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The Johns Hopkins University is a private research university in Baltimore, Maryland. Founded in 1876, the university was named after its first benefactor, the American entrepreneur, abolitionist, and philanthropist Johns Hopkins. His $7 million bequest—of which half financed the establishment of The Johns Hopkins Hospital—was the largest philanthropic gift in the history of the United States at the time. Daniel Coit Gilman, who was inaugurated as the institution's first president on February 22, 1876, led the university to revolutionize higher education in the U.S. by integrating teaching and research.The first research university in the Western Hemisphere and one of the founding members of the American Association of Universities, Johns Hopkins has ranked among the world’s top universities throughout its history. The National Science Foundation has ranked the university #1 among U.S. academic institutions in total science, medical, and engineering research and development spending for 31 consecutive years. Johns Hopkins is also ranked #12 in the U.S. News and World Report undergraduate program rankings for 2014 and was also ranked 11th in the U.S. News and World Report Best Global University Rankings of 2014, outranking Princeton University, Yale University, University of Pennsylvania, and Cornell University.Over the course of almost 140 years, 36 Nobel Prize winners have been affiliated with Johns Hopkins . Founded in 1883, the Blue Jays men’s lacrosse team has captured 44 national titles and joined the Big Ten Conference as an affiliate member in 2014.Johns Hopkins is organized into ten divisions on campuses in Maryland and Washington, D.C. with international centers in Italy, China, and Singapore. The two undergraduate divisions, the Krieger School of Arts and science and the Whiting School of Engineering, are located on the Homewood campus in Baltimore's Charles Village neighborhood. The medical school, the nursing school, and the Bloomberg School of Public Health are located on the Medical Institutions campus in East Baltimore. The university also consists of the Peabody Institute, the Applied Physics Laboratory, the Paul H. Nitze School of Advanced International Studies, the education school, the Carey Business School, and various other facilities. Wikipedia.

Bartlett J.G.,Johns Hopkins University
Anaerobe | Year: 2012

Anaerobic bacteria are relatively frequent pathogens in pulmonary infections that are associated with aspiration and its associated complications including aspiration pneumonitis, lung abscess, necrotizing pneumonia and empyema. These conditions have been studied since the early 1900's and substantial data with important clinical and microbiologic information are now readily available. However, the reports of these infections in the past 20 years have been sparse in number and much of the previous information relevant to this topic seems much less visible or apparent. The purpose of this report is to summarize the previous data and to celebrate the enormous contributions of Dr. Sydney Finegold to this topic. © 2012 .

Timlin H.,Johns Hopkins University
Lupus | Year: 2013

Ischemic stroke is increased in systemic lupus erythematosus (SLE) patients. The differential diagnosis of stroke in SLE is complex. Transient ischemic attack and ischemic stroke share pathophysiologic mechanisms, but prognosis may vary depending on severity and cause, and definitions are dependent on the timing and extent of the diagnostic evaluation. In SLE patients with a history of transient ischemic attacks, stroke occurred in 57%. Cerebrovascular events account for 20% to 30% of deaths in patients with SLE. In SLE, both disease-specific and traditional stroke risk factors are important.

Prabhakar N.R.,University of Chicago | Semenza G.L.,Johns Hopkins University
Journal of Molecular Medicine | Year: 2012

The carotid body is a sensory organ that detects acute changes in arterial blood oxygen (O2) levels and reflexly mediates systemic cardiac, vascular, and respiratory responses to hypoxia. This article provides a brief update of the roles of gas messengers as well as redox homeostasis by hypoxiainducible factors (HIFs) in hypoxic sensing by the carotid body. Carbon monoxide (CO) and nitric oxide (NO), generated by heme oxygenase-2 (HO-2) and neuronal nitric oxide synthase (nNOS), respectively, inhibit carotid body activity. Molecular O2 is a required substrate for the enzymatic activities of HO-2 and nNOS. Stimulation of carotid body activity by hypoxia may reflect reduced formation of CO and NO. Glomus cells, the site of O2 sensing in the carotid body, express cystathionine ?-lyase (CSE), an H2S generating enzyme. Cth?/? mice, which lack CSE, exhibit severely impaired hypoxia-induced H2S generation, sensory excitation, and stimulation of breathing in response to low O2. Hypoxiaevoked H2S generation in the carotid body requires the interaction of CSE with HO-2, which generates CO. Carotid bodies from Hif1a+/? mice with partial HIF-1? deficiency do not respond to hypoxia, whereas carotid bodies from mice with partial HIF-2? deficiency are hyper-responsive to hypoxia. The opposing roles of HIF-1? and HIF-2? in the carotid body have provided novel insight into molecular mechanisms of redox homeostasis and its role in hypoxia sensing. Heightened carotid body activity has been implicated in the pathogenesis of autonomic morbidities associated with sleepdisordered breathing, congestive heart failure, and essential hypertension. The enzymes that generate gas messengers and redox regulation by HIFs represent potential therapeutic targets for normalizing carotid body function and downstream autonomic output in these disease states. © Springer-Verlag 2012.

Sicherer S.H.,Mount Sinai School of Medicine | Wood R.A.,Johns Hopkins University
Journal of Allergy and Clinical Immunology: In Practice | Year: 2013

Peanut allergy is often severe, potentially fatal, usually persistent, and appears to have increased in prevalence. An accurate diagnosis is essential because there is a significant burden on quality of life. The tools available for diagnosis include the medical history, skin prick test (SPT), determination of serum peanut-specific IgE antibodies (PN-IgE), and medically supervised oral food challenges. Numerous studies, almost exclusively in children, have correlated clinical outcomes against SPTs and PN-IgE with informative results. The diagnostic utility of SPT and PN-IgE is maximized by considering the degree of positive result and consideration of the medical history (a priori estimation of risk). Emerging tests that evaluate IgE binding to specific proteins in peanut (component testing) add important additional diagnostic information in specific settings. Studies are increasingly focused on how the results of tests considered in combination (or performed serially) may increase diagnostic accuracy. Here, we review the utility of currently available tests and provide suggestions on how to best use them to accurately predict peanut allergy. Still, the physician-supervised oral food challenge remains the most definitive test available. © 2013 American Academy of Allergy, Asthma & Immunology.

Morgan D.J.,University of Maryland, Baltimore | Wright S.M.,Johns Hopkins University | Dhruva S.,University of California at Davis
JAMA Internal Medicine | Year: 2015

CONCLUSIONS AND RELEVANCE The literature on overuse of medical care is rapidly expanding. In 2013, both clinical trials and observational studies highlighted frequently overused or unnecessary care. Overuse of testing causes false-positive results and overdiagnosis. Negative test results do not appear to genuinely reassure patients. Overtreatment, with both medical therapies and procedural interventions, places patients at risk of unnecessary adverse events.OBJECTIVE To identify and highlight the most significant clinical articles published in 2013 related to medical overuse. EVIDENCE REVIEW A systematic review of English-language articles published in 2013 that related to medical overuse in adults.IMPORTANCE Overuse of medical care, consisting primarily of overdiagnosis and overtreatment, is a common clinical problem.FINDINGS We reviewed 478 published articles that met our inclusion criteria. Of these, 126 were ranked most relevant based on quality of methodology, strength of results, potential effects on patient care, and the number of patients potentially affected. The 10 most relevant articles were selected using the same criteria. These 10 articles (organized into the categories overdiagnosis, overtreatment, and methods to avoid overuse) were reviewed and interpreted for their effect on clinical medicine.

Mallory T.G.,Johns Hopkins University
Marine Policy | Year: 2013

This article examines China's distant water fishing industry, with a focus on China's bilateral fisheries access agreements in Africa. The article argues that China largely conforms to international norms and rules on sustainable fisheries, but that challenges remain in efforts to work with China on the sustainable management of fish stocks. Developed countries contribute to China's policies and behavior in international fisheries in both positive and negative ways. © 2012 Elsevier Ltd.

Jemc J.C.,Johns Hopkins University
Genesis | Year: 2011

Cell-cell signaling and adhesion are critical for establishing tissue architecture during development and for maintaining tissue architecture and function in the adult. Defects in adhesion and signaling can result in mislocalization of cells, uncontrolled proliferation and improper differentiation, leading to tissue overgrowth, tumor formation, and cancer metastasis. An important example is found in the germline. Germ cells that are not incorporated into the gonad exhibit a greater propensity for forming germ cell tumors, and defects in germline development can reduce fertility. While much attention is given to germ cells, their development into functional gametes depends upon somatic gonadal cells. The study of model organisms has provided great insights into how somatic gonadal cells are specified, the molecular mechanisms that regulate gonad morphogenesis, and the role of germline-soma communication in the establishment and maintenance of the germline stem cell niche. This work will be discussed in the context of Drosophila melanogaster. © 2011 Wiley-Liss, Inc.

Decamp M.,Johns Hopkins University
Journal of General Internal Medicine | Year: 2013

Physicians and patients increasingly use social media technologies, such as Facebook, Twitter, and weblogs (blogs), both professionally and personally. Amidst recent reports of physician misbehavior online, as well as concerns about social media's potential negative effect on trust in the medical profession, several national-level physician organizations have created professional guidelines on social media use by physicians. Missing from these guidelines is adequate attention to conflict of interest. Some guidelines do not explicitly mention conflict of interest; others recommend only disclosure. Recommending disclosure fails to appreciate the unique features of social media that make adequate disclosure difficult to accomplish. Moreover, in emphasizing disclosure alone, current guidelines are inconsistent with medicine's general trend toward management or elimination, not just disclosure, of potential conflicts. Because social media sites typically rely on physicians' voluntary compliance with professional norms, physicians necessarily play a major role in shaping these norms' content and scope. To achieve the benefits of social media and ensure the veracity of social media content while preserving trust in the profession, physicians must reaffirm their commitment to disclose potential conflicts; advocate for better electronic disclosure mechanisms; and develop concrete management strategies - including, where necessary, the elimination of conflicts altogether. © 2012 Society of General Internal Medicine.

Martin L.J.,Johns Hopkins University
Journal of Alzheimer's Disease | Year: 2010

Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are the second and third most common human adult-onset neurodegenerative diseases, respectively, after Alzheimer's disease. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of PD and ALS are inherited, and genes causing these diseases have been identified. Morphological, biochemical, and genetic, as well as cell and animal model, studies reveal that mitochondria could have a role in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review will present how mitochondrial pathobiology might contribute to neurodegeneration in PD and ALS and could serve as a target for drug therapy. © 2010 IOS Press and the authors. All rights reserved.

This review covers the physiological aspects of regulation of the arabinose operon in Escherichia coli and the physical and regulatory properties of the operon's controlling gene, araC. It also describes the light switch mechanism as an explanation for many of the protein's properties. Although many thousands of homologs of AraC exist and regulate many diverse operons in response to many different inducers or physiological states, homologs that regulate arabinose-catabolizing genes in response to arabinose were identified. The sequence similarities among them are discussed in light of the known structure of the dimerization and DNA-binding domains of AraC. © 2010 Federation of European Microbiological Societies.

Boyle M.P.,Johns Hopkins University | De Boeck K.,University Hospital of Leuven
The Lancet Respiratory Medicine | Year: 2013

Cystic fibrosis is caused by dysfunction or deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial chloride channel that has a key role in maintaining homoeostasis of the airway surface liquid layer in the lungs. More than 1900 CFTR mutations that might result in a disease phenotype have been identified; these can be grouped into classes on the basis of their effect on CFTR protein production, trafficking, function, and stability. In the past 2 years, landmark clinical trials have shown that correction of CFTR function leads to substantial clinical benefit for individuals with cystic fibrosis. These findings are ushering in a new era of cystic fibrosis treatments designed to correct the underlying CFTR defect caused by different mutation classes. With analysis of continuing trials and available patient registries, here we assess mutation types and the number and geographical distribution of patients who are likely to benefit from CFTR-correcting treatment. © 2013 Elsevier Ltd.

BOLD fMRI has provided new insights into postlesional brain language plasticity by providing a noninvasive in vivo approach to evaluate longitudinal changes in brain cortical activation during performance of language tasks. Specifically, BOLD fMRI has provided the opportunity to investigate not only changes in eloquent language cortex resulting from different types of brain pathology such as brain tumors, stroke, and epilepsy but also changes in eloquent language cortex occurring as a result of actual surgical resection of diseased but, nevertheless, partially functional tissue. In addition to reviewing the literature relating to stroke and epilepsy-related language plasticity as well as the more intriguing phenomenon of postsurgical plasticity in the setting of brain tumors, 2 unusual cases illustrating this latter manifestation of language plasticity are briefly described in this review article.

Cutting G.R.,Johns Hopkins University
Nature Reviews Genetics | Year: 2015

The availability of the human genome sequence and tools for interrogating individual genomes provide an unprecedented opportunity to apply genetics to medicine. Mendelian conditions, which are caused by dysfunction of a single gene, offer powerful examples that illustrate how genetics can provide insights into disease. Cystic fibrosis, one of the more common lethal autosomal recessive Mendelian disorders, is presented here as an example. Recent progress in elucidating disease mechanism and causes of phenotypic variation, as well as in the development of treatments, demonstrates that genetics continues to play an important part in cystic fibrosis research 25 years after the discovery of the disease-causing gene. © 2014 Macmillan Publishers Limited. All rights reserved.

Haber D.A.,Harvard University | Haber D.A.,Howard Hughes Medical Institute | Velculescu V.E.,Johns Hopkins University
Cancer Discovery | Year: 2014

The ability to study nonhematologic cancers through noninvasive sampling of blood is one of the most exciting and rapidly advancing fields in cancer diagnostics. This has been driven both by major technologic advances, including the isolation of intact cancer cells and the analysis of cancer cell-derived DNA from blood samples, and by the increasing application of molecularly driven therapeutics, which rely on such accurate and timely measurements of critical biomarkers. Moreover, the dramatic efficacy of these potent cancer therapies drives the selection for additional genetic changes as tumors acquire drug resistance, necessitating repeated sampling of cancer cells to adjust therapy in response to tumor evolution. Together, these advanced noninvasive diagnostic capabilities and their applications in guiding precision cancer therapies are poised to change the ways in which we select and monitor cancer treatments. Significance: Recent advances in technologies to analyze circulating tumor cells and circulating tumor DNA are setting the stage for real-time, noninvasive monitoring of cancer and providing novel insights into cancer evolution, invasion, and metastasis. © 2014 American Association for Cancer Research.

Kuntz K.D.,Johns Hopkins University | Snowden S.L.,NASA
Astrophysical Journal, Supplement Series | Year: 2010

Because M101 is nearly face-on, it provides an excellent laboratory in which to study the distribution of X-ray-emitting gas in a typical late-type spiral galaxy. We obtained a Chandra observation with a cumulative exposure of roughly 1 Ms to study the diffuse X-ray emission in M101. The bulk of the X-ray emission is correlated with the star formation traced by the far-UV (FUV) emission. The global FUV/X-ray correlation is nonlinear (the X-ray surface brightness is roughly proportional to the square root of the FUV surface brightness) and the small-scale correlation is poor, probably due to the delay between the FUV emission and the X-ray production in star-forming regions. The X-ray emission contains only minor contributions from unresolved stars (≲3%), unresolved X-ray point sources (≲4%), and individual supernova remnants (3%). The global spectrum of the diffuse emission can be reasonably well fitted with a three-component thermal model, but the fitted temperatures are not unique; many distributions of emission measure can produce the same temperatures when observed with the current CCD energy resolution. The spectrum of the diffuse emission depends on the environment; regions with higher X-ray surface brightnesses have relatively stronger hard components, but there is no significant evidence that the temperatures of the emitting components increase with surface brightness. © 2010. The American Astronomical Society. All rights reserved.

Thomas D.L.,Johns Hopkins University
Topics in Antiviral Medicine | Year: 2012

Since 2007, the annual age-adjusted mortality rate in hepatitis C virus (HCV) infection in the United States has been greater than that in HIV disease, reflecting the continuing decline in HIV-related mortality and the continuing increase in HCV-related mortality. The approval of 2 new direct-acting antivirals within the past year, as well as the promise offered by numerous other direct-acting agents in development, provides hope that we will be able to markedly improve our ability to cure HCV disease. The addition of a protease inhibitor (PI) to what has been the standard HCV therapy of peginterferon alfa and ribavirin dramatically improves sustained virologic response rates in treatment-naive patients with genotype 1 infection. Similar results have been observed in some treatment-experienced patients in whom prior peginterferon alfa/ribavirin therapy has failed. The use of these new agents has also permitted response-guided therapy, wherein early sustained virologic response to treatment allows for a shortened treatment duration. However, these new PIs add cost and adverse effects to HCV therapy. Boceprevir is associated with increased risk of anemia and dysgeusia, and telaprevir is associated with increased risk of anemia and skin and gastrointestinal adverse effects. Early studies indicate that the addition of PIs results in high response rates in patients with HCV/HIV coinfection. Other studies suggest that combinations of PIs and other direct-acting antivirals may ultimately permit cure when used in interferonsparing regimens. © 2011, IAS-USA.

Rose N.R.,Johns Hopkins University
Lupus | Year: 2010

The effect of infection in initiating autoimmune disease has been debated for many years. There are, even now, few instances of a human autoimmune disease clearly caused by prior infection, probably due to the frequent separation in time and space from the clinical outcomes. As our understanding of the immunologic consequences of the infectious process has deepened, we can re-think some of the issues by focusing attention on the varied adjuvant effects of microbial products. We are now able to distinguish some of the critical steps in progression from virus infection to benign autoimmunity to autoimmune disease in an experimental model of myocarditis. Immune regulators, such as cytokines and costimulatory molecules, serve as signposts in the process. The lessons learned may be broadly applicable to autoimmune disorders. © 2010 The Author(s).

Goes F.S.,Johns Hopkins University
Translational psychiatry | Year: 2012

Mood-incongruent psychotic features (MICP) are familial symptoms of bipolar disorder (BP) that also occur in schizophrenia (SZ), and may represent manifestations of shared etiology between the major psychoses. In this study we have analyzed three large samples of BP with imputed genome-wide association data and have performed a meta-analysis of 2196 cases with MICP and 8148 controls. We found several regions with suggestive evidence of association (P<10(-6)), although no marker met genome-wide significance criteria. The top associations were on chromosomes: 6q14.2 within the PRSS35/SNAP91 gene complex (rs1171113, P=9.67 × 10(-8)); 3p22.2 downstream of TRANK/LBA1 (rs9834970, P=9.71 × 10(-8)); and 14q24.2 in an intron of NUMB (rs2333194, P=7.03 × 10(-7)). These associations were present in all three samples, and both rs1171113 and rs2333194 were found to be overrepresented in an analysis of MICP cases compared with all other BP cases. To test the relationship of MICP with SZ, we performed polygenic analysis using the Psychiatric GWAS Consortium SZ results and found evidence of association between SZ polygenes and the presence of MICP in BP cases (meta-analysis P=0.003). In summary, our analysis of the MICP phenotype in BP has provided suggestive evidence for association of common variants in several genes expressed in the nervous system. The results of our polygenic analysis provides support for a modest degree of genetic overlap between BP with MICP and SZ, highlighting that phenotypic correlations across syndromes may be due to the influence of polygenic risk factors.

Hilpert M.,Johns Hopkins University
Geophysical Research Letters | Year: 2012

Standard theory for liquid infiltration into porous media cannot explain saturation overshoot at an infiltration front. Based on a recent generalization of the Green-Ampt approach, a new theory for variably-saturated flow is presented that assumes that capillary pressure does not only depend on liquid content but also on the flow velocity. The Eulerian expression for the nonequilibrium capillary pressure is rotationally invariant and attempts to capture the conjecture that dynamic effects are more pronounced if flow is associated with moving fluid-fluid interfaces which cause a dynamic contact angle. The new theory correctly predicts how overshoot depends on the downstream and upstream liquid contents as well as on grain size. The theory also yields the hydrostatic pressure distribution in the liquid and allows for liquid contents exceeding the saturated liquid content of the main imbibition curve that may occur for overshoot. Copyright 2012 by the American Geophysical Union.

Lorenz R.,Johns Hopkins University
Icarus | Year: 2011

Dust devil diameters, like many features in nature, have skewed distributions. I summarize, and present in a unified manner, literature values of dust devil optical diameters from seven terrestrial surveys, three rover-based surveys on Mars and two orbital surveys on Mars. The problems of appropriately treating these data are analogous to those for impact craters, and similar display and binning approaches are suggested. Remarkably, the Mars dust devil population remains better-known than Earth's. The theoretical justifications for possible log-normal, and (truncated) exponential and power-law descriptions of dust devil properties are discussed, and the challenges of discriminating between these candidate distributions with finite (and often, coarsely-binned) observation sets are noted: the best-sampled datasets so far appear well-described by power laws. Data required for advances in model discrimination are discussed: data binned in four or fewer ranges are useless for this purpose. Caution must be exercised in applying the notion of an 'average' dust devil and in calculating population-integral properties such as dust flux. © 2011 Elsevier Inc.

Golden S.H.,Johns Hopkins University
Journal of managed care pharmacy : JMCP | Year: 2012

Diabetes mellitus is defined as a group of metabolic diseases characterized by hyperglycemia, which when untreated can lead to long-term complications, including micro- and macrovascular complications. Tight glycemic control with intensive insulin therapy has been suggested to reduce the risk of such complications in several diabetes populations; however, such an approach can also be associated with risks and challenges. There are currently several modalities available to deliver insulin and monitor glucose levels to achieve glycemic goals in diabetic patients. In July 2012, the Agency for Healthcare Research and Quality (AHRQ) published a systematic review on the comparative effectiveness of insulin delivery systems and glucose-monitoring modalities in diabetic patients receiving intensive insulin therapy. Studies from 44 publications included in the review compared the effects of continuous subcutaneous insulin infusion (CSII) with multiple daily injections (MDI) and/or real time-continuous glucose monitoring (rt-CGM) with self-monitoring of blood glucose (SMBG) among children, adolescents, or adults with either type 1 (T1DM) or type 2 diabetes (T2DM), or pregnant women with pre-existing diabetes (either T1DM or T2DM). This comparative effectiveness review evaluated which modality results in improved glycemic control, less hypoglycemia, better quality of life, and/or improved clinical outcomes. The numerous technologies and the challenges that clinicians face when determining which patient population may benefit from different insulin delivery systems and glucose-monitoring approaches motivated AHRQ to synthesize the available information to assist health professionals in making evidence-based practice decisions for their patients. The review also delineates advances in insulin delivery and glucose-monitoring systems, practical methods to achieve tight glycemic control and strategies to minimize associated risks, as well as highlights gaps in research and areas that need to be addressed in the future.  To (a) educate health care professionals on the findings from AHRQ's 2012 comparative effectiveness review on insulin delivery and glucose-monitoring modalities in patients with diabetes; (b) apply review findings to make treatment decisions in clinical practice; and (c) identify shortcomings in the current research and future directions relating to the comparative effectiveness of insulin delivery and glucose-monitoring modalities for patients with diabetes. The AHRQ systematic review of randomized clinical trials reveals that both insulin delivery modalities (CSII and MDI) demonstrate similar effectiveness on glycemic control and severe hypoglycemia in children and adolescents with T1DM and in adults with T2DM. In adults with T1DM, hemoglobin A1c decreased more with CSII than with MDI with low strength of evidence, but one study heavily influenced these results. In children and adults with T1DM, the use of CSII was associated with improved quality of life compared with MDI, with low strength of evidence, while there was insufficient strength of evidence to make conclusions regarding the quality of life for adults with T2DM. The study investigators suggest that the modality to deliver intensive insulin therapy can be individualized to patient preference in order to maximize quality of life. On all measured outcomes, there was insufficient or low strength of evidence regarding pregnant women with pre-existing diabetes.The AHRQ investigators found studies comparing the effectiveness of glucose-monitoring modalities in individuals with T1DM only. The systematic review demonstrates that rt-CGM is associated with greater lowering of A1c compared with SMBG (high strength of evidence) without affecting the risk of severe hypoglycemia (low strength of evidence) or quality of life (low strength of evidence) in nonpregnant individuals with T1DM, particularly when compliance with device use is high. Additional findings suggest that the use of sensor-augmented insulin pumps (rt-CGM + CSII) is superior to the use of MDI/SMBG use in lowering A1c in nonpregnant individuals with T1DM (moderate strength of evidence). Comparison of other outcome measures did not yield firm conclusions due to low or insufficient evidence.

Osterholm M.T.,University of Minnesota | Kelley N.S.,University of Minnesota | Sommer A.,Johns Hopkins University | Belongia E.A.,Epidemiology Research Center
The Lancet Infectious Diseases | Year: 2012

Background: No published meta-analyses have assessed efficacy and effectiveness of licensed influenza vaccines in the USA with sensitive and highly specific diagnostic tests to confirm influenza. Methods: We searched Medline for randomised controlled trials assessing a relative reduction in influenza risk of all circulating influenza viruses during individual seasons after vaccination (efficacy) and observational studies meeting inclusion criteria (effectiveness). Eligible articles were published between Jan 1, 1967, and Feb 15, 2011, and used RT-PCR or culture for confirmation of influenza. We excluded some studies on the basis of study design and vaccine characteristics. We estimated random-effects pooled efficacy for trivalent inactivated vaccine (TIV) and live attenuated influenza vaccine (LAIV) when data were available for statistical analysis (eg, at least three studies that assessed comparable age groups). Findings: We screened 5707 articles and identified 31 eligible studies (17 randomised controlled trials and 14 observational studies). Efficacy of TIV was shown in eight (67%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 59% [95% CI 51-67] in adults aged 18-65 years). No such trials met inclusion criteria for children aged 2-17 years or adults aged 65 years or older. Efficacy of LAIV was shown in nine (75%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 83% [69-91]) in children aged 6 months to 7 years. No such trials met inclusion criteria for children aged 8-17 years. Vaccine effectiveness was variable for seasonal influenza: six (35%) of 17 analyses in nine studies showed significant protection against medically attended influenza in the outpatient or inpatient setting. Median monovalent pandemic H1N1 vaccine effectiveness in five observational studies was 69% (range 60-93). Interpretation: Influenza vaccines can provide moderate protection against virologically confirmed influenza, but such protection is greatly reduced or absent in some seasons. Evidence for protection in adults aged 65 years or older is lacking. LAIVs consistently show highest efficacy in young children (aged 6 months to 7 years). New vaccines with improved clinical efficacy and effectiveness are needed to further reduce influenza-related morbidity and mortality. Funding: Alfred P Sloan Foundation. © 2012 Elsevier Ltd.

Emens L.A.,Johns Hopkins University
Expert Review of Anticancer Therapy | Year: 2012

Breast cancer is immunogenic, and infiltrating immune cells in primary breast tumors convey important clinical prognostic and predictive information. Furthermore, the immune system is critically involved in clinical responses to some standard cancer therapies. Early breast cancer vaccine trials have established the safety and bioactivity of breast cancer immunotherapy, with hints of clinical activity. Novel strategies for modulating regulators of immunity, including regulatory T cells, myeloid-derived suppressor cells and immune checkpoint pathways (monoclonal antibodies specific for the cytotoxic T-lymphocyte antigen-4 or programmed death), are now available. In particular, immune checkpoint blockade has enormous therapeutic potential. Integrative breast cancer immunotherapies that strategically combine established breast cancer therapies with breast cancer vaccines, immune checkpoint blockade or both should result in durable clinical responses and increased cures. © 2012 2012 Expert Reviews Ltd.

Nutrients regulate gene transcription by the dynamic cycling of O-linked Nacetylglucosamine (O-GlcNAc) on proteins that constitute the transcriptional machinery. A study shows that O-GlcNAcylation of the nuclear factor êB (NF-êB) subunit c-Rel is required for its binding to the promoters of some, but not all, key T cell receptor-dependent genes; however, O-GlcNAcylation is dispensable for the binding of c-Rel to the promoters of tumor necrosis factor-á-dependent genes. This study not only illustrates how specifi c stimuli that act on the same transcription factor can elicit the expression of particular sets of genes, it also suggests a possible mechanism for autoimmunity in diabetes.

Hinnebusch A.G.,U.S. National Institutes of Health | Lorsch J.R.,Johns Hopkins University
Cold Spring Harbor Perspectives in Biology | Year: 2012

Translation initiation in eukaryotes is a highly regulated and complex stage of gene expression. It requires the action of at least 12 initiation factors, many of which are known to be the targets of regulatory pathways. Here we review our current understanding of the molecular mechanics of eukaryotic translation initiation, focusing on recent breakthroughs fromin vitro and in vivo studies. We also identify important unanswered questions that will require new ideas and techniques to solve. © 2012 Cold Spring Harbor Laboratory Press.

Stanley J.,Yale University | Krakauer J.W.,Johns Hopkins University
Frontiers in Human Neuroscience | Year: 2013

Those in 20th century philosophy, psychology, and neuroscience who have discussed the nature of skilled action have, for the most part, accepted the view that being skilled at an activity is independent of knowing facts about that activity, i.e., that skill is independent of knowledge of facts. In this paper we question this view of motor skill. We begin by situating the notion of skill in historical and philosophical context. We use the discussion to explain and motivate the view that motor skill depends upon knowledge of facts. This conclusion seemingly contradicts well-known results in cognitive science. It is natural, on the face of it, to take the case of H.M., the seminal case in cognitive neuroscience that led to the discovery of different memory systems, as providing powerful evidence for the independence of knowledge and skill acquisition. After all, H.M. seems to show that motor learning is retained even when previous knowledge about the activity has been lost. Improvements in skill generally require increased precision of selected actions, which we call motor acuity. Motor acuity may indeed not require propositional knowledge and has direct parallels with perceptual acuity. We argue, however, that reflection on the specifics of H.M.'s case, as well as other research on the nature of skill, indicates that learning to become skilled at a motor task, for example tennis, depends also on knowledge-based selection of the right actions. Thus skilled activity requires both acuity and knowledge, with both increasing with practice. The moral of our discussion ranges beyond debates about motor skill; we argue that it undermines any attempt to draw a distinction between practical and theoretical activities. While we will reject the independence of skill and knowledge, our discussion leaves open several different possible relations between knowledge and skill. Deciding between them is a task to be resolved by future research. © 2013 Stanley and Krakauer.

Anderson B.A.,Johns Hopkins University
Journal of Vision | Year: 2013

Attention selects stimuli for cognitive processing, and the mechanisms that underlie the process of attentional selection have been a major topic of psychological research for over 30 years. From this research, it has been well documented that attentional selection can proceed both voluntarily, driven by visual search goals, and involuntarily, driven by the physical salience of stimuli. In this review, I provide a conceptual framework for attentional control that emphasizes the need for stimulus selection to promote the survival and wellbeing of an organism. I argue that although goal-driven and salience-driven mechanisms of attentional selection fit within this framework, a central component that is missing is a mechanism of attentional selection that is uniquely driven by learned associations between stimuli and rewards. I go on to review recent evidence for such a value-driven mechanism of attentional selection, and describe how this mechanism functions independently of the well-documented salience-driven and goal-driven mechanisms. I conclude by arguing that reward learning modifies the attentional priority of stimuli, allowing them to compete more effectively for selection even when nonsalient and task-irrelevant. © 2013 ARVO.

Barnhill A.,Johns Hopkins University
American Journal of Public Health | Year: 2011

The state of New York recently petitioned the US Department of Agriculture (USDA) for permission to conduct a demonstration project in which sweetened beverages would be excluded from the foods eligible to be purchased with Supplemental Assistance Nutrition Program (SNAP) benefits (i.e., food stamps) in New York City. The USDA and advocacy groups have raised objections to new SNAP restrictions such as the proposed exclusion of sweetened beverages. Some objections rest on empirical issues best resolved by demonstration projects or pilot studies of new exclusions. Other objections question the equity of excluding sweetened beverages from SNAP; these objections are important but not ethically decisive. The USDA should approve the proposed demonstration project and should encourage other pilot studies to assess the effects of excluding sweetened beverages from SNAP.

Maruthur N.M.,Johns Hopkins University
Current Diabetes Reports | Year: 2013

Approximately 347 million persons were estimated to have diabetes worldwide in 2008, an increase of 194 million cases from 1980. Diabetes now affects both high- and low-income countries, with low-income countries bearing the majority of the burden. The epidemiologic transition from traditional health risks, such as poor hygiene, to modern health risks, such as sedentary lifestyle, has facilitated the increase in incidence in diabetes, especially in developing countries. The effect of these risk factors may be especially pronounced in some racial and ethnic populations. Increased surveillance for diabetes has contributed to increased diabetes prevalence in higher-income countries. Survival with and some risk factors for diabetes have improved in developed countries, but global diabetes mortality has increased by 20 % since 1990. Population growth and aging will only increase the burden of diabetes, and public health interventions are needed to address diabetes risk factors to stem the tide of this epidemic. © 2013 Springer Science+Business Media New York.

Ruff C.,Johns Hopkins University
Journal of Human Evolution | Year: 2010

Discovery of the first complete Early Pleistocene hominin pelvis, Gona BSN49/P27, attributed to Homo erectus, raises a number of issues regarding early hominin body size and shape variation. Here, acetabular breadth, femoral head breadth, and body mass calculated from femoral head breadth are compared in 37 early hominin (6.0-0.26 Ma) specimens, including BSN49/P27. Acetabular and estimated femoral head sizes in the Gona specimen fall close to the means for non-Homo specimens (Orrorin tugenesis, Australopithecus africanus, Paranthropus robustus), and well below the ranges of all previously described Early and Middle Pleistocene Homo specimens. The Gona specimen has an estimated body mass of 33.2 kg, close to the mean for the non-Homo sample (34.1 kg, range 24-51.5 kg, n = 19) and far outside the range for any previously known Homo specimen (mean = 70.5 kg; range 52-82 kg, n = 17). Inclusion of the Gona specimen within H. erectus increases inferred sexual dimorphism in body mass in this taxon to a level greater than that observed here for any other hominin taxon, and increases variation in body mass within H. erectus females to a level much greater than that observed for any living primate species. This raises questions regarding the taxonomic attribution of the Gona specimen. When considered within the context of overall variation in body breadth among early hominins, the mediolaterally very wide Gona pelvis fits within the distribution of other lower latitude Early and Middle Pleistocene specimens, and below that of higher latitude specimens. Thus, ecogeographic variation in body breadth was present among earlier hominins as it is in living humans. The increased M-L pelvic breadth in all earlier hominins relative to modern humans is related to an increase in ellipticity of the birth canal, possibly as a result of a non-rotational birth mechanism that was common to both australopithecines and archaic Homo. © 2009 Elsevier Ltd. All rights reserved.

Goes F.S.,Johns Hopkins University
Current Psychiatry Reports | Year: 2015

Anxiety symptoms and syndromes are common in bipolar disorders, occurring in over half of all subjects with bipolar disorder type I. Despite methodological and diagnostic inconsistencies, most studies have shown a robust association between the presence of a broadly defined comorbid anxiety disorder and important indices of clinical morbidity in bipolar disorder, including a greater number of depressive episodes, worse treatment outcomes, and elevated risk of attempting suicide. Anxiety symptoms and/or syndromes often precede the onset of bipolar disorder and may represent a clinical phenotype of increased risk in subjects with prodromal symptoms. Although the causal relationship between anxiety and bipolar disorders remains unresolved, the multifactorial nature of most psychiatric phenotypes suggests that even with progress towards more biologically valid phenotypes, the “phenomenon” of comorbidity is likely to remain a clinical reality. Treatment studies of bipolar patients with comorbid anxiety have begun to provide preliminary evidence for the role of specific pharmacological and psychotherapeutic treatments, but these need to be confirmed in more definitive trials. Hence, there is an immediate need for further research to help guide assessment and help identify appropriate treatments for comorbid conditions. © 2015, Springer Science+Business Media New York.

Serebruany V.L.,Johns Hopkins University | Atar D.,University of Oslo
Thrombosis and Haemostasis | Year: 2012

Central adjudication in randomised controlled outcome-driven trials represents a traditional approach to maintain data integrity by applying uniformed rules for assessment of clinical events. It was the purpose of this investigation to determine the patterns of myocardial infarction (Ml) adjudication in the TRITON, RECORD, and PLATO trials. We were matching centrally-adjudicated Mi's (CAMI's) from the official trial publication with the site-reported Ml (SRMI's) count from the Food and Drug Administration's secondary analyses for the investigational compounds prasugrel (TRITON), rosiglitazone (RECORD), and ticagrelor (PLATO). CAMI numbers showed a remarkable discrepancy to SRMI's by more than a doubling of the difference: from 72 to 145 events in TRITON favoring prasugrel (from a hazard ratio [HR]=0.76, p=0.08; to a HR=0.76, p<0.001), and from 44 to 89 events in favour of ticagrelor in PLATO (from a HR=0.94, p=0.095; to a HR=0.84, p<0.001). In contrast, in the RECORD trial, the CAMI count was less than the SRMI count (from 24 to 8 events, from a HR=1.42, p=0.93; to a HR=1.14, p=0.96), in this case diminishing cardiovascular hazards in favour of rosiglitazone. In conclusion, central adjudication in the TRITON, the RECORD, and the PLATO trial turned out to have a critical impact on study outcomes. Trial publications should in the future include site-reported major efficacy and safety endpoints to preserve data integrity. The regulatory authorities should consider independent audits when there is a major disagreement between centrally adjudicated and site reported events influencing the results of a major clinical trial. © Schattauer 2012.

Naik R.P.,Johns Hopkins University
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

Pregnancy poses a unique challenge to patients with sickle cell disease and β-thalassemia, who often have exacerbations of hemolysis or anemia during the gestational period, experience higher rates of obstetric and fetal complications, and may have distinct underlying comorbidities related to vasculopathy and iron overload that can endanger maternal health. Optimal management of pregnant women with hemoglobinopathies requires both an understanding of the physiologic demands of pregnancy and the pathophysiology of disease-specific complications of inherited blood disorders. A multidisciplinary team of expert hematologists and high-risk obstetricians is therefore essential to ensuring appropriate antenatal maternal screening, adequate fetal surveillance, and early recognition of complications. Fortunately, with integrated and targeted care, most women with sickle cell disease and β-thalassemia can achieve successful pregnancy outcomes.

Mueller T.,Johns Hopkins University
Physical Review B - Condensed Matter and Materials Physics | Year: 2012

I present a computational study on atomic order in 2-nm cuboctahedral Au-Pd nanoparticles. Equilibrium atomic structures, energies, and electronic surface d-band centers have been calculated across the entire range of compositions at different temperatures using a Bayesian approach to cluster expansions. The estimated prediction error in formation energies calculated by the cluster expansion, relative to density functional theory, is approximately 1 meV/atom. This prediction error would be low for a cluster expansion on a bulk material, and it is exceptionally low for a study of nanoparticles of this size. This result was accomplished by extending the Bayesian approach for cluster expansions to account for nonlocal, composition-dependent effects that might otherwise not be captured. For this system the Bayesian approach is estimated to be approximately five times as efficient as more common cluster selection techniques. © 2012 American Physical Society.

Tian Y.,Johns Hopkins University
Molecular & cellular proteomics : MCP | Year: 2012

Sialylation is one of the altered protein glycosylations associated with cancer development. The sialoglycoproteins in cancer cells, however, largely remain unidentified because of the lack of a method for quantitative analysis of sialoglycoproteins. This manuscript presents a high throughput method for quantitative analysis of N-linked sialoglycoproteins using conditional hydrazide chemistry, liquid chromatography, and tandem mass spectrometry. We further applied the sialoglycoproteomic method to the profiling of breast cancer tissues and compared findings with the results from the total glycoproteomic analysis using the original hydrazide chemistry method. We identified altered expression of sialoglycoproteins, as well as the total glycoprotein changes associated with breast cancer. Using lectin and Western blot analysis, we characterized one of the sialoglycoproteins, versican, and confirmed that versican was most sialylated and elevated in breast cancer. Furthermore, we showed that versican was detected in both cancer epithelial cells and peritumoral stromal cells using immunohistochemistry. Tissue microarray analysis revealed that epithelial expression of versican had significant relations to lymph node metastasis and pathological stages. This is the first quantitative sialoglycoproteomic and glycoproteomic analysis of breast cancer and noncancerous tissues. These findings present a significant addition of the method to the identification of altered expression of sialylated glycoproteins associated with breast cancer development.

Henderson D.A.,Johns Hopkins University
Vaccine | Year: 2011

The 30th anniversary of the declaration of smallpox eradication is a propitious time to look back on the evolutionary history of the program, its execution, and its legacy for the future. The eradication of history's most feared disease culminated a decade-long World Health Organization campaign which began despite skepticism and doubt and succeeded despite a never ending array of obstacles occasioned by floods, civil war, famine, and bureaucratic inertia. New concepts in public health management, surveillance, and the application of large-scale programs for vaccination were fostered and matured. A new generation of young health workers emerged who applied new approaches and experienced the gratification of public health achievement. A definitive legacy for the future was the extension of the program into an "Expanded Program on Immunization", now functioning world-wide and resulting in dramatic improvements in health through control of vaccine-preventable diseases. No less important are the growing number of multi-national programs whose foundations rest on the development of active case surveillance to measure achievement and to guide progress - poliomyelitis, measles, guinea worm, and rubella. © 2011 Elsevier Ltd.

Hamilton R.G.,Johns Hopkins University | Williams P.B.,University of Missouri - Kansas City
Journal of Allergy and Clinical Immunology | Year: 2010

The allergist/immunologist judiciously diagnoses allergic disease by using confirmatory IgE antibody data from in vivo and in vitro assays after the collection of a clinical history. After an overview of historical events, clinically available allergen-specific IgE assays from Phadia, Siemens, and Hycor are contrasted by their design and performance characteristics. The assays share comparable working ranges, analytical sensitivities, and excellent precision, reproducibility, and linearity to a performance standard of <15% coefficients of variation. However, multiple interlaboratory studies have confirmed that the 3 IgE antibody assays either detect different populations of IgE antibody or do not measure the same antibodies with comparable efficiencies. The clinical consequence is that IgE antibody results from the 3 assays are not interchangeable or equivalent. Data generated with one assay cannot be directly extrapolated to published predictive outcomes based on IgE antibody levels from a different assay. The transition from allergen extract-based to allergenic components reagents is discussed, emphasizing the chip-based microarray's strength in identifying IgE antibody cross-reactivity. US Food and Drug Administration-cleared point-of-care IgE antibody lateral flow cassettes are overviewed. Finally, IgE antibody concentration, affinity, clonality (epitope specificity), and specific activity (specific/total IgE ratio) are examined as humoral immune response parameters measured by serologic assays that affect effector cell degranulation and ultimately allergic disease expression. © 2010 American Academy of Allergy, Asthma & Immunology.

Loren R.D.,Johns Hopkins University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

The 'two-box model' of planetary climate is discussed. This model has been used to demonstrate consistency of the equator-pole temperature gradient on Earth, Mars and Titan with what would be predicted from a principle of maximum entropy production (MEP). While useful for exposition and for generating first-order estimates of planetary heat transports, it has too low a resolution to investigate climate systems with strong feedbacks. A two-box MEP model agrees well with the observed day : night temperature contrast observed on the extrasolar planet HD 189733b. ©2010 The Royal Society.

Chluba J.,Johns Hopkins University
Monthly Notices of the Royal Astronomical Society | Year: 2014

In the expanding Universe, the average temperature of the cosmic microwave background (CMB) is expected to depend like TCMB α(1 + z) on redshift z. Adiabatic photon production (or destruction) or deviations from isotropy and homogeneity could modify this scaling and several observational tests have been carried out in response. Here, we explain why 'adiabatic' conditions are extremely difficult to establish in the redshift range targeted by these tests. Thus, instead of leading to a simple rescaling of the CMB temperature, a spectral distortion should be produced, which can be constrained using COBE/FIRAS. For scenarios with late photon production, tests of the temperature-redshift relation (TRR) should therefore be reinterpreted as weak spectral distortion limits, directly probing the energy dependence of the photon production process. For inhomogeneous cosmologies, an average y-type distortion is produced, but this type of distortion can be created in several otherways.Here, we briefly discuss possible effects that may help disentangling different contributions to the distortion signal, finding this to be very challenging. We furthermore argue that tests of the TRR using the Sunyaev- Zeldovich effect have limited applicability and that for non-gravitational changes to the TRR, the CMB anisotropy spectrum should exhibit an additional y-type dependence. © 2014 The Author Published by Oxford University Press on behalf of the Royal Astronomical Society.

Issigonis M.,Johns Hopkins University
Developmental biology | Year: 2012

Stem cells sustain tissue regeneration by their remarkable ability to replenish the stem cell pool and to generate differentiating progeny. Signals from local microenvironments, or niches, control stem cell behavior. In the Drosophila testis, a group of somatic support cells called the hub creates a stem cell niche by locally activating the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway in two adjacent types of stem cells: germline stem cells (GSCs) and somatic cyst stem cells (CySCs). Here, we find that ken and barbie (ken) is autonomously required for the self-renewal of CySCs but not GSCs. Furthermore, Ken misexpression in the CySC lineage induces the cell-autonomous self-renewal of somatic cells as well as the nonautonomous self-renewal of germ cells outside the niche. Thus, Ken, like Stat92E and its targets ZFH1 (Leatherman and Dinardo, 2008) and Chinmo (Flaherty et al., 2010), is necessary and sufficient for CySC renewal. However, ken is not a JAK-STAT target in the testis, but instead acts in parallel to Stat92E to ensure CySC self-renewal. Ken represses a subset of Stat92E targets in the embryo (Arbouzova et al., 2006) suggesting that Ken maintains CySCs by repressing differentiation factors. In support of this hypothesis, we find that the global JAK-STAT inhibitor Protein tyrosine phosphatase 61F (Ptp61F) is a JAK-STAT target in the testis that is repressed by Ken. Together, our work demonstrates that Ken has an important role in the inhibition of CySC differentiation. Studies of ken may inform our understanding of its vertebrate orthologue B-Cell Lymphoma 6 (BCL6) and how misregulation of this oncogene leads to human lymphomas. Copyright © 2012 Elsevier Inc. All rights reserved.

Greer A.L.,University of Cambridge | Greer A.L.,Tohoku University | Cheng Y.Q.,Oak Ridge National Laboratory | Ma E.,Johns Hopkins University
Materials Science and Engineering R: Reports | Year: 2013

Shear-banding is a ubiquitous plastic-deformation mode in materials. In metallic glasses, shear bands are particularly important as they play the decisive role in controlling plasticity and failure at room temperature. While there have been several reviews on the general mechanical properties of metallic glasses, a pressing need remains for an overview focused exclusively on shear bands, which have received tremendous attention in the past several years. This article attempts to provide a comprehensive and up-to-date review on the rapid progress achieved very recently on this subject. We describe the shear bands from the inside out, and treat key materials-science issues of general interest, including the initiation of shear localization starting from shear transformations, the temperature and velocity reached in the propagating or sliding band, the structural evolution inside the shear-band material, and the parameters that strongly influence shear-banding. Several new discoveries and concepts, such as stick-slip cold shear-banding and strength/plasticity enhancement at sub-micrometer sample sizes, will also be highlighted. The understanding built-up from these accounts will be used to explain the successful control of shear bands achieved so far in the laboratory. The review also identifies a number of key remaining questions to be answered, and presents an outlook for the field. © 2013 Elsevier B.V. All rights reserved.

Rajasekhar A.,Florida College | Streiff M.B.,Johns Hopkins University
Blood Reviews | Year: 2013

Venous thromboembolism (VTE) is the common cause of morbidity and mortality. Vena cava filters (VCF) represent an important alternative to anticoagulation for management of VTE. VCF use has increased dramatically with the availability of retrievable filters. Since indiscriminate use of VCF can be associated with net patient harm, knowledge of the risks and benefits of these devices is essential to optimal evidence-based practice. In this review, we will examine the characteristics of available permanent and optional VCF, their efficacy and safety in management of VTE and discuss appropriate, extended and unsubstantiated indications for VCF use. We will also review the clinical outcomes of VCF in alternative placement sites (supra-renal inferior vena cava and superior vena cava) and in specialized patient populations (bariatric surgery, cancer, etc.), recommendations regarding anticoagulation for prevention of thrombosis as well as recommended follow up for patients with VCF. © 2013.

Thakor N.V.,National University of Singapore | Thakor N.V.,Johns Hopkins University
Science Translational Medicine | Year: 2013

Brain-machine and brain-computer interface technologies hold great promise for use in the recovery of sensory and motor functions lost as a result of nervous-system injuries or limb amputations. This Perspective describes the current state of noninvasive and invasive technologies with a view to potential applications. The scientific and technological challenges and barriers to translation are critically analyzed for a variety of approaches.

Ghanem K.G.,Johns Hopkins University
CNS Neuroscience and Therapeutics | Year: 2010

Treponema pallidum subspecies pallidum, the causative agent of syphilis, disseminates to the central nervous system within days after exposure. Clinical manifestations can occur during any stage of the infection, and include asymptomatic neurosyphilis, acute meningeal syphilis, meningovascular syphilis, paretic neurosyphilis, and tabetic neurosyphilis. The majority of cases are reported in HIV-infected patients but the epidemiology of modern neurosyphilis is not well defined because of the paucity of population-based data. Decreasing reports of late neurosyphilis have been countered with increasing reports of early neurologic involvement. This review summarizes the clinical manifestations, diagnosis, and therapy of neurosyphilis, focusing on areas of continued controversy, and highlighting several important questions that remain unanswered. Since 2000, the rates of syphilis continue to increase. Given the effectiveness of penicillin therapy, these trends suggest a failure of prevention. Regrettably, rather than become an infection of historical significance, syphilis in the era of HIV continues to challenge researchers and clinicians. Compilation © 2010 Blackwell Publishing Ltd.

Bartlett J.G.,Johns Hopkins University
Infection Control and Hospital Epidemiology | Year: 2010

There has been a recent surge of interest in Clostridium difficile infection, which reflects an impressive increase in the number and severity of these infections. This review addresses some of the newer methods for detection of C. difficile infection at the bedside and in the laboratory. Particularly important are the new rapid diagnostic tests that detect toxigenic C. difficile using polymerase chain reaction and the combination tests that, either simultaneously or sequentially, screen for C. difficile and test for toxins A and B. It is expected that these new testing methods will largely supplant the enzyme immunoassays for toxins, which are used by most laboratories, departments, and divisions. The present goal is to combine clinical, laboratory, and animal research related to C. difficile that reflects issues that are considered to be major contemporary challenges. Among this work is the pursuit of studies of immune mechanisms to better control this disease. © 2010 by The 5th Decennial on Healthcare-Associated Infections, LLC. All rights reserved.

Allen R.P.,Johns Hopkins University
International Review of Psychiatry | Year: 2014

Restless legs syndrome/Willis Ekbom disease (RLS/WED) has been recognized as a significant medical disorder since the 17th century. It was studied mostly in the last 50 years in relation to increasing interest in sleep medicine and health-related quality of life. This led to recognition that the disease is not well characterized as restless feelings in the legs. These symptoms are reported in many situations, but the subjective experience of RLS/WED patients differs from that experienced by others. Thus a new name has been introduced that avoids problems of symptom definition of a disease by naming it after those who first characterized it, i.e. 'Willis Ekbom disease'. This article emphasizes the importance of RLS/WED for psychiatry. The disease carries significant increased risk for depression and anxiety disorders. Treatment requires consideration of these co-morbid disorders. RLS/WED can exacerbate or even engender psychiatric disease, so treatment of psychiatric disease should also include consideration of RLS/WED. The need for attention to RLS/WED is particularly significant for depression. Most anti-depressants exacerbate or can even engender RLS/WED. Thus this article seeks to introduce RLS/WED in relation to psychiatric practice. It presents the RLS/WED disease, its overlap with psychiatry and the current treatment options. © 2014 Institute of Psychiatry.

Hamilton R.G.,Johns Hopkins University
Journal of Allergy and Clinical Immunology | Year: 2010

Clinical laboratory analyses aid in the diagnosis and management of human allergic (IgE-dependent) diseases. Diagnosis of immediate-type hypersensitivity begins with a thorough clinical history and physical examination. Once symptoms compatible with an allergic disorder have been identified, a skin test, blood test, or both for allergen-specific IgE antibodies provide confirmation of sensitization, which strengthens the diagnosis. Skin testing provides a biologically relevant immediate-type hypersensitivity response with resultant wheal-and-flare reactions within 15 minutes of allergen application. Allergen-specific IgE antibody in serum is quantified by using 3 laboratory-based autoanalyzers (ImmunoCAP, Immulite, and HYTEC-288) and novel microarray and lateral-flow immunoassays. Technologic advances in serologic allergen-specific IgE measurements have involved increased automation, with enhanced reproducibility, greater quantification, lower analytic sensitivity, and component-supplemented extract-based allergen use. In vivo provocation tests involving inhalation, ingestion, or injection of allergens serve to clarify discordant history and skin- or blood-based measures of sensitization. Other diagnostic allergy laboratory analyses include total and free serum IgE measurement, precipitating IgG antibodies specific for organic dusts, mast cell tryptase, and indicator allergen analyses to assess indoor environments to promote patient-targeted allergen avoidance programs. A critique is provided on the predictive utility of serologic measures of specific IgE for food allergy and asthma. Reasons for the lack of clinical utility for food-specific IgG/IgG4 measurements in allergy diagnosis are examined. When the specific IgE measures are inconsistent with the clinical history, they should be confirmed by means of repeat and alternative method analysis. Ultimately, the patient's clinical history remains the principal arbiter that determines the final diagnosis of allergic disease. © 2010 American Academy of Allergy, Asthma & Immunology.

Bennett W.L.,Johns Hopkins University
Journal of managed care pharmacy : JMCP | Year: 2012

In 2007, the Agency for Healthcare Research and Quality(AHRQ) published a systematic review on the comparative effectiveness of oral medications for type 2 diabetes. The review included studies on the benefits and risks of oral medications used for achieving glycemic control in patients with type 2 diabetes. AHRQ published an updated review in March 2011 that summarized the benefits and harms of medications (metformin,second-generation sulfonylureas, thiazolidinediones, meglitinides,dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists), as monotherapy and in combination, for the treatment of adults with type 2 diabetes. To (a) familiarize health care professionals with the methods and findings from AHRQ's 2011 comparative effectiveness review on medications for adults with type 2 diabetes, (b) encourage consideration of the clinical and managed care applications of the review findings, and(c) identify limitations and gaps in the existing research with respect to the benefits and risks of oral diabetes medications. Type 2 diabetes mellitus is a major public health burden. Since the 2007 AHRQ systematic review of oral medications for type 2 diabetes, the FDA has approved several new drug classes. Therefore, in 2011, the original systematic review was updated with comparisons including the newer oral diabetes medications. The updated report expands beyond the scope of the original 2007 review by including comparisons of 2-drug combinations and the addition of more head-to-head comparisons, as well as additional adverse outcomes. A high strength of evidence showed that most medications were similarly efficacious at lowering hemoglobin A1c by about 1 absolute percentage point compared with baseline values. The addition of most oral medications to initial monotherapy further improved glycemiccontrol by lowering A1c by another 1 percentage point. The only exception was the DPP-4 inhibitor class, which did not lower A1c to the same extent as metformin when used as monotherapy. Overall, metformin was found to have a more favorable effect on body weight when compared with other medications. Two-drug combinations compared with each other demonstrated similar reductions in A1c levels. Metformin decreased low-density lipoprotein cholesterol (LDL-C) relative to pioglitazone, sulfonylureas,and DPP-4 inhibitors. Sulfonylureas had a 4-fold higher risk of mild-to-moderate hypoglycemia compared with metformin alone, and, in combination with metformin, had more than a 5-fold increased risk compared with metformin plus a thiazolidinedione. Thiazolidinediones had an increased risk of congestive heart failure relative to sulfonylureas, and an increased risk for bone fractures relative to metformin. Diarrhea occurred more often for metformin users compared with thiazolidinedione users. Although the long-term risks and benefits of diabetes medications remain unclear, the evidence supports the use of metformin as a first-line agent.

Grados M.A.,Johns Hopkins University
Journal of the American Academy of Child and Adolescent Psychiatry | Year: 2010

Objective: To provide a contemporary perspective on genetic discovery methods applied to obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). Method: A review of research trends in genetics research in OCD and TS is conducted, with emphasis on novel approaches. Results: Genome-wide association studies (GWAS) are now in progress in OCD and TS and will provide a platform for future discovery of common gene variants. Optimally, newer next-generation genome sequencing methods can also be used to detect larger effect genes (rare gene variants), taking advantage of pedigrees. Studies of gene networks or sets rather than individual genes will be required to elucidate biological etiology, as neural systems appear to act redundantly. Newer phenotyping strategies, such as symptom-based subtypes, cross-disorder latent class types, and intermediate phenotypes (endophenotypes) will need to be developed and tested to better align clinical and physiological measures with genetic architecture. Conclusion: Although genetics research has made significant advances based on computational strength and bioinformatics advances, newer approaches to phenotyping and judicious study of gene etiological networks will be needed to uncover the genetic etiology of OCD and TS. © 2010 American Academy of Child and Adolescent Psychiatry.

Nath S.,Johns Hopkins University
Journal of neurovirology | Year: 2012

Currently, there is no effective treatment for neurological complications of infection with the human immunodeficiency virus that persists despite the use of combination antiretroviral therapy. A medium throughput assay was developed for screening neuroprotective compounds using primary mixed neuronal cells and mitochondrial toxin 3-nitropropionic acid. Using this assay, a library of 2,000 compounds was screened. Out of 256 compounds that showed variable degrees of neuroprotection, nine were related to epicatechin, a monomeric flavonoid found in cocoa and green tea leaves that readily crosses the blood-brain barrier. Hence, catechin, epicatechin, and the related compound, epigallocatechin gallate (EGCG) were further screened for their neuroprotective properties against HIV proteins Tat and gp120, and compared to those of resveratrol. Epicatechin and EGCG targets the brain-derived neurotrophic factor (BDNF) and its precursor proBDNF signaling pathways, normalizing both Tat-mediated increases in proapoptotic proBDNF and concomitant Tat-mediated decreases in the mature BDNF protein in hippocampal neurons. Epicatechin and epigallocatechin gallate were more potent than catechin or resveratrol as neuroprotectants. Due to its simpler structure and more efficient blood-brain barrier penetration properties, epicatechin might be the best therapeutic candidate for neurodegenerative diseases including HIV-associated neurocognitive disorders where oxidative stress is an important pathophysiological mechanism.

Cernak I.,Johns Hopkins University
Frontiers in Neurology | Year: 2010

Due to complex injurious environment where multiple blast effects interact with the body parallel, blast-induced neurotrauma is a unique clinical entity induced by systemic, local, and cerebral responses. Activation of autonomous nervous system; sudden pressure increase in vital organs such as lungs and liver; and activation of neuroendocrine-immune system are among the most important mechanisms that contribute significantly to molecular changes and cascading injury mechanisms in the brain. It has been hypothesized that vagally mediated cerebral effects play a vital role in the early response to blast: this assumption has been supported by experiments where bilateral vagotomy mitigated bradycardia, hypotension, and apnea, and also prevented excessive metabolic alterations in the brain of animals exposed to blast. Clinical experience suggests specific blast-body-nervous system interactions such as (1) direct interaction with the head either through direct passage of the blast wave through the skull or by causing acceleration and/or rotation of the head; and (2) via hydraulic interaction, when the blast overpressure compresses the abdomen and chest, and transfers its kinetic energy to the body's fluid phase, initiating oscillating waves that traverse the body and reach the brain. Accumulating evidence suggests that inflammation plays important role in the pathogenesis of long-term neurological deficits due to blast. These include memory decline, motor function and balance impairments, and behavioral alterations, among others. Experiments using rigid body- or head protection in animals subjected to blast showed that head protection failed to prevent inflammation in the brain or reduce neurological deficits, whereas body protection was successful in alleviating the blast-induced functional and morphological impairments in the brain. © 2010 Cernak.

Epstein J.I.,Johns Hopkins University
Journal of Urology | Year: 2010

Purpose: An update is provided of the Gleason grading system, which has evolved significantly since its initial description. Materials and Methods: A search was performed using the MEDLINE® database and referenced lists of relevant studies to obtain articles concerning changes to the Gleason grading system. Results: Since the introduction of the Gleason grading system more than 40 years ago many aspects of prostate cancer have changed, including prostate specific antigen testing, transrectal ultrasound guided prostate needle biopsy with greater sampling, immunohistochemistry for basal cells that changed the classification of prostate cancer and new prostate cancer variants. The system was updated at a 2005 consensus conference of international experts in urological pathology, under the auspices of the International Society of Urological Pathology. Gleason score 2-4 should rarely if ever be diagnosed on needle biopsy, certain patterns (ie poorly formed glands) originally considered Gleason pattern 3 are now considered Gleason pattern 4 and all cribriform cancer should be graded pattern 4. The grading of variants and subtypes of acinar adenocarcinoma of the prostate, including cancer with vacuoles, foamy gland carcinoma, ductal adenocarcinoma, pseudohyperplastic carcinoma and small cell carcinoma have also been modified. Other recent issues include reporting secondary patterns of lower and higher grades when present to a limited extent, and commenting on tertiary grade patterns which differ depending on whether the specimen is from needle biopsy or radical prostatectomy. Whereas there is little debate on the definition of tertiary pattern on needle biopsy, this issue is controversial in radical prostatectomy specimens. Although tertiary Gleason patterns are typically added to pathology reports, they are routinely omitted in practice since there is no simple way to incorporate them in predictive nomograms/tables, research studies and patient counseling. Thus, a modified radical prostatectomy Gleason scoring system was recently proposed to incorporate tertiary Gleason patterns in an intuitive fashion. For needle biopsy with different cores showing different grades, the current recommendation is to report the grades of each core separately, whereby the highest grade tumor is selected as the grade of the entire case to determine treatment, regardless of the percent involvement. After the 2005 consensus conference several studies confirmed the superiority of the modified Gleason system as well as its impact on urological practice. Conclusions: It is remarkable that nearly 40 years after its inception the Gleason grading system remains one of the most powerful prognostic factors for prostate cancer. This system has remained timely because of gradual adaptations by urological pathologists to accommodate the changing practice of medicine. © 2010 American Urological Association.

Best P.N.,Institute for Astronomy | Heckman T.M.,Johns Hopkins University
Monthly Notices of the Royal Astronomical Society | Year: 2012

A sample of 18286 radio-loud active galactic nuclei (AGN) is presented, constructed by combining the seventh data release of the Sloan Digital Sky Survey with the NRAO (National Radio Astronomy Observatory) VLA (Very Large Array) Sky Survey (NVSS) and the Faint Images of the Radio Sky at Twenty centimetres (FIRST) survey. Using this sample, the differences between radio galaxies of 'high-excitation' ('quasar-mode'; hereafer HERG) and 'low-excitation' ('radio-mode'; LERG) are investigated. A primary difference between the two radio source classes is the distinct nature of the Eddington-scaled accretion rate on to their central black holes: HERGs typically have accretion rates between one percent and 10 percent of their Eddington rate, whereas LERGs predominately accrete at a rate below one percent Eddington. This is consistent with models whereby the population dichotomy is caused by a switch between radiatively efficient and radiatively inefficient accretion modes at low accretion rates. Local radio luminosity functions are derived separately for the two populations, for the first time, showing that although LERGs dominate at low radio luminosity and HERGs begin to take over at L 1.4GHz~ 10 26WHz -1, examples of both classes are found at all radio luminosities. Using the V/V max test it is shown that the two populations show differential cosmic evolution at fixed radio luminosity: HERGs evolve strongly at all radio luminosities, while LERGs show weak or no evolution. This suggests that the luminosity dependence of the evolution previously seen in the radio luminosity function is driven, at least in part, by the changing relative contributions of these two populations with luminosity. The host galaxies of the radio sources are also distinct: HERGs are typically of lower stellar mass, with lower black hole masses, bluer colours, lower concentration indices and less pronounced 4000Å breaks indicating younger stellar populations. Even if samples are matched in radio luminosity and stellar and black hole masses, significant differences still remain between the accretion rates, stellar populations and structural properties of the host galaxies of the two radio source classes. These results offer strong support to the developing picture of radio-loud AGN in which HERGs are fuelled at high rates through radiatively efficient standard accretion discs by cold gas, perhaps brought in through mergers and interactions, while LERGs are fuelled via radiatively inefficient flows at low accretion rates. In this picture, the gas supplying the LERGs is frequently associated with the hot X-ray haloes surrounding massive galaxies, groups and clusters, as part of a radio-AGN feedback loop. © 2012 The Authors Monthly Notices of the Royal Astronomical Society © 2012 RAS.

Xing M.,Johns Hopkins University | Haugen B.R.,Aurora University | Schlumberger M.,University Paris - Sud
The Lancet | Year: 2013

Substantial developments have occurred in the past 5-10 years in clinical translational research of thyroid cancer. Diagnostic molecular markers, such as RET-PTC, RAS, and BRAFV600E mutations; galectin 3; and a new gene expression classifier, are outstanding examples that have improved diagnosis of thyroid nodules. BRAF mutation is a prognostic genetic marker that has improved risk stratification and hence tailored management of patients with thyroid cancer, including those with conventionally low risks. Novel molecular-targeted treatments hold great promise for radioiodine-refractory and surgically inoperable thyroid cancers as shown in clinical trials; such treatments are likely to become a component of the standard treatment regimen for patients with thyroid cancer in the near future. These novel molecular-based management strategies for thyroid nodules and thyroid cancer are the most exciting developments in this unprecedented era of molecular thyroid-cancer medicine.

Neyrinck M.C.,Johns Hopkins University
Astrophysical Journal | Year: 2011

It was recently shown that applying a Gaussianizing transform, such as a logarithm, to the nonlinear matter density field extends the range of useful applicability of the power spectrum by a factor of a few smaller. Such a transform dramatically reduces nonlinearities in both the covariance and the shape of the power spectrum. Here, analyzing Coyote Universe real-space dark-matter density fields, we investigate the consequences of these transforms for cosmological parameter estimation. The power spectrum of the log-density provides the tightest cosmological parameter error bars (marginalized or not), giving a factor of 2-3 improvement over the conventional power spectrum in all five parameters tested. For the tilt, ns, the improvement reaches a factor of five. Similar constraints are achieved if the log-density power spectrum and conventional power spectrum are analyzed together. Rank-order Gaussianization seems just as useful as a log transform to constrain n s, but not other parameters. Dividing the overdensity by its dispersion in few-Mpc cells, while it diagonalizes the covariance matrix, does not seem to help with parameter constraints. We also provide a code that emulates these power spectra over a range of concordance cosmological models. © 2011. The American Astronomical Society. All rights reserved.

Affrunti N.W.,Johns Hopkins University
Child psychiatry and human development | Year: 2012

Previous research has shown that maternal overcontrol is related to higher levels of child anxiety. It has been theorized, though not empirically tested, that maternal overcontrol decreases child perceived competence and mastery, which increases child anxiety. The present study investigated this theory using a sample of 89 mother-child dyads (children aged 6-13, 84.3% Caucasian, 6.7% African American, and 51.7% male). After statistically controlling for maternal anxiety level, child perceived competence was shown to partially mediate the relationship between maternal overcontrol and child anxiety. Though current findings are based on cross sectional data, they suggest multiple pathways through which maternal overcontrol impacts child anxiety. One pathway, described in theoretical models, posits that greater levels of parental control reduce children's opportunities to acquire appropriate developmental skills, lowering their perceived competence, and thus increasing their anxiety. Implications of these findings and directions for future research are discussed.

Genotype imputation has become a standard option for researchers to expand their genotype datasets to improve signal precision and power in tests of genetic association with disease. In imputations for family-based studies however, subjects are often treated as unrelated individuals: currently, only BEAGLE allows for simultaneous imputation for trios of parents and offspring; however, only the most likely genotype calls are returned, not estimated genotype probabilities. For population-based SNP association studies, it has been shown that incorporating genotype uncertainty can be more powerful than using hard genotype calls. We here investigate this issue in the context of case-parent family data. We present the statistical framework for the genotypic transmission-disequilibrium test (gTDT) using observed genotype calls and imputed genotype probabilities, derive an extension to assess gene-environment interactions for binary environmental variables, and illustrate the performance of our method on a set of trios from the International Cleft Consortium. In contrast to population-based studies, however, utilizing the genotype probabilities in this framework (derived by treating the family members as unrelated) can result in biases of the test statistics toward protectiveness for the minor allele, particularly for markers with lower minor allele frequencies and lower imputation quality. We further compare the results between ignoring relatedness in the imputation and taking family structure into account, based on hard genotype calls. We find that by far the least biased results are obtained when family structure is taken into account and currently recommend this approach in spite of its intense computational requirements. © 2012 Wiley Periodicals, Inc.

Carbary J.F.,Johns Hopkins University
Geophysical Research Letters | Year: 2013

Based on periodicities in the kilometric radio emissions, the Saturn Longitude System 4 (SLS4) was used to organize the far ultraviolet (120-150 nm) aurora observed by the Ultraviolet Imaging Spectrograph on the Cassini spacecraft. Individual Ultraviolet Imaging Spectrograph pixels were projected onto the ionosphere of Saturn, transformed into the SLS4 north and SLS4 south longitude systems, accumulated over all over auroral observations from 2007 to early 2009, and binned into 1°×1°bins of colatitude. The intensity of the northern aurora showed little variation in its SLS4 north system, but the intensity of the southern aurora exhibited an enhancement of over ∼10 kR between ∼140-280°SLS4 south longitude. This enhancement may represent the auroral signature of a southern ionospheric vortex proposed in MHD models of Saturn's magnetosphere to explain its periodicities. The loci of the northern intensity peaks and the 3 kR boundaries varied little over 360°of longitude, while the equatorward boundary of the southern aurora varied by ∼5°in SLS4 south longitude, reaching its most equatorward location of ∼23°colatitude between 100°and 180°longitude. The polygonal centroids of the aurora in both north and south were consistent with offsets of no more than ∼1°in both hemispheres. © 2013 American Geophysical Union. All Rights Reserved.

Bjornsson H.T.,Johns Hopkins University
Genome Research | Year: 2015

The Mendelian disorders of the epigenetic machinery are genetic disorders that involve disruption of the various components of the epigenetic machinery (writers, erasers, readers, and remodelers) and are thus expected to have widespread downstream epigenetic consequences. Studying this group may offer a unique opportunity to learn about the role of epigenetics in health and disease. Among these patients, neurological dysfunction and, in particular, intellectual disability appears to be a common phenotype; however, this is often seen in association with other more specific features in respective disorders. The specificity of some of the clinical features raises the question whether specific cell types are particularly sensitive to the loss of these factors. Most of these disorders demonstrate dosage sensitivity as loss of a single allele appears to be sufficient to cause the observed phenotypes. Although the pathogenic sequence is unknown for most of these disorders, there are several examples where disrupted expression of downstream target genes accounts for a substantial portion of the phenotype; hence, it may be useful to systematically map such disease-relevant target genes. Finally, two of these disorders (Rubinstein-Taybi and Kabuki syndromes) have shown post-natal rescue of markers of the neurological dysfunction with drugs that lead to histone deacetylase inhibition, indicating that some of these disorders may be treatable causes of intellectual disability. © 2015 Bjornsson.

Leung A.K.L.,Johns Hopkins University
Trends in Cell Biology | Year: 2015

MicroRNAs (miRNAs) are a conserved class of approximately 22 nucleotide (nt) short noncoding RNAs that normally silence gene expression via translational repression and/or degradation of targeted mRNAs in plants and animals. Identifying the whereabouts of miRNAs potentially informs miRNA functions, some of which are perhaps specialized to specific cellular compartments. In this review, the significance of miRNA localizations in the cytoplasm, including those at RNA granules and endomembranes, and the export of miRNAs to extracellular space will be discussed. How miRNA localizations and functions are regulated by protein modifications on the core miRNA-binding protein Argonaute (AGO) during normal and stress conditions will be explored, and in conclusion new AGO partners, non-AGO miRNA-binding proteins, and the emergent understanding of miRNAs found in the nucleoplasm, nucleoli, and mitochondria will be discussed. Mature miRNAs localize in multiple subcellular locations in the cytoplasm, such as RNA granules, endomembranes, and mitochondria, and are secreted out of cells via exosomes.Recent studies have revealed that mature miRNAs can also localize to the nucleus, where they could function in epigenetic regulation.The distributions of canonical and noncanonical forms of miRNA-induced silencing complexes suggest that different subcellular locations are required for the processing and degradation of miRNA itself, or for silencing or activation of miRNA targets.These subcellular distributions are differentially regulated by post-translational modifications as a function of cellular conditions, but one major question is whether such location-specific miRNAs are physiologically relevant. © 2015 Elsevier Ltd.

Levis M.,Johns Hopkins University
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2013

Patients with acute myeloid leukemia who harbor an FMS-like tyrosine kinase 3 (FLT3) mutation present several dilemmas for the clinician. The results of an FLT3 mutation test, which can be influenced by several variables, need to be interpreted according to the clinical setting and there is a need for internationally standardized FLT3 mutation assays. Because of the lack of prospective studies, the role of allogeneic transplantation as consolidation therapy is still somewhat controversial, but the preponderance of evidence suggests that transplantation in first remission, if possible, is probably the best option. Clinically useful FLT3 inhibitors are hopefully on the near horizon and are being studied in the context of current treatment paradigms.

Lario D.,Johns Hopkins University
Astrophysical Journal, Supplement Series | Year: 2010

We study the decay phase of solar near-relativistic (53-315keV) electron events as observed by the Advanced Composition Explorer (ACE) and the Ulysses spacecraft during solar cycle 23. By fitting an exponential function (exp - t/τ) to the time-intensity profile in the late phase of selected solar near-relativistic electron events, we examine the dependence of τ on electron energy, electron intensity spectra, event peak intensity, event fluence, and solar wind velocity, as well as heliocentric radial distance, heliolatitude, and heliolongitude of the spacecraft with respect to the parent solar event. The decay rates are found to be either independent or slightly decrease with the electron energy. No clear dependence is found between τ and the heliolongitude of the parent solar event, with the exception of well-connected events for which low values of τ are more commonly observed than for poorly-connected events. For those events concurrently observed by ACE and Ulysses, decay rates increase at distances >3AU. Events with similar decay rates at ACE and Ulysses were observed mainly when Ulysses was at high heliographic latitudes. We discuss the basic physical mechanisms that control the decay phase of the electron events and conclude that both solar wind convection and adiabatic deceleration effects influence the final shape of the decay phase of solar energetic particle events, but not as expressed by the models based on diffusive transport acting on an isotropic particle population. © 2010. The American Astronomical Society.

Wang S.B.,Johns Hopkins University
Trends in cardiovascular medicine | Year: 2013

Reversible cysteine oxidative post-translational modifications (Ox-PTMs) represent an important mechanism to regulate protein structure and function. In mitochondria, redox reactions can modulate components of the electron transport chain (ETC), the F(1)F(0)-ATP synthase complex, and other matrix proteins/enzymes. Emerging evidence has linked Ox-PTMs to mitochondrial dysfunction and heart failure, highlighting some potential therapeutic avenues. Ox-PTMs can modify a variety of amino acid residues, including cysteine, and have the potential to modulate the function of a large number of proteins. Among this group, there is a selected subset of amino acid residues that can function as redox switches. These unique sites are proposed to monitor the cell's oxidative balance through their response to the various Ox-PTMs. In this review, the role of Ox-PTMs in the regulation of the F(1)F(0)-ATP synthase complex is discussed in the context of heart failure and its possible clinical treatment. Copyright © 2013 Elsevier Inc. All rights reserved.

The health and economic burden from liver disease in the United States is substantial and rising. The objective of this study was to characterize temporal trends in mortality from chronic liver disease and liver cancer and the incidence of associated risk factors using population-based data over the past 30 years. Population-based mortality data were obtained from the National Vital Statistics System, and population estimates were derived from the national census for US adults (aged >45 years). Crude death rates (CDRs), age-adjusted death rates (ADRs), and average annual percentage change (AAPC) statistics were calculated. In total, 690,414 deaths (1.1%) were attributable to chronic liver disease, whereas 331,393 deaths (0.5%) were attributable to liver cancer between 1981 and 2010. The incidence of liver cancer was estimated at 7.1 cases per 100,000 population. Mortality rates from chronic liver disease and liver cancer increased substantially over the past 3 decades, with ADRs of 23.7 and 16.6 per 100,000 population in 2010, respectively. The AAPC from 2006 to 2010 demonstrated an increased ADR for chronic liver disease (AAPC, 1.5%; 95% confidence interval, 0.3%-2.8%) and liver cancer (AAPC, 2.6%; 95% confidence interval, 2.4%-2.7%). A comprehensive approach that involves primary and secondary prevention, increased access to treatment, and more funding for liver-related research is needed to address the high death rates associated with chronic liver disease and liver cancer in the United States. © 2014 American Cancer Society.

Dobrowsky T.M.,Johns Hopkins University
PLoS computational biology | Year: 2010

The fusion of the human immunodeficiency virus type 1 (HIV-1) with its host cell is the target for new antiretroviral therapies. Viral particles interact with the flexible plasma membrane via viral surface protein gp120 which binds its primary cellular receptor CD4 and subsequently the coreceptor CCR5. However, whether and how these receptors become organized at the adhesive junction between cell and virion are unknown. Here, stochastic modeling predicts that, regarding binding to gp120, cellular receptors CD4 and CCR5 form an organized, ring-like, nanoscale structure beneath the virion, which locally deforms the plasma membrane. This organized adhesive junction between cell and virion, which we name the viral junction, is reminiscent of the well-characterized immunological synapse, albeit at much smaller length scales. The formation of an organized viral junction under multiple physiopathologically relevant conditions may represent a novel intermediate step in productive infection.

Hwang J.,Johns Hopkins University | Romanski L.M.,University of Rochester
Journal of Neuroscience | Year: 2015

During communication we combine auditory and visual information. Neurophysiological research in nonhuman primates has shown that single neurons in ventrolateral prefrontal cortex (VLPFC) exhibit multisensory responses to faces and vocalizations presented simultaneously. However, whether VLPFC is also involved in maintaining those communication stimuli in working memory or combining stored information across different modalities is unknown, although its human homolog, the inferior frontal gyrus, is known to be important in integrating verbal information from auditory and visual working memory. To address this question, we recorded from VLPFC while rhesus macaques (Macaca mulatta) performed an audiovisual working memory task. Unlike traditional match-to-sample/ nonmatch-to-sample paradigms, which use unimodal memoranda, our nonmatch-to-sample task used dynamic movies consisting of both facial gestures and the accompanying vocalizations. For the nonmatch conditions, a change in the auditory component (vocalization), the visual component (face), or both components was detected. Our results show that VLPFC neurons are activated by stimulus and task factors: while some neurons simply responded to a particular face or a vocalization regardless of the task period, others exhibited activity patterns typically related to working memory such as sustained delay activity and match enhancement/suppression. In addition, we found neurons that detected the component change during the nonmatch period. Interestingly, some of these neurons were sensitive to the change of both components and therefore combined information from auditory and visual working memory. These results suggest that VLPFC is not only involved in the perceptual processing of faces and vocalizations but also in their mnemonic processing. © 2015 the authors.

Mojtabai R.,Johns Hopkins University
Archives of General Psychiatry | Year: 2011

Context: The DSM-IV criteria for major depressive episodes exclude brief episodes that are better accounted for by bereavement. However, a proposal has been made to remove this exclusion from the DSM-5. Objectives: To compare the demographic and psychiatric characteristics of participants with bereavementrelated, single, brief (<2 months) depressive episodes and other types of depressive episodes and to compare the future risk of depression between these groups and participants without a history of depression at baseline. Design: A longitudinal, community-based, epidemiologic study conducted from August 1, 2001, through May 31, 2002 (wave 1), and from August 1, 2004, through September 30, 2005 (wave 2). Setting: The US general population, including residents of Hawaii and Alaska. Participants: Participants in the National Epidemiologic Survey on Alcohol and Related Conditions waves 1 (n=43 093) and 2 (n=34 653). Main Outcome Measures: Demographic characteristics, age at onset, history of depression in first-degree relatives, impairment in role functioning, psychiatric comorbidities, lifetime mental health service use, and new depressive episodes during the 3-year follow-up period.Results: Compared with participants with other types of depression, those with bereavement-related, single, brief depressive episodes were more likely to experience later onset and to be black but less likely to have had impairment in role functioning, comorbid anxiety disorders, or a treatment history at baseline. Participants with bereavement- related, single, brief episodes were less likely than those with bereavement-unrelated, single, brief episodes to experience fatigue, increased sleep, feelings of worthlessness, and suicidal ideations. The risk of new depressive episodes during the follow-up period among participants with bereavement-related, single, brief episodes was significantly lower than among participants with bereavement-unrelated, single, brief episodes and other types of depression but similar to the risk among the participants from the general population with no baseline history of depression. Conclusions: Bereavement-related, single, brief depressive episodes have distinct demographic and symptom profiles compared with other types of depressive episodes and are not associated with increased risk of future depression. The findings support preserving the DSM-IV bereavement exclusion criterion for major depressive episodes in the DSM-5. ©2011 American Medical Association. All rights reserved.

Stress concentration factors due to the presence of geometrical discontinuities (circular holes) in functionally graded plates are derived. The material property inhomogeneity is assumed to be in the radial direction originating at the center of the plate. Variable separable closed-form solutions are obtained for the stresses and displacements in functionally graded plates (without and with holes) subjected to anti-plane shear loading. The stresses in functionally graded plates without a hole are not homogeneous as it is in the case of homogeneous plates. Either a stress concentration (more than the applied stress) or dilution (less than the applied stress) occurs depending on whether the modulus increases (hardening graded material) or decreases (softening graded material) away from the center of the graded plate without a hole. A novel definition of the stress concentration factor due to the geometrical discontinuity in functionally graded plates is derived. The effect of the circular hole in functionally graded plates is to magnify (compared to homogeneous plates) the stress concentration when the modulus decreases away from the center of the hole (softening material). Beneficial reduction of the stress concentration factor is achieved in hardening functionally graded materials. © 2013 Springer Science+Business Media Dordrecht.

Khurgin J.B.,Johns Hopkins University | Sun G.,University of Massachusetts Boston
Optics Express | Year: 2012

We develop a theoretical model for the semiconductor generator of the sub-wavelength surface plasmons, operating on a single mode and often referred to as a spaser. We show that input-output characteristics of the single mode spaser does not exhibit nonlinearity inherent in most lasers, but the linewidth of the emission collapses, as in any laser which allows us to define the threshold. Our rigorous derivations show that as long as the mode remains substantially sub-wavelength in all three dimensions, the threshold current (power) shows virtually no dependence on the gain material and geometry of the active layer and is determined solely by the intrinsic loss of the metal in the device. For the semiconductor single mode surface plasmon generators operating in the telecommunication range the threshold current is on the order of 10-20 μA, and the threshold current density grows fast with the decrease of the device size reaching 100's of kA/cm2 or more. This fact makes coherent sources of sub-wavelength SP's unattainable from our point of view, but there exists a room for efficient broad-band incoherent SP sources either optically or electrically pumped. © 2012 Optical Society of America.

Neyrinck M.C.,Johns Hopkins University
Astrophysical Journal | Year: 2011

We find a simple, accurate model for the covariance matrix of the real-space cosmological matter power spectrum on slightly nonlinear scales (k ∼ 0.1-0.8 h Mpc-1 at z = 0), where off-diagonal matrix elements become substantial. The model includes a multiplicative, scale-independent modulation of the power spectrum. It has only one parameter, the variance (among realizations) of the variance of the nonlinear density field in cells, with little dependence on the cell size between 2 and 8 h -1 Mpc. Furthermore, we find that this extra covariance can be modeled out by instead measuring the power spectrum of δ/σcell, i.e., the ratio of the overdensity to its dispersion in grid cells. Dividing δ by σcell essentially removes the non-Gaussian part of the covariance matrix, nearly diagonalizing it. © 2011. The American Astronomical Society. All rights reserved.

Budavari T.,Johns Hopkins University
Astrophysical Journal | Year: 2011

I discuss a novel approach to identifying cosmic events in separate and independent observations. The focus is on the true events, such as supernova explosions, that happen once and, hence, whose measurements are not repeatable. Their classification and analysis must make the best use of all available data. Bayesian hypothesis testing is used to associate streams of events in space and time. Probabilities are assigned to the matches by studying their rates of occurrence. A case study of Type Ia supernovae illustrates how to use light curves in the cross-identification process. Constraints from realistic light curves happen to be well approximated by Gaussians in time, which makes the matching process very efficient. Model-dependent associations are computationally more demanding but can further boost one's confidence. © 2011. The American Astronomical Society. All rights reserved.

Corden J.L.,Johns Hopkins University
Chemical Reviews | Year: 2013

The RNA polymerase II (Pol II) C-terminal domain (CTD) is a repetitive disordered domain that extends from the catalytic core of the enzyme. This tail domain is heavily modified by phosphorylation, glycosylation, and proline isomerization. In addition to the enzymes that modify the tail a number of RNA processing factors and chromatin modification factors interact with the CTD. Thus, this domain acts as a tether to bring into close proximity the machinery necessary to synthesize and process Pol II transcripts. Gene-specific aspects of CTD function will be discussed in accompanying reviews by Jeronimo et al. and Eick and Geyer. To set the stage for discussing the CTD the evolution of this domain is also considered. Genetic and gene expression effects of altering the CTD will then be considered.

A limited set of phosphoinositide membrane lipids regulate diverse cellular functions including proliferation, differentiation, and migration. We developed two techniques based on rapamycin-induced protein dimerization to rapidly change the concentration of plasma membrane phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)]. First, using a membrane-recruitable form of PI(4)P 5-kinase, we increased PI(4,5)P(2) synthesis from phosphatidylinositol 4-phosphate [PI(4)P] and found that COS-7, HeLa, and human embryonic kidney 293 cells formed bundles of motile actin filaments known as actin comets. In contrast, a second technique that increased the concentration of PI(4,5)P(2) without consuming PI(4)P induced membrane ruffles. These distinct phenotypes were mediated by dynamin-mediated vesicular trafficking and mutually inhibitory crosstalk between the small guanosine triphosphatases Rac and RhoA. Our results indicate that the effect of PI(4,5)P(2) on actin reorganization depends on the abundance of other phosphoinositides, such as PI(4)P. Thus, combinatorial regulation of phosphoinositide concentrations may contribute to the diversity of phosphoinositide functions.

Cell therapy has the potential to treat or cure a wide variety of diseases. Non-invasive cell tracking techniques are, however, necessary to translate this approach to the clinical setting. This protocol details methods to create microcapsules that are visible by X-ray, ultrasound (US) or magnetic resonance (MR) for the encapsulation and immunoisolation of cellular therapeutics. Three steps are generally used to encapsulate cellular therapeutics in an alginate matrix: (i) droplets of cell-containing liquid alginate are extruded, using an electrostatic generator, through a needle tip into a solution containing a dissolved divalent cation salt to form a solid gel; (ii) the resulting gelled spheres are coated with polycations as a cross-linker; and (iii) these complexes are then incubated in a second solution of alginate to form a semipermeable membrane composed of an inner and an outer layer of alginate. The microcapsules can be rendered visible during the first step by adding contrast agents to the primary alginate layer. Such contrast agents include superparamagnetic iron oxide for detection by (1)H MR imaging (MRI); the radiopaque agents barium or bismuth sulfate for detection by X-ray modalities; or perfluorocarbon emulsions for multimodal detection by (19)F MRI, X-ray and US imaging. The entire synthesis can be completed within 2 h.

Sule S.,Johns Hopkins University
Lupus | Year: 2012

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect almost any organ system, including the kidneys. Using a large national dataset, our goal was to compare the morbidity as measured by hospitalization and mortality rates between hemodialysis patients with end-stage renal disease (ESRD) secondary to SLE to those with ESRD due to other causes. The risk of hospitalization was calculated by Poisson regression with clustering for repeated measures using the United States Renal Data System (USRDS) Hospitalization Analytic File in strata of pediatric and adult patients. Cox proportional hazard ratio was used to assess the mortality risk in hospitalized patients. Subjects were censored at transplantation or end of follow-up. Adult patients with ESRD secondary to SLE were hospitalized more frequently than other adults (incidence rate ratio (IRR): 1.43, 95% confidence interval (CI): 1.15-1.77) and had a higher risk of death (hazard ratio (HR): 1.89, 95% CI: 1.66-2.5). Mortality was higher in hospitalized pediatric patients with SLE compared to pediatric patients with other causes of ESRD (HR: 2.01, 95% CI: 1.75-2.31) and adults with SLE (HR: 2.05, 95% CI: 1.79-2.34). Our study demonstrates that there is a trend toward increased hospitalization rates in pediatric and adult patients with SLE. Among these hospitalized patients with SLE, there is an increased risk of death due to cardiovascular disease.

Levy M.J.,Johns Hopkins University
Prehospital and disaster medicine | Year: 2013

Much attention has been given to the strategic placement of automated external defibrillators (AEDs). The purpose of this study was to examine the correlation of strategically placed AEDs and the actual location of cardiac arrests. A retrospective review of data maintained by the Maryland Institute for Emergency Medical Services Systems (MIEMSS), specifically, the Maryland Cardiac Arrest Database and the Maryland AED Registry, was conducted. Location types for AEDs were compared with the locations of out-of-hospital cardiac arrests in Howard County, Maryland. The respective locations were compared using scatter diagrams and r2 statistics. The r2 statistics for AED location compared with witnessed cardiac arrest and total cardiac arrests were 0.054 and 0.051 respectively, indicating a weak relationship between the two variables in each case. No AEDs were registered in the three most frequently occurring locations for cardiac arrests (private homes, skilled nursing facilities, assisted living facilities) and no cardiac arrests occurred at the locations where AEDs were most commonly placed (community pools, nongovernment public buildings, schools/educational facilities). A poor association exists between the location of cardiac arrests and the location of AEDs.

Xu J.,Johns Hopkins University
Proceedings. Biological sciences / The Royal Society | Year: 2013

As in biological evolution, multiple forces are involved in cultural evolution. One force is analogous to selection, and acts on differences in the fitness of aspects of culture by influencing who people choose to learn from. Another force is analogous to mutation, and influences how culture changes over time owing to errors in learning and the effects of cognitive biases. Which of these forces need to be appealed to in explaining any particular aspect of human cultures is an open question. We present a study that explores this question empirically, examining the role that the cognitive biases that influence cultural transmission might play in universals of colour naming. In a large-scale laboratory experiment, participants were shown labelled examples from novel artificial systems of colour terms and were asked to classify other colours on the basis of those examples. The responses of each participant were used to generate the examples seen by subsequent participants. By simulating cultural transmission in the laboratory, we were able to isolate a single evolutionary force-the effects of cognitive biases, analogous to mutation-and examine its consequences. Our results show that this process produces convergence towards systems of colour terms similar to those seen across human languages, providing support for the conclusion that the effects of cognitive biases, brought out through cultural transmission, can account for universals in colour naming.

Pardoll D.M.,Johns Hopkins University
Nature Reviews Cancer | Year: 2012

Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses. © 2012 Macmillan Publishers Limited. All rights reserved.

Chluba J.,Johns Hopkins University
Monthly Notices of the Royal Astronomical Society | Year: 2013

Energy release in the early Universe leads to spectral distortions of the cosmic microwave background (CMB) which in the future might allow probing different physical processes in the pre-recombination (z ≳103) epoch. Depending on the energy-injection history, the associated distortion partially thermalizes due to the combined action of Compton scattering, double Compton scattering and Bremsstrahlung emission, a problem that in general is hard to solve. Various analytic approximations describing the resulting distortion exist; however, for small distortions and fixed background, the cosmology Green's function of the problem can be pre-computed numerically. Here, we show that this approach gives very accurate results for a wide range of thermal histories, allowing fast and quasi-exact computation of the spectral distortion given the energy-release rate. Our method is thus useful for forecasts of possible constraints on early-universe physics obtained from future measurements of the CMB spectrum. © 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.

Rivkin A.S.,Johns Hopkins University
Icarus | Year: 2012

The Sloan Digital Sky Survey (SDSS) Moving Object Catalog contains spectrophotometric information for thousands of asteroids, presenting the opportunity to probe objects much fainter than are typically reached in spectroscopic surveys. Using two different approaches, it is estimated that 30. ±. 5% of the C-complex asteroids in the SDSS have a 0.7-μm band, implying that roughly two-thirds will have a 3-μm absorption band and hydrated minerals based on correlations between those two absorptions found by Howell et al. (Howell, E.S. et al. [2011]. EPSC-DPS Joint Meeting, p. 637). In an effort to avoid confusion with formal taxonomies, I call these objects Ch̃ in this work, with the C̃ group defined as those without evidence of a 0.7-μm band. This fraction appears fairly stable with solar distance, although there is evidence it is higher in the middle asteroid belt (2.50-2.82. AU) than outside those bounds. In the size range covered by the SDSS dataset, the Ch̃ fraction is most consistent with a flat distribution. Inclusion of the SMASS and S3OS2 datasets suggests an overall minimum in Ch̃ fraction from H. ∼. 12-14, though this distribution may be biased by the solar distance variation mentioned above. © 2012 Elsevier Inc.

Neyrinck M.C.,Johns Hopkins University
Monthly Notices of the Royal Astronomical Society | Year: 2013

We examine the Lagrangian divergence of the displacement field, arguably a more natural object than the density in a Lagrangian description of a cosmological large-scale structure. This quantity, which we denote Ψ, quantifies the stretching and distortion of the initially homogeneous lattice of dark-matter particles in the universe. Ψ encodes similar information as the density, but the correspondence has subtleties. It corresponds better to the log-density A than the overdensity d. A Gaussian distribution in Ψ produces a distribution in A with slight skewness; in d, we find that in many cases the skewness is further increased by 3. A local spherical-collapse-based (SC) fit found by Bernardeau gives a formula for Ψ's particle-by-particle behaviour that works quite well, better than applying the Lagrangian perturbation theory (LPT) at first or second (2LPT) order. In 2LPT, there is a roughly parabolic relation between initial and final Ψ that can give overdensities in deep voids, so low-redshift, high-resolution 2LPT realizations should be used with caution. The SC fit excels at predicting Ψ until streams cross; then, for particles forming haloes, Ψ plummets as in a waterfall to -3. This gives a new method for producing N-particle realizations. Compared to LPT realizations, such SC realizations give reduced stream-crossing, and better visual and 1-point-probability density function (PDF) correspondence to the results of full gravity. LPT, on the other hand, predicts large-scale flows and the large-scale power-spectrum amplitude better, unless an empirical correction is added to the SC formula.© 2012 The Author Published by Oxford University Press on behalfof the Royal Astronomical Society.

Stowe C.B.,Johns Hopkins University
Complementary Therapies in Clinical Practice | Year: 2011

Hypertension (HTN) is the most common disease found in patients in primary care [JNC-7 Guidelines. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hyper 2003; 42:1206.]. It eventually requires medication if lifestyle modifications are not initiated or do not control the blood pressure well enough. The majority of patients would prefer not to have to be medicated to manage their disease, and HTN can be found to be a comorbidity along with diabetes, CAD, and many other cardiovascular diseases. Adverse effects, forgetfulness and patient ignorance are multiple reasons for the hesitancy to begin drug management. Pomegranate juice is rich in tannins, possesses anti-atherosclerotic properties, has anti-aging effects, and potent anti-oxidative characteristics. As some antioxidants have been shown to reduce blood pressure, the purpose of this review was to discover the effect of pomegranate juice consumption on blood pressure and cardiovascular health. Pomegranate juice consumption may reduce systolic blood pressure, inhibits serum ACE activity, and is convincingly a heart-healthy fruit [Aviram M, Dornfeld L. Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure. Athero 2001; 158:195-8.]. More clinical research is needed as a number of the studies discussed include small sample sizes and few studies seem to have been undertaken in the recent 5-10 years. © 2010 Elsevier Ltd.

Arbab-Zadeh A.,Johns Hopkins University | Fuster V.,Mount Sinai School of Medicine
Journal of the American College of Cardiology | Year: 2015

The cardiovascular science community has pursued the quest to identify vulnerable atherosclerotic plaque in patients for decades, hoping to prevent acute coronary events. However, despite major advancements in imaging technology that allow visualization of rupture-prone plaques, clinical studies have not demonstrated improved risk prediction compared with traditional approaches. Considering the complex relationship between plaque rupture and acute coronary event risk suggested by pathology studies and confirmed by clinical investigations, these results are not surprising. This review summarizes the evidence supporting a multifaceted hypothesis of the natural history of atherosclerotic plaque rupture. Managing patients at risk of acute coronary events mandates a greater focus on the atherosclerotic disease burden rather than on features of individual plaques. © 2015 American College of Cardiology Foundation.

Resar L.M.S.,Johns Hopkins University
Cancer Research | Year: 2010

High mobility group A1 (HMGA1) is highly expressed during embryogenesis and in poorly differentiated cancers, and high levels portend a poor prognosis in some tumors. HMGA1 induces oncogenic transformation in cultured cells and causes aggressive cancers in transgenic mice, whereas blocking it interferes with transformation in experimental models. These findings suggest a pivotal role for HMGA1 in cancer. This review focuses on two recently described HMGA1 transcriptional targets that mediate inflammatory signals and drive malignant transformation because they could serve as biomarkers or therapeutic targets. Further elucidation of HMGA1 function in transformation promises to have a major impact on our war on cancer. ©2010 AACR.

Webster D.W.,Johns Hopkins University | Wintemute G.J.,University of California at Davis
Annual Review of Public Health | Year: 2015

This article summarizes and critiques available evidence from studies published between 1999 and August 2014 on the effects of policies designed to keep firearms from high-risk individuals in the United States. Some prohibitions for high-risk individuals (e.g., those under domestic violence restraining orders, violent misdemeanants) and procedures for checking for more types of prohibiting conditions are associated with lower rates of violence. Certain laws intended to prevent prohibited persons from accessing firearms - rigorous permit-to-purchase, comprehensive background checks, strong regulation and oversight of gun dealers, and requiring gun owners to promptly report lost or stolen firearms - are negatively associated with the diversion of guns to criminals. Future research is needed to examine whether these laws curtail nonlethal gun violence and whether the effects of expanding prohibiting conditions for firearm possession are modified by the presence of policies to prevent diversion. Copyright © 2015 by Annual Reviews. All rights reserved.

Zhong J.,Johns Hopkins University
Molecular & cellular proteomics : MCP | Year: 2012

Thymic stromal lymphopoietin (TSLP) is a cytokine that plays diverse roles in the regulation of immune responses. TSLP requires a heterodimeric receptor complex consisting of IL-7 receptor α subunit and its unique TSLP receptor (gene symbol CRLF2) to transmit signals in cells. Abnormal TSLP signaling (e.g. overexpression of TSLP or its unique receptor TSLPR) contributes to the development of a number of diseases including asthma and leukemia. However, a detailed understanding of the signaling pathways activated by TSLP remains elusive. In this study, we performed a global quantitative phosphoproteomic analysis of the TSLP signaling network using stable isotope labeling by amino acids in cell culture. By employing titanium dioxide in addition to antiphosphotyrosine antibodies as enrichment methods, we identified 4164 phosphopeptides on 1670 phosphoproteins. Using stable isotope labeling by amino acids in cell culture-based quantitation, we determined that the phosphorylation status of 226 proteins was modulated by TSLP stimulation. Our analysis identified activation of several members of the Src and Tec families of kinases including Btk, Lyn, and Tec by TSLP for the first time. In addition, we report TSLP-induced phosphorylation of protein phosphatases such as Ptpn6 (SHP-1) and Ptpn11 (Shp2), which has also not been reported previously. Co-immunoprecipitation assays showed that Shp2 binds to the adapter protein Gab2 in a TSLP-dependent manner. This is the first demonstration of an inducible protein complex in TSLP signaling. A kinase inhibitor screen revealed that pharmacological inhibition of PI-3 kinase, Jak family kinases, Src family kinases or Btk suppressed TSLP-dependent cellular proliferation making them candidate therapeutic targets in diseases resulting from aberrant TSLP signaling. Our study is the first phosphoproteomic analysis of the TSLP signaling pathway that greatly expands our understanding of TSLP signaling and provides novel therapeutic targets for TSLP/TSLPR-associated diseases in humans.

Dang C.V.,Johns Hopkins University
Genes and Cancer | Year: 2010

The enigmatic MYC oncogene, which participates broadly in cancers, revealed itself recently as the maestro of an unfolding symphony of cell growth, proliferation, death, and metabolism. The study of MYC is arguably most challenging to its students but at the same time exhilarating when MYC reveals its deeply held secrets. It is the excitement of our richer understanding of MYC that is captured in each review of this special issue of Genes & Cancer. Collectively, our deeper understanding of MYC reveals that it is a symphony conductor, controlling a large orchestra of target genes. Although MYC controls many orchestra sections, which are necessary but not sufficient for Myc function, ribosome biogenesis stands out to reveal Myc's primordial function particularly in fruit flies. Because ribosome biogenesis and the associated translational machinery are bioenergetically demanding, Myc's other target genes involved in energy metabolism must be coupled with energy demand to ensure that cells can replicate their genome and produce daughter cells. Normal cells have feedback loops that diminish MYC expression when nutrients are scarce. On the other hand, when deregulated Myc transforms cells, their constitutive bioenergetic demand can trigger cell death when energy is unavailable. This special issue captures the unfolding symphony of MYC-mediated tumorigenesis through reviews that span from a timeline of MYC research, fundamental understanding of how the MYC gene itself is regulated, the study of Myc in model organisms, Myc function, and target genes to translational research in search of new therapeutic modalities for the treatment of cancer. © The Author(s) 2010.

Johnson M.W.,Johns Hopkins University
Experimental and Clinical Psychopharmacology | Year: 2012

Delay discounting is the decline in a consequence's control of behavior as a function of its delay, and may be a fundamental behavioral process in drug dependence. Human delay-discounting studies have usually relied on choices between hypothetical rewards. Some human tasks have assessed delay discounting using operant procedures with consequences provided during the task, as in nonhuman animal studies. However, these tasks have limitations such as long duration, potentially indeterminate data, or confounding the effect of delay with probability. A study in 20 cocaine-dependent volunteers and 20 demographically matched non-cocaine-dependent volunteers was designed to investigate a novel operant delay-discounting task providing monetary reinforcement by coin delivery throughout the task (Quick Discounting Operant Task; QDOT). Participants completed a hypothetical delay-discounting procedure, a potentially real reward delay-discounting procedure, and an existing operant delay-discounting task: the Experiential Discounting Task (EDT). The QDOT resulted in complete data for all participants, showed systematic effects of delay that were well described by a hyperbolic function, had a maximum duration of 17 min, and resulted in relatively little variability in session earnings. QDOT performance was significantly, positively correlated with performance on the EDT but not the other tasks. The QDOT resulted in an effect size between the groups that was similar to most other delay-discounting tasks examined, and showed that the cocaine-dependent participants delay discounted significantly more than the control participants. The QDOT is an efficient operant human delay-discounting task that may be useful in a variety of experimental settings. (PsycINFO Database Record (c) 2012 APA, all rights reserved) © 2012 American Psychological Association.

Brady T.M.,Johns Hopkins University
Current Hypertension Reports | Year: 2016

Both obesity and hypertension have increased substantially among children over the last several decades. At the same time, mounting evidence has pointed to the role of these and other cardiovascular disease risk factors on the development of end organ damage such as left ventricular hypertrophy in children. While traditionally thought to occur in response to an increased afterload as in systemic hypertension, evidence demonstrates that obesity is associated with left ventricular hypertrophy independent of blood pressure. Both hemodynamic and non-hemodynamic factors contribute to the pathogenesis of obesity-related left ventricular remodeling. However, more contemporary research suggests that adiposity and blood pressure have a greater effect on left ventricular geometry when present together than when present alone. Normalization of left ventricular mass in obese hypertensive individuals requires achievement of both normotension and weight loss. Additional strategies are needed to promote the cardiovascular health of children, with greater emphasis placed on obesity prevention. © 2015, Springer Science+Business Media New York.

Kaplan A.E.,Johns Hopkins University
Physical Review Letters | Year: 2012

Wave transport in a media with a slow spatial gradient of its characteristics is found to exhibit a universal wave pattern ("gradient marker") in a vicinity of the maxima or minima of the gradient. The pattern is common for optics, quantum mechanics, and any other propagation governed by the same wave equation. Derived analytically, it has an elegantly simple yet nontrivial profile found in perfect agreement with numerical simulations for specific examples. We also find resonant states in continuum in the case of quantum wells, and formulated criteria for their existence. © 2012 American Physical Society.

Jiang H.,Johns Hopkins University
Physical Review Letters | Year: 2012

Dynamic sorting of lipids and proteins in cellular membranes plays a critical role in establishing and maintaining distinct compositions in various organelles. Recent experiments found that the lipid sorting in a membrane tube highly depends on the pulling speed at the tip. However, the mechanism of this velocity dependence has not yet been revealed. In this Letter, we found that when a membrane is deformed rapidly, the lipid flow induced by fast membrane shape change will significantly affect the sorting results. The competition between the curvature-driven lipid sorting and the pulling-induced lipid flow leads to novel behaviors. When a membrane tube is pulled out from a liquid ordered (L o) domain at a constant speed, slow pulling leads to the formation of a liquid disordered (L d) tube, while fast pulling results in a L o tube. Interestingly, in a membrane tube pulled at an intermediate speed, alternate L d and L o domains appear in the tube. The sorting dynamics and the corresponding pulling force were systematically studied. The results of this study could lead to a better understanding of the dynamic sorting and traffic of lipids and proteins in living cells. © 2012 American Physical Society.

Carter H.B.,Johns Hopkins University
Journal of the National Cancer Institute - Monographs | Year: 2012

The management of localized prostate cancer is controversial, and in the absence of comparative trials to inform best practice, choices are driven by personal beliefs with wide variation in practice patterns. Men with localized disease diagnosed today often undergo treatments that will not improve overall health outcomes, and active surveillance has emerged as one approach to reducing this overtreatment of prostate cancer. The selection of appropriate candidates for active surveillance should balance the risk of harm from prostate cancer without treatment, and a patient's personal preferences for living with a cancer and the potential side effects of curative treatments. Although limitations exist in assessing the potential for a given prostate cancer to cause harm, the most common metrics used today consider cancer stage, prostate biopsy features, and prostate-specific antigen level together with the risk of death from nonprostate causes based on age and overall state of health. © The Author 2012.

Jeong J.S.,Johns Hopkins University
Molecular & cellular proteomics : MCP | Year: 2012

To broaden the range of tools available for proteomic research, we generated a library of 16,368 unique full-length human ORFs that are expressible as N-terminal GST-His(6) fusion proteins. Following expression in yeast, these proteins were then individually purified and used to construct a human proteome microarray. To demonstrate the usefulness of this reagent, we developed a streamlined strategy for the production of monospecific monoclonal antibodies that used immunization with live human cells and microarray-based analysis of antibody specificity as its central components. We showed that microarray-based analysis of antibody specificity can be performed efficiently using a two-dimensional pooling strategy. We also demonstrated that our immunization and selection strategies result in a large fraction of monospecific monoclonal antibodies that are both immunoblot and immunoprecipitation grade. Our data indicate that the pipeline provides a robust platform for the generation of monoclonal antibodies of exceptional specificity.

Khurgin J.B.,Johns Hopkins University
Faraday Discussions | Year: 2015

We show that electric field confinement in surface plasmon polaritons propagating at metal/dielectric interfaces enhances the loss due to Landau damping, which effectively limits the degree of confinement itself. We prove that Landau damping, and associated with it surface collision damping, follow directly from the Lindhard formula for the dielectric constant of a free electron gas. Furthermore, we demonstrate that even if all of the conventional loss mechanisms, caused by phonons, electron-electron interactions, and interface roughness scattering, were eliminated, the maximum attainable degree of confinement and the loss accompanying it would not change significantly compared to the best existing plasmonic materials, such as silver. This journal is © The Royal Society of Chemistry.

Chluba J.,Johns Hopkins University
Monthly Notices of the Royal Astronomical Society | Year: 2013

Deviations of the cosmic microwave background (CMB) frequency spectrum from a pure blackbody tell an exciting story about the thermal history of our Universe. In this paper, we illustrate how well future CMB measurements might decipher this tale, envisioning a PIXIElike spectrometer, which could improve the distortion constraints obtained with COBE/FIRAS some 20 years ago by at least three orders of magnitude. This opens a large discovery space, offering deep insights to particle and early-universe physics, opportunities that no longer should be left unexplored. Specifically, we consider scenarios with annihilating and decaying relic particles, as well as signatures from the dissipation of primordial small-scale power. PIXIE can potentially rule out different early-universe scenarios and moreover will allow unambiguous detections in many of the considered cases, as we demonstrate here. We also discuss slightly more futuristic experiments, with several times improved sensitivities, to highlight the large potential of this new window to the pre-recombination universe. © 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.

Zachara N.E.,Johns Hopkins University
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2012

More than 1,000 proteins of the nucleus, cytoplasm, and mitochondria are dynamically modified by O-linked β-N-acetylglucosamine (O-GlcNAc), an essential posttranslational modification of metazoans. O-GlcNAc, which modifies Ser/Thr residues, is thought to regulate protein function in a manner analogous to protein phosphorylation and, on a subset of proteins, appears to have a reciprocal relationship with phosphorylation. Like phosphorylation, O-GlcNAc levels change dynamically in response to numerous signals including hyperglycemia and cellular injury. Recent data suggests that O-GlcNAc appears to be a key regulator of the cellular stress response, the augmentation of which is protective in models of acute vascular injury, trauma hemorrhage, and ischemia-reperfusion injury. In contrast to these studies, O-GlcNAc has also been implicated in the development of hypertension and type II diabetes, leading to vascular and cardiac dysfunction. Here we summarize the current understanding of the roles of O-GlcNAc in the heart and vasculature. © 2012 the American Physiological Society.

Campochiaro P.A.,Johns Hopkins University
Gene Therapy | Year: 2012

Diseases complicated by abnormal growth of vessels or excessive leakage are the most prevalent cause of moderate or severe vision loss in developed countries. Recent progress unraveling the molecular pathogenesis of several of these disease processes has led to new drug therapies that have provided major benefits to patients. However, those treatments often require frequent intraocular injections, and despite monthly injections, some patients have a suboptimal response. Gene transfer of antiangiogenic proteins is an alternative approach that has the potential to provide long-term suppression of neovascularization (NV) and/or excessive vascular leakage in the eye. Studies in animal models of ocular NV have demonstrated impressive results with a number of transgenes, and a clinical trial in patients with advanced neovascular age-related macular degeneration has provided proof-of-concept. Two ongoing clinical trials, one using an adeno-associated viral (AAV) vector to express a vascular endothelial growth factor-binding protein and another using a lentiviral vector to express endostatin and angiostatin, will provide valuable information that should help to inform future trials and provide a foundation on which to build. © 2012 Macmillan Publishers Limited All rights reserved.

Although the "Warburg effect", i.e., elevated glucose metabolism to lactic acid (glycolysis) even in the presence of oxygen, has been recognized as the most common biochemical phenotype of cancer for over 80 years, its biochemical and genetic basis remained unknown for over 50 years. Work focused on elucidating the underlying mechanism(s) of the "Warburg effect" commenced in the author's laboratory in 1969. By 1985 among the novel findings made two related most directly to the basis of the "Warburg effect", the first that the mitochondrial content of tumors exhibiting this phenotype is markedly decreased relative to the tissue of origin, and the second that such mitochondria have markedly elevated amounts of the enzyme hexokinase-2 (HK2) bound to their outer membrane. HK2 is the first of a number of enzymes in cancer cells involved in metabolizing the sugar glucose to lactic acid. At its mitochondrial location HK2 binds at/near the protein VDAC (voltage dependent anion channel), escapes inhibition by its product glucose-6-phosphate, and gains access to mitochondrial produced ATP. As shown by others, it also helps immortalize cancer cells, i.e., prevents cell death. Based on these studies, the author's laboratory commenced experiments to elucidate the gene basis for the overexpression of HK2 in cancer. These studies led to both the discovery of a unique HK2 promoter region markedly activated by both hypoxic conditions and moderately activated by several metabolites (e.g., glucose), Also discovered was the promoter's regulation by epigenetic events (i.e., methylation, demethylation). Finally, the author's laboratory turned to the most important objective. Could they selectively and completely destroy cancerous tumors in animals? This led to the discovery in an experiment conceived, designed, and conducted by Young Ko that the small molecule 3-bromopyruvate (3BP), the subject of this mini-review series, is an incredibly powerful and swift acting anticancer agent. Significantly, in subsequent experiments with rodents (19 animals with advanced cancer) Ko led a project in which 3BP was shown in a short treatment period to eradicate all (100%). Ko's and co-author's findings once published attracted global attention leading world-wide to many other studies and publications related to 3BP and its potent anti-cancer effect. This Issue of the Journal of Bioenergetics and Biomembranes (JOBB 44-1) captures only a sampling of research conducted to date on 3BP as an anticancer agent, and includes also a Case Report on the first human patient known to the author to be treated with specially formulated 3BP. Suffice it to say in this bottom line, "3BP, a small molecule, results in a remarkable therapeutic effect when it comes to treating cancers exhibiting a "Warburg effect". This includes most cancer types. © 2012 Springer Science+Business Media, LLC.

Contributions of dietary miRNAs to circulating small RNA profiles would have profound implications for interpretation of miRNA biomarker studies: presumptive disease-specific markers might instead indicate responses to disease-associated quantitative or qualitative dietary alteration. This examination weighs the evidence for a 2-fold hypothesis: first, that ingested biological matter contributes directly to the miRNA complement of body compartments; and second, that these diet-derived exogenous miRNAs (or "xenomiRs") affect total miRNA profiles as part of a circulating miRNA homeostasis that is altered in many diseases. Homeostasis of highdensity lipoprotein (HDL), a known miRNA carrier-provides a model as a proposed component of broader miRNA homeostasis. Further research into the dietary xenomiR hypothesis is needed to ensure rigor in the search for truly disease-specific miRNA biomarkers. © 2012 Landes Bioscience.

Klein A.P.,Johns Hopkins University
Molecular Carcinogenesis | Year: 2012

Pancreatic cancer is the fourth leading cause of cancer death in both men and women in the United States. However, it has the poorest prognosis of any major tumor type, with a 5-yr survival rate of approximately 5%. Cigarette smoking, increased body mass index, heavy alcohol consumption, and a diagnosis of diabetes mellitus have all been demonstrated to increase risk of pancreatic cancer. A family history of pancreatic cancer has also been associated with increased risk suggesting inherited genetic factors also play an important role, with approximately 5-10% of pancreatic cancer patients reporting family history of pancreatic cancer. While the genetic basis for the majority of the familial clustering of pancreatic cancer remains unclear, several important pancreatic cancer genes have been identified. These consist of high penetrance genes including BRCA2 or PALB2, to more common genetic variation associated with a modest increase risk of pancreatic cancer such as genetic variation at the ABO blood group locus. Recent advances in genotyping and genetic sequencing have accelerated the rate at which novel pancreatic cancer susceptibility genes have been identified with several genes identified within the past few years. This review addresses our current understanding of the familial aggregation of pancreatic cancer, established pancreatic cancer susceptablity genes and how this knowledge informs risk assessment and screening for high-risk families. © 2011 Wiley Periodicals, Inc..

Gaskin D.J.,Johns Hopkins University | Richard P.,Uniformed Services University of the Health Sciences
Journal of Pain | Year: 2012

In 2008, according to the Medical Expenditure Panel Survey (MEPS), about 100 million adults in the United States were affected by chronic pain, including joint pain or arthritis. Pain is costly to the nation because it requires medical treatment and complicates treatment for other ailments. Also, pain lowers worker productivity. Using the 2008 MEPS, we estimated 1) the portion of total U.S. health care costs attributable to pain; and 2) the annual costs of pain associated with lower worker productivity. We found that the total costs ranged from $560 to $635 billion in 2010 dollars. The additional health care costs due to pain ranged from $261 to $300 billion. This represents an increase in annual per person health care costs ranging from $261 to $300 compared to a base of about $4,250 for persons without pain. The value of lost productivity due to pain ranged from $299 to $335 billion. We found that the annual cost of pain was greater than the annual costs of heart disease ($309 billion), cancer ($243 billion), and diabetes ($188 billion). Our estimates are conservative because they do not include costs associated with pain for nursing home residents, children, military personnel, and persons who are incarcerated. Perspective: This study estimates that the national cost of pain ranges from $560 to $635 billion, larger than the cost of the nation's priority health conditions. Because of its economic toll on society, the nation should invest in research, education, and training to advocate the successful treatment, management, and prevention of pain. © 2012 by the American Pain Society.

Coppens I.,Johns Hopkins University
Essays in Biochemistry | Year: 2011

Several protozoan parasites undergo a complex life cycle that alternates between an invertebrate vector and a vertebrate host. Adaptations to these different environments by the parasites are achieved by drastic changes in their morphology and metabolism. The malaria parasites must be transmitted to a mammal from a mosquito as part of their life cycle. Upon entering the mammalian host, extracellular malaria sporozoites reach the liver and invade hepatocytes, wherein they meet the challenge of becoming replication-competent schizonts. During the process of conversion, the sporozoite selectively discards organelles that are unnecessary for the parasite growth in liver cells. Among the organelles that are cleared from the sporozoite are the micronemes, abundant secretory vesicles that facilitate the adhesion of the parasite to hepatocytes. Organelles specialized in sporozoite motility and structure, such as the inner membrane complex (a major component of the motile parasite's cytoskeleton), are also eliminated from converting parasites. The high degree of sophistication of the metamorphosis that occurs at the onset of the liver-form development cascade suggests that the observed changes must be multifactorial. Among the mechanisms implicated in the elimination of sporozoite organelles, the degradative process called autophagy contributes to the remodelling of the parasite interior and the production of replicative liver forms. In a broader context, the importance of the role played by autophagy during the differentiation of protozoan parasites that cycle between insects and vertebrates is nowadays clearly emerging. An exciting prospect derived from these observations is that the parasite proteins involved in the autophagic process may represent new targets for drug development. © 2011 Biochemical Society.

Gibbs R.G.,Johns Hopkins University
IEEE Transactions on Automatic Control | Year: 2011

We derive here an algorithm for a complete square root implementation of the modified Bryson-Frazier (MBF) smoother. The MBF algorithm computes the smoothed covariance as the difference of two symmetric matrices. Numerical errors in this differencing can result in the covariance matrix not being positive semi-definite. Earlier algorithms implemented the computation of intermediate quantities in square root form but still computed the smoothed covariance as the difference of two matrices. We show how to compute the square root of the smoothed covariance by solving an equation in the form CC T = AAT - BBT using QR decomposition with hyperbolic Householder transformations. © 2006 IEEE.

Dinkova-Kostova A.T.,University of Dundee | Dinkova-Kostova A.T.,Johns Hopkins University | Kostov R.V.,University of Dundee
Trends in Molecular Medicine | Year: 2012

Glucosinolates and isothiocyanates have both been objects of research for more than half a century. Interest in these unique phytochemicals escalated following the discovery that sulforaphane, an isothiocyanate from broccoli, potently induces mammalian cytoprotective proteins through the Keap1-Nrf2-ARE pathway. In parallel with the advances in understanding the molecular regulation of this pathway and its critical role in protection against electrophiles and oxidants, there have been increased efforts toward translating this knowledge to improve human health and combat disease. This review focuses on the animal studies demonstrating the beneficial effects of glucosinolates and isothiocyanates in models of carcinogenesis, and cardiovascular and neurological diseases, as well as on the intervention studies of their safety, pharmacokinetics, and efficacy in humans. © 2012 Elsevier Ltd.

Several of the nucleoside/nucleotide analogues used to treat HIV also inhibit HBV replication, with lamivudine being the oldest of this group. Thus, prior to licensing of tenofovir, many HIV - HBV-coinfected individuals received lamivudine as the only drug active against HBV as part of an anti-HIV regimen, which set the stage for the emergence of drug-resistant HBV. In coinfected persons, lamivudine-resistant HBV develops more rapidly than in HBV-moninfected persons, but it is not known if this is true for the newer agents. Owing to overlapping reading frames of the HBV polymerase and surface antigens, drug-resistant changes in HBV Pol can lead to mutations in the envelope. This review will discuss studies of drug-resistant HBV in HIV-infected persons including drug-resistant mutations that have been identified and clinical sequelae of these mutations. ©2010 International Medical Press.

Njoku D.B.,Johns Hopkins University
International Journal of Molecular Sciences | Year: 2014

Drug-induced hepatotoxicity is a significant cause of acute liver failure and is usually the primary reason that therapeutic drugs are removed from the commercial market. Multiple mechanisms can culminate in drug hepatotoxicity. Metabolism, genetics and immunology separately and in concert play distinct and overlapping roles in this process. This review will cover papers we feel have addressed these mechanisms of drug-induced hepatotoxicity in adults following the consumption of commonly used medications. The aim is to generate discussion around "trigger point" papers where the investigators generated new science or provided additional contribution to existing science. Hopefully these discussions will assist in uncovering key areas that need further attention. © 2014 by the authors; licensee MDPI, Basel, Switzerland.

Emens L.A.,Johns Hopkins University
Cancer Journal | Year: 2010

Cancer chemotherapy drugs are historically regarded as detrimental to immunity because of their myelosuppressive effects. However, accumulating data suggest that the antitumor activity of conventional cancer chemotherapy results in part from its ability to harness the innate and adaptive immune systems by inducing immunologically active tumor cell death. Additional data broaden the immunologic effect of cancer chemotherapy drugs, demonstrating that some drugs have the ability to disrupt pathways of immune suppression and immune tolerance in a manner that depends on the drug dose, and the timing of its administration in relation to immunotherapy. Understanding the cellular and molecular basis of the interactions between chemotherapy drugs and the immune system will facilitate the strategic development of chemoimmunotherapy treatment regimens that both maximize tumor regression and the antitumor immune response for the long-term clinical benefit of cancer patients. Copyright © Lippincott Williams & Wilkins.

Feinberg A.P.,Johns Hopkins University
Virchows Archiv | Year: 2010

Traditionally, the pathology of human disease has been focused on microscopic examination of affected tissues, chemical and biochemical analysis of biopsy samples, other available samples of convenience, such as blood, and noninvasive or invasive imaging of varying complexity, in order to classify disease and illuminate its mechanistic basis. The molecular age has complemented this armamentarium with gene expression arrays and selective analysis of individual genes. However, we are entering a new era of epigenomic profiling, i.e., genome-scale analysis of cell-heritable nonsequence genetic change, such as DNA methylation. The epigenome offers access to stable measurements of cellular state and to biobanked material for large-scale epidemiological studies. Some of these genome-scale technologies are beginning to be applied to create the new field of epigenetic epidemiology. © 2009 Springer-Verlag.

Evans J.P.,Johns Hopkins University
Annual Review of Physiology | Year: 2012

A crucial step of fertilization is the sperm-egg interaction that allows the two gametes to fuse and create the zygote. In the mouse, CD9 on the egg and IZUMO1 on the sperm stand out as critical players, as Cd9 -/- and Izumo1 -/- mice are healthy but infertile or severely subfertile due to defective sperm-egg interaction. Moreover, work on several nonmammalian organisms has identified some of the most intriguing candidates implicated in sperm-egg interaction. Understanding of gamete membrane interactions is advancing through characterization of in vivo and in vitro fertilization phenotypes, including insights from less robust phenotypes that highlight potential supporting (albeit not absolutely essential) players. An emerging theme is that there are varied roles for gamete molecules that participate in sperm-egg interactions. Such roles include not only functioning as fusogens, or as adhesion molecules for the opposite gamete, but also functioning through interactions in cis with other proteins to regulate membrane order and functionality. Copyright © 2012 by Annual Reviews. All rights reserved.

Xing M.,Johns Hopkins University
Molecular and Cellular Endocrinology | Year: 2010

Papillary thyroid cancer (PTC) is a common endocrine malignancy that frequently harbors the oncogenic T1799A BRAF mutation. As a novel prognostic molecular marker, this mutation has received considerable attention in recent years for its potential utility in the risk stratification and management of PTC. In PTC, BRAF mutation is closely associated with extrathyroidal extension, lymph node metastasis, advanced tumor stages, disease recurrence, and even patient mortality. Many of the responsible molecular derangements promoted by, or associated with, BRAF mutation have been identified, including over-expression of tumor-promoting genes, suppression of tumor-suppressor genes, and silencing of thyroid iodide-handling genes, resulting in impairment or loss of radioiodine avidity and hence the failure of radioiodine treatment of PTC. BRAF mutation can be readily tested on thyroid fine needle aspiration biopsy specimens, with high preoperative predictive probabilities for clinicopathological outcomes of PTC. As such, the knowledge of BRAF mutation status can facilitate more accurate risk stratification and better decision making at various steps in the management of PTC, from preoperative planning of initial surgical scale to postoperative decisions about appropriate radioiodine treatment and thyroid-stimulating hormone suppression, and to selections of appropriate surveillance modalities for PTC recurrence. The greatest utility of BRAF mutation status is in those cases where traditional clinicopathological criteria alone would otherwise be unreliable in the risk stratification and management of PTC. Use of this unique molecular marker, in conjunction with conventional clinicopathological risk factors, to assist the prognostication of PTC is likely to improve the efficiency of contemporary management of thyroid cancer. © 2009 Elsevier Ireland Ltd.

Mathias R.A.,Johns Hopkins University
Advances in Experimental Medicine and Biology | Year: 2014

While asthma is a heterogeneous disease, a strong genetic basis has been firmly established. Rather than being a single disease entity, asthma consists of related, overlapping syndromes [Barnes (Proc Am Thor Soc 8:143-148, 2011)] including three general domains: variable airway obstruction, airway hyperresponsiveness, and airway inflammation with a considerable proportion, but not all, of asthma being IgE-mediated further adding to its heterogeneity. This chapter reviews the approaches to the elucidation of genetics of asthma from the early evidence of familial clustering to the current state of knowledge with genome-wide approaches. The conclusion is that research efforts have led to a tremendous repository of genetic determinants of asthma, most of which fall into the above phenotypic domains of the syndrome. We now look to future integrative approaches of genetics, genomics (Chap. 10), and epigenetics (Chap. 11) to better understand the causal mechanism through which, these genetic loci act in manifesting asthma. © Springer Science+Business Media New York 2014.

Nath A.,Johns Hopkins University
Annals of the New York Academy of Sciences | Year: 2010

Human immunodeficiency virus (HIV) infection in the United States and increasingly in other parts of the world is now being driven by drug-abusing populations. Both HIV infection and drugs of abuse affect the basal ganglia, hippocampal structures, and the prefrontal cortex. Understanding the interactions between the two and their combined effects is critical. In vitro studies show that opiates, methamphetamine, and cocaine can potentiate HIV replication and can enhance or synergize with HIV proteins to cause glial cell activation, neurotoxicity, and breakdown of the blood-brain barrier. Many of these studies have been confirmed in vivo by using rodent models. However, the complexities of polydrug addiction and drug withdrawal have yet to be examined in simian models of HIV-associated neurocognitive disorder. Clinical studies in substance-abusing, HIV-positive patients pose multiple challenges whether aimed at studying disease pathogenesis or conducting clinical trials. This review examines the literature to date, lists the experimental challenges faced by researchers studying effects of drug addiction on HIV neuropathogenesis, and suggests future directions for research. © 2010 New York Academy of Sciences.

Lutsenko S.,Johns Hopkins University
Annals of the New York Academy of Sciences | Year: 2014

Wilson's disease (WD) is a human disorder of copper homeostasis caused by mutations in the copper-transporting ATPase ATP7B. WD is characterized by copper accumulation, predominantly in the liver and brain, hepatic pathology, and wide differences between patients in the age of onset and the spectrum of symptoms. Several factors contribute to the phenotypic variability of WD. The WD-causing mutations produce a wide range of changes in stability, activity, intracellular localization, and trafficking of ATP7B; the nonpathogenic genetic polymorphisms may contribute to the phenotype. In Atp7b-/- mice, a mouse model of WD, an abnormal intracellular distribution of copper in the liver triggers distinct changes in the transcriptome; these mRNA profiles might be used to more specifically define disease progression. The major effect of accumulating copper on lipid metabolism and especially cholesterol homeostasis in mice and humans suggests the importance of fat and cholesterol metabolism as modifying factors in WD. © 2014 New York Academy of Sciences.

Taylor M.S.,Johns Hopkins University
Methods in enzymology | Year: 2012

Ghrelin O-acyltransferase (GOAT) is responsible for catalyzing the attachment of the eight-carbon fatty acid octanoyl to the Ser3 side chain of the peptide ghrelin to generate the active form of this metabolic hormone. As such, GOAT is viewed as a potential therapeutic target for the treatment of obesity and diabetes mellitus. Here, we review recent progress in the development of cell and in vitro assays to measure GOAT action and the identification of several synthetic GOAT inhibitors. In particular, we discuss the design, synthesis, and characterization of the bisubstrate analog GO-CoA-Tat and its ability to modulate weight and blood glucose in mice. We also highlight current challenges and future research directions in our biomedical understanding of this fascinating ghrelin processing enzyme. Copyright © 2012 Elsevier Inc. All rights reserved.

Tarraf D.C.,Johns Hopkins University
IEEE Transactions on Automatic Control | Year: 2012

We consider the problem of approximating discrete-time plants with finite-valued sensors and actuators by deterministic finite memory systems for the purpose of certified-by-design controller synthesis. Building on ideas from robust control, we propose a control-oriented notion of finite state approximation for these systems, demonstrate its relevance to the control synthesis problem, and discuss its key features. © 1963-2012 IEEE.

Armanios M.,Johns Hopkins University
Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis | Year: 2012

Idiopathic pulmonary fibrosis (IPF) is the most common manifestation of telomere-mediated disorders. Germline mutations in the essential telomerase genes, hTERT and hTR, are the causal genetic defect in up to one-sixth of pulmonary fibrosis families. The presence of telomerase mutations in this subset is significant for clinical decisions as affected individuals can develop extra-pulmonary complications related to telomere shortening such as bone marrow failure and cryptogenic liver cirrhosis. There is also evidence that IPF is an ancestral manifestation of autosomal dominant telomere syndromes where, with successive generations, the disease evolves from pulmonary fibrosis into a bone marrow failure-predominant disorder, defining a unique form of genetic anticipation. Here I review the significance of telomere defects for understanding the genetics, disease patterns and pathophysiology of IPF. The importance of this diagnosis for patient care decisions will also be discussed. © 2011 Elsevier B.V.

Cheung K.J.,Fred Hutchinson Cancer Research Center | Ewald A.J.,Johns Hopkins University
Science | Year: 2016

Despite decades of study, there are still many unanswered questions about metastasis, the process by which a localized cancer becomes a systemic disease. One of these questions is the nature of the tumor cells that give rise to metastases. Although conventional models suggest that metastases are seeded by single cells from the primary tumor, there is growing evidence that seeding requires the collective action of tumor cells traveling together in clusters. Here, we review this evidence, which comes from analysis of both experimental models and patient samples. We present a model of metastatic dissemination that highlights the activities of clusters of tumor cells that retain and require their epithelial properties.

Ialongo N.,Johns Hopkins University
Development and Psychopathology | Year: 2010

Sterba and Bauer's Keynote Article does a superb job of reviewing the assumptions, strengths, and limitations of model-based person-oriented methodsclarifying which theoretical principles [researchers] can test and the compromises and trade-offs required to do so. Their writing is exceptionally clear, and the examples given highly instructive. At the same time, their arguments may be so convincing that the reader may be reluctant to pursue person-oriented analyses in a longitudinal context. The purpose of this Commentary is not to contradict Sterba and Bauer's arguments but to briefly review the steps that substantive researchers can take in building a scientifically strong case for either assuming continuously varied growth or that [trajectory groups] actually exist according to Raudenbush. These steps have been elaborated in a series of papers by Muthén and colleagues, but it is useful to briefly review them here. Copyright © Cambridge University Press 2010.

The FtsZ protein, a tubulin-like GTPase, plays a pivotal role in prokaryotic cell division. In vivo it localizes to the midcell and assembles into a ring-like structure-the Z-ring. The Z-ring serves as an essential scaffold to recruit all other division proteins and generates contractile force for cytokinesis, but its supramolecular structure remains unknown. Electron microscopy (EM) has been unsuccessful in detecting the Z-ring due to the dense cytoplasm of bacterial cells, and conventional fluorescence light microscopy (FLM) has only provided images with limited spatial resolution (200-300 nm) due to the diffraction of light. Hence, given the small sizes of bacteria cells, identifying the in vivo structure of the Z-ring presents a substantial challenge. Here, we used photoactivated localization microscopy (PALM), a single molecule-based super-resolution imaging technique, to characterize the in vivo structure of the Z-ring in E. coli. We achieved a spatial resolution of ∼35 nm and discovered that in addition to the expected ring-like conformation, the Z-ring of E. coli adopts a novel compressed helical conformation with variable helical length and pitch. We measured the thickness of the Z-ring to be ∼110 nm and the packing density of FtsZ molecules inside the Z-ring to be greater than what is expected for a single-layered flat ribbon configuration. Our results strongly suggest that the Z-ring is composed of a loose bundle of FtsZ protofilaments that randomly overlap with each other in both longitudinal and radial directions of the cell. Our results provide significant insight into the spatial organization of the Z-ring and open the door for further investigations of structure-function relationships and cell cycle-dependent regulation of the Z-ring.

While initiation of highly active antiretroviral therapy (HAART) during primary HIV-1 infection occasionally results in transient control of viral replication after treatment interruption, the vast majority of patients eventually experience a rebound in plasma viremia. Here we report a case of a patient who was started on HAART during symptomatic primary infection and who has subsequently maintained viral loads of < 50 copies/mL for more than nine years after the cessation of treatment. This patient had a high baseline viral load and has maintained a relatively high frequency of latently infected CD4(+) T cells. In addition, he does not have any known protective HLA alleles. Thus it is unlikely that he was destined to become a natural elite controller or suppressor. The mechanism of control of viral replication is unclear; he is infected with a CCR5/CXCR4 dual-tropic virus that is fully replication-competent in vitro. In addition, his spouse, who transmitted the virus to him, developed AIDS. The patient's CD4(+) T cells are fully susceptible to HIV-1 infection, and he has low titers of neutralizing antibodies to heterologous and autologous HIV-1 isolates. Furthermore, his CD8(+) T cells do not have potent HIV suppressive activity. This report suggests that some patients may be capable of controlling pathogenic HIV-1 isolates for extended periods of time after the cessation of HAART through a mechanism that is distinct from the potent cytotoxic T lymphocyte (CTL) mediated suppression that has been reported in many elite suppressors.

Chakravarti A.,Johns Hopkins University | Clark A.G.,Cornell University | Mootha V.K.,Massachusetts General Hospital
Cell | Year: 2013

Technologies for genome-wide sequence interrogation have dramatically improved our ability to identify loci associated with complex human disease. However, a chasm remains between correlations and causality that stems, in part, from a limiting theoretical framework derived from Mendelian genetics and an incomplete understanding of disease physiology. Here we propose a set of criteria, akin to Koch's postulates for infectious disease, for assigning causality between genetic variants and human disease phenotypes. © 2013 Elsevier Inc.

Greenberg M.M.,Johns Hopkins University
Accounts of Chemical Research | Year: 2014

Abasic lesions are a family of DNA modifications that lack Watson-Crick bases. The parent member of this family, the apurinic/apyrimidinic lesion (AP), occurs as an intermediate during DNA repair, following nucleobase alkylation, and from random hydrolysis of native nucleotides. In a given day, each cell produces between 10000 and 50000 AP lesions. A variety of oxidants including γ-radiolysis produce oxidized abasic sites, such as C4-AP, from the deoxyribose backbone. A number of potent, cytotoxic antitumor agents, such as bleomycin and the enediynes (e.g., calicheamicin, esperamicin, and neocarzinostatin) also lead to oxidized abasic sites in DNA.The absence of Watson-Crick bases prevents DNA polymerases from properly determining which nucleotide to incorporate opposite abasic lesions. Consequently, several studies have revealed that (oxidized) abasic sites are highly mutagenic. Abasic lesions are also chemically unstable, are prone to strand scission, and possess electrophilic carbonyl groups. However, researchers have only uncovered the consequences of the inherent reactivity of these electrophiles within the past decade. The development of solid phase synthesis methods for oligonucleotides that both place abasic sites in defined positions and circumvent their inherent alkaline lability has facilitated this research.Chemically synthesized oligonucleotides containing abasic lesions provide substrates that have allowed researchers to discover a range of interesting chemical properties of potential biological importance. For instance, abasic lesions form DNA-DNA interstrand cross-links, a particularly important family of DNA damage because they block replication and transcription absolutely. In addition, bacterial repair enzymes can convert an interstrand cross-link derived from C4-AP into a double-strand break, the most deleterious form of DNA damage. Oxidized abasic lesions can also inhibit DNA repair enzymes that remove damaged nucleotides. DNA polymerase β, an enzyme that is irreversibly inactivated, is vitally important in base excision repair and is overproduced in some tumor cells. Nucleosome core particles, the monomeric components that make up chromatin, accentuate the chemical instability of abasic lesions. In experiments using synthetic nucleosome core particles containing abasic sites, the histone proteins catalyze strand cleavage at the sites that incorporate these lesions. Furthermore, in the presence of the C4-AP lesion, strand scission is accompanied by modification of the histone protein.The reactivity of (oxidized) abasic lesions illustrates how seemingly simple nucleic acid modifications can have significant biochemical effects and may provide a chemical basis for the cytotoxicity of the chemotherapeutic agents that produce them. © 2013 American Chemical Society.

Interactions between cancer cells and stromal cells, including blood vessel endothelial cells (BECs), lymphatic vessel endothelial cells (LECs), bone marrow-derived angiogenic cells (BMDACs) and other bone marrow-derived cells (BMDCs) play important roles in cancer progression. Intratumoral hypoxia, which affects both cancer and stromal cells, is associated with a significantly increased risk of metastasis and mortality in many human cancers. Recent studies have begun to delineate the molecular mechanisms underlying the effect of intratumoral hypoxia on cancer progression. Reduced O 2 availability induces the activity of hypoxia-inducible factors (HIFs), which activate the transcription of target genes encoding proteins that play important roles in many critical aspects of cancer biology. Included among these are secreted factors, including angiopoietin 2, angiopoietin-like 4, placental growth factor, platelet-derived growth factor B, stem cell factor (kit ligand), stromal-derived factor 1, and vascular endothelial growth factor. These factors are produced by hypoxic cancer cells and directly mediate functional interactions with BECs, LECs, BMDACs and other BMDCs that promote angiogenesis, lymphangiogenesis, and metastasis. In addition, lysyl oxidase (LOX) and LOX-like proteins, which are secreted by hypoxic breast cancer cells, remodel extracellular matrix in the lungs, which leads to BMDC recruitment and metastatic niche formation. © 2013 Macmillan Publishers Limited All rights reserved.

Hinnov L.A.,Johns Hopkins University
Bulletin of the Geological Society of America | Year: 2013

Over the past 25yr, the science of stratigraphy has evolved to include time-correlative data from vastly disparate components of the Earth system. Not least of these is the global signal afforded by cyclostratigraphy, which has recorded the evolution of Earth's astronomical ("Milankovitch") forcing of insolation and the paleoclimate system. Fossil astronomical signals are collected from cyclic sedimentary sequences by detailed sampling and study of facies, geochemistry, mineralogy, rock magnetism, color, etc. In step with the documentation of astronomically forced paleoclimate from ever-older older geologic times, innovations in computational science have provided ever-longer high-accuracy astronomical model "targets" that can be used for time scale calibration. The Earth's orbit is affected by motions of other planets, notably the orbital perihelia of Venus and Jupiter, which impose a dominant 405 k.y. eccentricity cycle on Earth's orbital evolution. The large mass of Jupiter stabilizes this cycle over hundreds of millions of years. The cyclostratigraphic record of 405 k.y. cycles is therefore often used to correct chronologies affected by variable sedimentation. Earth's shape and rotation rate are infl uenced by tidal dissipation and climate friction; these effects affect Earth's precession rate through time. Thus, a record of Earth-Moon evolution is also embedded in cyclostratigraphy. The geochronologic value of cyclostratigraphy has been affirmed through intercalibration with high-precision radioisotope dating, which today has the potential to define the ages of stratigraphic horizons with 2σ uncertainties at the scale of a precession cycle. Precession index phasing relative to that of the obliquity elucidates the seasonal nature of astronomical forcing of the paleoclimate system. Cyclostratigraphy contributes to our knowledge of planetary dynamics for timesprior to the current ca. 50 Ma limit of accurate astronomical solutions, and it will guide our future understanding of solar system evolution and the evidence for chaotic diffusion. Astronomical modeling is undergoing its own revolution with development of new numerical integrators to extend accuracy further back in time. Finally, space exploration has revealed prominent sedimentary bedding and ice stratigraphy on the surface of Mars, with patterns suggestive of astronomical forcing analogous to Earth. © 2013 Geological Society of America.

Carvalho B.S.,University of Cambridge | Irizarry R.A.,Johns Hopkins University
Bioinformatics | Year: 2010

Motivation: The availability of flexible open source software for the analysis of gene expression raw level data has greatly facilitated the development of widely used preprocessing methods for these technologies. However, the expansion of microarray applications has exposed the limitation of existing tools. Results: We developed the oligo package to provide a more general solution that supports a wide range of applications. The package is based on the BioConductor principles of transparency, reproducibility and efficiency of development. It extends the existing tools and leverages existing code for visualization, accessing data and widely used preprocessing routines. The oligo package implements a unified paradigm for preprocessing data and interfaces with other BioConductor tools for downstream analysis. Our infrastructure is general and can be used by other BioConductor packages. © The Author 2010. Published by Oxford University Press. All rights reserved.

Singh S.,Johns Hopkins University
International journal of chronic obstructive pulmonary disease | Year: 2010

The benefit harm profile of inhaled corticosteroids, and their effect on patient oriented outcomes and comorbid pneumonia, osteoporosis and cardiovascular disease in patients with chronic obstructive pulmonary disease remain uncertain. An overview of the evidence on the risks and benefits of inhaled corticosteroids (fluticasone and budesonide) in chronic obstructive pulmonary disease from recent randomized controlled trials and systematic reviews. Observational studies on adverse effects were also evaluated. Evidence from recent meta-analysis suggests a modest benefit from inhaled corticosteroid long-acting beta-agonist combination inhalers on the frequency of exacerbations, (rate ratio [RR], 0.82; 95% confidence interval [CI]: 0.78 to 0.88), in improvements in quality of life measures, and forced expiratory volume in one second when compared to long-acting beta-agonists alone. On the outcome of pneumonia, our updated meta-analysis of trials (n = 24 trials; RR, 1.56; 95% CI: 1.40-1.74, P < 0.0001) and observational studies (n = 4 studies; RR, 1.44; 95% CI: 1.20-1.75, P = 0.0001) shows a significant increase in the risk of pneumonia with the inhaled corticosteroids currently available (fluticasone and budesonide). Evidence for any intraclass differences in the risk of pneumonia between currently available formulations is inconclusive due to the absence of head to head trials. Inhaled corticosteroids have no cardiovascular effects. Among patients with chronic obstructive pulmonary disease, clinicians should carefully balance these long-term risks of inhaled corticosteroid against their symptomatic benefits.

HIV pre-exposure prophylaxis trials with antiretroviral drugs have been variably successful. Even trials demonstrating the best efficacy leave room for improvement. Pharmacological data illuminate several sources of outcome variability, especially the impact of poor adherence, which is critical to manage PrEP in the clinic and to develop the next generation of PrEP candidates. © 2013 Elsevier Inc.

Chirikjian G.S.,Johns Hopkins University
Biochemical Society Transactions | Year: 2013

The present mini-review covers the local and global geometry of framed curves and the computation of twist and writhe in knotted DNA circles. Classical inequalities relating the total amount of bending of a closed space curve and associated knot parameters are also explained. © 2013 Biochemical Society.

Heide R.S.V.,Louisiana State University Health Sciences Center | Steenbergen C.,Johns Hopkins University
Circulation Research | Year: 2013

With the advent of thrombolytic therapy and angioplasty, it has become possible to reduce myocardial infarct size through early reperfusion. Enormous effort has been expended to find therapies that can further reduce infarct size after early intervention. Animal studies have identified many cardioprotective pathways that have the potential to reduce infarct size if activated before the onset of ischemia. More recently, interventions effective at the onset of reperfusion have been described. Although basic research has identified many targets, most has been conducted in rodent models which may not be directly applicable to human disease and even promising agents have been disappointing in large-scale clinical trials. There are many potential explanations for this failure which is the subject of this review. Potential factors include (1) the variability inherent in the patient population, whereas animal studies usually use single sex homogeneous groups maintained on standard diets in carefully controlled environments; (2) the duration of ischemia is generally shorter in animal studies, resulting in potentially more salvageable myocardium than is often the case in patients; (3) that the animals are usually young without comorbidities, whereas the patient population is generally older and has significant comorbidities; (4) animals are not treated with medications a priori, whereas the patient population is often taking medications that may affect ischemic injury; and (5) animal studies may not involve thorough assessment of effects on organs other than the heart, whereas patients can experience adverse effects of treatment in other organs that can preclude clinical use. © 2013 American Heart Association, Inc.

Manuel H.,CSIC - National Center for Metallurgical Research | Manuel H.,Johns Hopkins University
New England Journal of Medicine | Year: 2010

Deaths from pancreatic ductal adenocarcinoma, also known as pancreatic cancer, rank fourth among cancer-related deaths in the United States, yet the causes of pancreatic cancer remain unknown. This review article summarizes recent progress in the understanding and management of pancreatic cancer. Copyright © 2010 Massachusetts Medical Society.

Segev D.L.,Johns Hopkins University
Nature Reviews Nephrology | Year: 2012

In an effort to increase living donor transplantation while minimizing risk and morbidity, recent advances have been made in surgical technique, kidney paired donation, desensitization, identification of living donors and research into living donor outcomes. Single-port nephrectomy and vaginal extraction have reduced donor nephrectomy incision size. Transport of live donor kidneys has reduced geographic barriers to kidney paired donation, and participation of compatible pairs and nondirected donors has increased match opportunities for incompatible pairs participating in this modality. ABO-incompatible transplantation can now be successfully performed without high-intensity immunomodulation, and HLA-incompatible transplantation has been shown in a large single-center study to provide profound survival benefit compared with waiting for a compatible donor. Complement inhibition is an exciting, emerging approach that may facilitate incompatible transplantation and treat antibody-mediated rejection. Educational and communications interventions are proving valuable in helping patients find living donors, and large studies continue to provide reassurance to carefully screened living donors that risks are very low. As living donors are critical to addressing the profound organ shortage, efforts to increase living donation remain important. © 2012 Macmillan Publishers Limited. All rights reserved.

Maragakis L.L.,Johns Hopkins University
Critical Care Medicine | Year: 2010

Multidrug-resistant Gram-negative bacteria pose a serious and rapidly emerging threat to patients in healthcare settings and are especially prevalent and problematic in intensive care units. Few antimicrobial treatment options remain for patients infected with the most resistant of these pathogens. Recent data shed light on the extent of the multidrug-resistant Gram-negative problem and suggest potential strategies to prevent transmission and improve clinical outcomes. This review examines the clinical impact and epidemiology of multidrug-resistant Gram-negative bacteria as a cause of healthcare-associated infections in critically ill patients, discusses issues regarding detection and recognition of these organisms, and reviews recommended methods to prevent patient-to-patient transmission of these formidable pathogens. Recent guidance from the Centers for Disease Control and Prevention for detection and control of carbapenemase-producing Enterobacteriaceae is discussed, along with potential strategies to optimize the existing antimicrobial treatment options for patients with multidrug-resistant Gram-negative infections. © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

Dai L.,Johns Hopkins University
Physical Review Letters | Year: 2014

When a cosmic microwave background (CMB) photon travels from the surface of last scatter through spacetime metric perturbations, the polarization vector may rotate about its direction of propagation. This gravitational rotation is distinct from, and occurs in addition to, the lensing deflection of the photon trajectory. This rotation can be sourced by linear vector or tensor metric perturbations and is fully coherent with the curl deflection field. Therefore, lensing corrections to the CMB polarization power spectra as well as the temperature-polarization cross correlations due to nonscalar perturbations are modified. The rotation does not affect lensing by linear scalar perturbations, but needs to be included when calculations go to higher orders. We present complete results for weak lensing of the full-sky CMB power spectra by general linear metric perturbations, taking into account both deflection of the photon trajectory and rotation of the polarization. For the case of lensing by gravitational waves, we show that the B modes induced by the rotation largely cancel those induced by the curl component of deflection. © 2014 American Physical Society.

Carbary J.F.,Johns Hopkins University
Journal of Geophysical Research A: Space Physics | Year: 2015

Saturn's magnetospheric periodicities are commonly thought to have a dual nature, one period originating from the southern hemisphere and a slightly different period from the northern. Both periods vary a few percent over time intervals of years and apparently merged a few months after Saturn equinox. These periodicities have not been explained. The dual-period waveform is generally represented as the superposition of two sinusoids with nearly equal periods. However, dual-period waves can also result from an amplitude modulation of a carrier periodicity, from frequency modulation of the carrier, from random phase jumps in the carrier, and from small, random changes in the period itself. While such simple phenomena are well known in the radio community, they can serve as possible explanations for how a single planetary period can appear as the dual (or multiple) periods observed in Saturn's magnetosphere. Candidates for modulation and randomization include the solar wind pressure and speed, the orbital periods of moons of Saturn, or even the trajectory of the Cassini orbiter itself. Key Points Dual periods not always from superposed sinusoids Dual periods can result from amplitude or frequency modulation Dual periods can also result from random phase or frequency changes ©2015. American Geophysical Union. All Rights Reserved.

Younes L.,Johns Hopkins University
Foundations of Computational Mathematics | Year: 2012

We design optimal control strategies in spaces of diffeomorphisms and shape spaces in which the Eulerian velocities of the evolving deformations are constrained to belong to a suitably chosen finite-dimensional space, which is also following the motion. This results in a setting that provides a great flexibility in the definition of Riemannian metrics, extending previous approaches in which shape spaces are built as homogeneous spaces under the action of the diffeomorphism group equipped with a right-invariant metric. We provide specific instances of this general setting, and describe in detail the resulting numerical algorithms, with experimental illustrations in the case of plane curves. © 2011 SFoCM.

Bar E.E.,Johns Hopkins University
Brain Pathology | Year: 2011

Glioblastoma (GBM) prognosis remains dismal, with most patients succumbing to disease within 1 or 2 years of diagnosis. Recent studies have suggested that many solid tumors, including GBM, are maintained by a subset of cells termed cancer stem cells (CSCs). It has been shown that these cells are inherently radio- and chemotherapy resistant, and may be maintained in vivo in a niche characterized by reduced oxygen tension (hypoxia). This review examines the recently described effects of hypoxia on CSC in GBM, and the potential promise in targeting the hypoxic pathway therapeutically. © 2010 International Society of Neuropathology.

Robinson K.A.,Johns Hopkins University
The Cochrane database of systematic reviews | Year: 2013

Respiratory syncytial virus infection causes acute lung infection in infants and young children worldwide, resulting in considerable morbidity and mortality. Children with cystic fibrosis are prone to recurrent lung inflammation, bacterial colonisation and subsequent chronic airway disease, putting them at risk for severe respiratory syncytial virus infections requiring intensive care and respiratory support. No treatment currently exists, hence prevention is important. Palivizumab is effective in reducing respiratory syncytial virus hospitalisation rates and is recommended for prophylaxis in high-risk children with other conditions. It is unclear if palivizumab can prevent respiratory syncytial virus hospitalisations and intensive care unit admissions in children with cystic fibrosis. To determine the efficacy and safety of palivizumab (Synagis(®)) compared with placebo, no prophylaxis or other prophylaxis, in preventing hospitalisation and mortality from respiratory syncytial virus infection in children with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register and scanned references of the eligible study and related reviews.Date of last search: 11 October 2012. Randomised and quasi-randomised studies. The authors independently extracted data and assessed risk of bias. One study (186 infants up to two years old) comparing five monthly doses of palivizumab (N = 92) to placebo (N = 94) over one respiratory syncytial virus season was identified and met our inclusion criteria. At six months follow-up, one participant in each group was hospitalised due to respiratory syncytial virus; there were no deaths in either group. In the palivizumab and placebo groups, 86 and 90 children experienced any adverse event, while five and four children had related adverse events respectively. Nineteeen children receiving palivizumab and 16 receiving placebo suffered serious adverse events; one participant receiving palivizumab discontinued due to this. At 12 months follow-up, there were no significant differences between groups in number of Pseudomonas bacterial colonisations or change in weight-to-height ratio. We identified one randomised controlled trial comparing five monthly doses of palivizumab to placebo in infants up to two years old with cystic fibrosis. While the overall incidence of adverse events was similar in both groups, it is not possible to draw firm conclusions on the safety and tolerability of respiratory syncytial virus prophylaxis with palivizumab in infants with cystic fibrosis. Six months after treatment, the authors reported no clinically meaningful differences in outcomes. Additional randomised studies are needed to establish the safety and efficacy of palivizumab in children with cystic fibrosis.

Even though the dynamic modification of polypeptides by the monosaccharide, O-linked N-acetylglucosamine (O-GlcNAcylation) was discovered over 30 years ago, its physiological significance as a major nutrient sensor that regulates myriad cellular processes has only recently been more widely appreciated. O-GlcNAcylation, either on its own or by its interplay with other post-translational modifications, such as phosphorylation, ubiquitination, and others, modulates the activities of signaling proteins, regulates most components of the transcription machinery, affects cell cycle progression and regulates the targeting/turnover or functions of myriad other regulatory proteins, in response to nutrients. Acute increases in O-GlcNAcylation protect cells from stress-induced injury, while chronic deregulation of O-GlcNAc cycling contributes to the etiology of major human diseases of aging, such as diabetes, cancer, and neurodegeneration. Recent advances in tools to study O-GlcNAcylation at the individual site level and specific inhibitors of O-GlcNAc cycling have allowed more rapid progress toward elucidating the specific functions of O-GlcNAcylation in essential cellular processes. © 2014 Hart.

Haine T.W.N.,Johns Hopkins University
Geophysical Research Letters | Year: 2010

Denmark Strait ocean current transport exhibits quasi-regular fluctuations immediately south of the sill with periods of 2-4 days. The transport variability is similar to the mean transport itself. Using a circulation model we explore prospects to monitor the fluctuations. The model has realistic transport and shows water leaving Denmark Strait in equivalent-barotropic cyclones that are nearly geostrophic and correlate with sea-surface height (SSH). Existing satellite altimeter observations of SSH have adequate space/time sampling to reconstruct the transport fluctuations using a regression developed from the model results, but measurement error overwhelms the signal. From the model results, the pending Surface Water and Ocean Topography (SWOT) wide-swath altimeter appears accurate enough, and with good-enough coverage, to allow the transport fluctuations to be reconstructed. Bottom pressure recorders at the exit of the Denmark Strait can also reproduce the transport variability. Copyright 2010 by the American Geophysical Union.

Kong L.,Fudan University | Zang J.,Fudan University | Zang J.,Johns Hopkins University
Physical Review Letters | Year: 2013

We study the Skyrmion dynamics in thin films under a temperature gradient. Our numerical simulations show that both single and multiple Skyrmions in a crystal move towards the high temperature region, which is contrary to particle diffusion. Noticing a similar effect in the domain wall motion, we employ a theory based on magnon dynamics to explain this counterintuitive phenomenon. Unlike the temperature driven domain wall motion, the Skyrmion's topological charge plays an important role, and a transverse Skyrmion motion is observed. Our theory turns out to be in agreement with numerical simulations, both qualitatively and quantitatively. Our calculation indicates that a very promising Skyrmion dynamic phenomenon can be observed in experiments. © 2013 American Physical Society.

Van Meerbeke J.P.,Johns Hopkins University
Discovery medicine | Year: 2011

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder that causes degeneration of α-motor neurons. Frequently, muscle weakness is very severe causing affected infants to die before reaching two years of age, but mild forms of the disease can be characterized by relatively static muscle weakness for many years. SMA is caused by recessive mutations of the SMN1 gene, but all patients retain at least one copy of SMN2, a similar gene capable of producing low levels of full-length SMN protein. No treatments currently exist for SMA patients, but the identification of therapeutic targets and the development of suitable animal models for preclinical testing have resulted in increased drug development efforts in the past ten years. Here, we review the current status of many of these programs, including those designed to activate SMN2 gene expression, modulate splicing of SMN2 preRNAs, stabilize SMN protein, replace SMN1, provide neuroprotective support, and transplant neural cells.

Borodovsky A.,Johns Hopkins University
Current opinion in oncology | Year: 2012

IDH1/2 mutations occur in up to 70% of low-grade gliomas and secondary glioblastomas. Mutation of these enzymes reduces the wildtype function of the enzyme (conversion of isocitrate to α-ketoglutarate) while conferring a new enzymatic function, the production of D-2-hydroxyglutarate (D-2-HG) from α-ketoglutarate (α-KG). However, it is unclear how these enzymatic changes contribute to tumorigenesis. Here, we discuss the recent studies that demonstrate how IDH1/2 mutation may alter the metabolism and epigenome of gliomas, how these changes may contribute to tumor formation, and opportunities they might provide for molecular targeting. Metabolomic studies of IDH1/2 mutant cells have revealed alterations in glutamine, fatty acid, and citrate synthesis pathways. Additionally, D-2-HG produced by IDH1/2 mutant cells can competitively inhibit α-KG-dependent enzymes, including histone demethylases and DNA hydroxylases, potentially leading to a distinct epigenetic phenotype. Alterations in metabolism and DNA methylation present possible mechanisms of tumorigenesis. Recent attempts to improve outcomes for glioma patients have resulted in incremental gains. Studies of IDH1/2 mutations have provided mechanistic insights into tumorigenesis and potential avenues for therapeutic intervention. Further study of IDH1/2 mutations might allow for improved therapeutic strategies.

Hendrix C.W.,Johns Hopkins University
Current Opinion in HIV and AIDS | Year: 2012

PURPOSE OF REVIEW: Pre-exposure prophylaxis (PrEP) clinical trial results using antiretrovirals can seem confusing, if not conflicting. We review recent antiretroviral pharmacokinetic studies to help explain PrEP trial results. RECENT FINDINGS: Pharmacokinetic studies indicate that topical dosing, compared with oral dosing, achieves far higher colon and vaginal tissue drug concentrations, and far lower drug concentrations in blood. After oral dosing, higher tenofovir diphosphate concentrations are found in colon tissue than cervico-vaginal tissue, but the reverse is the case for emtricitabine triphosphate, although it does not persist as long. Vaginal dosing achieves measurable tenofovir concentrations in the rectum and vice versa. Within and among oral PrEP trials, increased drug concentration is associated with increased HIV protection, with drug concentration differences best explained by adherence, rather than pharmacokinetics. The poor level of protection in topical studies is not consistent with concentration-response in oral studies indicating unknown variables in need of further investigation. SUMMARY: Sparse pharmacokinetic sampling in large trials combined with more intensive sampling in smaller pharmacokinetic-focused studies help explain trial outcome differences due largely to differences in adherence, tissue pharmacokinetics, and type of HIV exposure. Pharmacokinetic analysis can identify protective drug concentration targets, guide dose optimization, and inform future trials. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Chander G.,Johns Hopkins University
Topics in Antiviral Medicine | Year: 2011

Alcohol use is common among persons with HIV infection and is associated with worse HIV treatment outcomes. Patients with hazardous levels of use are less likely to be receiving antiretroviral therapy, to be adherent to therapy, and to achieve virologic suppression. Screening, intervention, and referral to care for alcohol use disorder is an integral part of clinical care for individuals with HIV infection. Brief screening procedures can identify level of risk and determine whether patients require brief alcohol intervention or should be considered for behavioral therapy and pharmacologic treatment. Identification of concurrent mental health disorders is an important aspect of treating alcohol use disorders in HIV infection and other clinical settings. © 2011, IAS-USA.

Jelovac D.,Johns Hopkins University
Oncology (Williston Park, N.Y.) | Year: 2013

Human epidermal growth factor receptor 2 (HER2) overexpression drives the biology of 20% of breast cancers, and predicts a poor prognosis for patients. HER2-targeted therapies significantly improve outcomes for HER2-positive patients with both early and metastatic breast cancer. Currently three HER2-targeted agents, trastuzumab (Herceptin), lapatinib (Tykerb), and pertuzumab (Perjeta), are available for the treatment of HER2-positive metastatic breast cancer (MBC). Numerous studies have attempted to optimize their use by combining them with each other, or with endocrine and cytotoxic therapies. Most recently, the FDA approved the combination of trastuzumab, pertuzumab, and docetaxel as first-line treatment for MBC, and in late February 2013 approved a fourth HER2-targeted agent, trastuzumab emtansine (T-DM1, Kadcyla), for accelerated approval. These advances create a number of clinical dilemmas, including identification of the optimal sequence of HER2-targeted agents and the best drug combinations to use, as well as the recognition of primary and acquired drug resistance. In this article, we review clinical data informing the effective management of HER2-positive MBC.

Geem Z.W.,Johns Hopkins University
Journal of Construction Engineering and Management | Year: 2010

Completing a project with minimal time as well as minimal cost is a critical factor for scheduling a project. However, because completion speed tends to be correlated with cost (e.g., usually, time can be saved if more workers are hired), the relationship between time and cost is a trade-off. This study employed a phenomenon-mimicking algorithm, harmony search to perform this biobjective trade-off. The harmony search algorithm was applied to two test examples, and good Pareto solutions were obtained when compared with other algorithms, such as the genetic algorithm and the ant colony optimization algorithm. The harmony search algorithm explored only a small amount of total solution space in order to solve this combinatorial optimization problem. The model in this study has obtained good results with a network of up to 18 nodes, however it is anticipated that the model could be useful to solve bigger networks in practice without any difficult problem. © 2010 ASCE.

Wager T.D.,University of Colorado at Boulder | Atlas L.Y.,New York University | Lindquist M.A.,Johns Hopkins University | Roy M.,University of Colorado at Boulder | And 2 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: Persistent pain is measured by means of self-report, the sole reliance on which hampers diagnosis and treatment. Functional magnetic resonance imaging (fMRI) holds promise for identifying objective measures of pain, but brain measures that are sensitive and specific to physical pain have not yet been identified. METHODS: In four studies involving a total of 114 participants, we developed an fMRI-based measure that predicts pain intensity at the level of the individual person. In study 1, we used machine-learning analyses to identify a pattern of fMRI activity across brain regions - a neurologic signature - that was associated with heat-induced pain. The pattern included the thalamus, the posterior and anterior insulae, the secondary somatosensory cortex, the anterior cingulate cortex, the periaqueductal gray matter, and other regions. In study 2, we tested the sensitivity and specificity of the signature to pain versus warmth in a new sample. In study 3, we assessed specificity relative to social pain, which activates many of the same brain regions as physical pain. In study 4, we assessed the responsiveness of the measure to the analgesic agent remifentanil. RESULTS: In study 1, the neurologic signature showed sensitivity and specificity of 94% or more (95% confidence interval [CI], 89 to 98) in discriminating painful heat from nonpainful warmth, pain anticipation, and pain recall. In study 2, the signature discriminated between painful heat and nonpainful warmth with 93% sensitivity and specificity (95% CI, 84 to 100). In study 3, it discriminated between physical pain and social pain with 85% sensitivity (95% CI, 76 to 94) and 73% specificity (95% CI, 61 to 84) and with 95% sensitivity and specificity in a forced-choice test of which of two conditions was more painful. In study 4, the strength of the signature response was substantially reduced when remifentanil was administered. CONCLUSIONS: It is possible to use fMRI to assess pain elicited by noxious heat in healthy persons. Future studies are needed to assess whether the signature predicts clinical pain. (Funded by the National Institute on Drug Abuse and others.) Copyright © 2013 Massachusetts Medical Society.

Hamilton J.P.,Johns Hopkins University
Digestive Diseases | Year: 2011

Epigenetics is defined as heritable changes in gene expression that are, unlike mutations, not attributable to alterations in the sequence of DNA. The predominant epigenetic mechanisms are DNA methylation, modifications to chromatin, loss of imprinting and non-coding RNA. Epigenetic regulation of gene expression appears to have long-term effects and wide-ranging effects on health. Diet and environmental exposures may potentially alter the level and scope of epigenetic regulation, thus interesting developments in the study of epigenetics might explain correlations that researchers have found between lifestyle and risk of disease. Aberrant epigenetic patterns have been linked to a number of digestive diseases including Barrett's esophagus, cirrhosis, inflammatory bowel disease, and numerous gastrointestinal malignancies. In fact, many exciting discoveries about epigenetics in general have been made by studying diseases of the gastrointestinal tract and hepatobiliary tree. Epigenetic modifications of DNA in cancer and precancerous lesions offer hope and the promise of novel biomarkers for early cancer detection, prediction, prognosis, and response to treatment. Furthermore, reversal of epigenetic changes represents a potential target of novel therapeutic strategies and medication design. In the future, it is anticipated that innovative diagnostic tests, treatment regimens, and even lifestyle modifications will be based on epigenetic mechanisms and be incorporated into the practice of medicine. Copyright © 2011 S. Karger AG, Basel.

Zheng Y.,Carnegie Institution for Science | Iglesias P.A.,Johns Hopkins University
Cell | Year: 2013

Centrosome- and chromatin-based microtubule nucleation pathways have been implicated in spindle assembly. Using total internal reflection fluorescent microscopy and Xenopus egg extracts, Petry et al. demonstrate that new microtubules can also nucleate and branch out from existing ones in animal cells. © 2013 Elsevier Inc.

Walston J.D.,Johns Hopkins University
Current Opinion in Rheumatology | Year: 2012

Purpose of Review: Sarcopenia, or the decline of skeletal muscle tissue with age, is one of the most important causes of functional decline and loss of independence in older adults. The purpose of this article is to review the current definitions of sarcopenia, its potential causes and clinical consequences, and the potential for intervention. Recent Findings: Although no consensus diagnosis has been reached, sarcopenia is increasingly defined by both loss of muscle mass and loss of muscle function or strength. Its cause is widely regarded as multifactorial, with neurological decline, hormonal changes, inflammatory pathway activation, declines in activity, chronic illness, fatty infiltration, and poor nutrition, all shown to be contributing factors. Recent molecular findings related to apoptosis, mitochondrial decline, and the angiotensin system in skeletal muscle have highlighted biological mechanisms that may be contributory. Interventions in general continue to target nutrition and exercise. Summary: Efforts to develop a consensus definition are ongoing and will greatly facilitate the development and testing of novel interventions for sarcopenia. Although pharmaceutical agents targeting multiple biological pathways are being developed, adequate nutrition and targeted exercise remain the gold standard for therapy. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Dipietro J.A.,Johns Hopkins University
Journal of Adolescent Health | Year: 2012

There is significant current interest in the degree to which prenatal exposures, including maternal psychological factors, influence child outcomes. Studies that detect an association between prenatal maternal psychological distress and child developmental outcomes are subject to a number of interpretative challenges in the inference of causality. Some of these are common to many types of prenatal exposures that must necessarily rely on observational designs. Such challenges include the correlation between prenatal and postnatal exposures and the potential role of other sources of shared influence, such as genetic factors. Others are more specific to this area of research. These include confounding between maternal report of child outcomes and the maternal psychological attributes under study, difficulties in distinguishing maternal stress from more ubiquitous aspects of maternal personality, and the lack of association between cortisol and measures of maternal psychological stress. This article considers these methodological issues and offers an additional methodology focused on fetal neurobehavior for discerning potential mechanisms that may mediate associations between maternal psychological functioning and the developing fetal nervous system. © 2012 Society for Adolescent Health and Medicine.

Lui A.T.Y.,Johns Hopkins University
Journal of Geophysical Research: Space Physics | Year: 2011

We examine a near-Earth current disruption/dipolarization (CDD) event in which two THEMIS satellites were located at nearly identical equatorial projections but separated by the distance from the neutral sheet. One satellite was very close to the neutral sheet with Bx, By < 1.5 nT at CDD onset that coincided with ground signatures of substorm expansion onset. The cross-tail current density between the two satellites varied with a time scale of seconds during CDD and was reduced by ∼40% eventually. If the current density profile could be represented well by the combination of a dipole field and a one-dimensional current sheet, then the current density integrated over the current sheet thickness was reduced by only ∼12%. The difference can be attributed to plasma sheet expansion in association with CDD. There were occasional breakdowns of the frozen-in-field condition during CDD as well. The particle energization associated with CDD approached the satellite from the Earthward-dawnward direction near the neutral sheet based on the ion sounding technique, constituting compelling evidence that this near-Earth CDD arose from disturbances originating in the near-Earth region (Xgsm >-8.1 RE) and was not due to magnetic flux pileup (requiring frozen-in condition) or arrival of a dipolarization front from mid-tail (Xgsm <-15 RE) disturbances. Copyright 2011 by the American Geophysical Union.

West S.,Johns Hopkins University
Expert Review of Anti-Infective Therapy | Year: 2012

Trachoma, a chronic conjunctivitis caused by Chlamydia trachomatis, is the leading infectious cause of blindness worldwide. In recognition of this public health problem, the World Health Assembly has targeted the year 2020 to eliminate blinding trachoma, and a multifaceted strategy (SAFE) is recommended, including antibiotics for treatment of infection. Trachoma is a disease of entire communities, and the pool of infection resides largely in preschool age children. Thus, for endemic communities, mass treatment with antibiotics annually for at least 3-5 years is carried out. The antibiotics used, the effectiveness of this approach, and the challenges of antibiotic treatment of communities are discussed, concluding with a view towards the elimination of trachoma in the future. © 2012 Expert Reviews Ltd.

Dagnelie G.,Johns Hopkins University
Current Opinion in Neurology | Year: 2012

Purpose of review: This review summarizes the current status of retinal prostheses, recent accomplishments, and major remaining research, engineering, and rehabilitation challenges. Recent findings: Retinal research, materials and biocompatibility studies, and clinical trials in patients blind from retinitis pigmentosa are representative of an emerging field with considerable promise and sobering challenges. A summary of progress in dozens of laboratories, companies, and clinics around the world is presented through a synopsis of relevant studies, not only to summarize the progress but also to convey the remarkable increase in interest, effort, and outside funding this field has enjoyed. Summary: At present, clinical applications of retinal implant technology are dominated by one or two groups/companies, but the field is wide open for others to take the lead through novel approaches in technology, tissue interfacing, information transfer paradigms, and rehabilitation. Where the field will go in the next few years is almost anybody's guess, but that it will move forward is a certainty. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Kim K.S.,Johns Hopkins University
Current Opinion in Infectious Diseases | Year: 2012

Purpose of review: Neonatal Escherichia coli meningitis continues to be an important cause of mortality and morbidity throughout the world. The major contributing factors to this mortality and morbidity include our incomplete knowledge on its pathogenesis and an emergence of antimicrobial-resistant E. coli. Recent reports of neonatal meningitis caused by E. coli producing CTX-M-type or TEM-type extended-spectrum β-lactamases create a challenge, and innovative approaches are needed to identify potential targets for prevention and therapy of E. coli meningitis. Recent findings: E. coli invasion of the blood-brain barrier is a prerequisite for penetration into the brain and requires specific microbial-host factors as well as microbe-specific and host-specific signaling molecules. Recent studies identified additional microbial and host factors contributing to E. coli invasion of the blood-brain barrier and elucidated their underlying mechanisms. Blockade of the microbial-host factors contributing to E. coli invasion of the blood-brain barrier was shown to be efficient in preventing E. coli penetration into the brain. Summary: Continued investigation on the microbial-host factors contributing to E. coli invasion of the blood-brain barrier is needed to identify new targets for prevention and therapy of E. coli meningitis, thereby limiting the exposure to emerging antimicrobial-resistant E. coli. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Koch W.M.,Johns Hopkins University
Otolaryngologic Clinics of North America | Year: 2012

Head and neck squamous cell carcinoma (HNSCC) that arises as a result of the activity of human papillomavirus (HPV) malignant transformation has a distinct disease pattern that is the basis for its clinical presentation. A clear understanding of these distinct clinical features enables diagnosticians to maintain awareness and index of suspicion to avoid delays in detection and select the most effective and thorough measures of evaluating the disease and directing treatment selection. Attention is focused on the broader demographic at risk for developing HPV-related HNSCC, the phenomenon of cystic cervical nodal metastases, and the unknown or occult primary cancer. © 2012 Elsevier Inc.

Torrey E.F.,Stanley Medical Research Institute | Bartko J.J.,Stanley Medical Research Institute | Yolken R.H.,Johns Hopkins University
Schizophrenia Bulletin | Year: 2012

The failure to find genes of major effect in schizophrenia has refocused attention on nongenetic, including infectious factors. In a previous study, antibodies to Toxoplasma gondii were found to be elevated in 23 studies of schizophrenia (OR 2.73; 95% CI 2.10-3.60). The current study replicates this finding with 15 additional studies (OR 2.71; 95% CI 1.93-3.80) and compares this with other identified schizophrenia risk factors. The highest risk factors are having an affected mother (relative risks [RR] 9.31; 95% CI 7.24-11.96), father (RR 7.20; 95% CI 5.10-10.16), or sibling (RR 6.99; 95% CI 5.38-9.08) or being the offspring of immigrants from selected countries (RR 4.5; 95% CI 1.5-13.1). Intermediate risk factors, in addition to infection with T. gondii, include being an immigrant from and to selected countries (RR 2.7; 95% CI 2.3-3.2), being born in (RR 2.24; 95% CI 1.92-2.61) or raised in (RR 2.75; 95% CI 2.31-3.28) an urban area, cannabis use (OR 2.10-2.93; 95% CI 1.08-6.13), having minor physical anomalies (OR 2.23; 95% CI 1.42-3.58), or having a father 55 or older (OR 2.21-5.92; 95% CI 1.46-17.02). Low-risk factors include a history of traumatic brain injury (OR 1.65; 95% CI 1.17-2.32), sex abuse in childhood (OR 1.46; 95% CI 0.84-2.52), obstetrical complications (OR 1.29-1.38; 95% CI 1.00-1.84), having a father 45 or older (OR 1.21-1.66; 95% CI 1.09-2.01), specific genetic polymorphisms (OR 1.09-1.24; 95% CI 1.06-1.45), birth seasonality (OR 1.07-1.95; 95% CI 1.05-2.91), maternal exposure to influenza (RR 1.05; 95% CI 0.98-1.12), or prenatal stress (RR 0.98-1.00; 95% CI 0.85-1.16). © 2010 The Author.

Marsh B.D.,Johns Hopkins University
Contributions to Mineralogy and Petrology | Year: 2013

The age-old process of crystal fractionation leading to the diversity of the igneous rocks and Earth itself is an exceedingly well-understood chemical process in magmatism and physical chemistry. But the broader physical aspects of this and related processes have proven elusive on many fronts, especially in its relation to the spatial variations in rock composition, texture, and macroscopic features like layering. Magmatic systems, be they volcanic, dikes, sills, or plutons, are generally analyzed with a problem at hand and an end result in mind. The processes invoked to solve these problems, which are most often purely chemical, are often unique to each problem with few if any general principles emerging that are central to understanding the wider perspective of magmatic processes and problems. An attempt is made at the outset to provide a list of inviolate Magmatic First Principles that are relevant to analyzing most magmatic problems. These involve: initial conditions; critical crystallinity; solidification fronts; transport and emplacement fluxes; phenocrysts, xenocrysts, primocrysts; crystal size; layering and crystal sorting; thermal convection; magmatic processes are physical. Along with these principles, two reference magmatic systems are suggested where the initial conditions and outcome are unequivocal: the Sudbury impact melt sheet and the Hawaiian lava lakes. Sudbury formed in ~5 min by superheated magma crystallized to a near uniform sequence, while the tiny lava lakes, formed of crystal-laden slurries, form a highly differentiated layered sequence. The major difference is in the initial conditions of formation, especially the nature of the input materials. The challenge is to construct and analyze magmatic systems (i.e., magma chambers, sills, dikes, and lavas) using these reference end members and the suggested principles. The Hawaiian 500,000 year volcanic record exhibits what can be expected as input materials, namely a highly varied output of magma of an overall composition reflecting the abundance of entrained olivine primocrysts. The provenance of these crystals is varied, and within any single sample, the population may be highly heterogeneous in composition from crystal to crystal, yet the overall pattern of chemical fractionation is exceedingly regular and well defined. If similar inputs go to form large intrusions, these systems will undoubtedly be dominated by crystal-rich slurries, which provide a vast set of physical processes promoting exotic layering and, at the same time, given the effects of annealing and continued crystal growth, a final chemical record adhering to all the time-honored effects of crystal fractionation. The long assumed initial condition of instantaneously emplaced crystal-free magmas cannot reasonably produce the observed rock records. © 2013 The Author(s).

Alqahtani S.A.,Johns Hopkins University
Discovery medicine | Year: 2012

Successful transplant outcomes require optimal patient selection and timing. Currently the major limitation facing liver transplant centers is the shortage of organs. The limited availability of organs has led to long waiting periods for liver transplantation and consequently many patients become seriously ill or die while on the waiting list. This has major implications in the selection of patients, as well as the timing of transplant, for optimal use of these scarce organs. Indications and contraindications have changed slightly over the years and will be reviewed in this article. Timing for transplantation has changed more dramatically in recent years since major changes to organ allocation systems have been undertaken to provide clinicians with a better way to prioritize patients for liver transplant.

Fischer Walker C.L.,Johns Hopkins University
PLoS medicine | Year: 2011

Diarrhea remains a leading cause of mortality among young children in low- and middle-income countries. Although the evidence for individual diarrhea prevention and treatment interventions is solid, the effect a comprehensive scale-up effort would have on diarrhea mortality has not been estimated. We use the Lives Saved Tool (LiST) to estimate the potential lives saved if two scale-up scenarios for key diarrhea interventions (oral rehydration salts [ORS], zinc, antibiotics for dysentery, rotavirus vaccine, vitamin A supplementation, basic water, sanitation, hygiene, and breastfeeding) were implemented in the 68 high child mortality countries. We also conduct a simple costing exercise to estimate cost per capita and total costs for each scale-up scenario. Under the ambitious (feasible improvement in coverage of all interventions) and universal (assumes near 100% coverage of all interventions) scale-up scenarios, we demonstrate that diarrhea mortality can be reduced by 78% and 92%, respectively. With universal coverage nearly 5 million diarrheal deaths could be averted during the 5-year scale-up period for an additional cost of US$12.5 billion invested across 68 priority countries for individual-level prevention and treatment interventions, and an additional US$84.8 billion would be required for the addition of all water and sanitation interventions. Using currently available interventions, we demonstrate that with improved coverage, diarrheal deaths can be drastically reduced. If delivery strategy bottlenecks can be overcome and the international community can collectively deliver on the key strategies outlined in these scenarios, we will be one step closer to achieving success for the United Nations' Millennium Development Goal 4 (MDG4) by 2015.

Tzeng S.Y.,Johns Hopkins University
International journal of nanomedicine | Year: 2011

Biodegradable poly(ester amine) (PEA)-based and poly(amido amine) (PAA)-based nanoparticles were developed for efficient in vitro siRNA delivery to human umbilical vein endothelial cells (HUVECs). They were screened, characterized, and compared with traditionally studied DNA-containing particles. Several of the polymeric nanoparticles tested were found to be effective for delivering functional siRNA to green fluorescent protein (GFP) + HUVECs, achieving 60%-75% GFP knockdown while maintaining high viability. While PEAs have been used previously to form polyplexes or nanoparticles for DNA delivery, highly effective siRNA delivery in hard-to-transfect human cell types has not been previously reported. PEAs and linear nondendrimeric PAAs were also found to be effective for DNA delivery to HUVECs using GFP-encoding plasmid DNA (up to 50%-60% transfection efficiency). PEAs and PAAs can be separated into groups that form polymeric nanoparticles effective for siRNA delivery, for DNA delivery, or for both.

Johnson M.W.,Johns Hopkins University
Experimental and clinical psychopharmacology | Year: 2013

The Sexual Discounting Task uses the delay discounting framework to examine sexual HIV risk behavior. Previous research showed task performance to be significantly correlated with self-reported HIV risk behavior in cocaine dependence. Test-retest reliability and gender differences had remained unexamined. The present study examined the test-retest reliability of the Sexual Discounting Task. Cocaine-dependent individuals (18 men, 13 women) completed the task in two laboratory visits ∼7 days apart. Participants selected photographs of individuals with whom they were willing to have casual sex. Among these, participants identified the individual most (and least) likely to have a sexually transmitted infection (STI), and the individual with whom he or she most (and least) wanted to have sex. In reference to these individuals, participants rated their likelihood of having unprotected sex versus waiting to have sex with a condom, at various delays. A money delay discounting task was also completed at the first visit. Significant differences in discounting among partner conditions were shown. Differential stability was demonstrated by significant, positive correlations between test and retest for all four partner conditions. Absolute stability was demonstrated by statistical equivalence tests between test and retest, and also supported by a lack of significant differences between test and retest. Men generally discounted significantly more than women for sexual outcomes but not money. Results suggest the Sexual Discounting Task to be a reliable measure in cocaine-dependent individuals, which supports its use as a repeated measure in clinical research, for example, studies examining acute drug effects on sexual risk and the effects of addiction treatment and HIV prevention interventions on sexual risk. PsycINFO Database Record (c) 2013 APA, all rights reserved

Bottomley P.A.,Johns Hopkins University
NMR in Biomedicine | Year: 2016

This paper offers a critical review of the properties, methods and potential clinical application of sodium (23Na) MRI in human heart. Because the tissue sodium concentration (TSC) in heart is about ~40μmol/g wet weight, and the 23Na gyromagnetic ratio and sensitivity are respectively about one-quarter and one-11th of that of hydrogen (1H), the signal-to-noise ratio of 23Na MRI in the heart is about one-6000th of that of conventional cardiac 1H MRI. In addition, as a quadrupolar nucleus, 23Na exhibits ultra-short and multi-component relaxation behavior (T1 ~ 30ms; T2 ~ 0.5-4ms and 12-20ms), which requires fast, specialized, ultra-short echo-time MRI sequences, especially for quantifying TSC. Cardiac 23Na MRI studies from 1.5 to 7T measure a volume-weighted sum of intra- and extra-cellular components present at cytosolic concentrations of 10-15mM and 135-150mM in healthy tissue, respectively, at a spatial resolution of about 0.1-1ml in 10min or so. Currently, intra- and extra-cellular sodium cannot be unambiguously resolved without the use of potentially toxic shift reagents. Nevertheless, increases in TSC attributable to an influx of intra-cellular sodium and/or increased extra-cellular volume have been demonstrated in human myocardial infarction consistent with prior animal studies, and arguably might also be seen in future studies of ischemia and cardiomyopathies - especially those involving defects in sodium transport. While technical implementation remains a hurdle, a central question for clinical use is whether cardiac 23Na MRI can deliver useful information unobtainable by other more convenient methods, including 1H MRI. © 2016 John Wiley & Sons, Ltd.

Ovbiagele B.,University of California at San Diego | Nath A.,Johns Hopkins University
Neurology | Year: 2011

Background: Large-scale epidemiologic data on stroke in HIV-infected persons are scarce, especially in an era of combination antiretroviral therapies, which have prolonged patient survival, but may boost stroke risk. We assessed trends in the proportion of HIV infection among patients with stroke in the United States. Methods: Data were obtained from all states within the United States that contributed to the Nationwide Inpatient Sample. All patients admitted to hospitals between 1997 and 2006 with a primary discharge diagnosis of stroke (identified by the International Classification of Diseases, Ninth Revision procedure codes) were included. Time trends in the proportion of these patients with HIV diagnosis were computed, and independent predictors of comorbid HIV diagnosis evaluated using multivariable logistic regression. Results: Of all (ischemic and hemorrhagic) stroke hospitalizations, patients with comorbid HIV infection constituted 0.09% in 1997 vs 0.15% in 2006 (p < 0.0001). Actual numbers of overall US stroke hospitalizations lessened 7% (998,739 to 926,997), while actual numbers of stroke hospitalizations with coexisting HIV infection rose 60% (888 to 1,425). Patients with comorbid HIV infection comprised 0.08% of ischemic strokes in 1997 vs 0.18% in 2006 (p < 0.0001), but their proportion of hemorrhagic strokes did not significantly change. Factors independently associated with higher odds of comorbid HIV diagnosis were Medicaid insurance, urban hospital type, dementia, liver disease, renal disease, and cancer. CONCLUSION:: Over the last decade in the United States, there has been a substantial and significant rise in patients hospitalized for stroke with coexisting HIV infection. This has important public health and socioeconomic consequences. Copyright © 2011 by AAN Enterprises, Inc.

Fluorescence-activated cell sorting (FACS) is a sensitive and valuable technique to characterize cellular subpopulations and great advances have been made using this approach. Cells are often fixed with formaldehyde prior to the sorting process to preserve cell morphology and maintain the expression of surface molecules, as well as to ensure safety in the sorting of infected cells. It is widely recognized that formaldehyde fixation alters RNA and DNA structure and integrity, thus analyzing gene expression in these cells has been difficult. We therefore examined the effects of formaldehyde fixation on the stability and quantitation of nucleic acids in cell lines, primary leukocytes and also cells isolated from SIV-infected pigtailed macaques. We developed a method to extract RNA from fixed cells that yielded the same amount of RNA as our common method of RNA isolation from fresh cells. Quantitation of RNA by RT-qPCR in fixed cells was not always comparable with that in unfixed cells. In comparison, when RNA was measured by the probe-based NanoString system, there was no significant difference in RNA quantitation. In addition, we demonstrated that quantitation of proviral DNA in fixed cells by qPCR is comparable to that in unfixed cells when normalized by a single-copy cellular gene. These results provide a systematic procedure to quantitate gene expression in cells that have been fixed with formaldehyde and sorted by FACS.

Erlebacher J.,Johns Hopkins University | Margetis D.,University of Maryland University College
Physical Review Letters | Year: 2014

Shape fluctuations in nanoparticles strongly influence their stability. Here, we introduce a quantitative model of such shape fluctuations and apply this model to the important case of Pt-shell/transition metal-core nanoparticles. By using a Gibbs distribution for the initial shapes, we find that there is typically enough thermal energy at room temperature to excite random shape fluctuations in core-shell nanoparticles, whose amplitudes are sufficiently high that the cores of such particles are transiently exposed to the surrounding environment. If this environment is acidic and dissolves away the core, then a hollow shell containing a pinhole is formed; however, this pinhole quickly closes, leaving a hollow nanoparticle. These results favorably compare to experiment, much more so than competing models based on the room-temperature Kirkendall effect. © 2014 American Physical Society.

Song H.J.,Johns Hopkins University
Health promotion practice | Year: 2011

Based on substantial formative research, the authors developed and implemented a year-long corner store-based program in East Baltimore focusing on Korean American (KA) stores. To understand acceptability of the intervention by storeowners, the authors examined the motivating factors for program participation, barriers to program implementation, perceived effectiveness of intervention materials, and perceptions about the program. Data collection methods included in-depth interviews with seven corner store owners, field notes by interventionists, and a follow-up survey. Stores varied considerably in terms of owners' perceptions about the program, supportive atmosphere, and acceptability of intervention strategies. The storeowners who showed strong or moderate support for the program were more likely to sustain the stocking of promoted foods such as cooking spray and baked or low-fat chips after the program was completed as compared to less supportive stores. The level of support and active participation of storeowners can greatly influence the success of corner store-based nutrition interventions.

Kellam S.G.,Johns Hopkins University
Addiction science & clinical practice | Year: 2011

The Good Behavior Game (GBG), a universal classroom behavior management method, was tested in first- and second-grade classrooms in Baltimore beginning in the 1985-1986 school year. Followup at ages 19-21 found significantly lower rates of drug and alcohol use disorders, regular smoking, antisocial personality disorder, delinquency and incarceration for violent crimes, suicide ideation, and use of school-based services among students who had played the GBG. Several replications with shorter followup periods have provided similar early results. We discuss the role of the GBG and possibly other universal prevention programs in the design of more effective systems for promoting children's development and problem prevention and treatment services.

Schroeder J.T.,Johns Hopkins University
Immunological Reviews | Year: 2011

After approximately 130years since their discovery as rare granulocytes that circulate in blood, basophils are just now gaining respect as significant contributors in the pathogenesis underlying allergic inflammation and disease. While long known for secreting preformed and newly synthesized mediators and for selectively infiltrating tissue during immunoglobulin E (IgE)-mediated inflammation, their role has largely been viewed as redundant to that of tissue mast cells in functioning as effector cells. This line of thought has persisted even though it has been known in humans for approximately 20years that basophils additionally produce relatively large quantities of cytokines, e.g. interleukin-4 (IL-4)/IL-13, that are central for the manifestations of allergic disease. Studies using novel IL-4 reporter mice have significantly added to the in vivo importance of basophils as IL-4 producing cells, with recent findings indicating that these cells also function as antigen-presenting cells essential in initiating T-helper 2 responses. If confirmed and translated to humans, these provocative findings will give new meaning to the role basophils have in allergic disease, and in immunology overall. © 2011 John Wiley & Sons A/S.

Knierim J.J.,Johns Hopkins University
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2014

The hippocampus receives its major cortical input from the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC). It is commonly believed that the MEC provides spatial input to the hippocampus, whereas the LEC provides non-spatial input. We review new data which suggest that this simple dichotomy between 'where' versus 'what' needs revision. We propose a refinement of this model, which is more complex than the simple spatial-non-spatial dichotomy. MEC is proposed to be involved in path integration computations based on a global frame of reference, primarily using internally generated, self-motion cues and external input about environmental boundaries and scenes; it provides the hippocampus with a coordinate system that underlies the spatial context of an experience. LEC is proposed to process information about individual items and locations based on a local frame of reference, primarily using external sensory input; it provides the hippocampus with information about the content of an experience.

Oakley C.B.,Johns Hopkins University
Current pain and headache reports | Year: 2014

Individually, childhood epilepsy and migraine are two of the most common conditions seen in pediatric neurology. What complicates matters is that there can be marked similarities between migraine and epilepsy as well as a variety of underlying conditions that predispose children to both seizures and headache. Thus, separating epilepsy from migraine may not be easy, but can be done with a detailed history as well as timely use of ancillary testing. Once children have been diagnosed with epilepsy, migraine, or both, treatment options become essential in attempts to manage these common, yet often disabling, neurological conditions. Acute interventions tend to be condition specific while preventative options may overlap for migraine and epilepsy. In the following review, we will discuss the epidemiology of childhood epilepsy and headache, the association between them, as well as how to differentiate epilepsy from migraine. Treatment strategies will follow before concluding with a discussion on prognosis.

Cline M.S.,University of California at Santa Cruz | Karchin R.,Johns Hopkins University
Bioinformatics | Year: 2011

Motivation: The past decade has seen the introduction of fast and relatively inexpensive methods to detect genetic variation across the genome and exponential growth in the number of known single nucleotide variants (SNVs). There is increasing interest in bioinformatics approaches to identify variants that are functionally important from millions of candidate variants. Here, we describe the essential components of bionformatics tools that predict functional SNVs. Results: Bioinformatics tools have great potential to identify functional SNVs, but the black box nature of many tools can be a pitfall for researchers. Understanding the underlying methods, assumptions and biases of these tools is essential to their intelligent application. © The Author 2010. Published by Oxford University Press. All rights reserved.

Lorenz R.D.,Johns Hopkins University
Geophysical Research Letters | Year: 2014

We use a simple box model to explore possible differences in the liquid composition of Titan's seas. Major variations in the abundance of involatile ethane, somewhat analogous to salinity in terrestrial waters, arise from the hydrological cycle, which introduces more "fresh" methane rainfall at the highest latitudes in summer. The observed composition of Ligeia Mare, flushed by methane rainfall and exporting its solutes to Kraken via a narrow labyrinth of channels, may have a methane-rich (>~80%) composition, well out of thermodynamic equilibrium with the atmosphere, whereas the basins of Kraken are relatively well mixed and will have an ethane-dominated (~60%) composition. These variations, analogous to Earth's salinity gradient between the Black Sea and the Mediterranean, may be detectable with Cassini measurements and are important for future exploration. © 2014. American Geophysical Union.

Moffitt R.A.,Johns Hopkins University
Demography | Year: 2015

Contrary to the popular view that the U.S. welfare system has been in a contractionary phase after the expansions of the welfare state in the 1960s, welfare spending resumed steady growth after a pause in the 1970s. However, although aggregate spending is higher than ever, there have been redistributions away from non-elderly and nondisabled families to families with older adults and to families with recipients of disability programs; from non-elderly, nondisabled single-parent families to married-parent families; and from the poorest families to those with higher incomes. These redistributions likely reflect long-standing, and perhaps increasing, conceptualizations by U.S. society of which poor are deserving and which are not. © 2015, Population Association of America.

Zhang Q.,Johns Hopkins University
Cellular and molecular life sciences : CMLS | Year: 2014

Mitochondria move, fuse and divide in cells. The dynamic behavior of mitochondria is central to the control of their structure and function. Three conserved mitochondrial dynamin-related GTPases (i.e., mitofusin, Opa1 and Drp1 in mammals and Fzo1, Mgm1 and Dnm1 in yeast) mediate mitochondrial fusion and division. In addition to dynamins, recent studies demonstrated that phospholipids in mitochondria also play key roles in mitochondrial dynamics by interacting with dynamin GTPases and by directly changing the biophysical properties of the mitochondrial membranes. Changes in phospholipid composition also promote mitophagy, which is a selective mitochondrial degradation process that is mechanistically coupled to mitochondrial division. In this review, we will discuss the biogenesis and function of mitochondrial phospholipids.

Hart G.W.,Johns Hopkins University
Cell Metabolism | Year: 2013

While cellular circadian clocks are set by the light/dark cycle, these clocks can be reset by what we eat. Two papers in this issue of Cell Metabolism reveal that O-GlcNAcylation of clock proteins, which is dependent on nutrients, adjusts our circadian clock (Kaasik et al., 2013; Li et al., 2013). © 2013 Elsevier Inc.

Carter H.,Johns Hopkins University
BMC genomics | Year: 2013

Whole exome sequencing studies identify hundreds to thousands of rare protein coding variants of ambiguous significance for human health. Computational tools are needed to accelerate the identification of specific variants and genes that contribute to human disease. We have developed the Variant Effect Scoring Tool (VEST), a supervised machine learning-based classifier, to prioritize rare missense variants with likely involvement in human disease. The VEST classifier training set comprised ~ 45,000 disease mutations from the latest Human Gene Mutation Database release and another ~45,000 high frequency (allele frequency >1%) putatively neutral missense variants from the Exome Sequencing Project. VEST outperforms some of the most popular methods for prioritizing missense variants in carefully designed holdout benchmarking experiments (VEST ROC AUC = 0.91, PolyPhen2 ROC AUC = 0.86, SIFT4.0 ROC AUC = 0.84). VEST estimates variant score p-values against a null distribution of VEST scores for neutral variants not included in the VEST training set. These p-values can be aggregated at the gene level across multiple disease exomes to rank genes for probable disease involvement. We tested the ability of an aggregate VEST gene score to identify candidate Mendelian disease genes, based on whole-exome sequencing of a small number of disease cases. We used whole-exome data for two Mendelian disorders for which the causal gene is known. Considering only genes that contained variants in all cases, the VEST gene score ranked dihydroorotate dehydrogenase (DHODH) number 2 of 2253 genes in four cases of Miller syndrome, and myosin-3 (MYH3) number 2 of 2313 genes in three cases of Freeman Sheldon syndrome. Our results demonstrate the potential power gain of aggregating bioinformatics variant scores into gene-level scores and the general utility of bioinformatics in assisting the search for disease genes in large-scale exome sequencing studies. VEST is available as a stand-alone software package at http://wiki.chasmsoftware.org and is hosted by the CRAVAT web server at http://www.cravat.us.

Baldwin R.L.,Stanford University | Rose G.D.,Johns Hopkins University
Current Opinion in Structural Biology | Year: 2013

The exquisite side chain close-packing in the protein core and at binding interfaces has prompted a conviction that packing selectivity is the primary mechanism for molecular recognition in folding and/or binding reactions. Contrary to this view, molten globule proteins can adopt native topology and bind targets tightly and specifically in the absence of side chain close-packing. The molten globule is a highly dynamic form with native-like secondary structure and a loose protein core that admits solvent. The related (but still controversial) dry molten globule is an expanded form of the native protein with largely intact topology but a tighter protein core that excludes solvent. Neither form retains side chain close-packing, and therefore both structure and function must result from other factors, assuming that the reality of the dry molten globule is accepted. This simplifying realization calls for a re-evaluation of established models. © 2012 Elsevier Ltd.

Viswanathan M.C.,Johns Hopkins University
Circulation research | Year: 2014

Regulation of striated muscle contraction is achieved by Ca2+ -dependent steric modulation of myosin cross-bridge cycling on actin by the thin filament troponin-tropomyosin complex. Alterations in the complex can induce contractile dysregulation and disease. For example, mutations between or near residues 112 to 136 of cardiac troponin-T, the crucial TnT1 (N-terminal domain of troponin-T)-tropomyosin-binding region, cause cardiomyopathy. The Drosophila upheld(101) Glu/Lys amino acid substitution lies C-terminally adjacent to this phylogenetically conserved sequence. Using a highly integrative approach, we sought to determine the molecular trigger of upheld(101) myofibrillar degeneration, to evaluate contractile performance in the mutant cardiomyocytes, and to examine the effects of the mutation on the entire Drosophila heart to elucidate regulatory roles for conserved TnT1 regions and provide possible mechanistic insight into cardiac dysfunction. Live video imaging of Drosophila cardiac tubes revealed that the troponin-T mutation prolongs systole and restricts diastolic dimensions of the heart, because of increased numbers of actively cycling myosin cross-bridges. Elevated resting myocardial stiffness, consistent with upheld(101) diastolic dysfunction, was confirmed by an atomic force microscopy-based nanoindentation approach. Direct visualization of mutant thin filaments via electron microscopy and 3-dimensional reconstruction resolved destabilized tropomyosin positioning and aberrantly exposed myosin-binding sites under low Ca2+ conditions. As a result of troponin-tropomyosin dysinhibition, upheld(101) hearts exhibited cardiac dysfunction and remodeling comparable to that observed during human restrictive cardiomyopathy. Thus, reversal of charged residues about the conserved tropomyosin-binding region of TnT1 may perturb critical intermolecular associations required for proper steric regulation, which likely elicits myopathy in our Drosophila model.

Erlebacher J.,Johns Hopkins University
Physical Review Letters | Year: 2011

Coarsening of crystalline nanoporous metals involves complex changes in topology associated with the reduction of genus via both ligament pinch-off and void bubble formation. Although void bubbles in metals are often associated with vacancy agglomeration, we use large-scale kinetic MonteCarlo simulations to show that both bubble formation and ligament pinch-off are natural results of a surface-diffusion-controlled solid-state Rayleigh instability that controls changes in the topology of the porous material during coarsening. This result is used to find an effective activation energy for coarsening in nanoporous metals that is associated with the reduction of topological genus, and not the reduction of local surface roughness. © 2011 American Physical Society.

Ratovitski E.A.,Johns Hopkins University
Current Genomics | Year: 2013

Non-coding microRNAs are involved in multiple regulatory mechanisms underlying response of cancer cells to stress leading to apoptosis, cell cycle arrest and autophagy. Many molecular layers are implicated in such cellular response including epigenetic regulation of transcription, RNA processing, metabolism, signaling. The molecular interrelationship between tumor protein (TP)-p53 family members and specific microRNAs is a key functional network supporting tumor cell response to chemotherapy and potentially playing a decisive role in chemoresistance of human epithelial cancers. TP63 was shown to modulate the expression of numerous microRNAs involved in regulation of epithelial cell proliferation, differentiation, senescence, "stemness" and skin maintenance, epithelial/ mesenchymal transition, and tumorigenesis in several types of epithelial cancers (e.g. squamous cell carcinoma, ovarian carcinoma, prostate carcinoma, gastric cancer, bladder cancer, and breast tumors), as well as in chemoresistance of cancer cells. TP63/microRNA network was shown to be involved in cell cycle arrest, apoptosis, autophagy, metabolism and epigenetic transcriptional regulation, thereby providing the groundwork for novel chemotherapeutic venues. © 2013 Bentham Science Publishers.

Singer H.S.,Johns Hopkins University
Annals of the New York Academy of Sciences | Year: 2013

Tourette syndrome (TS) and primary complex motor stereotypies (CMS) are two relatively common, distinctly different movement disorders of childhood. Despite their frequency, the precise underlying pathophysiological mechanism(s) for tics and stereotypies remains unknown. Both are likely to involve cortical-striatal-thalamo-cortical (CSTC) pathways or their interconnecting brain regions. In recent studies, distinct, separate cortical-striatal pathways have been identified for goal-directed and habitual behavioral activity with important influences from structures, such as the hippocampus, amygdala, dorsolateral prefrontal cortex, cerebellum, ventral tegmental area, and substantia nigra pars compacta. Determining the specific site of abnormality within these circuits remains an active area of research. At the synaptic level, numerous neurotransmitters are involved in the transmission of messages through CSTC pathways, and many have been proposed as potential pathophysiological mechanisms. Which, if any, transmitter is the primary pathological factor in TS and primary CMS remains to be definitively determined. © 2013 New York Academy of Sciences.

Kazhdan M.,Johns Hopkins University | Hoppe H.,Microsoft
ACM Transactions on Graphics | Year: 2013

Poisson surface reconstruction creates watertight surfaces from oriented point sets. In this work we extend the technique to explicitly incorporate the points as interpolation constraints. The extension can be interpreted as a generalization of the underlying mathematical framework to a screened Poisson equation. In contrast to other image and geometry processing techniques, the screening term is defined over a sparse set of points rather than over the full domain. We show that these sparse constraints can nonetheless be integrated efficiently. Because the modified linear system retains the same finite-element discretization, the sparsity structure is unchanged, and the system can still be solved using a multigrid approach. Moreover we present several algorithmic improvements that together reduce the time complexity of the solver to linear in the number of points, thereby enabling faster, higher-quality surface reconstructions. © 2013 ACM.

Armanios M.,Johns Hopkins University
Nature reviews. Genetics | Year: 2012

There has been mounting evidence of a causal role for telomere dysfunction in a number of degenerative disorders. Their manifestations encompass common disease states such as idiopathic pulmonary fibrosis and bone marrow failure. Although these disorders seem to be clinically diverse, collectively they comprise a single syndrome spectrum defined by the short telomere defect. Here we review the manifestations and unique genetics of telomere syndromes. We also discuss their underlying molecular mechanisms and significance for understanding common age-related disease processes.

Ma E.,Johns Hopkins University | Zhang Z.,Zhejiang University
Nature Materials | Year: 2011

The internal structure of amorphous alloys was initially described as random packing of hard spheres. The internal structure of amorphous alloys was initially described as random packing of hard spheres. Even high-resolution transmission electron microscope (TEM) images, which otherwise are able to resolve lattice fringes in crystals, display only a maze-like pattern with no discernable structure. The subnanometer beam size used by Hirata and colleagues, in contrast, is sufficiently small to address individual polyhedra, and the researchers are consequently able to observe distinct diffraction spots in symmetric patterns that resemble those for single crystals to some extent. The dependence of local structure on alloy composition may now be confirmed experimentally.

Lutsenko S.,Johns Hopkins University
Current Opinion in Chemical Biology | Year: 2010

Copper plays an essential role in normal human physiology. Copper misbalance affects heart development, CNS and liver function, influences lipid metabolism, inflammation, and resistance to chemotherapeutic drugs. Recent studies yielded new information on the structure, function, and regulation of human copper transporters, uncovered unanticipated functions for copper chaperones, and established connections between copper homeostasis and other metabolic pathways. It has become apparent that the copper trafficking machinery is regulated at several levels and that the cross-talk between cell compartments contributes to the intracellular copper balance. The human copper regulon is emerging. © 2010 Elsevier Ltd. All rights reserved.

McLeod D.S.A.,Royal Brisbane and Womens Hospital | McLeod D.S.A.,Queensland Institute of Medical Research | Sawka A.M.,University of Toronto | Cooper D.S.,Johns Hopkins University
The Lancet | Year: 2013

In many parts of the world, incidence of papillary thyroid cancer is increasing faster than any other malignancy. Most papillary thyroid cancers that are diagnosed are small and are generally regarded as being low risk, with little or no effect on mortality. Papillary thyroid cancer is a clinical challenge because it is difficult to prove benefit from the traditional therapeutic triad for this disorder (ie, total thyroidectomy with or without prophylactic central neck dissection, radioiodine remnant ablation, and suppression of serum thyroid-stimulating hormone with levothyroxine). However, risk of disease recurrence might be reduced by these therapies in a subset of patients with more aggressive disease. In the past decade, professional societies and other groups have established evidence-based clinical practice guidelines for management of papillary thyroid cancer, but these efforts have been made difficult by a paucity of randomised controlled trials. In this review, we summarise epidemiological data for disease incidence, discuss some controversies in disease management, and outline a therapeutic framework founded in the best available medical evidence and existing recommendations from clinical practice guidelines.

Tao Y.-X.,Johns Hopkins University
Neuroscience Bulletin | Year: 2012

Activity-dependent postsynaptic receptor trafficking is critical for long-term synaptic plasticity in the brain, but it is unclear whether this mechanism actually mediates the spinal cord dorsal horn central sensitization (a specific form of synaptic plasticity) that is associated with persistent pain. Recent studies have shown that peripheral inflammation drives changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit trafficking in the dorsal horn and that such changes contribute to the hypersensitivity that underlies persistent pain. Here, we review current evidence to illustrate how spinal cord AMPARs participate in the dorsal horn central sensitization associated with persistent pain. Understanding these mechanisms may allow the development of novel therapeutic strategies for treating persistent pain. © 2012 Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg.

Rebok G.W.,Johns Hopkins University
Journal of aging and health | Year: 2013

Data from the memory training arm (n = 629) of the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial were examined to characterize change in memory performance through 5 years of follow-up as a function of memory training, booster training, adherence to training, and other characteristics. Latent growth model analyses revealed that memory training was associated with improved memory performance through Year 5 but that neither booster training nor training adherence significantly influenced this effect. Baseline age was associated with change in memory performance attributable to the passage of time alone (i.e., to aging). Higher education and better self-rated health were associated with greater change in memory performance after training. These findings confirm that memory training can aid in maintaining long-term improvements in memory performance. Booster training and adherence to training do not appear to attenuate rates of normal age-related memory decline.

Dinkova-Kostova A.T.,Johns Hopkins University | Abramov A.Y.,University College London
Free Radical Biology and Medicine | Year: 2015

The transcription factor NF-E2 p45-related factor 2 (Nrf2; gene name NFE2L2) allows adaptation and survival under conditions of stress by regulating the gene expression of diverse networks of cytoprotective proteins, including antioxidant, anti-inflammatory, and detoxification enzymes as well as proteins that assist in the repair or removal of damaged macromolecules. Nrf2 has a crucial role in the maintenance of cellular redox homeostasis by regulating the biosynthesis, utilization, and regeneration of glutathione, thioredoxin, and NADPH and by controlling the production of reactive oxygen species by mitochondria and NADPH oxidase. Under homeostatic conditions, Nrf2 affects the mitochondrial membrane potential, fatty acid oxidation, availability of substrates (NADH and FADH2/succinate) for respiration, and ATP synthesis. Under conditions of stress or growth factor stimulation, activation of Nrf2 counteracts the increased reactive oxygen species production in mitochondria via transcriptional upregulation of uncoupling protein 3 and influences mitochondrial biogenesis by maintaining the levels of nuclear respiratory factor 1 and peroxisome proliferator-activated receptor γ coactivator 1α, as well as by promoting purine nucleotide biosynthesis. Pharmacological Nrf2 activators, such as the naturally occurring isothiocyanate sulforaphane, inhibit oxidant-mediated opening of the mitochondrial permeability transition pore and mitochondrial swelling. Curiously, a synthetic 1,4-diphenyl-1,2,3-triazole compound, originally designed as an Nrf2 activator, was found to promote mitophagy, thereby contributing to the overall mitochondrial homeostasis. Thus, Nrf2 is a prominent player in supporting the structural and functional integrity of the mitochondria, and this role is particularly crucial under conditions of stress. © 2015 The Authors.

Montell C.,Johns Hopkins University
Pflugers Archiv European Journal of Physiology | Year: 2011

The transient receptor potential (TRP) family of cation channels has redefined our understanding of sensory physiology. In one animal or another, all senses depend on TRP channels. These include vision, taste, smell, hearing, and various forms of touch, including the ability to sense changes in temperature. The first trp gene was identified because it was disrupted in a Drosophila mutant with defective vision. However, there was no clue as to its biochemical function until the cloning, and analysis of the deduced amino acid sequence suggested that trp encoded a cation channel. This concept was further supported by subsequent electrophysiological studies, including alteration of its ion selectivity by an amino acid substitution within the pore loop. The study of TRP channels emerged as a field with the identification of mammalian homologs, some of which are direct sensors of environmental temperature. At least one TRP channel is activated downstream of a thermosensory signaling cascade, demonstrating that there exist two modes of activation, direct and indirect, through which TRP channels respond to changes in temperature. Mutations in many TRP channels result in disease, including a variety of sensory impairments. © 2011 Springer-Verlag.

Slawson C.,University of Kansas | Hart G.W.,Johns Hopkins University
Nature Reviews Cancer | Year: 2011

O-GlcNAcylation is the covalent attachment of Î 2-D-N- acetylglucosamine (GlcNAc) sugars to serine or threonine residues of nuclear and cytoplasmic proteins, and it is involved in extensive crosstalk with other post-translational modifications, such as phosphorylation. O-GlcNAcylation is becoming increasing realized as having important roles in cancer-relevant processes, such as cell signalling, transcription, cell division, metabolism and cytoskeletal regulation. However, currently little is known about the specific roles of aberrant O-GlcNAcylation in cancer. In this Opinion article, we summarize the current understanding of O-GlcNAcylation in cancer and its emerging functions in transcriptional regulation at the level of chromatin and transcription factors. © 2011 Macmillan Publishers Limited. All rights reserved.

Dunn K.E.,Johns Hopkins University
Experimental and clinical psychopharmacology | Year: 2013

Oral naltrexone has high potential for use as a relapse prevention pharmacotherapy for opiate dependence yet suffers from notoriously poor adherence. This study evaluated whether entry to a therapeutic workplace could reinforce adherence with oral naltrexone. Opiate-dependent and cocaine-using injection drug users were detoxified, inducted onto oral naltrexone, and randomly assigned to a contingency (n = 35) or prescription (n = 32) group for a 26-week period. Contingency participants were required to ingest naltrexone under staff observation to gain access to the therapeutic workplace. Prescription participants received a take-home supply of naltrexone and could access the workplace independent of naltrexone ingestion. Primary outcome measures were percent of urine samples positive for naltrexone at 30-day assessments and negative for opiates and cocaine at 30-day assessments. Contingency participants provided significantly more urine samples that were positive for naltrexone compared with prescription participants (72% vs. 21%, p < .01); however, no effect of experimental group was observed on percent opiate-negative (71% vs. 60%, p = .19.) or cocaine-negative (56% vs. 53%, p = .82) samples in the contingency and prescription groups, respectively. Opiate-positive samples were significantly more likely to occur in conjunction with cocaine (p < .001) and when not protected by naltrexone (p < .02), independent of experimental group. Overall, these results show that contingent access to a therapeutic workplace significantly promoted adherence to oral naltrexone, and that the majority of opiate use occurred in conjunction with cocaine use, suggesting that untreated cocaine use may limit the effectiveness of oral naltrexone in promoting opiate abstinence. (c) 2013 APA, all rights reserved.

Clader B.D.,Johns Hopkins University
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2014

We describe an adiabatic state-transfer mechanism that allows for high-fidelity transfer of a microwave quantum state from one cavity to another through an optical fiber. The conversion from microwave frequency to optical frequency is enabled by an optomechanical transducer. The transfer process utilizes a combined dark state of the mechanical oscillator and fiber modes, making it robust against both mechanical and fiber loss. We anticipate this scheme being an enabling component of a hybrid quantum computing architecture consisting of superconducting qubits with optical interconnects. © 2014 American Physical Society.

Checkoway S.,Johns Hopkins University
International Conference on Architectural Support for Programming Languages and Operating Systems - ASPLOS | Year: 2013

In recent years, researchers have proposed systems for running trusted code on an untrusted operating system. Protection mechanisms deployed by such systems keep a malicious kernel from directly manipulating a trusted application's state. Under such systems, the application and kernel are, conceptually, peers, and the system call API defines an RPC interface between them. We introduce Iago attacks, attacks that a malicious kernel can mount in this model. We show how a carefully chosen sequence of integer return values to Linux system calls can lead a supposedly protected process to act against its interests, and even to undertake arbitrary computation at the malicious kernel's behest. Iago attacks are evidence that protecting applications from malicious kernels is more difficult than previously realized. Categories and Subject Descriptors D.4.6 [Operating Systems]: Security and Protection General Terms Security. Copyright © 2013 ACM.

BACKGROUND: The cancer/testis antigens (CTAs) are a unique group of proteins normally expressed in germ cells but aberrantly expressed in several types of cancers including prostate cancer (PCa). However, their role in PCa has not been fully explored. METHODS: CTA expression profiling in PCa samples and cell lines was done utilizing a custom microarray that contained probes for two-thirds of all CTAs. The data were validated by quantitative PCR (Q-PCR). Functional studies were carried out by silencing gene expression with siRNA. DNA methylation was determined by methylation-specific PCR. RESULTS: A majority of CTAs expressed in PCa are located on the X chromosome (CT-X antigens). Several CT-X antigens from the MAGEA/CSAG subfamilies are coordinately upregulated in castrate-resistant prostate cancer (CRPC) but not in primary PCa. In contrast, PAGE4 is highly upregulated in primary PCa but is virtually silent in CRPC. Further, there was good correlation between the extent of promoter DNA methylation and CTA expression. Finally, silencing the expression of MAGEA2 the most highly upregulated member, significantly impaired proliferation of prostate cancer cells while increasing their chemosensitivity. CONCLUSIONS: Considered together, the remarkable stage-specific expression patterns of the CT-X antigens strongly suggests that these CTAs may serve as unique biomarkers that could potentially be used to distinguish men with aggressive disease who need treatment from men with indolent disease not requiring immediate intervention. The data also suggest that the CT-X antigens may be novel therapeutic targets for CRPC for which there are currently no effective therapeutics. © 2010 Wiley-Liss, Inc.

Nguyen T.D.,Johns Hopkins University
Polymer Reviews | Year: 2013

Shape-memory behavior in polymers allows the material to undergo large controllable shape changes in response to a specific environmental stimulus. The shape-memory performance depends on the coordination of multiple physical mechanisms, and considerable opportunities exist to tailor the polymer structure and shape-memory programming procedure to achieve the desired performance. Because of the inherent complexity of the material response, theoretical and computational models provide efficient tools to explore different combinations of design options. They also provide an investigative platform to evaluate the importance of various physical mechanisms for the shape-memory response and determine the relationship between polymer properties and shape-memory performance. This article reviews recent advances in constitutive modeling of thermally induced and photo-induced shape-memory behavior in polymers. © 2013 Copyright Taylor and Francis Group, LLC.

Drake C.G.,Johns Hopkins University
Cancer Journal | Year: 2011

The recent approval of Sipuleucel-T (Dendreon, Seattle, WA) from the Food and Drug Administration for the treatment of men with asymptomatic or minimally symptomatic castrate-resistant prostate cancer was a landmark in cancer immunotherapy, making this the first cancer "vaccine" approved for use in a treatment setting. This approval has led to renewed interest in cancer vaccines and to the recognition that prostate cancer represents an immunologically sensitive disease. At the current time, several vaccine approaches are under clinical investigation. These include viral vectors, antigen-loaded dendritic cells, and DNA vaccines. Each approach has its own set of advantages and disadvantages. This review will introduce the basic technology underlying these different vaccines and briefly discuss completed and ongoing clinical trials. As a great number of prostate cancer vaccines have been investigated in both preclinical and clinical settings, we will focus primarily on vaccines that are currently in clinical trials, as ascertained by a recent inquiry of the clinical trials database, www.clinicaltrials.gov.

Wilky B.A.,Johns Hopkins University
Oncogene | Year: 2015

RNA helicase DDX3 has oncogenic activity in breast and lung cancers and is required for translation of complex mRNA transcripts, including those encoding key cell-cycle regulatory proteins. We sought to determine the expression and function of DDX3 in sarcoma cells, and to investigate the antitumor activity of a novel small molecule DDX3 inhibitor, RK-33. Utilizing various sarcoma cell lines, xenografts and human tissue microarrays, we measured DDX3 expression at the mRNA and protein levels, and evaluated cytotoxicity of RK-33 in sarcoma cell lines. To study the role of DDX3 in Ewing sarcoma, we generated stable DDX3-knockdown Ewing sarcoma cell lines using DDX3-specific small hairpin RNA (shRNA), and assessed oncogenic activity. DDX3-knockdown and RK-33-treated Ewing sarcoma cells were compared with wild-type cells using an isobaric mass-tag quantitative proteomics approach to identify target proteins impacted by DDX3 inhibition. Overall, we found high expression of DDX3 in numerous human sarcoma subtypes compared with non-malignant mesenchymal cells, and knockdown of DDX3 by RNA interference inhibited oncogenic activity in Ewing sarcoma cells. Treatment with RK-33 was preferentially cytotoxic to sarcoma cells, including chemotherapy-resistant Ewing sarcoma stem cells, while sparing non-malignant cells. Sensitivity to RK-33 correlated with DDX3 protein expression. Growth of human Ewing sarcoma xenografts expressing high DDX3 was inhibited by RK-33 treatment in mice, without overt toxicity. DDX3 inhibition altered the Ewing sarcoma cellular proteome, especially proteins involved in DNA replication, mRNA translation and proteasome function. These data support further investigation of the role of DDX3 in sarcomas, advancement of RK-33 to Ewing sarcoma clinical trials and development of RNA helicase inhibition as a novel anti-neoplastic strategy.Oncogene advance online publication, 14 September 2015; doi:10.1038/onc.2015.336. © 2015 Macmillan Publishers Limited

Montgomery J.R.,Johns Hopkins University
Transplantation | Year: 2012

Background: ABO incompatible (ABOi) kidney transplantation is an important modality to facilitate living donor transplant for incompatible pairs. To date, reports of the outcomes from this practice in the United States have been limited to single-center studies. Methods: Using the Scientific Registry of Transplant Recipients, we identified 738 patients who underwent live-donor ABOi kidney transplantation between January 1, 1995, and March 31, 2010. These were compared with matched controls that underwent ABO compatible live-donor kidney transplantation. Subgroup analyses among ABOi recipients were performed according to donor blood type, recipient blood type, and transplant center ABOi volume. Results: When compared with ABO compatible-matched controls, long-term patient survival of ABOi recipients was not significantly different between the cohorts (P=0.2). However, graft loss was significantly higher, particularly in the first 14 days posttransplant (subhazard ratio, 2.34; 95% confidence interval, 1.43-3.84; P=0.001), with little to no difference beyond day 14 (subhazard ratio, 1.28; 95% confidence interval, 0.99-1.54; P=0.058). In subgroup analyses among ABOi recipients, no differences in survival were seen by donor blood type, recipient blood type, or transplant center ABOi volume. Conclusions: These results support the use and dissemination of ABOi transplantation when a compatible live donor is not available, but caution that the highest period of risk is immediately posttransplant. Copyright © 2012 by Lippincott Williams & Wilkins.

Golden D.B.K.,Johns Hopkins University
Journal of Allergy and Clinical Immunology: In Practice | Year: 2015

Large local reactions (LLRs) are IgE-mediated late-phase inflammatory reactions that can cause great morbidity but are associated with a relatively low risk of future anaphylaxis. Patients with LLR may benefit from consultation with an allergist to help clarify the relative risk, to plan the best treatment for future stings, and to determine whether or not to pursue testing or venom immunotherapy (VIT). The chance of anaphylaxis to future stings is <5%, so VIT is not generally recommended to people who have had LLR. Whether to prescribe an epinephrine injector is often determined by the frequency of exposure, the proximity to medical care, and the impact on quality of life. For people who have unavoidable exposure and need treatment almost every year for LLR, VIT can be recommended with confidence that it will significantly and safely reduce the severity of LLR to stings. © 2015 American Academy of Allergy, Asthma & Immunology.

Cooper D.S.,Johns Hopkins University | Biondi B.,University of Naples Federico II
The Lancet | Year: 2012

Subclinical thyroid diseases - subclinical hyperthyroidism and subclinical hypothyroidism - are common clinical entities that encompass mild degrees of thyroid dysfunction. The clinical significance of mild thyroid overactivity and underactivity is uncertain, which has led to controversy over the appropriateness of diagnostic testing and possible treatment. In this Seminar, we discuss the definition, epidemiology, differential diagnoses, risks of progression to overt thyroid disease, potential effects on various health outcomes, and management of subclinical hyperthyroidism and subclinical hypothyroidism. Treatment recommendations are based on the degree to which thyroid-stimulating hormone concentrations have deviated from normal and underlying comorbidities. Large-scale randomised trials are urgently needed to inform how to best care for individuals with subclinical thyroid disease. © 2012 Elsevier Ltd.

Heckman T.M.,Johns Hopkins University | Best P.N.,Institute for Astronomy
Annual Review of Astronomy and Astrophysics | Year: 2014

We summarize what large surveys of the contemporary Universe have taught us about the physics and phenomenology of the processes that link the formation and evolution of galaxies with their central supermassive black holes. We present a picture in which the population of active galactic nuclei (AGNs) can be divided into two distinct populations. The radiative-mode AGNs are associated with black holes (BHs) that produce radiant energy powered by accretion at rates in excess of ∼1% of the Eddington limit. They are primarily associated with less massive BHs growing in high-density pseudobulges at a rate sufficient to produce the total mass budget in these BHs in ∼10 Gyr. The circumnuclear environment contains high-density cold gas and associated star formation. Major mergers are not the primary mechanism for transporting this gas inward; secular processes appear dominant. Stellar feedback is generic in these objects, and strong AGN feedback is seen only in the most powerful AGNs. In jet-mode AGNs the bulk of energetic output takes the form of collimated outflows (jets). These AGNs are associated with the more massive BHs in more massive (classical) bulges and elliptical galaxies. Neither the accretion onto these BHs nor star formation in their host bulge is significant today. These AGNs are probably fueled by the accretion of slowly cooling hot gas that is limited by the feedback/heating provided by AGN radio sources. Surveys of the high-redshift Universe paint a similar picture. Noting that the volume-averaged ratio of star formation to BH growth has remained broadly constant over the past 10 Gyrs, we argue that the processes that linked the cosmic evolution of galaxies and BHs are still at play today. Copyright © 2014 by Annual Reviews.

Sulkowski M.S.,Johns Hopkins University
Journal of Hepatology | Year: 2014

Due to shared routes of transmission, acute and chronic infection with hepatitis C virus is common among persons living with HIV infection in many regions of the world. In the era of effective antiretroviral therapy, acute HCV infection has been increasingly recognized in HIV-infected persons, particularly men who have sex with men, and liver disease, including hepatocellular carcinoma, has emerged as a leading cause of morbidity and mortality in those with chronic HCV infection, particularly older adults with long-standing coinfection. Over the past decade, the foundation for the management of acute and chronic HCV infection has been interferon alfa. However, due the high burden of treatment-related side effects and low likelihood of sustained virologic response, the impact of treatment with peginterferon/ribavirin on the burden of HCV disease in has been limited. However, the anticipated availability of safe, tolerable and highly efficacious interferon-free, oral HCV direct-acting antiviral combination therapies promise to dramatically change the management of acute and chronic HCV infection in HIV-infected persons. Preliminary data from studies of such oral DAA regimens in HIV/HCV coinfected patients suggest that coinfection with HIV will not impair HCV cure with these regimens. Indeed, in the coming era of high effective oral HCV DAA treatments, the only special feature concerning treatment of acute and chronic HCV infection in HIV-infected patients may be drug interactions between the antiretroviral drugs for HIV infection and direct-acting antiviral drugs for HCV infection. © 2014 European Association for the Study of the Liver.

Lorenz R.D.,Johns Hopkins University
Planetary and Space Science | Year: 2013

In a survey of dust devil activity at a desert playa using continuous monitoring by a pressure logger, we have detected a number of pressure drops with complex structures: simple and symmetric drops make up only 25-30% of the total. In contrast to the simple, symmetric single-dip profiles expected for single-cell vertical vortices gliding past the pressure sensor, many profiles have an asymmetric shape, double dips, or 'shoulders' where a broad shallow dip is superposed on a narrow deeper one. A double dip in Mars Phoenix data was attributed in prior work to a near-simultaneous encounter with two dust devils, while laboratory experiments with two-cell vortices find a local peak in pressure at the center, also yielding a double dip in a transect profile. However, we suggest instead that a likely explanation for many complex pressure profiles measured in the field and on Mars is in fact the trochoidal path of a dust devil across the terrain, rather than the straight-line constant-speed path usually assumed. Images of the Martian surface show that many dust devil tracks have such a trochoidal or cycloidal path, which can be parametrically described. A model of the pressure profile driven by this parametric path description can reproduce observations.© 2013 Elsevier Ltd. All rights reserved.

Gonzalez-Fernandez M.,Johns Hopkins University
Archives of Physical Medicine and Rehabilitation | Year: 2014

Upper extremity prosthetic technology has significantly changed in recent years. The devices available and those under development are more and more able to approximate the function of the lost limb; however, other challenges remain. This article provides a brief perspective on the most advanced upper limb prostheses available and the challenges present for continued development of the technology. © 2014 by the American Congress of Rehabilitation Medicine.

Netto G.J.,Johns Hopkins University
Seminars in Diagnostic Pathology | Year: 2013

The clinical management of solid tumor patients has recently undergone a paradigm shift as the result of the accelerated advances in cancer genetics and genomics. Molecular diagnostics is now an integral part of routine clinical management in lung, colon, and breast cancer patients. In a disappointing contrast, molecular biomarkers remain largely excluded from current management algorithms of urologic malignancies. The need for new treatment alternatives and validated prognostic molecular biomarkers that can help clinicians identify patients in need of early aggressive management is pressing. Identifying robust predictive biomarkers that can stratify response to newly introduced targeted therapeutics is another crucially needed development. The following is a brief discussion of some promising candidate biomarkers that may soon become a part of clinical management of bladder cancers. © 2013.

Hagan L.M.,Emory University | Sulkowski M.S.,Johns Hopkins University | Schinazi R.F.,Emory University
Hepatology | Year: 2014

Treatment guidance for chronic hepatitis C (CHC) released by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) offers two options for interferon (IFN)-ineligible/intolerant individuals with genotype 1 infection: sofosbuvir/ribavirin (SOF/RBV) for 24 weeks or sofosbuvir/simeprevir (SOF/SMV) for 12 weeks. A 24-week course of SOF/RBV costs approximately US$169,000, with sustained virologic response (SVR) rates ranging from 52% to 84%; 12 weeks of SOF/SMV costs approximately $150,000, with SVR between 89% and 100%. Because SOF/SMV is currently used off-label, debate exists among physicians and payers about whether it should be prescribed and covered. This article presents a cost-effectiveness analysis of these two treatment regimens accounting for costs of drugs, treatment-related medical care, retreatment for individuals who do not achieve SVR, and natural history of continued HCV infection after failed retreatment. Analysis uses a Markov model with a lifetime horizon and a societal perspective. In the base-case scenario, SOF/SMV dominated SOF/RBV in a modeled 50-year-old cohort of treatment-naïve and -experienced subjects, excluding those who failed earlier therapy with telaprevir or boceprevir. SOF/SMV yielded lower costs and more quality-adjusted life years (QALYs) for the average subject, compared to SOF/RBV ($165,336 and 14.69 QALYs vs. $243,586 and 14.45 QALYs, respectively). In base-case cost analysis, the SOF/SMV treatment strategy saved $91,590 per SVR, compared to SOF/RBV. Under all one-way sensitivity scenarios, SOF/SMV remained dominant and resulted in cost savings. Conclusions: These results suggest that a 12-week course of SOF/SMV is a more cost-effective treatment for genotype 1 CHC than 24 weeks of SOF/RBV among IFN-ineligible/intolerant individuals, supporting the AASLD/IDSA guidance and offering implications for both clinical and regulatory decision making as well as pharmaceutical pricing. © 2014 by the American Association for the Study of Liver Diseases.

Vucic S.,University of Sydney | Vucic S.,Neurosciences Research Australia | Rothstein J.D.,Johns Hopkins University | Kiernan M.C.,Neurosciences Research Australia | Kiernan M.C.,University of Sydney
Trends in Neurosciences | Year: 2014

Amyotrophic lateral sclerosis (ALS) is the most frequently occurring of the neuromuscular degenerative disorders, with a median survival time of 3-5 years. The pathophysiological mechanisms underlying ALS are multifactorial, with a complex interaction between genetic factors and molecular pathways. To date 16 genes and loci have been associated with ALS, with mutations in DNA/RNA-regulating genes including the recently described c9orf72 (chromosome 9 open reading frame 72) gene, suggesting an important role for dysregulation of RNA metabolism in ALS pathogenesis. Further, dysfunction of molecular pathways, including glutamate-mediated excitotoxicity, has been identified in sporadic and familial ALS, indicating the existence of a common pathogenic pathway. These pathophysiological insights have suggested novel therapeutic approaches, including stem cell and genetics-based strategies, providing hope for feasible treatment of ALS. © 2014 Elsevier Ltd.

Frueh D.P.,Johns Hopkins University
Progress in Nuclear Magnetic Resonance Spectroscopy | Year: 2014

NMR has matured into a technique routinely employed for studying proteins in near physiological conditions. However, applications to larger proteins are impeded by the complexity of the various correlation maps necessary to assign NMR signals. This article reviews the data analysis techniques traditionally employed for resonance assignment and describes alternative protocols necessary for overcoming challenges in large protein spectra. In particular, simultaneous analysis of multiple spectra may help overcome ambiguities or may reveal correlations in an indirect manner. Similarly, visualization of orthogonal planes in a multidimensional spectrum can provide alternative assignment procedures. We describe examples of such strategies for assignment of backbone, methyl, and nOe resonances. We describe experimental aspects of data acquisition for the related experiments and provide guidelines for preliminary studies. Focus is placed on large folded monomeric proteins and examples are provided for 37, 48, 53, and 81 kDa proteins. © 2013 Elsevier B.V. All rights reserved.

Mateen F.J.,Johns Hopkins University
Neurology | Year: 2013

A growing number of international stakeholders are engaged with neurologic diseases. This article provides a brief overview of important international stakeholders in the practice of neurology, including global disease-specific programs, United Nations agencies, governmental agencies with international influence, nongovernmental organizations, international professional organizations, large private donors, private-public partnerships, commercial interests, armed forces, and universities and colleges. The continued engagement of neurologists is essential for the growing number of international organizations that can and should incorporate neurologic disease into their global agendas. © 2013 American Academy of Neurology.

Khurgin J.B.,Johns Hopkins University
Optics Express | Year: 2015

Using metal-clad (or plasmonic) waveguide structures in semiconductor lasers carries a promise of reduced size, threshold, and power consumption. This promise is put to a rigorous theoretical test, that takes into account increased waveguide loss, Auger recombination, and Purcell enhancement of spontaneous recombination. The conclusion is that purported benefits of metal waveguides are small to nonexistent for all the band-to-band and intersubband lasers operating from UV to Mid-IR range, with a prominent exception of far-IR and THz quantum cascade lasers. For these devices, however, metal waveguides already represent the state of the art, and the guiding mechanism in them has far more in common with a ubiquitous transmission line than with plasmonics. ©2015 Optical Society of America.

Flavahan N.A.,Johns Hopkins University
Nature Reviews Rheumatology | Year: 2015

During exposure to cold, our bodies attempt to maintain normal core temperature by restricting heat loss through cutaneous vasoconstriction, and by increasing heat production through shivering and nonshivering thermogenesis. In selected areas of human skin (including on the fingers and toes), the vascular system has specialized structural and functional features that enable it to contribute to thermoregulation. These features include arteriovenous anastomoses, which directly connect the arterial and venous systems and bypass the nutritional capillaries supplying blood to the skin tissue. Of note, Raynaud phenomenon predominantly affects the arterial territories supplying these specialized areas of skin. Indeed, Raynaud phenomenon can be considered a disorder of vascular thermoregulatory control. This Review presents an understanding of Raynaud phenomenon in the context of vascular and thermoregulatory control mechanisms, including the role of unique thermosensitive vascular structural and functional specialization, and describes the potential role of thermogenesis in this disorder. This new approach provides remarkable insight into the disease process and builds a framework to critically appraise the existing knowledge base. This paradigm also explains the deficiencies in some current therapeutic approaches, and highlights new areas of potential relevance to the pathogenesis and treatment of Raynaud phenomenon that should be expanded and explored. © 2015 Macmillan Publishers Limited.

Ladenheim E.E.,Johns Hopkins University
Drug Design, Development and Therapy | Year: 2015

The prevalence of obesity worldwide has nearly doubled since 1980 with current estimates of 2.1 billion in 2013. Overweight and obesity lead to numerous adverse conditions including type 2 diabetes, cardiovascular disease, stroke, and certain cancers. The worldwide spread of obesity and associated comorbidities not only threatens quality of life but also presents a significant economic burden. While bariatric surgery has proven to be a viable treatment option for the morbidly obese, there is clearly a need for less invasive alternatives. Recent research has suggested that long-acting analogs of the gut hormone, glucagon-like peptide 1 (GLP-1), may have potential as an antiobesity treatment. The GLP-1 receptor agonist, liraglutide (trade name Saxenda), was recently approved by the US Food and Drug Administration as an obesity treatment option and shown in clinical trials to be effective in reducing and sustaining body weight loss. This review presents the basis for GLP-1-based therapies with a specific focus on animal and human studies examining liraglutide’s effects on food intake and body weight. © 2015 Ladenheim.

Neufeld D.A.,Johns Hopkins University
Astrophysical Journal | Year: 2012

Motivated by recent observations with Herschel/PACS, and the availability of new rate coefficients for the collisional excitation of CO, the excitation of warm astrophysical CO is revisited with the use of numerical and analytic methods. For the case of an isothermal medium, results have been obtained for a wide range of gas temperatures (100-5000K) and H2 densities (10 3-109 cm-3), and presented in the form of rotational diagrams, in which the logarithm of the column density per magnetic substate, log (NJ /gJ ), is plotted for each state, as a function of its energy, EJ . For rotational transitions in the wavelength range accessible to Herschel/PACS, such diagrams are nearly linear when n(H2) ≥ 108 cm-3. When n(H2) 106.8-108cm-3, they exhibit significant negative curvature, whereas when n(H2) ≤ 104.8cm -3, the curvature is uniformly positive throughout the PACS-accessible range. Thus, the observation of a positively curved CO rotational diagram does not necessarily require the presence of multiple temperature components. Indeed, for some sources observed with Herschel/PACS, the CO rotational diagrams show a modest positive curvature that can be explained by a single isothermal component. Typically, the required physical parameters are densities in the 104-105cm-3 range and temperatures close to the maximum at which CO can survive. Other sources exhibit rotational diagrams with more curvature than can be accounted for by a single temperature component. For the case of a medium with a power-law distribution of gas temperatures, dN/dTT -b, results have been obtained for H2 densities 103-109 cm -3 and power-law indices, b, in the range 1-5; such a medium can account for a CO rotational diagram that is more positively curved than any resulting from an isothermal medium. © 2012. The American Astronomical Society. All rights reserved.

Ziessman H.A.,Johns Hopkins University
Seminars in Nuclear Medicine | Year: 2012

Sincalide cholescintigraphy was first reported to have clinical utility in 1980. Since then, many publications have found that a reduced gallbladder ejection fraction (GBEF) can confirm the clinical diagnosis of acalculous chronic gallbladder disease and predict symptomatic relief with cholecystectomy. However, some publications had not found the test clinically predictive. Many different sincalide infusion methods and normal values have been used. It had been suspected that the different infusion methods and normal values might account for the variability in reported utility. Furthermore, clinical review articles have raised questions about the evidence-based quality of the published data on the diagnostic utility of sincalide cholescintigraphy. A recently published multicenter trial has established the optimal methodology for sincalide infusion and normal values. A subsequent multispecialty consensus publication has recommended that this method be the standard method for sincalide infusion, specifically, a 60-minute infusion of 0.02 μg/kg (abnormal GBEF, <38%). The consensus publication also recommended that a large, multicenter, randomized, prospective trial was needed to confirm the utility of a low GBEF to predict acalculous chronic gallbladder disease and the patient's response to cholecystectomy. © 2012 Elsevier Inc. All rights reserved.

Price G.D.,University of Plymouth | Passey B.H.,Johns Hopkins University
Geology | Year: 2013

Sub-arctic Cretaceous (Berriasian-late Valanginian, ca. 145-134 Ma) marine temperatures obtained from fossil mollusks (belemnites) are determined using carbonate clumped isotope thermometry, an approach based on the "clumping" of 13C and 18O in the carbonate mineral lattice into bonds with each other. From our analyses we infer sub-arctic Early Cretaceous marine temperatures ranging from 10 °C to 20 °C. These possibly seasonally biased, warm sub-arctic temperatures are warmer than present mean summer water temperatures at 60-65°N and are therefore consistent with a warmer "greenhouse" world featuring a shallow (equable) latitudinal temperature gradient. Our combined temperature and δ18Obelemnite data imply seawater δ18O values that have a remarkably modern character in that they are similar to modern high-latitude seawater but more positive than modeled Cretaceous seawater. We identify a cooler late Valanginian interval (ca. 134 Ma) with temperatures consistent with polar regions a few degrees above freezing and also coincident with increased δ18O seawater values. Thus we find evidence of intervals when polar ice was unlikely, and also when polar ice was plausible. Both scenarios support the view of generally warm but dynamic polar climates during greenhouse intervals that were punctuated by periods of ice growth. © 2013 Geological Society of America.

We summarize data from Earth and Mars on the duration of dust devils as a function of their diameter: a strong positive correlation is seen (duration in minutes appears to vary as ~0.66d0.66, where d is the diameter in meters). This duration information allows orbital measurements at Mars (where only one observation per day is typical) to be compared with landed or terrestrial surveys with continuous monitoring. Counts from orbit appear higher than those from the surface, possibly due to higher detection efficiency from near-vertical orbital imaging where the dust loading integrated along the line-of-sight may be higher than for near-horizontal field/landed imaging due to the slender aspect ratio (~5) of dust devils, indicated by both Earth and Mars data. The diameter dependence of duration results in an enhancement in the effective detection area for large devils for small-area surveys which do not discriminate between devils that form within their defined nominal survey areas, and those that are advected into it by winds. © 2013 Elsevier Inc.

Armanios M.,Johns Hopkins University
Journal of Clinical Investigation | Year: 2013

Telomere length shortens with age and predicts the onset of replicative senescence. Recently, short telomeres have been linked to the etiology of degenerative diseases such as idiopathic pulmonary fibrosis, bone marrow failure, and cryptogenic liver cirrhosis. These disorders have recognizable clinical manifestations, and the telomere defect explains their genetics and informs the approach to their treatment. Here, I review how telomere biology has become intimately connected to clinical paradigms both for understanding pathophysiology and for individualizing therapy decisions. I also critically examine nuances of interpreting telomere length measurement in clinical studies.

Klein E.Y.,Johns Hopkins University
International Journal of Antimicrobial Agents | Year: 2013

The emergence of resistance to former first-line antimalarial drugs has been an unmitigated disaster. In recent years, artemisinin class drugs have become standard and they are considered an essential tool for helping to eradicate the disease. However, their ability to reduce morbidity and mortality and to slow transmission requires the maintenance of effectiveness. Recently, an artemisinin delayed-clearance phenotype was described. This is believed to be the precursor to resistance and threatens local elimination and global eradication plans. Understanding how resistance emerges and spreads is important for developing strategies to contain its spread. Resistance is the result of two processes: (i) drug selection of resistant parasites; and (ii) the spread of resistance. In this review, we examine the factors that lead to both drug selection and the spread of resistance. We then examine strategies for controlling the spread of resistance, pointing out the complexities and deficiencies in predicting how resistance will spread. © 2013 Elsevier B.V. and the International Society of Chemotherapy.

Cutting G.R.,Johns Hopkins University
Annals of the New York Academy of Sciences | Year: 2010

In the past three decades, scientists have had immense success in identifying genes and their variants that contribute to an array of diseases. While the identification of such genetic variants has informed our knowledge of the etiologic bases of diseases, there continues to be a substantial gap in our understanding of the factors that modify disease severity. Monogenic diseases provide an opportunity to identify modifiers as they have uniform etiology, detailed phenotyping of affected individuals, and familial clustering. Cystic fibrosis (CF) is among the more common life-shortening recessive disorders that displays wide variability in clinical features and survival. Considerable progress has been made in elucidating the contribution of genetic and nongenetic factors to CF. Allelic variation in CFTR, the gene responsible for CF, correlates with some aspects of the disease. However, lung function, neonatal intestinal obstruction, diabetes, and anthropometry display strong genetic control independent of CFTR, and candidate gene studies have revealed genetic modifiers underlying these traits. The application of genome-wide techniques holds great promise for the identification of novel genetic variants responsible for the heritable features and complications of CF. Since the genetic modifiers are known to alter the course of disease, their protein products become immediate targets for therapeutic intervention. © 2010 New York Academy of Sciences.

Anderson B.A.,Johns Hopkins University | Folk C.L.,Villanova University
Psychological Science | Year: 2014

One aspect of effective cognitive control is the ability to withhold contextually inappropriate responses. The inhibition of a response can be elicited by a goal-relevant stop signal, which has been characterized as a voluntary cognitive process. Cases in which inhibition is triggered automatically by a stimulus have been reported but are limited to instances in which the withholding of a response is associated with the same stimulus over repeated trials, which reflects the gradual emergence of automaticity through associative learning. Findings such as these suggest that inhibitory control is driven by two dissociable mechanisms, one that is flexible but deliberate and another that is automatic but inflexibly learned. In the present study, we showed that response inhibition can be involuntarily triggered when stimulus-response mapping varies unpredictably, without contributions from associative learning. Our findings demonstrate that automatic response inhibition can be flexibly conditioned on top-down goals, which has broad implications for theories of cognitive control. © The Author(s) 2013.

Koffarnus M.N.,Johns Hopkins University | Woods J.H.,University of Michigan
Addiction Biology | Year: 2013

Substance abusers, including cocaine abusers, discount delayed rewards to a greater extent than do matched controls. In the current experiment, individual differences in discounting of delayed rewards in rats (choice of one immediate over three delayed sucrose pellets) were assessed for associations with demand for either sucrose pellets or an intravenous dose of 0.1 mg/kg/infusion cocaine. Twenty-four male Sprague Dawley rats were split into three groups based on sensitivity to delay to reinforcement. Then, demand for sucrose pellets and cocaine was determined across a range of fixed-ratio values. Delay discounting was then reassessed to determine the stability of this measure over the course of the experiment. Individual differences in impulsive choice were positively associated with elasticity of demand for cocaine, a measure of reinforcer value, indicating that rats having higher discount rates also valued cocaine more. Impulsive choice was not associated with the level of cocaine consumption as price approached 0 or with any parameter associated with demand for sucrose. Individual sensitivity to delay was correlated with the initial assessment when reassessed at the end of the experiment, although impulsive choice increased for this cohort of rats as a whole. These findings suggest that impulsive choice in rats is positively associated with valuation of cocaine, but not sucrose. © 2011 Society for the Study of Addiction.

Riedel S.,Johns Hopkins University
Diagnostic Microbiology and Infectious Disease | Year: 2012

Sepsis and severe sepsis cause significant morbidity and mortality among populations worldwide; the rapid diagnosis poses a considerable challenge to physicians in acute care settings. An ideal biomarker should allow, with high diagnostic accuracy, for an early and rapid recognition of sepsis. Procalcitonin (PCT) is a recently rediscovered biomarker that fulfills many of these requirements, especially in comparison to "older" and commonly used biomarkers, and that has demonstrated superior diagnostic accuracy for a variety of infections, including sepsis. While blood cultures are still considered the "gold standard" for the diagnosis of bacteremia and sepsis, and are perhaps one of the most important functions of the clinical microbiology laboratory, PCT provides important information in early stages of sepsis as well as during antimicrobial treatment. In fact, PCT can be useful for antimicrobial stewardship and its utilization may safely lead to significant reduction of unnecessary antimicrobial therapy. However, PCT is also less than a universal and perfect biomarker, as it can also be increased in noninfectious disease conditions. Laboratories and clinicians must appreciate the complexity of diagnostic algorithms for sepsis and understand the particular information that biomarkers, such as PCT, can offer. In that context, it is necessary to not only recognize the importance of critical clinical awareness and thorough physical patient examination, but also to understand traditional microbiological methods and the need for highly sensitive biomarker assays in order to facilitate an early diagnosis and goal-directed therapy in patients suspected of sepsis. This review is intended to provide additional information for clinicians and microbiologists to better understand the physiology and diagnostic utility of procalcitonin for sepsis and other infectious disease conditions. © 2012 Elsevier Inc.

Halushka M.K.,Johns Hopkins University
Cardiovascular Pathology | Year: 2012

Genetic diseases that affect the vasculature primarily affect the aortic root and ascending aorta. These conditions lead to aortic root dilatation, which, if not treated, will result in dissection and death. Often, aortic disease is just one manifestation of a syndrome with diverse findings. Some of these diseases were described over 100 years ago based on physical manifestations, and their causative genes are among the first described Mendelian causes of cardiovascular disease. Within the pediatric and young adult population, there are over 15 causes of ascending aortic disease. Previously, these diverse diseases, along with their histopathology, have been extensively characterized. Most genetic causes of root aneurysm are extremely rare. Amongst these, five diseases are relatively common with known genetic mutations for which pathologists should be familiar. These are Marfan syndrome, vascular Ehlers-Danlos syndrome, Loeys-Dietz syndrome, Turner syndrome, and familial thoracic aneurysm and dissection. This review will focus on these important causes of genetic aortic disease. The aim is to briefly describe the historical record and physical manifestations and then focus on cardiovascular complications, the causative genes, and current research into these entities. © 2012 Elsevier Inc. All rights reserved.

Neu A.M.,Johns Hopkins University
Pediatric Nephrology | Year: 2012

Children with chronic kidney disease (CKD) are at increased risk for vaccine-preventable diseases. These patients may have a reduced response to and/or reduced duration of antibody after immunization and therefore monitoring of antibody levels or titers is indicated for some vaccines. In addition, pediatric CKD patients require immunizations not routinely provided to healthy children. Unfortunately, studies in pediatric CKD patients, including those on dialysis and awaiting kidney transplantation, have demonstrated sub-optimal immunization rates. In order to minimize the risk for vaccine-preventable disease in pediat-ric CKD patients, it is imperative that all who care for these patients remain abreast of the recommended childhood immunization schedule, as well as alterations to this schedule required for children with CKD, including end-stage kidney disease. This article reviews recent changes to the recommended childhood immunization schedule and alterations and additions to this schedule recommended for children with CKD. Where available, data on antibody response to immunizations in children with CKD are presented. © 2011 IPNA.

Nakata N.,Johns Hopkins University
Engineering Structures | Year: 2010

The purpose of earthquake simulators is to reproduce reference accelerations on a shake table. However, acceleration control is extremely difficult in earthquake simulators due to an inability to directly control acceleration with feedback, inherent nonlinearities in servo hydraulic systems, control-structure interactions, etc. This study presents a control method called acceleration trajectory tracking control (ATTC) that improves the acceleration control performance of earthquake simulators. The ATTC method consists of an acceleration feed-forward controller, a system dynamics command shaping, an intentional time-delay, a Kalman filter for displacement measurement, and an actuator displacement feedback controller. The ATTC method not only provides acceleration tracking capability, but also ensures stability of the system. Following the theoretical description of the ATTC method, an experimental investigation is presented. The ATTC method is successfully implemented in the control system for the uniaxial earthquake simulator at Johns Hopkins University, and the experimental results show the superior performance of the ATTC method over the conventional displacement feedback with command shaping. Furthermore, repeatability of the ATTC method is experimentally verified. © 2010 Elsevier Ltd.

Witwer K.W.,Johns Hopkins University
Clinical Chemistry | Year: 2015

Background: Circulating microRNAs have been proposed as disease biomarkers that may aid in risk assessment, diagnosis, prognosis, and monitoring of treatment response. The perceived opportunity has loomed particularly large in neoplastic disease, where alterations in cancer cells are thought to be reflected in the extracellular space as affected cells release upregulated miRNAs or fail to release apparently downregulated species.Despite the promise of miRNA biomarkers, evaluation of the diagnostic specificity and reproducibility of reported markers suggests that realizing this promise remains a work in progress.Contents: This review examines issues of diagnostic specificity and reproducibility that have afflicted circulating miRNA studies. Surveying the breast cancer literature as an example, few miRNAs are reported consistently. Furthermore, it is posited that the assumptions underlying models of direct contributions of diseased tissue to biofluid miRNA profiles may not hold. Suggestions for improving diagnostic specificity and reliability are provided.Summary: To maximize the likelihood of return on investment as miRNAs continue to be evaluated as specific and clinically useful markers, a focus is needed on miRNAs found in specific carriers, such as extracellular vesicles. Alternative sampling techniques should be developed, and nonblood biofluids should be considered. Careful optimization and standardization of preanalytical and analytical methods is needed to ensure that future results, positive or negative, are reliable. © 2014 American Association for Clinical Chemistry.

Netto G.J.,Johns Hopkins University
Nature Reviews Urology | Year: 2012

The unprecedented advances in cancer genetics and genomics are rapidly affecting the clinical management of solid tumors. Molecular diagnostics are now an integral part of routine clinical management for patients with lung, colon, and breast cancer. In sharp contrast, molecular biomarkers have been largely excluded from current management algorithms for urologic malignancies. The need for new treatment options that can improve upon the modest outcomes currently associated with muscle-invasive bladder cancer is evident, and validated prognostic molecular biomarkers that can help clinicians to identify patients in need of early, aggressive management are lacking. Robust predictive biomarkers that are able to forecast and stratify responses to emerging targeted therapies are also needed. © 2011 Macmillan Publishers Limited. All rights reserved.

Rudin C.M.,Johns Hopkins University
Clinical Cancer Research | Year: 2012

Vismodegib (GDC-0449), an orally bioavailable small-molecule inhibitor of Hedgehog signaling, was recently approved by the U.S. Food and Drug Administration for the treatment of basal cell carcinoma that is either metastatic or locally advanced in patients who are not candidates for surgical resection or radiation. Given the absence of previously defined effective drug therapy for this disease, approval was granted primarily on the basis of outcome of a nonrandomized parallel cohort phase II study of 99 patients with advanced basal cell carcinoma, with a primary endpoint of objective response rate. Response rates of 30.3% and 42.9% were observed in metastatic and locally advanced cohorts in this study, respectively, associated with median progression-free survival in both cohorts of 9.5 months. Ongoing clinical investigations include evaluation of the potential efficacy of vismodegib in a variety of diseases and in combination with other agents. The mechanism of action, preclinical and clinical data, and potential utility in other disease contexts are reviewed here. ©2012 AACR.

Atta M.G.,Johns Hopkins University
Advances in Chronic Kidney Disease | Year: 2010

HIV-associated nephropathy (HIVAN) is a largely distinctive phenotype induced by HIV-1 infection and is the most recognized and detrimental kidney disease in HIV-infected patients. Host and viral characteristics have been implicated in the pathogenesis of HIVAN that may explain its exclusive predilection to patients of African descent. In untreated patients, the disorder is clinically manifested by an acute decline in kidney function, most often in conjunction with high-grade proteinuria and uncontrolled HIV-1 infection. Histologically, proliferating glomerular epithelial cells are the prominent feature of the disease. Data have evolved over the past decade suggesting that highly active antiretroviral therapy (HAART) can change the natural history of HIVAN, not only by preventing its development but also by halting its progression once developed. Consequently, with the widespread use of HAART, the prevalence of HIVAN is declining in Western countries. In contrast, the epidemiology of the disease is not well defined in the poorest areas in the world, which bear a disproportionate share of the HIV-1 epidemic's burden. Corticosteroids and inhibition of the renin-angiotensin axis are recommended as adjunctive agents in treating patients with established HIVAN and are potentially helpful in delaying the need for renal replacement therapy. However, the long-term value and potential risks of using corticosteroids in this population are unclear. © 2010 National Kidney Foundation, Inc.

A differential Kennel-Petschek (KP) flux limit for magnetospheric energetic ions is devised taking into account multiple ion species effects on electromagnetic ion cyclotron (EMIC) waves that scatter the ions. The idea is that EMIC waves may limit the highest ion intensities during acceleration phases of storms and substorms (∼ hour) while other mechanisms (e.g., charge exchange) may account for losses below those limits and over longer periods of time. This approach is applied to published Earth magnetosphere energetic ion spectra (∼ keV to ∼1 MeV) for radial positions (L) 3 to 6.7 R E. The flatness of the most intense spectral shapes for <100 keV indicate sculpting by just such a mechanism, but modifications of traditional KP parameters are needed to account for maximum fluxes up to 5.4 times greater than expected. Future work using the new capabilities of the Van Allen Probes mission will likely resolve outstanding uncertainties. © 2013. American Geophysical Union. All Rights Reserved.

Although more than 2,400 genes have been shown to contain variants that cause Mendelian disease, there are still several thousand such diseases yet to be molecularly defined. The ability of new whole-genome sequencing technologies to rapidly indentify most of the genetic variants in any given genome opens an exciting opportunity to identify these disease genes. Here we sequenced the whole genome of a single patient with the dominant Mendelian disease, metachondromatosis (OMIM 156250), and used partial linkage data from her small family to focus our search for the responsible variant. In the proband, we identified an 11 bp deletion in exon four of PTPN11, which alters frame, results in premature translation termination, and co-segregates with the phenotype. In a second metachondromatosis family, we confirmed our result by identifying a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Sequencing PTPN11 exon 4 in 469 controls showed no such protein truncating variants, supporting the pathogenicity of these two mutations. This combination of a new technology and a classical genetic approach provides a powerful strategy to discover the genes responsible for unexplained Mendelian disorders.

Bowman G.D.,Johns Hopkins University | Poirier M.G.,Ohio State University
Chemical Reviews | Year: 2015

Post-translational modifications (PTMs) of histones can modulate dynamics by directly altering the energy landscape of the nucleosome and by influencing binding of histone chaperones and chromatin remodelers. PTMs near histone-DNA interfaces can promote DNA unwrapping, which increases access for DNA-binding proteins such as transcription factors, or can destabilize the entire nucleosome by perturbing energetically important contacts near the dyad. PTMs that enhance the specificity of chromatin remodelers may not only promote nucleosome sliding, disassembly, and histone exchange but also direct remodelers to maintain the integrity of the chromatin barrier in the presence of disruptive machinery such as RNA polymerase II. In addition to perturbing nucleosome dynamics, PTMs on the histone core may also be utilized to recruit other factors. The binding of reader domains to core histone PTMs would likely stabilize nucleosomes in altered conformations, further enhancing nucleosome dynamics. A continuing technical challenge in studying PTMs on the histone core is raising good antibodies for chromatin immunoprecipitation.

Prosperetti A.,Johns Hopkins University
Physics of Fluids | Year: 2012

The small-amplitude oscillations of constrained drops, bubbles, and plane liquid surfaces are studied theoretically. The constraints have the form of closed lines of zero thickness which prevent the motion of the liquid in the direction normal to the undisturbed free surface. It is shown that, by accounting explicitly for the singular nature of the curvature of the interface and the force exerted by the constraint, methods of analysis very close to the standard ones applicable to the unconstrained case can be followed. Weak viscous effects are accounted for by means of the dissipation function. Graphical and numerical results for the oscillations of constrained drops and bubbles are presented. Examples of two- and three-dimensional gravity-capillary waves are treated by the same method. A brief consideration of the Rayleigh-Taylor unstable configuration shows that the nature of the instability is not affected, although its growth rate is decreased. © 2012 American Institute of Physics.

Few studies have addressed changes in physical activity participation over time among the elderly. The authors hypothesized that there were distinct trajectories of physical activity level over time and identifiable predictors of such trajectories, as well as that the maintenance of regular physical activity, even below recommended levels, was associated with lower mortality risk. Using longitudinal data (1994-2009) from 433 initially high-functioning older women aged 70-79 years at baseline, a joint latent class and survival mixture model identified 4 activity trajectory classes: always active (16.6%), fast declining (19.2%), stable moderate (32.3%), and always sedentary (31.9%). Obesity, coronary artery disease, chronic obstructive pulmonary disease, depressive symptoms, low self-efficacy, mobility disability, and low energy were associated with sedentary behavior and/or a fast decline in activity. Women in the fast declining and always sedentary classes had hazard ratios for death of 2.34 (95% confidence interval: 1.20, 4.59) and 3.34 (95% confidence interval: 1.72, 6.47), respectively, compared with the always active class; no mortality difference was found between the stable moderate and always active groups (hazard ratio = 1.24, 95% confidence interval: 0.63, 2.47). Our findings suggest that physical activity does not have to be vigorous to be beneficial and that the gain may be the greatest among women who reported the lowest levels of activity.

Meneveau C.,Johns Hopkins University
Physics of Fluids | Year: 2012

It has now been over 20 years since the introduction of the Germano identity. Mostly, the identity has been applied to closures for the subgrid-scale fluxes required in large eddy simulations in the bulk of turbulent flows. However, the basic ideas underlying the Germano identity can be applied in various other contexts. In recent years a number of such generalizations have been developed, and several of these are surveyed in this paper. The survey is based on an interpretation of the Germano identity stating that the sum of resolved and modeled contributions to basic quantities of intrinsic physical interest must be independent of filter scale. The focus of this survey is on the conceptual bases of the various generalizations and their common features, as a way of pointing to possible further extensions. © 2012 American Institute of Physics.

Johnston R.J.,Johns Hopkins University
Annals of the New York Academy of Sciences | Year: 2013

Metazoans require highly diverse collections of cell types to sense, interpret, and react to the environment. Developmental programs incorporate deterministic and stochastic strategies in different contexts or different combinations to establish this multitude of cell fates. Precise genetic dissection of the processes controlling terminal photoreceptor differentiation in the Drosophila retina has revealed complex regulatory mechanisms required to generate differences in gene expression and cell fate. In this review, I discuss how a gene regulatory network interprets stochastic and regional inputs to determine the specification of color-detecting photoreceptor subtypes in the Drosophila retina. These combinatorial gene regulatory mechanisms will likely be broadly applicable to nervous system development and cell fate specification in general. © 2013 New York Academy of Sciences.

Benowitz N.L.,University of California at San Francisco | Henningfield J.E.,Johns Hopkins University
Tobacco Control | Year: 2013

Nicotine is highly addictive and is primarily responsible for the maintenance of cigarette smoking. In 1994, Benowitz and Henningfield proposed the idea of federal regulation of the nicotine content of cigarettes such that the nicotine content of cigarettes would be reduced over time, resulting in lower intake of nicotine and a lower level of nicotine dependence. When nicotine levels get very low, cigarettes would be much less addictive. As a result, fewer young people who experiment with cigarettes would become addicted adult smokers and previously addicted smokers would find it easier to quit smoking when they attempt to do so. The regulatory authority to promulgate such a public health strategy was provided by the Family Smoking Prevention and Tobacco Control Act. Although it precludes 'reducing nicotine to zero', the act does not prohibit the Food and Drug Administration from setting standards for cigarette nicotine content that would prevent them from being capable of causing addiction. This paper reviews the assumptions implicit in a nicotine reduction strategy, examines the available data on the feasibility and safety of nicotine reduction, and discusses the public education, surveillance and support services that would be needed for the implementation of such a policy.

Gaydos C.A.,Johns Hopkins University
Infectious Disease Clinics of North America | Year: 2013

Community-acquired pneumonia (CAP) accounts for major morbidity and mortality in the United States. With improved broad-spectrum antibiotics, the implementation of diagnostic studies has declined and most patients do not have an etiologic pathogen of CAP identified. To enhance the appropriate use of antiviral agents and prevent overuse of antibiotics, the successful management of CAP requires rapid and accurate diagnosis of the etiologic agent of CAP. This article provides an overview of the new rapid molecular tests for the diagnosis of influenza, other respiratory viruses, and bacteria compared with nonmolecular tests and how their use for directed therapy can enhance and improve the management of CAP. © 2013 Elsevier Inc.

Brodsky R.A.,Johns Hopkins University
Immunologic Research | Year: 2010

High-dose cyclophosphamide (high-CY) is a potent immunosuppressive regimen that is increasingly used to mitigate both autoimmune and alloimmune conditions. Differential expression of aldehyde dehydrogenase between hematopoietic stem cells and lymphocytes accounts for the differential sensitivity of these cells to high-CY and explains why this regimen is immunosuppressive but not myeloablative. This article describes the clinical translation of high-CY for the treatment of autoimmune and alloimmune conditions. © 2010 Springer Science+Business Media, LLC.

Katz J.,Johns Hopkins University | Sheng J.,University of Minnesota
Annual Review of Fluid Mechanics | Year: 2010

The quantification of three-dimensional (3D) flow structures and particle dynamics is crucial for unveiling complex interactions in turbulent flows. This review summarizes recent advances in volumetric particle detection and 3D flow velocimetry involving holography. We introduce the fundamental principle of holography and discuss the debilitating depth-of-focus problem, along with methods that have been implemented to circumvent it. The focus of this review is on recent advances in the development of in-line digital holography in general, and digital holographic microscopy in particular. A mathematical background for the numerical reconstruction of digital holograms is followed by a summary of recently introduced 3D particle tracking and velocity measurement techniques. The review concludes with sample applications, including 3D velocity measurements that fully resolve the flow in the inner part of a turbulent boundary layer, the diffusion of oil droplets in high-Reynolds number turbulence, and predator-prey interactions among swimming microorganisms in dense suspensions, as well as oceanic and atmospheric field experiments. Copyright © 2010 by Annual Reviews. All rights reserved.

Dang C.V.,Johns Hopkins University
Cold Spring Harbor Symposia on Quantitative Biology | Year: 2011

Studies from many laboratories document that the MYC oncogene produces a pleiotropic transcription factor, Myc, which influences genes driven by all three RNA polymerases to orchestrate nutrient import with biomass accumulation for cell division. Myc has been shown to activate genes involved in glycolysis, glutaminolysis, and mitochondrial biogenesis to provide ATP and anabolic substrates for cell mass accumulation. Myc stimulates ribosome biogenesis and orchestrates the energetic demand for biomass accumulation through its regulation of glucose and glutamine import and metabolism. When normal cells are deprived of nutrients, endogenous MYC expression diminishes and cells withdraw from the cell cycle. However, ectopic MYC-driven cancer cells are locked in a state of deregulated biomass accumulation, which renders them addicted to glucose and glutamine. This addictive state can be exploited for cancer therapy, because nutrient deprivation kills Myc-driven cells and inhibition of the Myc targets, lactate dehydrogenase A or glutaminase, diminishes tumor xenograft growth in vivo. © 2011 Cold Spring Harbor Laboratory Press.

Streiff M.B.,Johns Hopkins University
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

Venous thromboembolism (VTE) is an important cause of preventable morbidity and mortality in medically ill patients. Randomized controlled trials indicate that pharmacologic prophylaxis reduces deep venous thrombosis (relative risk [RR] = 0.46; 95% confidence interval [CI], 0.36-0.59) and pulmonary embolism (RR = 0.49; 95% CI, 0.33-0.72) with a nonsignificant trend toward more bleeding (RR = 1.36; 95% CI, 0.80-2.33]. Low-molecular-weight heparin (LMWH) and unfractionated heparin are equally efficacious in preventing deep venous thrombosis (RR = 0.85; 95% CI, 0.69-1.06) and pulmonary embolism (RR = 1.05; 95% CI, 0.47-2.38), but LMWH is associated with significantly less major bleeding (RR = 0.45; 95% CI, 0.23-0.85). LMWH is favored for VTE prophylaxis in critically ill patients. New VTE and bleeding risk stratification tools offer the potential to improve the risk-benefit ratio for VTE prophylaxis in medically ill patients. Intermittent pneumatic compression devices should be used for VTE prophylaxis in patients with contraindications to pharmacologic prophylaxis. Graduated compression stockings should be used with caution. VTE prevention in medically ill patients using extended-duration VTE prophylaxis and new oral anticoagulants warrant further investigation. VTE prophylaxis prescription and administration rates are suboptimal and warrant multidisciplinary performance improvement strategies.

Finucane T.E.,Johns Hopkins University
Journal of the American Geriatrics Society | Year: 2012

The deep-seated faith in tight glycemic control for patients with type 2 diabetes mellitus shows signs of moderating, especially for elderly adults, but faith in the importance of a glycosylated hemoglobin goal of 7% retains a strong influence over many clinicians. This faith persists despite weak evidence from randomized controlled trials of any meaningful benefit from "tight control" in any patient group, consistent evidence of lack of benefit for many outcomes, and an almost complete lack of evidence about elderly adults or those with extensive vascular disease. Clinicians who care for these vulnerable individuals face a strong public belief in "tight control" and an orchestrated campaign to increase medication use. Although no benefit has been shown in elderly adults, some harms are clear, and others are likely. © 2012, Copyright the Author Journal compilation © 2012, The American Geriatrics Society.

Iglesias P.A.,Johns Hopkins University
Science Signaling | Year: 2012

The social amoebae Dictyostelium discoideum has long proved a powerful model organism for studying how cells sense and interpret chemoattractant gradients. Because of the rich behavior observed in its response to chemoattractants, as well as the complex nature of the signaling pathways involved, this research has attracted and benefited from the use of theoretical models. Recent quantitative experiments provide support for a popular model: the local excitation, global inhibition mechanism of gradient sensing. Here, I discuss these findings and suggest some important open problems.

Fuchs E.J.,Johns Hopkins University
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

The fundamental obstacle to the successful application of partially HLA-mismatched related donor, or HLA-haploidentical stem cell transplantation, is the strength of the host and donor T-cell response to allogeneic HLA molecules, which results in increased incidences of graft failure, GVHD, and nonrelapse mortality. The holy grail of haplo-SCT is to mitigate host-versus-graft and graft-versus-host responses while preserving immune responses to infection and the patient's malignancy. Two strategies have been taken to achieve this goal. The first strategy is to supplement a T cell-depleted graft with pathogen-specific T cells or populations of T cells in which alloreactivity can be controlled. The second strategy is to eliminate alloreactive T cells selectively from a T cell-replete graft. Substantial progress has been made with both approaches so that the safety of haplo-SCT now approaches that of SCT using grafts of umbilical cord blood or from HLA-matched donors. In light of the rapid and near universal availability of HLA-haploidentical related donors, it should now be possible to identify and mobilize a donor for every patient referred for allogeneic SCT. Prospective comparisons between haploidentical SCT and unrelated donor SCT should be performed to identify the most efficacious approach to alternative donor transplantation.

Meyer G.J.,Johns Hopkins University
ACS Nano | Year: 2010

The 2010 Millennium Technology Grand Prize was awarded to Michael Gratzel for his ground-breaking research that has led to the practical application of dye-sensitized solar cells. Although Gratzel began his research well before nanotechnology had the "buzz" that it does today, the mesoscopic thin films he has developed have paved the way for generations of scientists to exploit the nanoscale for energy conversion. In addition to practical application, his research has led to a deeper understanding of photoinitiated charge-transfer processes at semiconductor interfaces. Here, the key scientific developments that guided early progress in dye-sensitized solar cells are summarized, with emphasis on