of Pennsylvania
Science | Year: 2013

Comparing the origins of AIDS and malaria may provide insight for gauging the prospect of future pathogen transmissions from apes to humans.

Morgan R.E.,University of Pennsylvania
Pediatric Obesity | Year: 2013

The consumption of high-fructose corn syrup (HFCS) beverages has increased since the 1970s. At the same time, childhood obesity is on the rise, causing children to be at risk of heart disease, diabetes and other diseases. Healthcare providers have attributed childhood obesity to the consumption of HFCS in the form of beverages. This article will look at the available research and determine if there is scientific evidence underlying the idea that sweetened soft drinks, especially those containing HFCS, could cause or contribute to childhood obesity. A thorough literature search was performed using the ISI Web of Sciences, PubMed and Scopus databases within the years 2006-2012. The search generated 19 results. The articles were screened, and six were deemed eligible: four systematic reviews and two meta-analyses. Two systematic reviews found that there is no relationship between consumption of HFCS beverages and obesity in children. The other two systematic reviews found possible links between HFCS and childhood obesity. The metaanalysis articles found that consumption of HFCS beverages can contribute to childhood obesity, and limitation of sweetened beverages may help decrease obesity in children. Available research studies demonstrate inconclusive scientific evidence definitively linking HFCS to obesity in children. © 2013 The Authors.

Sperling R.A.,Brigham and Womens Hospital | Karlawish J.,University of Pennsylvania | Johnson K.A.,Harvard University
Nature Reviews Neurology | Year: 2013

There is growing recognition that the pathophysiological process of Alzheimer disease (AD) begins many years prior to clinically obvious symptoms, and the concept of a presymptomatic or preclinical stage of AD is becoming more widely accepted. Advances in biomarker studies have enabled detection of AD pathology in vivo in clinically normal older individuals. The predictive value of these biomarkers at the individual patient level, however, remains to be elucidated. The ultimate goal of identifying individuals in the preclinical stages of AD is to facilitate early intervention to delay and perhaps even prevent emergence of the clinical syndrome. A number of challenges remain to be overcome before this concept can be validated and translated into clinical practice. © 2013 Macmillan Publishers Limited. All rights reserved.

Grandner M.A.,University of Pennsylvania
International Review of Psychiatry | Year: 2014

There is increasing awareness of the role of sleep disturbance as an important factor in health and disease. Although sub-clinical sleep disturbances (insufficient sleep duration or inadequate sleep quality) may be difficult to assess with conceptual and/or methodological clarity, this review attempts to summarize and synthesize these findings. First, the concept of sleep disturbance in a public health context is introduced, to provide context and rationale. Second, operational definitions of 'cardiometabolic disease' and 'sleep disturbance' are offered, to address many unclear operationalizations. Third, the extant literature is summarized regarding short or long sleep duration and/or insufficient sleep, insomnia and insomnia symptoms, general (non-specific sleep disturbances), circadian rhythm abnormalities that result in sleep disturbances, and, briefly, sleep-disordered breathing. Fourth, the review highlights the social/behavioural context of sleep, including discussions of sleep and race/ethnicity, socio-economic position, and other social/environmental factors, in order to place these findings in a social-environmental context relevant to public health. Fifth, the review highlights the issue of sleep as a domain of health behaviour and addresses issues regarding development of healthy sleep interventions. Finally, a research agenda of future directions is proposed. © 2014 Institute of Psychiatry.

Fortune H.T.,University of Pennsylvania
Physical Review C - Nuclear Physics | Year: 2013

Using a simple model for low-lying positive-parity resonances in 13Be as 10Be x (sd)3 and 12Be1p x (sd), I find that the lowest 5/2 + state is predominantly (sd)3. I give predictions for several additional states. © 2013 American Physical Society.

Vitek V.,University of Pennsylvania
Progress in Materials Science | Year: 2011

Computer modelling is at present as important method of the study of materials and their properties as experiments. Yet, experiments have been being performed for several thousands years while computer modelling started about fifty years ago. In this introductory paper we first present a historical account of the advancement of computer modelling. Since defects in crystalline materials control most of their properties but their atomic level structure and properties cannot be treated analytically, they provided the impetus for the advancement of computer modelling in materials science. In between the plethora of defects we concentrate here on dislocations since it was established via modelling that it is the non-planarity of the cores of screw dislocations in BCC metals which controls their plastic properties. This understanding than lead to the recognition that the non-planarity of dislocation cores is common in many materials and frequently determines their properties. This atomic level aspect of dislocations is considered in more details, not only for the BCC metals, and relation to the macroscopic plastic behaviour discussed. Computer modelling plays, of course, important role in studies of many other defects, such as interfaces, surfaces, irradiation induced defects etc., as well as glasses and liquids, and the last part of the paper is devoted to discussing the possible future developments, in particular from the point of view of available descriptions of atomic interactions that are the precursor of any atomistic modelling. © 2011 Elsevier Ltd. All rights reserved.

Marchlinski F.E.,University of Pennsylvania
Journal of the American College of Cardiology | Year: 2012

Objectives: This study sought to assess the value of left ventricular (LV) endocardial unipolar electroanatomical mapping (EAM) in identifying irreversibility of LV systolic dysfunction in patients with left ventricular nonischemic cardiomyopathy (LVCM). Background: Identifying irreversibility of LVCM would be helpful but cannot be reliably accomplished by bipolar EAM or cardiac magnetic resonance identification of macroscopic scar. Methods: Detailed endocardial LV EAM was performed in 3 groups: 1) 24 patients with irreversible LVCM (I-LVCM) but with no or minimal macroscopic scar (<15% LV surface) evidenced on bipolar voltage EAM and/or cardiac magnetic resonance; 2) 14 patients with reversible ventricular premature depolarization-mediated LVCM (R-LVCM); and 3) 17 patients with structurally normal hearts. LV endocardial unipolar electrogram amplitude and area of unipolar amplitude abnormality were defined after excluding macroscopic scar. Results: Unipolar amplitude differed in the 3 groups: median of 7.6 (interquartile range [IQR]: 5.5 to 9.7) mV in I-LVCM group, 13.2 (IQR: 10.4 to 16.2) mV in R-LVCM group, and 16.3 (IQR: 13.6 to 19.8) mV in structurally normal hearts group (p < 0.001). Areas of unipolar abnormality represented a large proportion of total LV surface in I-LVCM, 64.7% (IQR: 47.5% to 75.9%) compared with R-LVCM, 5.2% (IQR: 0.0% to 19.1%) and structurally normal hearts, 0.1% (IQR: 0.0% to 0.9%), groups (p < 0.001). A unipolar abnormality area cutoff of 32% of total LV surface was 96% sensitive and 100% specific in identifying irreversible cardiomyopathy among patients with LV dysfunction (I-LVCM and R-LVCM), p < 0.001. Conclusions: Detailed unipolar voltage mapping can identify irreversible myocardial dysfunction consistent with fibrosis, even in the absence of bipolar EAM or cardiac magnetic resonance abnormalities, and may serve as valuable prognostic tool in patients presenting with LVCM to facilitate clinical decision making. © 2012 American College of Cardiology Foundation.

Barton E.R.,University of Pennsylvania
Journal of Biological Chemistry | Year: 2010

Limb girdle muscular dystrophy 2C is caused by mutations in the γ-sarcoglycan gene (gsg) that results in loss of this protein, and disruption of the sarcoglycan (SG) complex. Signal transduction after mechanical perturbation is mediated, in part, through the SG complex and leads to phosphorylation of tyrosines on the intracellular portions of the sarcoglycans. This study tested if the Tyr6 in the intracellular region of γ-sarcoglycan protein (γ-SG) was necessary for proper localization of the protein in skeletal muscle membranes or for the normal pattern of ERK1/2 phosphorylation after eccentric contractions. Viral mediated gene transfer of wild type gsg (WTgsg) and mutant gsg lacking Tyr6 (Y6Agsg) was performed into the muscles of gsg-/- mice. Muscles were examined for production and stability of the γ-SG, as well as the level of ERK1/2 phosphorylation before and after eccentric contraction. Sarcolemmal localization of γ-SG was achieved regardless of which construct was expressed. However, only expression of WTgsg corrected the aberrant ERK1/2 phosphorylation associated with the absence of γ-SG, whereas Y6Agsg failed to have any effect. This study shows that localization of γ-SG does not require Tyr6, but localization alone is insufficient for restoration of normal signal transduction patterns after mechanical perturbation. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Dang W.,University of Pennsylvania
Drug Discovery Today: Technologies | Year: 2014

The controversy around sirtuins and their functions in aging has drawn in the past few years as much attention, if not more, from the scientific community and the public as they did when first proposed as the key conserved aging regulators in eukaryotes. With some of the basic observations on sirtuin longevity promoting functions being questioned in popular model systems, researchers are wondering if this family of conserved enzymes still holds strong potential as therapeutic targets. This review examines the several controversial issues around sirtuins and their functions in aging, calorie restriction, as well as age-related diseases in light of recent studies in mammalian systems and discusses whether modulators of sirtuins still hold the secret of life. © 2012 Elsevier Ltd.

Conant E.F.,University of Pennsylvania
Radiologic Clinics of North America | Year: 2014

Digital breast tomosynthesis is rapidly being implemented in breast imaging clinics across the world as early clinical data demonstrate that this innovative technology may address some of the long-standing limitations of conventional mammography. This article reviews the recent clinical data supporting digital breast tomosynthesis implementation, the basics of digital breast tomosynthesis image interpretation using case-based illustrations, and potential issues to consider as this new technology is integrated into daily clinical use. © 2014 Elsevier Inc.

Gestational diabetes (GDM) affects up to 200,000 deliveries in the United States each year. With the growing obesity epidemic, delayed childbearing, and multiple gestations, the diagnosis of GDM is expected to continue to rise. GDM unmasks a beta-cell defect that persists after pregnancy and typically worsens over time imparting the increased risk of type 2 diabetes mellitus after the index pregnancy. In addition, coexisting obesity and progressive weight gain are additive factors for progression to type 2 DM. Obstetricians play an integral role in informing GDM women about their lifelong risk of type 2 diabetes (T2DM) and can help bridge the care to primary care physicians, as it relates to recommended screening and long-term follow-up. © 2015 Elsevier Inc.

Namdari S.,University of Pennsylvania
The Journal of bone and joint surgery. American volume | Year: 2013

Although many residents partake in academic pursuits, including the publication of clinical studies, laboratory research, case reports, and review articles, it is uncertain whether such experiences are associated with a career-long interest in an academic orthopaedic career. This single-institution study was conducted with use of data from an urban academic university-based residency program. An academic career was defined as attainment of a teaching title signifying inclusion in, or affiliation with, a teaching department. Additionally, an academic career was subclassified as either full academic or semi-academic on the basis of employment characteristics. A PubMed search was conducted for publications by all 130 orthopaedic surgery residents who began their training in our residency program during the 1987-1988 through 2003-2004 academic years. An analysis was performed to determine whether the number or type of publications during residency or demographic variables were associated with selection of an academic career on completion of training. The mean total number of publications during residency was greater for individuals who chose an academic career (4.8) than for those who chose a nonacademic career (2.4). When the year of residency graduation was considered, a greater number of publications during residency correlated with a more recent year of graduation in residents who selected an academic position. There were no differences with regard to sex, possession of advanced degrees, or completion of an additional research year between individuals who selected an academic compared with a nonacademic career. Graduates of our orthopaedic residency program who pursued an academic career were likely to have published more articles during residency compared with their nonacademic peers.

Vaughn D.J.,University of Pennsylvania
Journal of Clinical Oncology | Year: 2015

An 18-year-old man developed acute right testicular pain. He saw his primary care physician who noted an enlarged tender firm right testicle. An ultrasound demonstrated a 6-cm solid mass in the right testicle. He was referred to urology for further evaluation. Laboratory studies showed serum α-fetoprotein (AFP) 1.4 ng/mL (normal < 6.1 ng/mL) and human chorionic gonadotropin (HCG) 10 mIU/mL (normal α 5 mIU/mL). A computed tomography (CT) scan of the abdomen and pelvis demonstrated no evidence of retroperitoneal lymphade-nopathy, and chest x-ray showed no pulmonary nodules. The patient underwent a right inguinal orchiectomy for a 6-cm seminoma, classic type, confined to the testicle. The tumor involved the rete testis but not the epididymis or tunica vaginalis. Lymphovascular invasion was noted. After orchiectomy, his serum HCG was less than 5 mIU/mL. He is referred to medical oncology to discuss ongoing management. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.

Barnhart K.T.,University of Pennsylvania
Fertility and Sterility | Year: 2014

The rationale to freeze all embryos to avoid transfer into a supraphysiologic environment to improve safety and efficacy is compelling, but not yet proven. How do we decide? © 2014 by American Society for Reproductive Medicine.

Mehta P.,University of Pennsylvania
Current Opinion in Obstetrics and Gynecology | Year: 2014

Purpose of review To summarize the newest available evidence on maternal and reproductive health disparities, and to describe elements of the Affordable Care Act most likely to impact these disparities. Recent findings Significant racial and ethnic disparities in maternal and reproductive health outcomes have persisted in recent years, contributing to poor outcomes and increasing costs. Pregnancy-related mortality ratios are up to three times higher in Black women compared with non-Hispanic White women, with the risk of severe maternal morbidity also significantly higher in Black and Hispanic women. Unintended pregnancy is twice as likely in minority women. Insurance status, socioeconomic status, and broader social determinants of health are implicated in these disparities. Coverage changes associated with the Affordable Care Act may provide some opportunities to reach communities most at risk. Delivery innovation, payment reform, and further public financing of key services are examples of further management approaches that can be used to address reproductive health disparities. Summary The Affordable Care Act offers important opportunities to address persistent reproductive health disparities, but significant gaps remain. Efforts must be made to reduce the negative outcomes and high financial and human costs associated with disparities in reproductive health. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Couch F.J.,Mayo Medical School | Nathanson K.L.,University of Pennsylvania | Offit K.,Sloan Kettering Cancer Center | Offit K.,New York Medical College
Science | Year: 2014

The cloning of the breast cancer susceptibility genes BRCA1 and BRCA2 nearly two decades ago helped set in motion an avalanche of research exploring how genomic information can be optimally applied to identify and clinically care for individuals with a high risk of developing cancer. Genetic testing for mutations in BRCA1, BRCA2, and other breast cancer susceptibility genes has since proved to be a valuable tool for determining eligibility for enhanced screening and prevention strategies, as well as for identifying patients most likely to benefit from a targeted therapy. Here, we discuss the landscape of inherited mutations and sequence variants in BRCA1 and BRCA2, the complexities of determining disease risk when the pathogenicity of sequence variants is uncertain, and current strategies for clinical management of women who carry BRCA1/2 mutations.

Live-imaging technology has markedly advanced in the field of neural injury and axon degeneration; however, studies are still predominantly performed in in vitro settings such as cultured neuronal cells or in model organisms such as Caenorhabditis elegans in which axons lack glial wrappings. We recently developed a new in vivo model for adult-stage neural injury in Drosophila melanogaster, using the highly accessible wing of the animal. Because the Drosophila wing is translucent and dispensable for survival, it allows clear and direct visualization of injury-induced progressive responses of axons and glia highlighted by fluorescent protein (FP) markers in live animals over time. Moreover, unlike previous Drosophila models of neural injury, this procedure does not require dissection of the CNS. Thus, the key preparation steps for in vivo imaging of the neural injury response described in this protocol can be completed within 30 min.

Waldfogel J.,University of Pennsylvania
Information Economics and Policy | Year: 2010

A growing empirical literature examines the relationship between music file sharing and legal purchases of music, but existing studies examine the period before consumers had attractive legal digital a la carte options. The iTunes Music Store has grown quickly since its appearance in 2003, and digital music now accounts for a third of US recorded music sales. Using two new surveys of University of Pennsylvania undergraduates in 2009 and 2010, we ask how music file sharing and sales displacement operate in the iTunes era, when the alternative to file sharing is purchasing individual songs, rather than entire albums. We find large amounts of file sharing in this population. Respondents have more stolen than paid music, but the music obtained via file sharing is, for the most part, low-valuation music which the respondents would likely not have purchased. The rate of sales displacement implied by the relationship between stolen and purchased music across respondents in both samples is between -0.15 and -0.3. That is, an additional song stolen reduces paid consumption by between a third and a sixth of song. Perhaps surprisingly, this is about the same as the CD sales displacement rate found for the pre-iTunes era using a similar empirical approach on a similar study population. © 2010 Elsevier B.V.

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

Bipolar disorder is a chronic illness that requires long-term treatment, the goal of which is to shorten or prevent mood episodes without increasing cycle frequency, thereby increasing the length of well periods. Treatment guidelines recommend mood stabilizers as first-line medications, and several atypical antipsychotics are also approved as monotherapy or as adjuncts to mood stabilizers for maintenance treatment. Combination therapy with 2 mood stabilizers or with a mood stabilizer and an antipsychotic may be necessary to achieve or maintain remission of the patient's symptoms. When treating patients with mood stabilizers and atypical antipsychotics during the maintenance phase, physicians should systematically monitor for adverse effects, particularly weight gain, and tolerability issues, and address those issues in a timely manner in order to enhance treatment adherence and improve patient outcomes. © Copyright 2012 Physicians Postgraduate Press, Inc.

Hogenesch J.B.,University of Pennsylvania | Ueda H.R.,Center for Developmental Biology
Nature Reviews Genetics | Year: 2011

After several decades dominated by reductionist approaches in biology, researchers are returning to the study of complex biology with a litany of new and old techniques " this paradigm has been termed systems biology. Here we detail how systems biology is being used to uncover complex systems-level properties of the circadian clock. These properties include robustness, periodicity and temperature compensation. We describe how clock researchers are using systems-biology techniques, such as genetic perturbations, kinetic luminescence imaging, synthetic biology and mathematical modelling, to untangle these complex properties in mammals, fungi and bacteria. The strategies developed in the context of circadian clocks may prove useful for tackling similar problems in other systems. © 2011 Macmillan Publishers Limited. All rights reserved.

Despite improvements in live imaging, fixation followed by embedding and sectioning for light or electron microscopy remains an indispensible approach in biology. During processing, small or delicate samples can be lost, damaged or poorly oriented. Here we present a protocol for overcoming these issues when, along with chemical fixation, the sample is fixed mechanically. The protocol features two alternatives for mechanical fixation: the sample is encased either in a rectangular block of agarose or between Formvar films suspended on a wire loop. We also provide methods for key steps all the way through to sectioning. We illustrate the method on the root of Arabidopsis thaliana, an object that is ∼0.15 mm in diameter and difficult to process conventionally. With this protocol, well-oriented sections can be obtained with excellent ultrastructural preservation. The protocol takes about 1 week.

Wand A.J.,University of Pennsylvania
Current Opinion in Structural Biology | Year: 2013

Historically it has been virtually impossible to experimentally determine the contribution of residual protein entropy to fundamental protein activities such as the binding of ligands. Recent progress has illuminated the possibility of employing NMR relaxation methods to quantitatively determine the role of changes in conformational entropy in molecular recognition by proteins. The method rests on using fast internal protein dynamics as a proxy. Initial results reveal a large and variable role for conformational entropy in the binding of ligands by proteins. Such a role for conformational entropy in molecular recognition has significant implications for enzymology, signal transduction, allosteric regulation and the development of protein-directed pharmaceuticals. © 2012 Elsevier Ltd.

Phillips M.C.,University of Pennsylvania
Journal of Lipid Research | Year: 2013

Apolipoprotein (apo)A-I is the principal protein component of HDL, and because of its conformational adaptability, it can stabilize all HDL subclasses. The amphipathic α-helix is the structural motif that enables apoA-I to achieve this functionality. In the lipid-free state, the helical segments unfold and refold in seconds and are located in the N-terminal two thirds of the molecule where they are loosely packed as a dynamic, four-helix bundle. The C-terminal third of the protein forms an intrinsically disordered domain that mediates initial binding to phospholipid surfaces, which occurs with coupled α-helix formation. The lipid affinity of apoA-I confers detergent-like properties; it can solubilize vesicular phospholipids to create discoidal HDL particles with diameters of approximately 10 nm. Such particles contain a segment of phospholipid bilayer and are stabilized by two apoA-I molecules that are arranged in an anti-parallel, double-belt conformation around the edge of the disc, shielding the hydrophobic phospholipid acyl chains from exposure to water. The apoA-I molecules are in a highly dynamic state, and they stabilize discoidal particles of different sizes by certain segments forming loops that detach reversibly from the particle surface. The flexible apoAI molecule adapts to the surface of spherical HDL particles by bending and forming a stabilizing trefoil scaffold structure. The above characteristics of apoA-I enable it to partner with ABCA1 in mediating efflux of cellular phospholipid and cholesterol and formation of a heterogeneous population of nascent HDL particles. Novel insights into the structure-function relationships of apoA-I should help reveal mechanisms by which HDL subclass distribution can be manipulated. Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc.

Goncharova E.A.,University of Pennsylvania
FASEB Journal | Year: 2013

Mammalian target of rapamycin (mTOR) is a major regulator of cellular metabolism, proliferation, and survival that is implicated in various proliferative and metabolic diseases, including obesity, type 2 diabetes, hamartoma syndromes, and cancer. Emerging evidence suggests a potential critical role of mTOR signaling in pulmonary vascular remodeling. Remodeling of small pulmonary arteries due to increased proliferation, resistance to apoptosis, and altered metabolism of cells forming the pulmonary vascular wall is a key currently irreversible pathological feature of pulmonary hypertension, a progressive pulmonary vascular disorder with high morbidity and mortality. In addition to rare familial and idiopathic forms, pulmonary hypertension is also a life-threatening complication of several lung diseases associated with hypoxia. This review aims to summarize our current knowledge and recent advances in understanding the role of the mTOR pathway in pulmonary vascular remodeling, with a specific focus on the hypoxia component, a confirmed shared trigger of pulmonary hypertension in lung diseases. We also discuss the emerging role of mTOR as a promising therapeutic target and mTOR inhibitors as potential pharmacological approaches to treat pulmonary vascular remodeling in pulmonary hypertension.

Wells R.G.,University of Pennsylvania
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2013

Mechanical forces are essential to the development and progression of fibrosis, and are likely to be as important as soluble factors. These forces regulate the phenotype and proliferation of myofibroblasts and other cells in damaged tissues, the activation of growth factors, the structure and mechanics of the matrix, and, potentially, tissue patterning. Better understanding of the variety and magnitude of forces, the characteristics of those forces in biological tissues, and their impact on fibrosis in multiple tissues is needed and may lead to identification of important new therapeutic targets. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. © 2013 Elsevier B.V.

Tambe P.,New York University | Hitt L.M.,University of Pennsylvania
Information Systems Research | Year: 2012

This paper uses newly collected panel data that allow for significant improvements in the measurement and modeling of information technology (IT) productivity to address some longstanding empirical limitations in the IT business value literature. First, we show that using generalized method of moments-based estimators to account for the endogeneity of IT spending produces coefficient estimates that are only about 10% lower than unadjusted estimates, suggesting that the effects of endogeneity on IT productivity estimates may be relatively small. Second, analysis of the expanded panel suggests that (a) IT returns are substantially lower in midsize firms than in Fortune 500 firms; (b) they materialize more slowly in large firms-in midsize firms, unlike in larger firms, the short-run contribution of IT to output is similar to the long-run output contribution; and (c) the measured marginal product of IT spending is higher from 2000 to 2006 than in any previous period, suggesting that firms, and especially large firms, have been continuing to develop new, valuable IT-enabled business process innovations. Furthermore, we show that the productivity of IT investments is higher in manufacturing sectors and that our productivity results are robust to controls for IT labor quality and outsourcing levels. © 2012 INFORMS.

Shabalina S.A.,U.S. National Center for Biotechnology Information | Spiridonov N.A.,U.S. Food and Drug Administration | Kashina A.,University of Pennsylvania
Nucleic Acids Research | Year: 2013

Messenger RNA is a key component of an intricate regulatory network of its own. It accommodates numerous nucleotide signals that overlap protein coding sequences and are responsible for multiple levels of regulation and generation of biological complexity. A wealth of structural and regulatory information, which mRNA carries in addition to the encoded amino acid sequence, raises the question of how these signals and overlapping codes are delineated along non-synonymous and synonymous positions in protein coding regions, especially in eukaryotes. Silent or synonymous codon positions, which do not determine amino acid sequences of the encoded proteins, define mRNA secondary structure and stability and affect the rate of translation, folding and post-translational modifications of nascent polypeptides. The RNA level selection is acting on synonymous sites in both prokaryotes and eukaryotes and is more common than previously thought. Selection pressure on the coding gene regions follows three-nucleotide periodic pattern of nucleotide base-pairing in mRNA, which is imposed by the genetic code. Synonymous positions of the coding regions have a higher level of hybridization potential relative to non-synonymous positions, and are multifunctional in their regulatory and structural roles. Recent experimental evidence and analysis of mRNA structure and interspecies conservation suggest that there is an evolutionary tradeoff between selective pressure acting at the RNA and protein levels. Here we provide a comprehensive overview of the studies that define the role of silent positions in regulating RNA structure and processing that exert downstream effects on proteins and their functions. © 2012. Published by Oxford University Press.

Le Ny J.,Ecole Polytechnique de Montreal | Pappas G.J.,University of Pennsylvania
IEEE Transactions on Automatic Control | Year: 2014

Emerging systems such as smart grids or intelligent transportation systems often require end-user applications to continuously send information to external data aggregators performing monitoring or control tasks. This can result in an undesirable loss of privacy for the users in exchange of the benefits provided by the application. Motivated by this trend, this paper introduces privacy concerns in a system theoretic context, and addresses the problem of releasing filtered signals that respect the privacy of the user data streams. Our approach relies on a formal notion of privacy from the database literature, called differential privacy, which provides strong privacy guarantees against adversaries with arbitrary side information. Methods are developed to approximate a given filter by a differentially private version, so that the distortion introduced by the privacy mechanism is minimized. Two specific scenarios are considered. First, the notion of differential privacy is extended to dynamic systems with many participants contributing independent input signals. Kalman filtering is also discussed in this context, when a released output signal must preserve differential privacy for the measured signals or state trajectories of the individual participants. Second, differentially private mechanisms are described to approximate stable filters when participants contribute to a single event stream, extending previous work on differential privacy under continual observation. © 1963-2012 IEEE.

Schwartz J.L.,University of Pennsylvania
American Journal of Public Health | Year: 2010

Developments regarding human papillomavirus (HPV) vaccines will transform HPV vaccination in the United States while simultaneously raising several new policy and ethical concerns. Policymakers, vaccine manufacturers, and the public health community must now respond to the presence of competing vaccines that are similar but distinct, particularly with respect to genital wart prevention and the benefits of vaccinating males. This work arises in the shadow of the contentious introduction of the HPV vaccine Gardasil (Merck & Co, Inc. Whitehouse Station, NJ) in 2006, particularly the opposition to efforts in many states to require the vaccine for school attendance. I review the current status of HPV vaccine policy in the united States and examine issues of public health ethics and policy central to ongoing and future HPV vaccination programs.

Barnhart K.T.,University of Pennsylvania
Fertility and Sterility | Year: 2012

The evolution of the diagnosis and management of women with an early pregnancy loss has been a success story. The mortality from ectopic pregnancy has objectively been decreased in the past few decades. However, modern management has resulted in a new set of issues. Over-interpretation of a single ultrasound, misunderstanding of the utility of serial hCG values, and inappropriate use of methotrexate can result in iatrogenic complications. Modern management has successfully improved the diagnosis of ectopic pregnancy before rupture; it should now also focus on ensuring that an intrauterine pregnancy is not interrupted as a result of diagnosis and treatment. This article reviews some of the pitfalls of the modern management of early pregnancy failure and introduces a series of articles on the subject. Copyright © 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.

Hersperger A.R.,University of Pennsylvania
PLoS pathogens | Year: 2010

Many immune correlates of CD8(+) T-cell-mediated control of HIV replication, including polyfunctionality, proliferative ability, and inhibitory receptor expression, have been discovered. However, no functional correlates using ex vivo cells have been identified with the known ability to cause the direct elimination of HIV-infected cells. We have recently discovered the ability of human CD8(+) T-cells to rapidly upregulate perforin--an essential molecule for cell-mediated cytotoxicity--following antigen-specific stimulation. Here, we examined perforin expression capability in a large cross-sectional cohort of chronically HIV-infected individuals with varying levels of viral load: elite controllers (n = 35), viremic controllers (n = 29), chronic progressors (n = 27), and viremic nonprogressors (n = 6). Using polychromatic flow cytometry and standard intracellular cytokine staining assays, we measured perforin upregulation, cytokine production, and degranulation following stimulation with overlapping peptide pools encompassing all proteins of HIV. We observed that HIV-specific CD8(+) T-cells from elite controllers consistently display an enhanced ability to express perforin directly ex vivo compared to all other groups. This ability is not restricted to protective HLA-B haplotypes, does not require proliferation or the addition of exogenous factors, is not restored by HAART, and primarily originates from effector CD8(+) T-cells with otherwise limited functional capability. Notably, we found an inverse relationship between HIV-specific perforin expression and viral load. Thus, the capability of HIV-specific CD8(+) T-cells to rapidly express perforin defines a novel correlate of control in HIV infection.

Dominguez R.,University of Pennsylvania
Trends in Biochemical Sciences | Year: 2016

Two types of sequences, proline-rich domains (PRDs) and the WASP-homology 2 (WH2) domain, are found in most actin filament nucleation and elongation factors discovered thus far. PRDs serve as a platform for protein-protein interactions, often mediating the binding of profilin-actin. The WH2 domain is an abundant actin monomer-binding motif comprising ∼17 amino acids. It frequently occurs in tandem repeats, and functions in nucleation by recruiting actin subunits to form the polymerization nucleus. It is found in Spire, Cordon Bleu (Cobl), Leiomodin (Lmod), Arp2/3 complex activators (WASP, WHAMM, WAVE, etc.), the bacterial nucleators VopL/VopF and Sca2, and some formins. Yet, it is argued here that the WH2 domain plays only an auxiliary role in nucleation, always synergizing with other domains or proteins for this activity. WH2-domain-related sequences have been found in the majority of actin filament nucleation and elongation factors discovered thus far, including several formins.Tandem repeats of WH2 domains, found in proteins such as Spire, Cobl, VopL/VopF, and Sca2, are no longer considered sufficient to drive efficient nucleation. These proteins cooperate with other proteins or present other domains necessary for efficient nucleation.It is now understood that optimal nucleation activity by several formins requires sequences C terminal to the FH2 domain that either directly recruit actin monomers via WH2-like domains or bind to other proteins that contribute actin subunits during nucleation.Cooperation among different subfamilies of actin nucleators and dimerization are emerging as two widespread features in actin nucleation. © 2016 Elsevier Ltd.

Carlson G.C.,University of Pennsylvania
Pharmacology Biochemistry and Behavior | Year: 2012

There is strong evidence that metabotropic and ionotropic glutamate receptors are affected in autism spectrum disorders (ASD), but there are few candidate genes indicating involvement of these receptors. This suggests that glutamate receptor dysregulation may primarily be involved in the expression of ASD, but is an uncommon etiology. Directly implicated in models of fragile-X with ASD phenotypes is metabotropic glutamate receptor type 5 (mGluR5), which appears to be an effective pharmacologic target in a number of models of ASD. The review of other ASD models demonstrates that there is also evidence of a role for kainate, NMDA, and AMPA receptors in the neuropathophysiology of ASD, though the relationship between dysfunction in those receptors and ASD-associated phenotypes is not well understood. Current models indicate a way forward to delineate the role of glutamate receptors in ASD. Further development of preclinical models focusing on glutamate receptors may provide tools to target a clinically important subset of ASD symptoms. © 2011 Elsevier Inc. All rights reserved.

Scherer S.S.,University of Pennsylvania
Journal of the peripheral nervous system : JPNS | Year: 2012

The X-linked form of Charcot-Marie-Tooth disease (CMT1X) is the second most common form of hereditary motor and sensory neuropathy. The clinical phenotype is characterized by progressive muscle atrophy and weakness, areflexia, and variable sensory abnormalities; central nervous system manifestations occur, too. Affected males have moderate to severe symptoms, whereas heterozygous females are usually less affected. Neurophysiology shows intermediate slowing of conduction and distal axonal loss. Nerve biopsies show more prominent axonal degeneration than de/remyelination. More than 400 different mutations in GJB1, the gene that encodes the gap junction (GJ) protein connexin32 (Cx32), cause CMT1X. Many Cx32 mutants fail to form functional GJs, or form GJs with abnormal biophysical properties. Schwann cells and oligodendrocytes express Cx32, and the GJs formed by Cx32 play an important role in the homeostasis of myelinated axons. Animal models of CMT1X demonstrate that loss of Cx32 in myelinating Schwann cells causes a demyelinating neuropathy. An effective therapy remains to be developed. © 2012 Peripheral Nerve Society.

Rea P.A.,University of Pennsylvania
Physiologia Plantarum | Year: 2012

Of the mechanisms known to protect vascular plants and some algae, fungi and invertebrates from the toxic effects of non-essential heavy metals such as As, Cd or Hg, one of the most sophisticated is the enzyme-catalyzed synthesis of phytochelatins (PCs). PCs, (γ-Glu-Cys) nGly polymers, which serve as high-affinity, thiol-rich cellular chelators and contribute to the detoxification of heavy metal ions, are derived from glutathione (GSH; γ-Glu-Cys-Gly) and related thiols in a reaction catalyzed by phytochelatin synthases (PC synthases, EC Using the enzyme from Arabidopsis thaliana (AtPCS1) as a model, the reasoning and experiments behind the conclusion that PC synthases are novel papain-like Cys protease superfamily members are presented. The status of S-substituted GSH derivatives as generic PC synthase substrates and the sufficiency of the N-terminal domain of the enzyme from eukaryotic and its half-size equivalents from prokaryotic sources, for net PC synthesis and deglycylation of GSH and its derivatives, respectively, are emphasized. The question of the common need or needs met by PC synthases and their homologs is discussed. Of the schemes proposed to account for the combined protease and peptide polymerase capabilities of the eukaryotic enzymes vs the limited protease capabilities of the prokaryotic enzymes, two that will be considered are the storage and homeostasis of essential heavy metals in eukaryotes and the metabolism of S-substituted GSH derivatives in both eukaryotes and prokaryotes. © Physiologia Plantarum 2012.

Silberberg D.,University of Pennsylvania | Anand N.P.,U.S. National Institutes of Health | Michels K.,U.S. National Institutes of Health | Kalaria R.N.,Northumbria University
Nature | Year: 2015

This is an exciting time for scientific discovery that aims to reduce the frequency and impact of neurological, mental health and substance-use disorders. As it became increasingly clear that low-and middle-income countries have a disproportionate share of these disorders, and that many of the problems are best addressed by indigenous researchers who can seek context-sensitive solutions, the US National Institutes of Health and other research funders began to invest more in low-and middle-income country-focused research and research capacity-building to confront this significant public health challenge. In an effort to identify existing information, knowledge gaps, and emerging research and research capacity-building opportunities that are particularly relevant to low-and middle-income countries, in February 2014 the Center for Global Health Studies at the National Institutes of Health Fogarty International Center held a workshop to explore these issues with scientific experts from low-and middle-income countries and the United States. This evolved into the preparation of the Reviews in this supplement, which is designed to highlight opportunities and challenges associated with topical areas in brain-disorders research over the coming decade. This Introduction highlights some of the over-arching and intersecting priorities for addressing causes, prevention, treatment and rehabilitation as well as best practices to promote overall nervous system health. We review some brain disorders in low-and middle-income countries, while the Reviews describe relevant issues and the epidemiology of particular conditions in greater depth.This article has not been written or reviewed by Nature editors. Nature accepts no responsibility for the accuracy of the information provided.

Wu Y.,University of Pennsylvania | Verdu S.,Princeton University
IEEE Transactions on Information Theory | Year: 2012

In addition to exploring its various regularity properties, we show that the minimum mean-square error (MMSE) is a concave functional of the input-output joint distribution. In the case of additive Gaussian noise, the MMSE is shown to be weakly continuous in the input distribution and Lipschitz continuous with respect to the quadratic Wasserstein distance for peak-limited inputs. Regularity properties of mutual information are also obtained. Several applications to information theory and the central limit theorem are discussed. © 2011 IEEE.

Sorenson S.B.,University of Pennsylvania
American Journal of Public Health | Year: 2011

Objectives: The purpose of this study is to update knowledge about gender differences in injury mortality. Methods: Data were drawn from the Web-based Injury Query System, which contains US injury mortality data from 1981 to 2007. Male-to-female rate ratios in injury mortality are calculated for key variables, and age and ethnic group comparisons are made. Results: Boys and men were more likely than girls and women to die of injury. From 1981 to 2007, the male-to-female age-adjusted rate ratio decreased by 20% to 2.15 for unintentional injury and increased by 11% to 3.91 for violence-related injury. Excess male mortality existed in manner of death, cause of death, and within ethnic and age groups. Additionally, with rare exception, the gender disparity was greater than ethnic and age disparities in unintentional and violence-related injury mortality. Conclusions: Gender disparities in injury mortality are consistent and persistent. Gender patterns in injury mortality do not follow typical social justice analyses of health, in that men are at greater risk. Lifestyle and behavioral risks as well as masculine socialization merit consideration.

Kendon A.,University of Pennsylvania | Kendon A.,University College London
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

Sign language descriptions that use an analytic model borrowed from spoken language structural linguistics have proved to be not fully appropriate. Pictorial and action-like modes of expression are integral to how signed utterances are constructed and to how they work. However, observation shows that speakers likewise use kinesic and vocal expressions that are not accommodated by spoken language structural linguistic models, including pictorial and action-like modes of expression. These, also, are integral to how speaker utterances in face-to-face interaction are constructed and to how they work. Accordingly, the object of linguistic inquiry should be revised, so that it comprises not only an account of the formal abstract systems that utterances make use of, but also an account of how the semiotically diverse resources that all languaging individuals use are organized in relation to one another. Both language as an abstract system and languaging should be the concern of linguistics. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Levine M.S.,University of Pennsylvania | Carucci L.R.,Virginia Commonwealth University
Radiology | Year: 2014

Obesity is a disease that has reached epidemic proportions in the United States and around the world. During the past 2 decades, bariatric surgery has become an increasingly popular form of treatment for morbid obesity. The most common bariatric procedures performed include laparoscopic Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, and laparoscopic sleeve gastrectomy. Fluoroscopic upper gastrointestinal examinations and abdominal computed tomography (CT) are the major imaging tests used to evaluate patients after these various forms of bariatric surgery. The purpose of this article is to present the surgical anatomy and normal imaging findings and postoperative complications for these bariatric procedures at fluoroscopic examinations and CT. Complications after Roux-en-Y gastric bypass include anastomotic leaks and strictures, marginal ulcers, jejunal ischemia, small bowel obstruction, internal hernias, intussusception, and recurrent weight gain. Complications after laparoscopic adjustable gastric banding include stomal stenosis, malpositioned bands, pouch dilation, band slippage, perforation, gastric volvulus, intraluminal band erosion, and port- and bandrelated problems. Finally, complications after sleeve gastrectomy include postoperative leaks and strictures, gastric dilation, and gastroesophageal reflux. The imaging features of these various complications of bariatric surgery are discussed and illustrated. © RSNA, 2014.

Dranoff J.A.,Yale University | Wells R.G.,University of Pennsylvania
Hepatology | Year: 2010

Portal fibroblasts are an important yet often overlooked nonparenchymal cell population in the liver. They are distinct from hepatic stellate cells, yet like stellate cells differentiate in the setting of chronic injury to fibrogenic myofibroblasts, playing an important role in collagen production in the fibrotic liver. Portal fibroblasts (PFs) are located adjacent to bile duct epithelia and thus play a particularly significant role in biliary fibrosis. New data suggest that they may also have key functions independent of fibrogenesis. This review addresses the definition and characteristics of PFs as well as their signaling pathways, interactions with the biliary epithelium, and contributions to liver pathobiology. Conclusion: PFs are an important and multifunctional nonparenchymal cell population in need of further study. Copyright © 2010 by the American Association for the Study of Liver Diseases.

Wu L.,University of Pennsylvania
Information Systems Research | Year: 2013

By studying the change in employees' network positions before and after the introduction of a social networking tool, I find that information-rich networks (low in cohesion and rich in structural holes), enabled by social media, have a positive effect on various work outcomes. Contrary to the notion that network positions are difficult to alter, I show that social media can induce a change in network structure, one from which individuals can derive economic benefits. In addition, I consider two intermediate mechanisms by which an information-rich network is theorized to improve work performance-information diversity and social communication-and quantify their effects on productivity and job security. Analysis shows that productivity, as measured by billable revenue, is more associated with information diversity than with social communication. However, the opposite is true for job security. Social communication is more correlated with reduced layoff risks than with information diversity. This, in turn, suggests that information-rich networks enabled through the use of social media can drive both work performance and job security, but that there is a trade-off between engaging in social communication and gathering diverse information. © 2013 INFORMS.

Kim S.F.,University of Pennsylvania
Nitric Oxide - Biology and Chemistry | Year: 2011

The biosynthesis of nitric oxide (NO) and prostaglandin share many similarities. Two major forms of nitric oxide synthase (NOS) and cyclooxygenase (COX) have been identified: constitutive versus inducible. In general, the constitutive form functions in housekeeping and physiologic roles whereas the inducible form is up-regulated by mitogenic or inflammatory stimuli and is responsible for pathophysiological responses. The cross talk between the COX and NOS pathways was initially reported in 1993 and since then, numerous studies have been undertaken to delineate the functional consequences of this interaction as well as the potential mechanism by which each pathway interacts. This review will focus in particular on recent advances in this field that extend our understanding of these two pathways under various systems. © 2011 Elsevier Inc. All rights reserved.

Vollmer C.M.,University of Pennsylvania
Surgical Clinics of North America | Year: 2013

Pancreas surgery is a paradigm for high-acuity surgical specialization. Given the current intrigue over containing health care expenditures, pancreas surgery provides an ideal model to investigate the cost of care. This article explores the economics of this field from literature accrued over the last 2 decades. The cost of performing a pancreatic resection is established and then embellished with a discussion of the effects of clinical care paths. Then the influence of complications on costs is explored. Next, cost is investigated as an emerging outcome metric regarding variations in pancreatic surgical care. Finally, the societal-level fiscal impact is considered. © 2013 Elsevier Inc.

Burd C.G.,University of Pennsylvania
Traffic | Year: 2011

Bidirectional traffic between the Golgi apparatus and the endosomal system sustains the functions of the trans-Golgi network (TGN) in secretion and organelle biogenesis. Export of cargo from the TGN via anterograde trafficking pathways depletes the organelle of sorting receptors, processing proteases, SNARE molecules, and other factors, and these are subsequently retrieved from endosomes via the retrograde pathway. Recent studies indicate that retrograde trafficking is vital to early metazoan development, nutrient homeostasis, and for processes that protect against Alzheimer's and other neurological diseases. © 2011 John Wiley & Sons A/S.

Lampson M.A.,University of Pennsylvania | Cheeseman I.M.,Whitehead Institute For Biomedical Research
Trends in Cell Biology | Year: 2011

Maintaining genome integrity during cell division requires regulated interactions between chromosomes and spindle microtubules. To ensure that daughter cells inherit the correct chromosomes, the sister kinetochores must attach to opposite spindle poles. Tension across the centromere stabilizes correct attachments, whereas phosphorylation of kinetochore substrates by the conserved Ipl1/Aurora B kinase selectively eliminates incorrect attachments. Here, we review our current understanding of how mechanical forces acting on the kinetochore are linked to biochemical changes to control chromosome segregation. We discuss models for tension sensing and regulation of kinetochore function downstream of Aurora B, and mechanisms that specify Aurora B localization to the inner centromere and determine its interactions with substrates at distinct locations. © 2010 Elsevier Ltd.

Grice E.A.,University of Pennsylvania
Seminars in cutaneous medicine and surgery | Year: 2014

A vast diversity of microorganisms, including bacteria, fungi, viruses, and arthropods, colonize the human skin. Culture-independent genomic approaches for identifying and characterizing microbial communities have provided glimpses into the topographical, temporal, and interpersonal complexity that defines the skin microbiome. Identification of changes associated with cutaneous disease, including acne, atopic dermatitis, rosacea, and psoriasis, are being established. In this review, our current knowledge of the skin microbiome in health and disease is discussed, with particular attention to potential opportunities to leverage the skin microbiome as a diagnostic, prognostic, and/or therapeutic tool.

Idema T.,University of Pennsylvania
PloS one | Year: 2013

Mitosis in the early syncytial Drosophila embryo is highly correlated in space and time, as manifested in mitotic wavefronts that propagate across the embryo. In this paper we investigate the idea that the embryo can be considered a mechanically-excitable medium, and that mitotic wavefronts can be understood as nonlinear wavefronts that propagate through this medium. We study the wavefronts via both image analysis of confocal microscopy videos and theoretical models. We find that the mitotic waves travel across the embryo at a well-defined speed that decreases with replication cycle. We find two markers of the wavefront in each cycle, corresponding to the onsets of metaphase and anaphase. Each of these onsets is followed by displacements of the nuclei that obey the same wavefront pattern. To understand the mitotic wavefronts theoretically we analyze wavefront propagation in excitable media. We study two classes of models, one with biochemical signaling and one with mechanical signaling. We find that the dependence of wavefront speed on cycle number is most naturally explained by mechanical signaling, and that the entire process suggests a scenario in which biochemical and mechanical signaling are coupled.

Apter A.J.,University of Pennsylvania
Journal of Allergy and Clinical Immunology | Year: 2010

There is a growing need to standardize and validate outcomes for asthma research. In this review of asthma-related publications from the Journal in 2009, efforts to standardize methodology and reporting of translational research, the influence of the environment, therapeutics, and management of asthma are highlighted. © 2010 American Academy of Allergy, Asthma & Immunology.

Cai T.T.,University of Pennsylvania | Wang L.,Massachusetts Institute of Technology
IEEE Transactions on Information Theory | Year: 2011

We consider the orthogonal matching pursuit (OMP) algorithm for the recovery of a high-dimensional sparse signal based on a small number of noisy linear measurements. OMP is an iterative greedy algorithm that selects at each step the column, which is most correlated with the current residuals. In this paper, we present a fully data driven OMP algorithm with explicit stopping rules. It is shown that under conditions on the mutual incoherence and the minimum magnitude of the nonzero components of the signal, the support of the signal can be recovered exactly by the OMP algorithm with high probability. In addition, we also consider the problem of identifying significant components in the case where some of the nonzero components are possibly small. It is shown that in this case the OMP algorithm will still select all the significant components before possibly selecting incorrect ones. Moreover, with modified stopping rules, the OMP algorithm can ensure that no zero components are selected. © 2011 IEEE.

Levine M.A.,University of Pennsylvania
Current Opinion in Endocrinology, Diabetes and Obesity | Year: 2012

PURPOSE OF REVIEW: To provide the reader with a review of contemporary literature describing the evolving understanding of the molecular pathobiology of pseudohypoparathyroidism (PHP). RECENT FINDINGS: The features of PHP type 1 reflect imprinting of the GNAS gene, which encodes the α subunit of the heterotrimeric G protein (Gαs) that couples heptahelical receptors to activation of adenylyl cyclase. Transcription of Gαs is biallelic in most cells, but is primarily from the maternal allele in some tissues (e.g. proximal renal tubules, thyroid, pituitary somatotropes, gonads). Patients with PHP 1a have heterozygous mutations within the exons of the maternal GNAS allele that encode Gαs, whereas patients with PHP 1b have methylation defects in the GNAS locus that reduce transcription of Gαs from the maternal allele. In both PHP 1a and PHP 1b, paternal imprinting of Gαs leads to resistance to parathyroid hormone and TSH. Although brachydactyly is characteristic of PHP 1a, it is sometimes present in patients with PHP 1b. SUMMARY: Molecular studies enable a distinction between PHP 1a and PHP 1b, with different mechanisms accounting for Gαs deficiency. Clinical overlap between these two forms of PHP type 1 is likely due to the variable levels of Gαs activity expressed in specific cell types. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Li L.Z.,University of Pennsylvania
Journal of Bioenergetics and Biomembranes | Year: 2012

Cellular redox states can regulate cell metabolism, growth, differentiation, motility, apoptosis, signaling pathways, and gene expressions etc. A growing body of literature suggest the importance of redox status for cancer progression. While most studies on redox state were done on cells and tissue lysates, it is important to understand the role of redox state in a tissue in vivo/ex vivo and image its heterogeneity. Redox scanning is a clinical-translatable method for imaging tissue mitochondrial redox potential with a submillimeter resolution. Redox scanning data in mouse models of human cancers demonstrate a correlation between mitochondrial redox state and tumor metastatic potential. I will discuss the significance of this correlation and possible directions for future research. © Springer Science+Business Media, LLC 2012.

Rader D.J.,University of Pennsylvania | Hovingh G.K.,University of Amsterdam
The Lancet | Year: 2014

The cholesterol contained within HDL is inversely associated with risk of coronary heart disease and is a key component of predicting cardiovascular risk. However, despite its properties consistent with atheroprotection, the causal relation between HDL and atherosclerosis is uncertain. Human genetics and failed clinical trials have created scepticism about the HDL hypothesis. Nevertheless, drugs that raise HDL-C concentrations, cholesteryl ester transfer protein inhibitors, are in late-stage clinical development, and other approaches that promote HDL function, including reverse cholesterol transport, are in early-stage clinical development. The final chapters regarding the effect of HDL-targeted therapeutic interventions on coronary heart disease events remain to be written. © 2014 Elsevier Ltd.

Albenberg L.G.,Childrens Hospital of Philadelphia | Wu G.D.,University of Pennsylvania
Gastroenterology | Year: 2014

The mutual relationship between the intestinal microbiota and its mammalian host is influenced by diet. Consumption of various nutrients affects the structure of the microbial community and provides substrates for microbial metabolism. The microbiota can produce small molecules that are absorbed by the host and affect many important physiological processes. Age-dependent and societal differences in the intestinal microbiota could result from differences in diet. Examples include differences in the intestinal microbiota of breastfed vs formula-fed infants or differences in microbial richness in people who consume an agrarian plant-based vs a Western diet, which is high in meat and fat. We review how diet affects the structure and metabolome of the human intestinal microbiome and may contribute to health or the pathogenesis of disorders such as coronary vascular disease and inflammatory bowel disease. © 2014 by the AGA Institute.

Buchon N.,Cornell University | Silverman N.,University of Massachusetts Medical School | Cherry S.,University of Pennsylvania
Nature Reviews Immunology | Year: 2014

Since the discovery of antimicrobial peptide responses 40 years ago, the fruit fly Drosophila melanogaster has proven to be a powerful model for the study of innate immunity. Early work focused on innate immune mechanisms of microbial recognition and subsequent nuclear factor-κ B signal transduction. More recently, D. melanogaster has been used to understand how the immune response is regulated and coordinated at the level of the whole organism. For example, researchers have used this model in studies investigating interactions between the microbiota and the immune system at barrier epithelial surfaces that ensure proper nutritional and immune homeostasis both locally and systemically. In addition, studies in D. melanogaster have been pivotal in uncovering how the immune response is regulated by both endocrine and metabolic signalling systems, and how the immune response modifies these systems as part of a homeostatic circuit. In this Review, we briefly summarize microbial recognition and antiviral immunity in D. melanogaster, and we highlight recent studies that have explored the effects of organism-wide regulation of the immune response and, conversely, the effects of the immune response on organism physiology. © 2015 Macmillan Publishers Limited.

Grill H.J.,University of Pennsylvania
Frontiers in Neuroendocrinology | Year: 2010

The development of effective pharmacotherapy for obesity will benefit from a more complete understanding of the neural pathways and the neurochemical signals whose actions result in the reduction of the size of meals. This review examines the neural control of meal size and the integration of two principal sources of that control - satiation signals arising from the gastrointestinal tract and CNS leptin signaling. Four types of integrations that are central to the control of meal size are described and each involves the neurons of the nucleus tractus solitarius (NTS) in the dorsal hindbrain. Data discussed show that NTS neurons integrate information arising from: (1) ascending GI-derived vagal afferent projections, (2) descending neuropeptidergic projections from leptin-activated arcuate and paraventricular nucleus neurons, (3) leptin signaling in NTS neurons themselves and (4) melanocortinergic projections from NTS and hypothalamic POMC neurons to NTS neurons and melanocortinergic modulation of vagal afferent nerve terminals that are presynaptic to NTS neurons. © 2009 Elsevier Inc. All rights reserved.

Lu C.,Sloan Kettering Cancer Center | Lu C.,University of Pennsylvania | Thompson C.B.,Sloan Kettering Cancer Center
Cell Metabolism | Year: 2012

How cells sense and respond to environmental cues remains a central question of biological research. Recent evidence suggests that DNA transcription is regulated by chromatin organization. However, the mechanism for relaying the cytoplasmic signaling to chromatin remodeling remains incompletely understood. Although much emphasis has been put on delineating transcriptional output of growth factor/hormonal signaling pathways, accumulated evidence from yeast and mammalian systems suggest that metabolic signals also play critical roles in determining chromatin structure. Here we summarize recent progress in understanding the molecular connection between metabolism and epigenetic modifications of chromatin implicated in a variety of diseases including cancer. © 2012 Elsevier Inc.

Pierce E.A.,Massachusetts Eye and Ear Infirmary | Bennett J.,University of Pennsylvania
Cold Spring Harbor Perspectives in Medicine | Year: 2015

Several groups have reported the results of clinical trials of gene augmentation therapy for Leber congenital amaurosis (LCA) because of mutations in the RPE65 gene. These studies have used subretinal injection of adeno-associated virus (AAV) vectors to deliver the human RPE65 cDNA to the retinal pigment epithelial (RPE) cells of the treated eyes. In all of the studies reported to date, this approach has been shown to be both safe and effective. The successful clinical trials of gene augmentation therapy for retinal degeneration caused by mutations in the RPE65 gene sets the stage for broad application of gene therapy to treat retinal degenerative disorders. © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

BACKGROUND: Heparin-induced thrombocytopenia and thrombosis (HITT) is characterized by thrombocytopenia due to the formation of antibodies against heparin: platelet factor 4 (PF4) complexes. Despite the exposure to heparin during treatment and predisposition of patients with atherosclerosis to HITT, HITT in patients undergoing low-density lipoprotein (LDL) apheresis is rare. We investigated the possibility that LDL apheresis decreases PF4 on platelet (PLT) surfaces and/or plasma HITT antibody levels, either of which would disfavor HITT. STUDY DESIGN AND METHODS: We enrolled 25 patients undergoing LDL apheresis at the Hospital of the University of Pennsylvania. Blood samples were drawn before and after treatment. Plasma samples were drawn proximal and distal to the LA-15 treatment column. PF4, HITT antibodies, heparin levels, and P-selectin were measured. RESULTS: No patient had clinical symptoms of HITT. The LA-15 column was found to efficiently remove PF4. PF4 levels in peripheral blood plasma did not change significantly after LDL apheresis. However, PLT surface PF4 significantly decreased after treatment. HITT antibodies were found in only two patients and were nonfunctional. PLT surface P-selectin did not change during treatment. CONCLUSIONS: We have demonstrated that LDL apheresis via dextran sulfate absorption removes plasma PF4 and reduces the amount of PF4 on the surface of circulating PLTs. Reduced surface PF4 may decrease antibody formation and/or recognition by HITT antibodies. These data provide a potential explanation for the near lack of HITT in hypercholesterolemic patients undergoing LDL apheresis. They also suggest the possibility that LDL apheresis using dextran sulfate adsorption may have therapeutic value in the treatment of HITT. © 2010 American Association of Blood Banks.

Rustgi A.K.,University of Pennsylvania | El-Serag H.B.,Baylor College of Medicine
New England Journal of Medicine | Year: 2014

Esophageal adenocarcinoma has become the predominant type of esophageal cancer in North America and Europe, and gastroesophageal reflux disease (GERD) and obesity are the main risk factors. Barrett's esophagus, the recognized precursor lesion, can be detected by means of endoscopic screening, which is followed by treatment of precancerous lesions and monitoring for the development of neoplastic progression. Esophageal squamous-cell carcinoma remains the predominant esophageal cancer in Asia, Africa, and South America and among African Americans in North America. Alcohol and tobacco use are the main risk factors, and esophageal squamous dysplasia is the precursor lesion. The 5-year survival rate for patients with esophageal cancer, although generally poor, has improved during the past decade, and long-term survival is increasingly possible for patients with early or locally advanced disease. This review discusses the epidemiologic aspects and pathogenesis of these two esophageal cancers, as well as prevention and therapy, focusing on recent advances. Copyright © 2014 Massachusetts Medical Society. All rights reserved.

Johnson V.E.,University of Pennsylvania
Nature reviews. Neuroscience | Year: 2010

Traumatic brain injury (TBI) has devastating acute effects and in many cases seems to initiate long-term neurodegeneration. Indeed, an epidemiological association between TBI and the development of Alzheimer's disease (AD) later in life has been demonstrated, and it has been shown that amyloid-β (Aβ) plaques - one of the hallmarks of AD - may be found in patients within hours following TBI. Here, we explore the mechanistic underpinnings of the link between TBI and AD, focusing on the hypothesis that rapid Aβ plaque formation may result from the accumulation of amyloid precursor protein in damaged axons and a disturbed balance between Aβ genesis and catabolism following TBI.

Hajishengallis G.,University of Pennsylvania
Trends in Immunology | Year: 2014

Recent studies have uncovered novel mechanisms underlying the breakdown of periodontal host-microbe homeostasis, which can precipitate dysbiosis and periodontitis in susceptible hosts. Dysbiotic microbial communities of keystone pathogens and pathobionts are thought to exhibit synergistic virulence whereby not only can they endure the host response but can also thrive by exploiting tissue-destructive inflammation, which fuels a self-feeding cycle of escalating dysbiosis and inflammatory bone loss, potentially leading to tooth loss and systemic complications. Here, I discuss new paradigms in our understanding of periodontitis, which may shed light into other polymicrobial inflammatory disorders. In addition, I highlight gaps in knowledge required for an integrated picture of the interplay between microbes and innate and adaptive immune elements that initiate and propagate chronic periodontal inflammation. © 2013 Elsevier Ltd.

Cuker A.,University of Pennsylvania
Seminars in Thrombosis and Hemostasis | Year: 2014

Heparin-induced thrombocytopenia (HIT) is a clinicopathologic disorder that predisposes to thrombosis. Diagnosis rests on a compatible clinical picture and laboratory evidence of antiplatelet factor 4 (PF4)/heparin antibodies that activate platelets in a heparin-dependent manner. Rapid and accurate diagnosis is paramount to avoid the perils of misdiagnosis. Clinical evaluation may be guided by scoring systems such as the 4Ts and HIT Expert Probability (HEP) score. Laboratory tests include immunoassays, such as the PF4/heparin enzyme-linked immunosorbent assay (ELISA) and functional tests such as the 14C-serotonin release assay and heparin-induced platelet activation assay. Clinical scoring systems and commercially available immunoassays have high sensitivity but modest specificity. Functional assays are more specific, but they are technically demanding. Novel laboratory assays with faster turnaround times, greater specificity, and lesser technical complexity are in development. A Bayesian approach that combines the 4T score and the PF4/heparin ELISA result may be used to estimate the probability of HIT and guide clinical decision making. © 2014 by Thieme Medical Publishers, Inc.

Boettiger D.,University of Pennsylvania