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Richmond, VA, United States

Virginia Commonwealth University is a public research university located in Richmond, Virginia. VCU was founded in 1838 as the medical department of Hampden–Sydney College, becoming the Medical College of Virginia in 1854. In 1968, the Virginia General Assembly merged MCV with the Richmond Professional Institute, founded in 1917, to create Virginia Commonwealth University. Today, more than 31,000 students pursue 222 degree and certificate programs through VCU's 13 schools and one college. The VCU Health System supports the university's health care education, research and patient care mission.With a record $256 million in sponsored research funding in the fiscal year 2011, VCU is designated as a research university with very high research activity by the Carnegie Classification of Institutions of Higher Education. A broad array of university-approved centers and institutes of excellence, involving faculty from multiple disciplines in public policy, biotechnology and health care discoveries, supports the university's research mission. Twenty-eight graduate and first-professional programs are ranked by U.S. News and World Report as among the best in the country. VCU's athletic teams compete in Division I of the NCAA and are collectively known as the VCU Rams. They are members of the Atlantic 10 Conference. The VCU campus includes historic buildings such as the Ginter House, now used by the school's provost. Wikipedia.

Although age-associated gene expression and methylation changes have been reported throughout the literature, the unifying epigenomic principles of aging remain poorly understood. Recent explosion in availability and resolution of functional/regulatory genome annotation data (epigenomic data), such as that provided by the ENCODE and Roadmap Epigenomics projects, provides an opportunity for the identification of epigenomic mechanisms potentially altered by age-associated differentially methylated regions (aDMRs) and regulatory signatures in the promoters of age-associated genes (aGENs). In this study we found that aDMRs and aGENs identified in multiple independent studies share a common Polycomb Repressive Complex 2 signature marked by EZH2, SUZ12, CTCF binding sites, repressive H3K27me3, and activating H3K4me1 histone modification marks, and a “poised promoter” chromatin state. This signature is depleted in RNA Polymerase II-associated transcription factor binding sites, activating H3K79me2, H3K36me3, H3K27ac marks, and an “active promoter” chromatin state. The PRC2 signature was shown to be generally stable across cell types. When considering the directionality of methylation changes, we found the PRC2 signature to be associated with aDMRs hypermethylated with age, while hypomethylated aDMRs were associated with enhancers. In contrast, aGENs were associated with the PRC2 signature independently of the directionality of gene expression changes. In this study we demonstrate that the PRC2 signature is the common epigenomic context of genomic regions associated with hypermethylation and gene expression changes in aging. © 2015, Taylor and Francis Group, LLC. Source

Rottier B.L.,University of Groningen | Rubin B.K.,Virginia Commonwealth University
Paediatric Respiratory Reviews | Year: 2013

Asthma is usually treated with inhaled corticosteroids (ICS) and bronchodilators generated from pressurized metered dose inhalers (pMDI), dry powder inhalers (DPI), or nebulizers. The target areas for ICS and beta 2-agonists in the treatment of asthma are explained. Drug deposition not only depends on particle size, but also on inhalation manoeuvre. Myths regarding inhalation treatments lead to less than optimal use of these delivery systems. We discuss the origin of many of these myths and provide the background and evidence for rejecting them. © 2013. Source

Kendler K.S.,Virginia Commonwealth University
Psychological Medicine | Year: 2013

This article describes the history of the Scientific Review Committee (SRC) for DSM-5 and reviews its background, procedures and deliberative processes, and conceptual/philosophical framework. The results of its work and the most important and contentious issues that arose in its efforts are reviewed. The central role of the SRC was to provide external review for all proposals for diagnostic change in DSM-5, evaluate them on their level of empirical support using objectively structured rules of evidence agreed upon in advance and make appropriate recommendations to the leadership of the American Psychiatric Association. While the creation of the SRC necessitated a great deal of additional work on the part of the SRC, the workgroups and the DSM-5 Task Force, the SRC succeeded in increasing the focus on empirical standards for nosologic change and providing a greater degree of consistency and objectivity in the DSM review process. The article concludes with recommendations, based on lessons learned, for similar efforts that might be included in future iterations of our psychiatric nosology. Copyright © Cambridge University Press 2013. Source

Rosenblum W.I.,Virginia Commonwealth University
Neurobiology of Aging | Year: 2014

Before amyloid formation, peptides cleaved from the amyloid precursor protein (APP) exist as soluble oligomers. These are extremely neurotoxic. Their concentration is strongly correlated with synaptic impairment in animals and parallel cognitive decline in animals and humans. Clinical trials have largely been aimed at removing insoluble beta amyloid in senile plaques and have not reduced soluble load. Even treatment that should remove soluble oligomers has not consistently reduced the load. Failure to significantly improve cognition has frequently been attributed to failure of the amyloid hypothesis or to irreversible alteration in the brain. Instead, trial failures may be because of failure to significantly reduce load of toxic Aβ oligomers. Moreover, targeting only synthesis of Aβ peptides, only the oligomers themselves, or only the final insoluble amyloid may fail to significantly reduce soluble load because of the interrelationship between these 3 points in the amyloid cascade. Thus, treatments may fail unless trials target simultaneously all 3 points in the equation-"triple therapy". Cerebrospinal fluid analysis and other monitoring tools may in the future provide reliable measurement of soluble load. But currently, only analysis of autopsied brains can provide this data and thus enable proper evaluation and explanation of the outcome of clinical trials. These data are essential before attributing trial failures to the advanced nature of the disease or asserting that failures prove that the theory linking Alzheimer's disease to products of amyloid precursor protein is incorrect. © 2014 Elsevier Inc. Source

Many factors influencing disease transmission vary throughout and across populations. For diseases spread through multiple transmission pathways, sources of variation may affect each transmission pathway differently. In this paper we consider a disease that can be spread via direct and indirect transmission, such as the waterborne disease cholera. Specifically, we consider a system of multiple patches with direct transmission occurring entirely within patch and indirect transmission via a single shared water source. We investigate the effect of heterogeneity in dual transmission pathways on the spread of the disease. We first present a 2-patch model for which we examine the effect of variation in each pathway separately and propose a measure of heterogeneity that incorporates both transmission mechanisms and is predictive of R(0). We also explore how heterogeneity affects the final outbreak size and the efficacy of intervention measures. We conclude by extending several results to a more general n-patch setting. Source

Amaya M.,Virginia Commonwealth University
Blood | Year: 2013

An understanding of the human fetal to adult hemoglobin switch offers the potential to ameliorate β-type globin gene disorders such as sickle cell anemia and β-thalassemia through activation of the fetal γ-globin gene. Chromatin modifying complexes, including MBD2-NuRD and GATA-1/FOG-1/NuRD, play a role in γ-globin gene silencing, and Mi2β (CHD4) is a critical component of NuRD complexes. We observed that knockdown of Mi2β relieves γ-globin gene silencing in β-YAC transgenic murine chemical inducer of dimerization hematopoietic cells and in CD34(+) progenitor-derived human primary adult erythroid cells. We show that independent of MBD2-NuRD and GATA-1/FOG-1/NuRD, Mi2β binds directly to and positively regulates both the KLF1 and BCL11A genes, which encode transcription factors critical for γ-globin gene silencing during β-type globin gene switching. Remarkably, <50% knockdown of Mi2β is sufficient to significantly induce γ-globin gene expression without disrupting erythroid differentiation of primary human CD34(+) progenitors. These results indicate that Mi2β is a potential target for therapeutic induction of fetal hemoglobin. Source

Glennon R.A.,Virginia Commonwealth University
Advances in pharmacology (San Diego, Calif.) | Year: 2014

The term "synthetic cathinones" is fairly new, but, although the abuse of synthetic cathinones is a recent problem, research on cathinone analogs dates back >100 years. One structural element cathinone analogs have in common is an α-aminophenone moiety. Introduction of amine and/or aryl substituents affords a large number of agents. Today, >40 synthetic cathinones have been identified on the clandestine market and many have multiple "street names." Many cathinone analogs, although not referred to as such until the late 1970s, were initially prepared as intermediates in the synthesis of ephedrine analogs. The cathinones do not represent a pharmacologically or mechanistically homogeneous class of agents. Currently abused synthetic cathinones are derived from earlier agents and seem to produce their actions primarily via the dopamine, norepinephrine, and/or serotonin transporter; that is, they either release and/or inhibit the reuptake of one or more of these neurotransmitters. The actions of these agents can resemble those of central stimulants such as methamphetamine, cocaine, and/or empathogens such as 1-(3,4-methylenedioxyphenyl)-2-aminopropane (Ecstasy) and/or produce other effects. Side effects are primarily of a neurological and/or cardiovascular nature. The use of the "and/or" term is emphasized because synthetic cathinones represent a broad class of agents that produce a variety of actions; the agents cannot be viewed as being pharmacologically equivalent. Until valid structure-activity relationships are formulated for each behavioral/mechanistic action, individual synthetic cathinones remain to be evaluated on a case-by-case basis. Treatment of synthetic cathinone intoxication requires more "basic science" research. At this time, treatment is mostly palliative. © 2014 Elsevier Inc. All rights reserved. Source

Li P.-L.,Virginia Commonwealth University
Antioxidants and Redox Signaling | Year: 2015

Significance: In response to infection or cellular stress, inflammasomes are assembled and activated to mediate host defense and to initiate or promote the development of different diseases, in particular, autoinflammatory diseases and chronic degenerative diseases. Understanding of inflammasomes and related physiological and pathological relevance to the cardiovascular system will open a new chapter on the pathogenesis of inflammation and related diseases and will help develop novel therapeutic strategies for prevention or treatment of cardiovascular diseases. Recent Advances: The inflammasome, in particular the nucleotide oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome, has been recently recognized as a fundamental mechanism to mediate or promote the pathogenesis of degenerative diseases. Some important mechanisms responsible for NLRP3 inflammasome activation have been proposed and many molecular targets associated with this inflammasome activation are shown to be the possible candidates of therapeutic targets for treatment of cardiovascular diseases. Critical Issues: The concepts that NLRP3 inflammasome activation occurs just in immune cells or phagocytes and that its role is only for the inflammatory progression of cardiovascular diseases are oversimplified. A large body of other cell types are capable of NLRP3 inflammasome activation, and many uncanonical effects of this inflammasome may also be implicated in the development of cardiovascular diseases, which are discussed in a great detail by this Forum. Future Directions: More mechanistic and translational studies will rapidly widen the horizon of knowledge on NLRP3 inflammasome activation and regulation, which may help develop novel effective therapeutic strategies to target this inflammasome for treatment or prevention of cardiovascular diseases. © 2015 Copyright 2015, Mary Ann Liebert, Inc. Source

Storey C.,City University London | Kahn K.B.,Virginia Commonwealth University
Journal of Service Research | Year: 2010

Are service firms that enact strategies to manage their new service development (NSD) knowledge able to generate a sustainable competitive advantage (SCA)? Based on analysis of data from a large survey of service companies, the answer is yes. The authors find that companies employing the knowledge management strategies of codification and personalization reflect higher levels of NSD knowledge. However, the two strategies vary in their individual performance outcomes, with codification promoting NSD proficiency (an ability to execute NSD activities) and personalization promoting greater NSD innovativeness (market perception of the company as novel and as an innovator). When used together, the two strategies magnify NSD knowledge, which when combined with NSD proficiency and NSD innovativeness, promote an SCA. Therefore, companies planning to invest in a knowledge management system should heed the outcomes desired from their NSD process. A system based on documentation exemplifies a codification strategy and will drive NSD proficiency; a system emphasizing interpersonal communication exemplifies a personalization strategy and will drive NSD innovativeness. A system that blends the two strategies appears the most advantageous for service companies' NSD efforts aiming to build a long-term sustainable competitive advantage. © The Author(s) 2010. Source

Kontos M.C.,Virginia Commonwealth University | Diercks D.B.,University of California at Davis | Kirk J.D.,University of California at Davis
Mayo Clinic Proceedings | Year: 2010

The management of patients with chest pain is a common and challenging clinical problem. Although most of these patients do not have a life-threatening condition, the clinician must distinguish between those who require urgent management of a serious problem such as acute coronary syndrome (ACS) and those with more benign entities who do not require admission. Although clinical judgment continues to be paramount in meeting this challenge, new diagnostic modalities have been developed to assist in risk stratification. These include markers of cardiac injury, risk scores, early stress testing, and noninvasive imaging of the heart. The basic clinical tools of history, physical examination, and electrocardiography are currently widely acknowledged to allow early identification of low-risk patients who have less than 5% probability of ACS. These patients are usually initially managed in the emergency department and transitioned to further outpatient evaluation or chest pain units. Multiple imaging strategies have been investigated to accelerate diagnosis and to provide further risk stratification of patients with no initial evidence of ACS. These include rest myocardial perfusion imaging, rest echocardiography, computed tomographic coronary angiography, and cardiac magnetic resonance imaging. All have very high negative predictive values for excluding ACS and have been successful in reducing unnecessary admissions for patients at low to intermediate risk of ACS. As patients with acute chest pain transition from the evaluation in the emergency department to other outpatient settings, it is important that all clinicians involved in the care of these patients understand the tools used for assessment and risk stratification. © 2010 Mayo Foundation for Medical Education and Research. Source

Purpose: Instrument development consistent with best practices is necessary for effective assessment and evaluation of learners and programs across the medical education continuum. The author explored the extent to which current factor analytic methods and other techniques for establishing validity are consistent with best practices. Method: The author conducted electronic and hand searches of the English-language medical education literature published January 2006 through December 2010. To describe and assess current practices, she systematically abstracted reliability and validity evidence as well as factor analysis methods, data analysis, and reported evidence from instrument development articles reporting the application of exploratory factor analysis and principal component analysis. Results: Sixty-two articles met eligibility criteria. They described 64 instruments and 95 factor analyses. Most studies provided at least one source of evidence based on test content. Almost all reported internal consistency, providing evidence based on internal structure. Evidence based on response process and relationships with other variables was reported less often, and evidence based on consequences of testing was not identified. Factor analysis findings suggest common method selection errors and critical omissions in reporting. Conclusions: Given the limited reliability and validity evidence provided for the reviewed instruments, educators should carefully consider the available supporting evidence before adopting and applying published instruments. Researchers should design for, test, and report additional evidence to strengthen the argument for reliability and validity of these measures for research and practice. Source

Reimers M.,Virginia Commonwealth University
PLoS Computational Biology | Year: 2010

This article describes the typical stages in the analysis of microarray data for nonspecialist researchers in systems biology and medicine. Particular attention is paid to significant data analysis issues that are commonly encountered among practitioners, some of which need wider airing. The issues addressed include experimental design, quality assessment, normalization, and summarization of multiple-probe data. This article is based on the ISMB 2008 tutorial on microarray data analysis. An expanded version of the material in this article and the slides from the tutorial can be found at http://www.people.vcu.edu/~mreimers/OGMDA/index.html. © 2010 Mark Reimers. Source

Sabik L.M.,Virginia Commonwealth University
Health Services Research | Year: 2012

Objective To investigate the effect of local uninsurance rates on access to health care for the uninsured and insured and improve on recent studies by controlling for time-invariant differences across markets. Data Sources Individual-level data from the 1996 and 2003 Community Tracking Study, and market-level data from other sources, including the Area Resource File and the Bureau of Primary Healthcare. Study Design Market-level fixed effects models estimate the effect of changes in uninsurance rates within markets on access to care, measured by whether individuals report forgoing necessary care. Instrumental variables models are also estimated. Principal Findings Increases in the rate of uninsurance are associated with poorer access to necessary care among the uninsured. In contrast with recent evidence, increases in uninsurance had no effect on access to care among the insured. Instrumental variables results are similar, although not statistically significant. Conclusions Changes in rates of insurance coverage are likely to affect access to care for both previously and continuously uninsured. In contrast with earlier studies, there is no evidence of spillover effects on the insured, suggesting that such policy changes may have little effect on access for those who are already insured. © Health Research and Educational Trust. Source

Foster M.,Virginia Commonwealth University
Clinical Journal of Oncology Nursing | Year: 2014

The neutropenic diet historically has been a mainstay in oncology practice, with many providers continuing to adhere tightly to the diet for patients with neutropenia. However, clinically sound evidence remains limited and weak and does not support the diet as a foundation for policy and practice. Therefore, two questions remain: Does evidence exist to support the effectiveness of the neutropenic diet in reducing infection rates in the neutropenic oncology population? Based on limited evidence supporting the neutropenic diet in this population, what clinically sound diet strategies are best for these patients? © Oncology Nursing Society. Source

Bajaj J.S.,Virginia Commonwealth University
Alimentary Pharmacology and Therapeutics | Year: 2016

Background Progressive gut milieu (microbiota) changes occur in patients with cirrhosis and are associated with complications [e.g. hepatic encephalopathy (HE)]. Aim To examine the role of rifaximin in the management of HE and other complications of cirrhosis, including potential mechanisms of action and the need for future studies. Methods A literature search was conducted using the keywords 'rifaximin', 'hepatic encephalopathy', 'ascites', 'variceal bleeding', 'peritonitis', 'portal hypertension', 'portopulmonary hypertension' and 'hepatorenal syndrome'. Results The nonsystemic agent rifaximin reduces the risk of HE recurrence and HE-related hospitalisations in cirrhosis. In patients with cirrhosis, rifaximin modulates the bacterial composition of the gut microbiota without a consistent effect on overall faecal microbiota composition. However, rifaximin can impact the function or activities of the gut microbiota. For example, rifaximin significantly increased serum levels of long-chain fatty acids and carbohydrate metabolism intermediates in patients with minimal HE. Rifaximin also favourably affects serum proinflammatory cytokine and faecal secondary bile acid levels. Conclusions The gut microenvironment and associated microbiota play an important role in the pathogenesis of HE and other cirrhosis-related complications. Rifaximin's clinical activity may be attributed to effects on metabolic function of the gut microbiota, rather than a change in the relative bacterial abundance. © 2015 John Wiley & Sons Ltd. Source

Matzke G.R.,Virginia Commonwealth University
Annals of Pharmacotherapy | Year: 2012

The health reforms of the last several years at the federal and state levels have created many opportunities for pharmacists to become actively involved in the direct patient care provision. Indeed, the statutory language in some sections of the Affordable Care Act of 2010 creates expectations of pharmacists that will require practice transformation if we are to arise to accept the responsibilities associated with these expectations. These new opportunities open the door for pharmacists to benefit community-dwelling patients with chronic medical conditions, those with acute/emergent care needs, those experiencing a transition between chronic and acute care and vice versa, as well as others in long-term care settings. Although the profession has demonstrated value in many practice environments, our contributions to improved medication-related patient outcomes through medication therapy management (MTM) and the other pharmaceutical care services remain to be rigorously quantified. Incorporation of pharmacists either by their physical presence within the practice or through the design of effective community linkages, such as electronic health records, must be developed to meet the needs of rural and urban patients seen in a variety of practice settings. New business models that build upon cognitive and direct patient care services in addition to the provision of drug products will surely need to emerge for the profession to become a viable and vital component of the US health care system. © 2012 by Harvey Whitney Books Company. Source

Rubin B.K.,Virginia Commonwealth University
Respiratory Care | Year: 2010

This paper reviews the history of aerosol therapy; discusses patient, drug, and device factors that can influence the success of aerosol therapy; and identifies trends that will drive the science of aerosol therapy in the future. Aerosol medication is generally less expensive, works more rapidly, and produces fewer side effects than the same drug given systemically. Aerosol therapy has been used for thousands of years by steaming and burning plant material. In the 50 years since the invention of the pressurized metered-dose inhaler, advances in drugs and devices have made aerosols the most commonly used way to deliver therapy for asthma and COPD. The requirements for aerosol therapy depend on the target site of action and the underlying disease. Medication to treat airways disease should deposit on the conducting airways. Effective deposition of airway particles generally requires particle size between 0.5 and 5 μm mass median aerodynamic diameter; however, a smaller particle size neither equates to greater side effects nor greater effectiveness. However, medications like peptides intended for systemic absorption, need to deposit on the alveolar capillary bed. Thus ultrafine particles, a slow inhalation, and relatively normal airways that do not hinder aerosol penetration will optimize systemic delivery. Aerosolized antimicrobials are often used for the treatment of cystic fibrosis or bronchiectasis, and mucoactive agents to promote mucus clearance have been delivered by aerosol. As technology improves, a greater variety of novel medications are being developed for aerosol delivery, including for therapy of pulmonary hypertension, as vaccines, for decreasing dyspnea, to treat airway inflammation, for migraine headache, for nicotine and drug addiction, and ultimately for gene therapy. Common reasons for therapeutic failure of aerosol medications include the use of inactive or depleted medications, inappropriate use of the aerosol device, and, most importantly, poor adherence to prescribed therapy. The respiratory therapist plays a key role in patient education, device selection, and outcomes assessment. © 2010 Daedalus Enterprises. Source

Gomez-Suarez R.A.,Virginia Commonwealth University
Journal of Pediatric Gastroenterology and Nutrition | Year: 2016

OBJECTIVE:: Determine clinical and manometric parameters associated with success of antegrade continence enemas (ACE) administered via cecostomy in the treatment of constipation and fecal overflow incontinence. METHODS:: We performed a retrospective review of clinical symptoms and manometry (colonic and anorectal) before cecostomy in 40 pediatric patients (20 males, 20 females). The mean age at time of follow-up was 9.5?±?4.4 years with a mean follow-up time of 12.2?±?10.9 months. Clinical outcomes were defined as good if subjects had greater than 3 bowel movements per week less than 2 episodes of soiling per week, and absence of pain at the time of follow up after cecostomy. RESULTS:: Before cecostomy, the mean duration of constipation and/or fecal incontinence was 7.7?±?4.4 years, mean number of BMs was 1.5?±?0.9 per week, and soiling episodes 4.12?±?3.5 per week; 24 (60%) patients had abdominal pain. At follow up 30 out of 40 patients had a good outcome, and 10 had a poor outcome; with a difference in the number of weekly BM of 5.7?±?2.2 vs. 1.5?±?0.9, p? Source

Nestler J.E.,Virginia Commonwealth University
Transactions of the American Clinical and Climatological Association | Year: 2012

We conducted a pilot project to test the hypothesis that decreasing insulin concentrations with diazoxide would affect parameters of vitamin D in obese women with and without polycystic ovary syndrome (PCOS). Eight obese women with PCOS and nine matched controls participated in the study. Diazoxide was administered orally 100 mg three times daily for 10 days, and parameters of vitamin D were measured at baseline and end-of-study. At baseline, women with polycystic ovary syndrome had significantly lower serum 25-hydroxyvitamin D (25[OH]D) levels than controls. After treatment with diazoxide, there were no significant changes in vitamin D parameters when PCOS and control women were evaluated separately. Diazoxide exhibited differential effects on 25(OH)D concentrations in PCOS as compared with normal women (P for interaction=0.045), and serum 25(OH)D levels converged after diazoxide treatment. Obese women with PCOS had significantly lower serum 25(OH)D levels at baseline than age- and body mass index-matched controls. Short-term administration with diazoxide seemed to have differential effects on 25(OH)D levels in PCOS as compared with control women. Further studies are necessary to confirm this finding. Source

Zellmer W.A.,Foresight | Zellmer W.A.,Virginia Commonwealth University
Annals of Pharmacotherapy | Year: 2012

Key factors outside of health-system pharmacy that will shape this sector of the profession in the coming years are (1) the national economy, (2) national politics, (3) the debt of the federal government, (4) global megatrends (including terrorism and economic globalization), (5) health care reform, and (6) trends in the development and use of medicines. These factors will translate into payment cutbacks to hospitals, expanded mandates to improve the quality of health care, increased focus on patient-centered care, more team-based care, and a higher degree of integration across the range of health care settings and providers. In this environment, pharmacists in hospitals and other health systems will have rich opportunities to help improve patient care and institutional sustainability by continuing to move from order-fulfillment and product-preparation functions toward team leadership of drug therapy management. The American Society of Health-System Pharmacists Pharmacy Practice Model Initiative (PPMI) was created to encourage hospital and health-system practice leaders to examine how they deploy their resources (ie, pharmacist time, technician time, and technology) to ensure that the efforts of the pharmacy department are aligned with the most urgent needs of patients and institutions. Key recommendations of the PPMI and evidence about gaps in the provision of drug therapy management services are presented. It is important for every pharmacist and pharmacy technician in health-system practice to understand the imperatives for changing the profession's practice model and to actively pursue appropriate changes in that model. © 2012 by Harvey Whitney Books Company. Source

Estes T.S.,Virginia Commonwealth University
Chronic Respiratory Disease | Year: 2011

The United States health care system is at a pivotal point in its ability to manage chronic illness. The demands and philosophical differences between the management of acute and chronic illnesses suggest the need for different strategies for effective and efficient management of chronic illness. The purpose of this article is to discuss the Chronic Care Model and the collaborative approach to managing chronic illnesses. Asthma, as an exemplar, will be used to illustrate the need for the development of new models of collaborative care for the treatment of chronic illnesses. © 2011 The Author(s). Source

Hasnain M.,Memorial University of Newfoundland | Vieweg W.V.R.,Virginia Commonwealth University
CNS Drugs | Year: 2014

We comprehensively reviewed published literature to determine whether it supported the link between corrected QT (QTc) interval prolongation and torsade de pointes (TdP) for the 11 second-generation antipsychotics and seven second-generation antidepressants commonly implicated in these complications. Using PubMed and EMBASE, we identified four thorough QT studies (one each for iloperidone, ziprasidone, citalopram, and escitalopram), 40 studies specifically designed to assess QTc interval prolongation or TdP, 58 publications based on data from efficacy and safety trials, 18 toxicology studies, and 102 case reports. Thorough QT studies, QTc prolongation-specific studies, and studies based on efficacy and safety trials did not link drug-associated QTc interval prolongation with TdP. They only showed that the drugs reviewed caused varying degrees of QTc interval prolongation, and even that information was not clear and consistent enough to stratify individual drugs for this risk. The few toxicology studies provided valuable information but their findings are pertinent only to situations of drug overdose. Case reports were most informative about the drug-QTc interval prolongation-TdP link. At least one additional well established risk factor for QTc prolongation was present in 92.2 % of case reports. Of the 28 cases of TdP, six (21.4 %) experienced it with QTc interval <500 ms; 75 % of TdP cases occurred at therapeutic doses. There is little evidence that drug-associated QTc interval prolongation by itself is sufficient to predict TdP. Future research needs to improve its precision and broaden its scope to better understand the factors that facilitate or attenuate progression of drug-associated QTc interval prolongation to TdP. © 2014 Springer International Publishing Switzerland. Source

Kuemmerle J.F.,Virginia Commonwealth University
Gastroenterology | Year: 2012

Technology-based education tools provide GI faculty and fellows compelling new instructional possibilities that can portray anatomic and physiologic processes with remarkable clarity. They offer instruction tailored to meet educators' and trainees' needs by allowing learners to practice skills in a safe environment, standardize their instruction and assessment, and be offered anywhere and anytime. Today's digital learners are also accustomed to working within technology-enhanced environments. There is also no doubt that technologies in GI education will evolve and become integrated into our daily professional and personal lives. It is incumbent on clinical educators of gastroenterology to be active leaders in this arena and optimize learning by our trainees through traditional and technologically enhanced methods. The advantages accruing to our trainees who are typically "digital natives" are easy to recognize. The advantage to departments of gastroenterology, which must make a monetary investment in the tech ology, and to GI faculty, who are typically "digital immigrants" and must make a time investment, are less obvious. I am confident that, in the long run, developing new education materials and methods that are technologically based will be a time-saving investment for GI faculty members and will help us to cope with our increasing responsibilities and increasing time constraints. The applicability of technologically advanced educational opportunities does not stop with training in gastroenterology. Many are equally applicable and effective tools for the continuing professional development and life-long learning of practicing gastroenterologists. The material I have presented in this review is one snapshot in time. Technology and its applications are changing and improving at a staggering rate. As yet unimagined opportunities wait in the wings for innovative gastroenterologists and GI trainees to explore and implement. © 2012 AGA Institute. Source

Roy K.,Virginia Commonwealth University | Roy K.,Purdue University
Applied Physics Letters | Year: 2013

The primary impediment to continued downscaling of traditional charge-based electronic devices in accordance with Moore's law is the excessive energy dissipation that takes place in the device during switching of bits. One very promising solution is to utilize multiferroic heterostructures, comprised of a single-domain magnetostrictive nanomagnet strain-coupled to a piezoelectric layer, in which the magnetization can be switched between its two stable states while dissipating minuscule amount of energy. However, no efficient and viable means of computing is proposed so far. Here we show that such single multiferroic composites can act as universal logic gates for computing purposes, which we demonstrate by solving the stochastic Landau-Lifshitz-Gilbert equation of magnetization dynamics in the presence of room-temperature thermal fluctuations. The proposed concept can overwhelmingly simplify the design of large-scale circuits and portend a highly dense yet an ultra-low-energy computing paradigm for our future information processing systems. © 2013 AIP Publishing LLC. Source

Rinella M.E.,Northwestern University | Sanyal A.J.,Virginia Commonwealth University
Nature Reviews Gastroenterology and Hepatology | Year: 2016

NAFLD is the most prevalent form of liver disease in the USA, affecting an estimated 30% of the population. The condition is associated with increased mortality related to cardiovascular disease, malignancy and liver disease. Identification of patients who might be at increased risk of adverse outcomes is critical as it is not feasible to screen all patients with suspected NAFLD. Patients with NASH, the progressive subtype of NAFLD, should be targeted for treatment, especially if they have concomitant fibrosis because such patients are more likely than those without fibrosis to have adverse outcomes. Treatment goals in patients with NAFLD vary depending on the disease stage owing to differential risk of progression and the particularities of an individual's comorbid disease. Lifestyle intervention is important for all patients irrespective of disease stage, but other therapies should be targeted to those most likely to benefit. In this Review, we highlight risk factors for disease progression and offer a stage-based treatment approach for patients with NAFLD. Source

Dickinson A.J.G.,Virginia Commonwealth University
Seminars in Cell and Developmental Biology | Year: 2016

In this review I discuss how Xenopus laevis is an effective model to dissect the mechanisms underlying orofacial defects. This species has been particularly useful in studying the understudied structures of the developing face including the embryonic mouth and primary palate. The embryonic mouth is the first opening between the foregut and the environment and is critical for adult mouth development. The final step in embryonic mouth formation is the perforation of a thin layer of tissue covering the digestive tube called the buccopharyngeal membrane. When this tissue does not perforate in humans it can pose serious health risks for the fetus and child. The primary palate forms just dorsal to the embryonic mouth and in non-amniotes it functions as the roof of the adult mouth. Defects in the primary palate result in a median oral cleft that appears similar across the vertebrates. In humans, these median clefts are often severe and surgically difficult to repair. Xenopus has several qualities that make it advantageous for craniofacial research. The free living embryo has an easily accessible face and we have also developed several new tools to analyze the development of the region. Further, Xenopus is readily amenable to chemical screens allowing us to uncover novel gene-environment interactions during orofacial development, as well as to define underlying mechanisms governing such interactions. In conclusion, we are utilizing Xenopus in new and innovative ways to contribute to craniofacial research. © 2016. Source

Leung J.G.,University of Pittsburgh | Breden E.L.,Virginia Commonwealth University
Annals of Pharmacotherapy | Year: 2011

OBJECTIVE: To evaluate the safety and effectiveness of tetrabenazine for the treatment of tardive dyskinesia. DATA SOURCES: Literature was accessed through MEDLINE (1966-September 2010) and The Cochrane Library using the terms tetrabenazine, tardive dyskinesia, and movement disorders. In addition, references from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were reviewed. DATA SYNTHESIS: Options available for the management of tardive dyskinesia are limited. Tetrabenazine is a central monoamine-depleting agent approved by the Food and Drug Administration for chorea associated with Huntington's disease. Three prospective studies of tetrabenazine in the treatment of tardive dyskinesia were identified, as well as 8 additional trials, 1 case series, and 8 case reports. Tetrabenazine may provide benefit in managing symptoms of tardive dyskinesia unresponsive to other treatment modalities. Treatment of tardive dyskinesia with tetrabenazine may be limited by cost and clinically significant adverse effects such as depression, parkinsonism, and somnolence. CONCLUSIONS: Small trials indicate tetrabenazine may be effective for the treatment of tardive dyskinesia. However, larger, well-conducted trials are needed to confirm these findings. Currently, there is a lack of data coupled with the risk of significant adverse effects to recommend the routine use of tetrabenazine in the management of tardive dyskinesia. Before using tetrabenazine for the management of tardive dyskinesia, all other options should be exhausted and careful monitoring employed. Source

Bear H.D.,Virginia Commonwealth University
Surgical Oncology Clinics of North America | Year: 2010

Neoadjuvant chemotherapy (NAC) is being used with increasing frequency in the multidisciplinary care of women with breast cancer. NAC can increase the chances for successful breast conservation and may decrease the need for axillary node dissection in selected patients. Some patients with chemoresistant tumors may benefit more from hormonal neoadjuvant therapy. The greatest potential for this approach is to predict responses of different breast cancers to therapy based on molecular profiles. This will accelerate better understanding of breast cancer biology and progress toward improved and more individualized therapy. © 2010 Elsevier Inc. Source

Kates S.L.,Virginia Commonwealth University
Injury | Year: 2016

This manuscript will evaluate the published evidence on efficacy of organized hip fracture programs to determine if they improve patient outcomes. A detailed literature search was conducted to find manuscripts published in the past 20 years about organized hip fracture care programs. Seventeen programs with published results were identified from this detailed search and these were evaluated and synthesized in the following manuscript. Organized hip fracture programs offer significant benefits to patients, care providers and health systems. The more complex program designs have a more profound effect on improvement in outcomes for hip fracture patients. Most programs have reported reduced length of stay, reduced in-hospital mortality rates, and reduced complications. Some programs have reported reduced costs and reduced readmission rates after implementing an organized hip fracture program. © 2016 Elsevier Ltd. Source

Sawalha A.H.,University of Michigan | Dozmorov M.G.,Virginia Commonwealth University
Journal of Autoimmunity | Year: 2016

Systemic vasculitides are poorly understood inflammatory diseases of the blood vessels that are frequently associated with significant organ damage. Genetic risk variants contribute to the susceptibility of vasculitis, but functional consequences of these genetic variants are largely unknown. Most genetic risk variants in immune-mediated diseases, including systemic vasculitis, are localized to non-coding genetic regions suggesting they might increase disease risk by influencing regulatory elements within the genome. Long range regulatory interactions pose an additional obstacle in localizing functional consequences associated with risk variants to specific genes or cell types. We used cell-type specific enrichment patterns of histone changes that mark poised, primed, and active enhancers, and DNase hypersensitivity to identify specific immune cells mediating genetic risk in vasculitis. Our data suggest that genetic risk variants in ANCA-associated vasculitis are significantly enriched in enhancer elements in Th17 cells, supporting a role for Th17 cells in this disease. Primed and active enhancer elements in B cells can be potentially affected by genetic risk variants associated with Kawasaki disease. Genetic risk in Behçet's disease and Takayasu arteritis might affect enhancer elements in multiple cell types, possibly explained by influencing enhancers in hematopoietic stem cells. Interestingly, our analyses indicate a role for B cells in Kawasaki disease, Behçet's disease, and Takayasu arteritis, and suggest that further work to characterize the involvement of B cells in these diseases is warranted. © 2015 The Authors. Source

Siminoff L.A.,Virginia Commonwealth University | Step M.M.,Case Western Reserve University
Journal of Health Communication | Year: 2011

Many observational coding schemes have been offered to measure communication in health care settings. These schemes fall short of capturing multiple functions of communication among providers, patients, and other participants. After a brief review of observational communication coding, the authors present a comprehensive scheme for coding communication that is (a) grounded in communication theory, (b) accounts for instrumental and relational communication, and (c) captures important contextual features with tailored coding templates: the Siminoff Communication Content Affect Program (SCCAP). To test SCCAP reliability and validity, the authors coded data from two communication studies. The SCCAP provided reliable measurement of communication variables including tailored content areas and observer ratings of speaker immediacy, affiliation, confirmation, and disconfirmation behaviors. Copyright © Taylor & Francis Group, LLC. Source

Individual differences in initial sensitivity to ethanol are strongly related to the heritable risk of alcoholism in humans. To elucidate key molecular networks that modulate ethanol sensitivity we performed the first systems genetics analysis of ethanol-responsive gene expression in brain regions of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens, and ventral midbrain) across a highly diverse family of 27 isogenic mouse strains (BXD panel) before and after treatment with ethanol. Acute ethanol altered the expression of ~2,750 genes in one or more regions and 400 transcripts were jointly modulated in all three. Ethanol-responsive gene networks were extracted with a powerful graph theoretical method that efficiently summarized ethanol's effects. These networks correlated with acute behavioral responses to ethanol and other drugs of abuse. As predicted, networks were heavily populated by genes controlling synaptic transmission and neuroplasticity. Several of the most densely interconnected network hubs, including Kcnma1 and Gsk3β, are known to influence behavioral or physiological responses to ethanol, validating our overall approach. Other major hub genes like Grm3, Pten and Nrg3 represent novel targets of ethanol effects. Networks were under strong genetic control by variants that we mapped to a small number of chromosomal loci. Using a novel combination of genetic, bioinformatic and network-based approaches, we identified high priority cis-regulatory candidate genes, including Scn1b, Gria1, Sncb and Nell2. The ethanol-responsive gene networks identified here represent a previously uncharacterized intermediate phenotype between DNA variation and ethanol sensitivity in mice. Networks involved in synaptic transmission were strongly regulated by ethanol and could contribute to behavioral plasticity seen with chronic ethanol. Our novel finding that hub genes and a small number of loci exert major influence over the ethanol response of gene networks could have important implications for future studies regarding the mechanisms and treatment of alcohol use disorders. Source

Cunningham P.J.,Virginia Commonwealth University
Health Affairs | Year: 2015

The patient-centered medical home (PCMH) is being embraced as a way to improve access to and quality of care and to control health care costs. However, it is not known what proportion of the Medicaid population receives care from practices that incorporate PCMH goals. Nationally representative data for 2008-12 indicate that the majority of Medicaid beneficiaries with no other coverage who reported having a usual source of care described it as consistent with at least three of five key PCMH attributes: serving multiple health needs, ease of phone contact, extended office hours, coordination of prescriptions, and shared decision making. Younger, healthier, and higher-income Medicaid beneficiaries tended to report care sources with multiple attributes, compared to the older, sicker, and lower-income beneficiaries, who may be more likely to benefit from access to such care. Most attributes were associated with higher perceived quality of care and greater access, although the findings regarding health care expenditures were inconclusive. Challenges to widespread adoption of PCMH principles in Medicaid programs include targeting delivery of care consistent with those principles to high-need, high-cost populations and ensuring an adequate supply of usual sources of primary care. © 2015 by Project HOPE-The People-to-People Health Foundation, Inc. Source

Salloum F.N.,Virginia Commonwealth University
Pharmacology and Therapeutics | Year: 2015

Hydrogen sulfide (H2S) has been long recognized as a highly poisonous gas that is rapidly lethal in intoxicating dosage. However, discoveries during the last decade on the endogenous synthesis of H2S in the mammalian system and its protective role in combating cellular necrosis, apoptosis, oxidative stress, inflammation as well as promoting angiogenesis and modulation of mitochondrial respiration in the setting of myocardial ischemia and reperfusion injury have prompted vast interest in the possibility of developing new therapies based around mimicry or facilitation of endogenous H2S for cardioprotection. These observations have inspired rapid development of H2S-releasing drugs in hopes of swift clinical translation in patients with cardiovascular disease. This review will discuss our current understanding of the protective signaling pathways elicited by H2S in the heart with an emphasis on the versatile benefits of this gasotransmitter and its potential for clinical translation in patients with cardiovascular disease. © 2015 Elsevier Ltd. All rights reserved. Source

Cunningham P.,Virginia Commonwealth University | Carrier E.,Center for Studying Health System Change
American Journal of Managed Care | Year: 2014

Objectives: To examine trends in out-of-pocket spending and the financial burden of care for persons with diabetes between 2001 and 2009, and to examine whether these trends are consistent with trends in access to prescription drugs and utilization of hospital services. Study Design and Methods: Data are from the 2001 to 2009 Medical Expenditure Panel Survey (MEPS). The sample includes persons aged 18 to 64 years with diagnosed diabetes. The primary outcome variable is the percent of people with out-of-pocket spending on insurance premiums and services that exceed 10% of family income. Secondary outcome measures include the percent with diabetes-related prescription drug use, perceived access to prescription drugs, hospital inpatient stays, and emergency department use in the past 12 months. Multiple regression analysis is used to control for changes in comorbid chronic conditions and other characteristics of persons with diabetes. Results: Both out-of-pocket spending and the percent with high financial burden decreased markedly for persons with diabetes between 2001 to 2003 and 2007 to 2009. The decrease in spending was driven primarily by a decrease in spending on prescription drugs, including diabetes-related prescriptions. The shift from brand name drugs to generics accounts for much of this decline, although decreases in out-of-pocket spending for both brand name and generic drugs also contributed. During the same period, utilization of and access to diabetes-related prescriptions increased, and hospital use decreased. Conclusions: Although the prevalence of diagnosed diabetes continues to increase, treatment is becoming more affordable, especially prescription drugs. This may offset some of the costs to the healthcare system of higher prevalence by reducing complications of uncontrolled diabetes that result in more costly hospital use. Source

Banks M.L.,Virginia Commonwealth University
Experimental and Clinical Psychopharmacology | Year: 2014

Preclinical drug discrimination procedures have been useful in understanding the pharmacological mechanisms of the subjective-like effects of abused drugs. Converging lines of evidence from neurochemical and behavioral studies implicate a potential role of nicotinic acetylcholine (nACh) receptors in the abuse-related effects of cocaine. The aim of the present study was to determine the effects of the nACh receptor antagonist mecamylamine on the discriminative stimulus effects of cocaine in nonhuman primates. The effects of mecamylamine on the cocaine-like discriminative stimulus effects of nicotine were also examined. Male rhesus monkeys (n = 5) were trained to discriminate 0.32 mg/kg, IM cocaine from saline in a 2-key, food-reinforced discrimination procedure. Initially, potency and time course of cocaine-like discriminative stimulus effects were determined for nicotine and mecamylamine alone. Test sessions were then conducted examining the effects of mecamylamine on cocaine or the cocaine-like discriminative stimulus effects of nicotine. Curiously, mecamylamine produced partial cocaine-like discriminative stimulus effects. Mecamylamine did not significantly alter the discriminative stimulus effects of cocaine up to doses that significantly decreased rates of operant responding. Mecamylamine and nicotine combinations were not different than saline. These results confirm previous nonhuman primate studies of partial substitution with nicotine and extend these findings with mecamylamine. Furthermore, these results extend previous results in rats suggesting cocaine may have nACh receptor antagonist properties. © 2014 American Psychological Association. Source

Rubin B.K.,Virginia Commonwealth University
Paediatric Respiratory Reviews | Year: 2015

Although the symptom complex we call asthma has been well described since antiquity, our understanding of the causes and therapy of asthma has evolved. Even with this evolution in our understanding, there are persistent myths (widely held but false beliefs) and dogma (entrenched beliefs) regarding the causes, classification, and therapy of asthma. It is sobering that some of the knowledge we hold dear today, will become the mythology of tomorrow. © 2014 Elsevier Ltd. Source

Ghapheryc J.,Library Information Systems | White E.,Virginia Commonwealth University
Information Technology and Libraries | Year: 2012

This paper describes the ways in which libraries are currently implementing and managing web-based research guides (a.k.a. Pathfinders, LibGuides, Subject Guides, etc.) by examining two sets of data from the spring of 2011. One set of data was compiled by visiting the websites of ninety-nine American university ARL libraries and recording the characteristics of each site's research guides. The other set of data is based on an online survey of librarians about the ways in which their libraries implement and maintain research guides. In conclusion, a discussion follows that includes implications for the library technology community. Source

Dick D.M.,Virginia Commonwealth University
Annual Review of Clinical Psychology | Year: 2011

There has been an explosion of interest in studying gene-environment interactions (GxE) as they relate to the development of psychopathology. In this article, I review different methodologies to study gene-environment interaction, providing an overview of methods from animal and human studies and illustrations of gene-environment interactions detected using these various methodologies. Gene-environment interaction studies that examine genetic influences as modeled latently (e.g., from family, twin, and adoption studies) are covered, as well as studies of measured genotypes. Importantly, the explosion of interest in gene-environment interactions has raised a number of challenges, including difficulties with differentiating various types of interactions, power, and the scaling of environmental measures, which have profound implications for detecting gene-environment interactions. Taking research on gene-environment interactions to the next level will necessitate close collaborations between psychologists and geneticists so that each field can take advantage of the knowledge base of the other. Copyright © 2011 by Annual Reviews. All rights reserved. Source

Zilberberg M.D.,University of Massachusetts Amherst | Zilberberg M.D.,EviMed Research Group | De Wit M.,Virginia Commonwealth University | Shorr A.F.,Washington Hospital Center
Critical Care Medicine | Year: 2012

Objectives: Patients requiring prolonged acute mechanical ventilation (mechanical ventilation ≥ 96 hrs) have hospital survival rates similar to those requiring <96 hrs of mechanical ventilation and consume approximately two-thirds of hospital resources devoted to mechanical ventilation care. Using 2000-2005 data, we previously estimated that their volume will go from approximately 250,000 cases in 2000 to 605,898 by year 2020. With 2006-2008 data becoming available, we explored the precision of our previous formulas and estimates. Design: We utilized National Inpatient Sample/Health Care Utilization Project of the Agency for Healthcare Research and Quality data from 2000 to 2008 to calculate historic annual age-adjusted prolonged acute mechanical ventilation incidence rates using estimated population statistics from the U.S. Census Bureau. To predict future growth by age group, we fit linear regression models to the historic incidence rate changes. Age-adjusted estimates were computed using population projections obtained from the U.S. Census Bureau. Setting: U.S. hospitals. Patients: Nationally representative sample of U.S. hospital discharges with prolonged acute mechanical ventilation (International Classification of Diseases version 9 code 96.72). Interventions: None. Measurements and Main Results: Formulas based on the 2000-2005 data predicted the 2008 prolonged acute mechanical ventilation volume within a 1.9% margin. The historic annualized increase in adult prolonged acute mechanical ventilation increased from 5.0% to 5.2% after incorporating the 2006-2008 data. Factoring in the 2006-2008 data altered our 2020 prolonged acute mechanical ventilation estimates from 605,898 (95% confidence interval 456,695-779,806) to 625,298 (95% confidence interval 552,168-698,838), an upward revision of 3.2%. Conclusion: Our original projections for growth of the adult prolonged acute mechanical ventilation population in the U.S. hospitals by the year 2020 are altered only slightly by adding the 2006-2008 data. Relatively precise prediction of the 2008 prolonged acute mechanical ventilation numbers by the original formulas lends internal validity to the methodology. By virtue of being a large, resource-intensive, and rapidly increasing population, this group of mechanical ventilation Patients requires continued close monitoring over time to optimize our preparedness to meet their growing healthcare needs. © 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins. Source

Waguespack S.G.,University of Houston | Francis G.,Virginia Commonwealth University
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2010

Children with differentiated thyroid cancer (DTC) often present with metastatic disease and have a high risk for recurrence, but rarely die of the disease. This article reviews DTC in children and discusses current approaches to their initial care and follow-up. These recommendations take into account the greater risk for recurrence and lower disease-specific mortality in these patients. Total thyroidectomy and central compartment lymph node dissection are appropriate for most children, but should be performed by a high-volume thyroid surgeon. Radioactive iodine (RAI) should generally be prescribed for those at very high risk for recurrence or known to have microscopic residual disease, and those with iodine-avid distant metastases. RAI should be considered in other patients only after carefully weighing the relative risks and benefits and the aggressiveness of the clinical presentation, because RAI may be associated with an increased risk for second malignancies and an increase in overall morbidity and mortality. All patients should be treated with thyroid hormone suppression, and follow-up should be lifelong. However, the degree of thyroid hormone suppression and frequency of disease surveillance usually decrease over time as patients are determined to be disease-free. © JNCCN - Journal of the National Comprehensive Cancer Network. Source

Mansingh G.,University of the West Indies | Osei-Bryson K.-M.,Virginia Commonwealth University | Reichgelt H.,Southern Polytechnic State University
Information Sciences | Year: 2011

Data mining is used to discover hidden patterns or structures in large databases. Association rule induction extracts frequently occurring patterns in the form of association rules. However, this technique has a drawback as it typically generates a large number of association rules. Several methods have been proposed to prune the set of extracted rules in order to present only those which are of interest to the domain experts. Some of these methods involve subjective analysis based on prior domain knowledge, while others can be considered to involve objective, data-driven analysis based on numerical measures that provide a partial description of the interestingness of the extracted association rules. Recently it has been proposed that ontologies could be used to guide the data mining process. In this paper, we propose a hybrid pruning method that involve the use of objective analysis and subjective analysis, with the latter involving the use of an ontology. We demonstrate the applicability of this hybrid method using a medical database. © 2010 Elsevier Inc. All rights reserved. Source

Hamric A.B.,Virginia Commonwealth University
HEC Forum | Year: 2012

Studying a concept as complex as moral distress is an ongoing challenge for those engaged in empirical ethics research. Qualitative studies of nurses have illuminated the experience of moral distress and widened the contours of the concept, particularly in the area of root causes. This work has led to the current understanding that moral distress can arise from clinical situations, factors internal to the individual professional, and factors present in unit cultures, the institution, and the larger health care environment. Corley et al. (2001) was the first to publish a quantitative measure of moral distress, and her scale has been adapted for use by others, including studies of other disciplines (Hamric and Blackhall 2007; Schwenzer and Wang 2006). Other scholars have proposed variations on Jameton's core definition (Sporrong et al. 2006, 2007), developing measures for related concepts such as moral sensitivity (Lutzen et al. 2006), ethics stress (Raines 2000), and stress of conscience (Glasberg et al. 2006). The lack of consistency and consensus on the definition of moral distress considerably complicates efforts to study it. Increased attention by researchers in disciplines other than nursing has taken different forms, some problematic. Cultural differences in the role of the nurse and understanding of actions that represent threats to moral integrity also challenge efforts to build a cohesive research-based understanding of the concept. In this paper, research efforts to date are reviewed. The importance of capturing root causes of moral distress in instruments, particularly those at unit and system levels, to allow for interventions to be appropriately targeted is highlighted. In addition, the issue of studying moral distress and interaction over time with moral residue is discussed. Promising recent work is described along with the potential these approaches open for research that can lead to interventions to decrease moral distress. Finally, opportunities for future research and study are identified, and recommendations for moving the research agenda forward are offered. © 2012 Springer Science+Business Media B.V. All rights reserved. Source

Lund H.G.,Virginia Commonwealth University | Reider B.D.,Thomas University | Whiting A.B.,Massachusetts General Hospital | Prichard J.R.,Thomas University
Journal of Adolescent Health | Year: 2010

Purpose: To characterize sleep patterns and predictors of poor sleep quality in a large population of college students. This study extends the 2006 National Sleep Foundation examination of sleep in early adolescence by examining sleep in older adolescents. Method: One thousand one hundred twenty-five students aged 17 to 24 years from an urban Midwestern university completed a cross-sectional online survey about sleep habits that included the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale, the Horne-Ostberg Morningness-Eveningness Scale, the Profile of Mood States, the Subjective Units of Distress Scale, and questions about academic performance, physical health, and psychoactive drug use. Results: Students reported disturbed sleep; over 60% were categorized as poor-quality sleepers by the PSQI, bedtimes and risetimes were delayed during weekends, and students reported frequently taking prescription, over the counter, and recreational psychoactive drugs to alter sleep/wakefulness. Students classified as poor-quality sleepers reported significantly more problems with physical and psychological health than did good-quality sleepers. Students overwhelmingly stated that emotional and academic stress negatively impacted sleep. Multiple regression analyses revealed that tension and stress accounted for 24% of the variance in the PSQI score, whereas exercise, alcohol and caffeine consumption, and consistency of sleep schedule were not significant predictors of sleep quality. Conclusions: These results demonstrate that insufficient sleep and irregular sleep-wake patterns, which have been extensively documented in younger adolescents, are also present at alarming levels in the college student population. Given the close relationships between sleep quality and physical and mental health, intervention programs for sleep disturbance in this population should be considered. © 2010 Society for Adolescent Medicine. Source

Iyer S.,Virginia Commonwealth University
Discovery Medicine | Year: 2013

Many human childhood mitochondrial disorders result from abnormal mitochondrial DNA (mtDNA) and altered bioenergetics. These abnormalities span most of the mtDNA, demonstrating that there are no "unique" positions on the mitochondrial genome that when deleted or mutated produce a disease phenotype. This diversity implies that the relationship between mitochondrial genotype and clinical phenotype is very complex. The origins of clinical phenotypes are thus unclear, fundamentally difficult-totreat, and are usually clinically devastating. Current treatment is largely supportive and the disorders progress relentlessly causing significant morbidity and mortality. Vitamin supplements and pharmacological agents have been used in isolated cases and clinical trials, but the efficacy of these interventions is unclear. In spite of recent advances in the understanding of the pathogenesis of mitochondrial diseases, a cure remains elusive. An optimal cure would be gene therapy, which involves introducing the missing gene(s) into the mitochondria to complement the defect. Our recent research results indicate the feasibility of an innovative protein-transduction ("protofection") technology, consisting of a recombinant mitochondrial transcription factor A (TFAM) that avidly binds mtDNA and permits efficient targeting into mitochondria in situ and in vivo. Thus, the development of gene therapy for treating mitochondrial disease offers promise, because it may circumvent the clinical abnormalities and the current inability to treat individual disorders in affected individuals. This review aims to focus on current treatment options and future therapeutics in mitochondrial disease treatment with a special emphasis on Leber's hereditary optic neuropathy. © 2013, Discovery Medicine. Source

Reshchikov M.A.,Virginia Commonwealth University
Physical Review B - Condensed Matter and Materials Physics | Year: 2012

We observed tunable two-step thermal quenching of photoluminescence in high-resistivity Zn-doped GaN. The characteristic temperatures of the first and second steps increase with increasing excitation intensity. The effect is explained within a phenomenological model involving shallow donors, nonradiative deep donors, and two types of acceptors. © 2012 American Physical Society. Source

Kendler K.S.,Virginia Commonwealth University
Psychological Medicine | Year: 2015

A fundamental debate in the philosophy of science is whether our central concepts are true or only useful instruments to help predict and manipulate the world. The first position is termed 'realism' and the second 'instrumentalism'. Strong support for the instrumentalist position comes from the 'pessimistic induction' (PI) argument. Given that many key scientific concepts once considered true (e.g. humors, ether, epicycles, phlogiston) are now considered false, how, the argument goes, can we assert that our current concepts are true? The PI argument applies strongly to psychiatric diagnoses. Given our long history of abandoned diagnoses, arguments that we have finally 'gotten it right' and developed definitive psychiatric categories that correspond to observer-independent reality are difficult to defend. For our current diagnostic categories, we should settle for a less ambitious vision of truth. For this, the coherence theory, which postulates that something is true when it fits well with the other things we confidently know about the world, can serve us well. Using the coherence theory, a diagnosis is real to the extent that it is well integrated into our accumulating scientific data base. Furthermore, the coherence theory establishes a framework for us to evaluate our diagnostic categories and can provide a set of criteria, closely related to our concept of validators, for deciding when they are getting better. Finally, we need be much less skeptical about the truth status of the aggregate concept of psychiatric illness than we are regarding the specific categories in our current nosology. Copyright © Cambridge University Press 2014. Source

Adler S.P.,Virginia Commonwealth University
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | Year: 2013

Reported maternal-to-fetal rates of primary cytomegalovirus (CMV) infection during pregnancy have been between 30% and 50%. The highest rate of symptomatic congenital infection and sequelae occurs in about 25% of infected infants born of mothers with a primary infection during pregnancy. Symptomatic infants demonstrate a constellation of clinical features that reflect placental dysfunction and probable viral infection of the central nervous system of the fetus. In the United States, we estimate that about 8000 affected infants are born each year. Two options may be available to prevent or treat maternal CMV infection during pregnancy, especially for women with exposure to young children in the home. The first is hygienic intervention. Two studies support the simplicity, harmlessness, and effectiveness of hygienic intervention to prevent child-to-mother transmission of CMV among high-risk pregnant women who know they are susceptible. The second is CMV immunoglobulin. A meta-analysis of 2 clinical trials showed an efficacy of 50% if immunoglobulin is given to pregnant women who have acquired a primary CMV infection during pregnancy. These results mean that seronegative pregnant women have options to prevent fetal infection. Source

Gunsolley J.C.,Virginia Commonwealth University
Journal of Dentistry | Year: 2010

The goal of this report is to present the current state of the evidence evaluating the efficacy of anti-plaque, anti-gingivitis mouthrinses and to determine the clinical relevance of the evidence. To accomplish this goal a two stage approach was used. First a systematic review of the literature was done to find any systematic review that evaluated the efficacy of anti-plaque, anti-gingivitis mouthrinses from long term (six months) randomized placebo controlled clinical trials. Secondly, the clinical relevance was determined by comparing the percent reduction in plaque and gingivitis attributable to the anti-plaque, anti-gingivitis mouthrinses to change over time in the placebo groups attributable to adult prophylaxis and oral hygiene instructions. Three systematic reviews and one meta-analysis were found that evaluated the efficacy of anti-plaque, anti-gingivitis mouthrinses. The systematic reviews concluded that there is strong evidence supporting the efficacy of chlorhexidine and essential oils as anti-plaque, anti-gingivitis mouthrinses. The evidence for cetyl pyridinium chloride (CPC) was weaker due to few clinical trials testing the same formulations of CPC. There was one meta-analysis of studies from a manufacure of Delmopinol, but it was not a systematic review of the literature. The report based on the meta-analysis concluded that Delmopinol was an effective anti-plaque, anti-gingivitis agent. Evaluation of clinical relevance by estimating percent reduction due to the active agents and changes over time in the placebo groups, demonstrated that the clinical effect of both chlorhexidine and essential oil containing mouthrinses met or exceeded reductions over time for placebo groups. Again the results for CPC were less consistent, but were similar to reductions over time in the placebo groups. These results suggest that the clinical benefits of anti-plaque, anti-gingivitis mouthrinses are similar to the benefits of oral prophylaxis and oral hygiene instructions at six month recall appointments. © 2010 Elsevier Ltd. Source

Roth E.M.,Sterling Research Group | McKenney J.M.,Virginia Commonwealth University | Hanotin C.,Sanofi S.A. | Asset G.,Sanofi S.A. | Stein E.A.,Metabolic and Atherosclerosis Research Center
New England Journal of Medicine | Year: 2012

BACKGROUND: Serum proprotein convertase subtilisin/kexin 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, increasing the degradation of LDL receptors and reducing the rate at which LDL cholesterol is removed from the circulation. REGN727/SAR236553 (designated here as SAR236553), a fully human PCSK9 monoclonal antibody, increases the recycling of LDL receptors and reduces LDL cholesterol levels. METHODS: We performed a phase 2, multicenter, double-blind, placebo-controlled trial involving 92 patients who had LDL cholesterol levels of 100 mg per deciliter (2.6 mmol per liter) or higher after treatment with 10 mg of atorvastatin for at least 7 weeks. Patients were randomly assigned to receive 8 weeks of treatment with 80 mg of atorvastatin daily plus SAR236553 once every 2 weeks, 10 mg of atorvastatin daily plus SAR236553 once every 2 weeks, or 80 mg of atorvastatin daily plus placebo once every 2 weeks and were followed for an additional 8 weeks after treatment. RESULTS: The least-squares mean (±SE) percent reduction from baseline in LDL cholesterol was 73.2±3.5 with 80 mg of atorvastatin plus SAR236553, as compared with 17.3±3.5 with 80 mg of atorvastatin plus placebo (P<0.001) and 66.2±3.5 with 10 mg of atorvastatin plus SAR236553. All the patients who received SAR236553, as compared with 52% of those who received 80 mg of atorvastatin plus placebo, attained an LDL cholesterol level of less than 100 mg per deciliter, and at least 90% of the patients who received SAR236553, as compared with 17% who received 80 mg of atorvastatin plus placebo, attained LDL cholesterol levels of less than 70 mg per deciliter (1.8 mmol per liter). CONCLUSIONS: In a randomized trial involving patients with primary hypercholesterolemia, adding SAR236553 to either 10 mg of atorvastatin or 80 mg of atorvastatin resulted in a significantly greater reduction in LDL cholesterol than that attained with 80 mg of atorvastatin alone. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials. gov number, NCT01288469.) Copyright © 2012 Massachusetts Medical Society. All rights reserved. Source

Sakao S.,Chiba University | Tatsumi K.,Chiba University | Voelkel N.F.,Virginia Commonwealth University
American Journal of Respiratory Cell and Molecular Biology | Year: 2010

Vascular remodeling is an important pathological feature of pulmonary arterial hypertension (PAH), which leads to increased pulmonary vascular resistance, with marked proliferation of pulmonary artery smooth muscle cells (SMC) and/or endothelial cells (EC). Successful treatment of experimental PAH with a platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitor offers the perspective of "reverse remodeling" (i.e., the regression of established pulmonary vascular lesions). Here we ask the question: which forms of pulmonary vascular remodeling are reversible and can such remodeling caused by angiogenic proliferation of EC be reversed? It is important to emphasize that the report showing reduction of vascular remodeling by PDGF receptor tyrosine kinase inhibitor showed only a reduction of the pulmonary artery muscularization in chronic hypoxia and monocrotaline models, which lack the feature of clustered proliferated EC in the lumen of pulmonary arteries. The regression of vascular muscularization is an important manifestation, whereby proliferative adult SMC convert back to a nonproliferative state. In contrast, in vitro experiments assessing the contribution of EC to the development of PAH demonstrated that phenotypically altered EC generated as a consequence of a vascular endothelial growth factor receptor blockade did not reverse to normal EC. Whereas it is suggested that the proliferative state of SMC may be reversible, it remains unknown whether phenotypically altered EC can switch back to a normal monolayer-forming EC. This article reviews the pathogenetic concepts of severe PAH and explains the many forms in PAH with reversible or irreversible remodeling. Source

Negus S.S.,Virginia Commonwealth University
Lab Animal | Year: 2013

Pain is often associated with clinically relevant depression of behavior and mood, and relief of pain-related depression is a common goal of treatment in both human and veterinary medicine. In the development of pharmacological compounds to treat pain and related depression, preclinical studies may be used to evaluate the analgesic potential of new drugs. Such studies require reliable, accurate assays of pain-related behavioral depression in animals. Intracranial self-stimulation (ICSS) is a type of operant conditioning procedure that produces stable baseline behavioral response rates. The author reviews recent research on the use of ICSS to evaluate the expression and pharmacological modulation of pain-related behavioral depression in rats. Results suggest that assays of pain-depressed behavior using ICSS may serve as a useful new tool to improve the translation of preclinical findings to clinical results in analgesic drug development. Source

Kendler K.S.,Virginia Commonwealth University
Molecular Psychiatry | Year: 2013

Psychiatric genetics has taught us a great deal about the nature of psychiatric disorders. Traditional family, twin and adoption studies have demonstrated the substantial role of genetic factors in their etiology, clarified the role of genetic factors in comorbidity, elucidated development pathways, and documented the importance of gene-environment correlation and interaction. We have also received some hard lessons when we were unable to detect replicable genes of large effect size and found that our much-valued candidate genes did not live up to their expected promise. With more mature molecular and statistical methods, we are entering now a different era. Statistical analyses of aggregate molecular signals are validating earlier heritability estimates. Replicated findings from genome-wide association studies are beginning to emerge, as are discoveries of large-effect size rare genomic variants. The number of such findings is likely to soon grow dramatically. The most pressing question facing the field is what biological picture these results will reveal. I articulate four possible scenarios that reflect (i) no, (ii) minimal, (iii) moderate and (iv) high biological coherence in the replicated molecular variant findings, which are soon likely to emerge. I discuss the factors that will likely influence these patterns, including the problems of etiological heterogeneity and multiple realizability. These findings could provide critical insights into the underlying biology of our psychiatric syndromes and potentially permit us to perceive, 'through a glass darkly,' the levels of the mind-brain system that are disordered. © 2013 Macmillan Publishers Limited All rights reserved. Source

Kendler K.S.,Virginia Commonwealth University
World Psychiatry | Year: 2016

A foundational question for the discipline of psychiatry is the nature of psychiatric disorders. What kinds of things are they? In this paper, I review and critique three major relevant theories: realism, pragmatism and constructivism. Realism assumes that the content of science is real and independent of human activities. I distinguish two "flavors" of realism: chemistry-based, for which the paradigmatic example is elements of the periodic table, and biology-based, for which the paradigm is species. The latter is a much better fit for psychiatry. Pragmatism articulates a sensible approach to psychiatric disorders just seeking categories that perform well in the world. But it makes no claim about the reality of those disorders. This is problematic, because we have a duty to advocate for our profession and our patients against other physicians who never doubt the reality of the disorders they treat. Constructivism has been associated with anti-psychiatry activists, but we should admit that social forces play a role in the creation of our diagnoses, as they do in many sciences. However, truly socially constructed psychiatric disorders are rare. I then describe powerful arguments against a realist theory of psychiatric disorders. Because so many prior psychiatric diagnoses have been proposed and then abandoned, can we really claim that our current nosologies have it right? Much of our current nosology arose from a series of historical figures and events which could have gone differently. If we re-run the tape of history over and over again, the DSM and ICD would not likely have the same categories on every iteration. Therefore, we should argue more confidently for the reality of broader constructs of psychiatric illness rather than our current diagnostic categories, which remain tentative. Finally, instead of thinking that our disorders are true because they correspond to clear entities in the world, we should consider a coherence theory of truth by which disorders become more true when they fit better into what else we know about the world. In our ongoing project to study and justify the nature of psychiatric disorders, we ought to be broadly pragmatic but not lose sight of an underlying commitment, despite the associated difficulties, to the reality of psychiatric illness. Source

Atkinson R.L.,Virginia Commonwealth University
International Journal of Pediatric Obesity | Year: 2011

There is increasing evidence that obesity in humans is associated with infection with human adenovirus-36 (Adv36). Infection of experimental animals with Adv36 demonstrates that this virus causes obesity. Human studies have shown a prevalence of Adv36 infection of 30% or greater in obese adult humans, but a correlation with obesity has not always been demonstrated. In contrast, three published studies and one presented study with a total of 559 children all show that there is an increase in prevalence of Adv36 infection in obese children (28%) compared to non-obese children (10%). The explanation for the apparently more robust correlation of Adv36 infection with obesity in children vs. adults is not clear. The data in animals and people suggests that Adv36 has contributed to the worldwide increase in childhood obesity. More research is needed to identify prevalences and consequences of Adv36 infection in people of all age groups and geographic locations. © 2011 Informa Healthcare. Source

Villalba-Galea C.A.,Virginia Commonwealth University
Biophysical Journal | Year: 2014

The voltage sensing domain (VSD) of the voltage-gated proton channel Hv1 mediates a H+-selective conductance that is coordinately controlled by the membrane potential (V) and the transmembrane pH gradient (ΔpH). Allosteric control of Hv1 channel opening by ΔpH (V-ΔpH coupling) is manifested by a characteristic shift of approximately 40 mV per ΔpH unit in the activation. To further understand the mechanism for V-ΔpH coupling in Hv1, H+ current kinetics of activation and deactivation in excised membrane patches were analyzed as a function of the membrane potential and the pH in the intracellular side of the membrane (pHI). In this study, it is shown for the first time to our knowledge that the opening of Hv1 is preceded by a voltage-independent transition. A similar process has been proposed to constitute the step involving coupling between the voltage-sensing and pore domains in tetrameric voltage-gated channels. However, for Hv1, the VSD functions as both the voltage sensor and the conduction pathway, suggesting that the voltage independent transition is intrinsic to the voltage-sensing domain. Therefore, this article proposes that the underlying mechanism for the activation of Hv1 involves a process similar to VSD relaxation, a process previously described for voltage-gated channels and voltage-controlled enzymes. Finally, deactivation seemingly occurs as a strictly voltage dependent process, implying that the kinetic event leading to opening of the proton conductance are different than those involved in the closing. Thus, from this work it is proposed that Hv1 activity displays hysteresis. © 2014 Biophysical Society. Source

Ellenbogen K.A.,Virginia Commonwealth University | Gunderson B.D.,Medtronic | Stromberg K.D.,Medtronic | Swerdlow C.D.,University of California at Los Angeles
Circulation: Arrhythmia and Electrophysiology | Year: 2013

Background-The Lead Integrity Alert (LIA) was developed for Medtronic implantable cardioverter defibrillators to reduce inappropriate shocks for rapid oversensing caused by conductor fractures and reported for Medtronic Fidelis conductor fractures. The goal of this study was to compare the performance of LIA with conventional impedance monitoring for identifying lead system events (LSEs) and lead failures (LFs) in lead families that differ from Fidelis. Methods and Results-We analyzed data from 12 793 LIA enabled implantable cardioverter-defibrillator and lead combinations including 6123 St. Jude Riata or Durata, 5114 Boston Scientific Endotak, and 1556 Fidelis combinations followed in the CareLink remote monitoring network for LSEs and LFs. Each alert was adjudicated based on implantable cardioverterdefibrillator stored electrograms/diagnostics and clinical data as an LSE or non-lead system event by 2 physicians after reviewing the electrograms and clinical data. During 13 562 patient-years of LIA follow-up, there were 179 adjudicated alerts, of which 84 were LSEs (including 65 LFs) and 95 were non-lead system events. LIA identified >66% more LSE and >67% more LF compared with conventional impedance monitoring and did not differ by lead family for LSE (P=0.573) or LF (P=0.332). Isolated spikes on electrogram were associated more often with LF in St. Jude leads (71%) compared with Endotak (9%; P<0.001) and Fidelis leads (11%; P<0.001). The non-lead system event detection rate was different among lead families (P<0.001) ranging from 1 in every 78.5 years (Endotak), 228.9 years (St. Jude leads), and 627.6 years (Fidelis). Conclusions-LIA markedly increased the detection rate of LSE compared with conventional impedance monitoring. © 2013 American Heart Association, Inc. Source

Iyengar S.G.,Syracuse University | Niu R.,Virginia Commonwealth University | Varshney P.K.,Syracuse University
IEEE Transactions on Signal Processing | Year: 2012

In this paper, we consider a binary decentralized detection problem where the local sensor observations are quantized before their transmission to the fusion center. Sensor observations, and hence their quantized versions, may be heterogeneous as well as statistically dependent. A composite binary hypothesis testing problem is formulated, and a copula-based generalized likelihood ratio test (GLRT) based fusion rule is derived given that the local sensors are uniform multilevel quantizers. An alternative computationally efficient fusion rule is also designed which involves injecting a deliberate random disturbance to the local sensor decisions before fusion. Although the introduction of external noise causes a reduction in the received signal-to-noise ratio (SNR), it is shown that the proposed approach can result in a detection performance comparable to the GLRT detector without external noise, especially when the number of quantization levels is large. © 1991-2012 IEEE. Source

Kendler K.S.,Virginia Commonwealth University
Molecular Psychiatry | Year: 2015

This essay traces the history of concepts of genetic variation and schizophrenia from Darwin and Mendel to the present. For Darwin, the important form of genetic variation for evolution is continuous in nature and small in effect. Biometricians led by Pearson agreed and developed statistical genetic approaches utilizing trait correlations in relatives. Mendel studied discontinuous traits and subsequent Mendelians, led by Bateson, assumed that important genetic variation was large in effect producing discontinuous phenotypes. Although biometricians studied 'insanity', schizophrenia genetics under Kraepelin and Rüdin utilized Mendelian approaches congruent with their anatomical-clinical disease model of dementia praecox. Fisher showed, assuming many genes of small effect, Mendelian and Biometrical models were consilient. Echoing prior conflicts, psychiatric genetics since then has utilized both biometrical models, largely in twins, and Mendelian models, based on advancing molecular techniques. In 1968, Gottesman proposed a polygenic model for schizophrenia based on a threshold version of Fisher's theory. Since then, rigorous studies of the schizophrenia spectrum suggest that genetic risk for schizophrenia is more likely continuous than categorical. The last 5 years has seen increasingly convincing evidence from genome-wide association study (GWAS) and sequencing that genetic risk for schizophrenia is largely polygenic, and congruent with Fisher's and Gottesman's models. The gap between biometrical and molecular Mendelian models for schizophrenia has largely closed. The efforts to ground a categorical biomedical model of schizophrenia in Mendelian genetics have failed. The genetic risk for schizophrenia is widely distributed in human populations so that we all carry some degree of risk. © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15. Source

Masazade E.,Syracuse University | Niu R.,Virginia Commonwealth University | Varshney P.K.,Syracuse University
IEEE Transactions on Signal Processing | Year: 2012

In this paper, we study the target tracking problem in wireless sensor networks (WSNs) using quantized sensor measurements where the total number of bits that can be transmitted from sensors to the fusion center is limited. At each time step of tracking, a total of available bits need to be distributed among the sensors in the WSN for the next time step. The optimal solution for the bit allocation problem can be obtained by using a combinatorial search which may become computationally prohibitive for large and . Therefore, we develop two new suboptimal bit allocation algorithms which are based on convex optimization and approximate dynamic programming (A-DP). We compare the mean squared error (MSE) and computational complexity performances of convex optimization and A-DP with other existing suboptimal bit allocation schemes based on generalized Breiman, Friedman, Olshen, and Stone (GBFOS) algorithm and greedy search. Simulation results show that, A-DP, convex optimization and GBFOS yield similar MSE performance, which is very close to that based on the optimal exhaustive search approach and they outperform greedy search and nearest neighbor based bit allocation approaches significantly. Computationally, A-DP is more efficient than the bit allocation schemes based on convex optimization and GBFOS, especially for a large sensor network. © 2012 IEEE. Source

Mital M.,Virginia Commonwealth University
Applied Thermal Engineering | Year: 2013

Thermal management issues are limiting barriers to high density electronics packaging and miniaturization. Liquid cooling using micro and mini channels is an attractive alternative to large and bulky aluminum or copper heat sinks. These channels can be integrated directly into a chip or a heat spreader, and cooling can be further enhanced using nanofluids (liquid solutions with dispersed nanometer-sized particles) due to their enhanced heat transfer effects reported in literature. The goals of this study are to evaluate heat transfer improvement of a nanofluid heat sink with developing laminar flow forced convection, taking into account the pumping power penalty. The phrase heat transfer enhancement ratio (HTR) is used to denote the ratio of average heat transfer coefficient of nanofluid to water at the same pumping power. The proposed model uses semi-empirical correlations to calculate nanofluid thermophysical properties. The predictions of the model are found to be in good agreement with experimental studies. The validated model is used to identify important design variables (Reynolds number, volume fraction and particle size) related to thermal and flow characteristics of the microchannel heat sink with nanofluids. Statistical analysis of the model showed that the volume fraction is the most significant factor impacting the HTR, followed by the particle diameter. The impact of the Reynolds number and other interaction terms is relatively weak. The HTR is maximized at smallest possible particle diameter (since smaller particles improve heat transfer but do not impact pumping power). Then, for a given Reynolds number, an optimal value of volume fraction can be obtained to maximize HTR. The overall aim is to present results that would be useful for understanding and optimal design of microchannel heat sinks with nanofluid flow. © 2012 Elsevier Ltd. All rights reserved. Source

Chen-Scarabelli C.,University of Michigan | Scarabelli T.M.,Zena And Michael A Wiener Cardiovascular Institute | Ellenbogen K.A.,Virginia Commonwealth University | Halperin J.L.,Zena And Michael A Wiener Cardiovascular Institute
Journal of the American College of Cardiology | Year: 2015

Atrial fibrillation (AF) is the most common clinically significant arrhythmia and conveys an increased risk of stroke, regardless of whether it is symptomatic. Despite multiple studies supporting an association between subclinical atrial tachyarrhythmias (ATs) detected by cardiac implantable electronic devices and increased risk of thromboembolic events, clinical intervention for device-detected AT remains sluggish, with some clinicians delaying treatment and instead opting for continued surveillance for additional or longer episodes. However, the 2014 updated clinical practice guidelines on AF recommend use of the CHA2DS2-VASc stroke risk score for nonvalvular AF, with oral anticoagulation recommended for scores ≥2, regardless of whether AF is paroxysmal, persistent, or permanent. This paper reviews the epidemiology of AF and mechanisms of stroke in AF, and discusses device-detected AF and its clinical implications. © 2015 American College of Cardiology Foundation. Source

Aubree Shay L.,University of Texas at San Antonio | Lafata J.E.,Virginia Commonwealth University
Medical Decision Making | Year: 2015

Background. Despite widespread advocacy for shared decision making (SDM), the empirical evidence regarding its effectiveness to improve patient outcomes has not been systematically reviewed. The purpose of this study was to systematically review the empirical evidence linking patient outcomes and SDM, when the decision-making process has been explicitly measured, and to identify under what measurement perspectives SDM is associated with which types of patient outcomes (affective-cognitive, behavioral, and health).Data Sources. PubMed (through December 2012) and hand search of article bibliographies.Study Selection. Studies were included if they empirically 1) measured SDM in the context of a patient-clinician interaction and 2) evaluated the relationship between SDM and at least 1 patient outcome.Data Extraction. Study results were categorized by SDM measurement perspective (patient-reported, clinician-reported, or observer-rated) and outcome type (affective-cognitive, behavioral, or health).Data Synthesis. Thirty-nine studies met inclusion criteria. Thirty-three used patient-reported measures of SDM, 6 used observer-rated measures, and 2 used clinician-reported measures. Ninety-seven unique patient outcomes were assessed; 51% affective-cognitive, 28% behavioral, and 21% health. Only 43% of assessments (n = 42) found a significant and positive relationship between SDM and the patient outcome. This proportion varied by SDM measurement perspective and outcome category. It was found that 52% of outcomes assessed with patient-reported SDM were significant and positive, compared with 21% with observer-rated and 0% with clinician-reported SDM. Regardless of measurement perspective, SDM was most likely to be associated with affective-cognitive patient outcomes (54%), compared with 37% of behavioral and 25% of health outcomes.Limitations. The relatively small number of studies precludes meta-analysis. Because the study inclusion and exclusion criteria required both an empirical measure of SDM and an assessment of the association between that measure and a patient outcome, most included studies were observational in design.Conclusions. SDM, when perceived by patients as occurring, tends to result in improved affective-cognitive outcomes. Evidence is lacking for the association between empirical measures of SDM and patient behavioral and health outcomes. © 2014 The Author(s). Source

Olsen C.M.,QIMR Berghofer Medical Research Institute | Williams P.F.,Virginia Commonwealth University | Whiteman D.C.,QIMR Berghofer Medical Research Institute
Journal of the American Academy of Dermatology | Year: 2014

Background Keratinocyte cancers (basal cell carcinoma, squamous cell carcinoma) are the commonest cancers in human beings. Population data on incidence trends are scant because few jurisdictions reliably record diagnoses or treatments. Objective We sought to examine temporal trends of treating keratinocyte cancers in Australia. Methods We analyzed Medicare Australia data relating to the diagnosis and treatment of keratinocyte skin cancer between 2000 and 2011. We examined counts and rates for each procedure, and the average annual percentage rate of change. Results There were significant increases in excision rates for keratinocyte cancers (3.3% per annum for men and 2.2% per annum for women), however temporal trends differed significantly by age group. Although annual increases in excision rates were highest for men aged 75 to 84 years (8.6% per annum), they declined significantly for men and women younger than 45 years. Skin biopsy rates increased substantially in all age groups over the study period, suggesting no lessening in skin cancer surveillance in any age group. Limitations The Medicare data do not include services provided in public hospitals, however fewer than 2% of skin cancers are treated in these settings. Conclusions Although overall treatment rates for keratinocyte cancers have increased substantially during the past decade, excision rates are declining in younger Australians. © 2014 by the American Academy of Dermatology, Inc. Source

Lister J.A.,Virginia Commonwealth University
Methods in Cell Biology | Year: 2011

On the strengths of forward genetics and embryology, the zebrafish Danio rerio has become an ideal system for the study of early vertebrate development. However, additional tools will be needed to perform more sophisticated analyses and to successfully carry this model into new areas of study such as adult physiology, cancer, and aging. As improved tools make transgenesis more and more efficient, the stage has been set for precise modification of the zebrafish genome such as are done in other model organisms. Genome engineering strategies employing site-specific recombinase (SSR) systems such as Cre/. lox and Flp/. FRT have become invaluable to the study of gene function in the mouse and Drosophila and are now being exploited in zebrafish as well. My laboratory has begun to use another such SSR, the integrase encoded by the Streptomyces bacteriophage PhiC31, for manipulation of the zebrafish genome. The PhiC31 integrase promotes recombination between an attachment site in the phage (attP) and another on the bacterial chromosome (attB). Here I describe strategies using the PhiC31 integrase to mediate recombination of transgenes containing attP and attB sites in cis to excise elements with spatial and temporal specificity. The feasibility of the intramolecular recombination approach having been established, I discuss prospects for employing PhiC31 integrase for intermolecular recombination, i.e., transgene integration at defined sites in the genome. © 2011 Elsevier Inc. Source

Jayaraman S.,Virginia Commonwealth University
The Cochrane database of systematic reviews | Year: 2014

Injury is responsible for an increasing global burden of death and disability. As a result, new models of trauma care have been developed. Many of these, though initially developed in high-income countries (HICs), are now being adopted in low and middle-income countries (LMICs). One such trauma care model is advanced trauma life support (ATLS) training in hospitals, which is being promoted in LMICs as a strategy for improving outcomes for victims of trauma. The impact of this health service intervention, however, has not been rigorously tested by means of a systematic review in either HIC or LMIC settings. To quantify the impact of ATLS training for hospital staff on injury mortality and morbidity in hospitals with and without such a training program. The search for studies was run on the 16th May 2014. We searched the Cochrane Injuries Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (Ovid), ISI WOS (SCI-EXPANDED, SSCI, CPCI-S & CPSI-SSH), CINAHL Plus (EBSCO), PubMed and screened reference lists. Randomised controlled trials, controlled trials and controlled before-and-after studies comparing the impact of ATLS-trained hospital staff versus non-ATLS trained hospital staff on injury mortality and morbidity. Three authors applied the eligibility criteria to trial reports for inclusion, and extracted data. None of the studies identified by the search met the inclusion criteria for this review. There is no evidence from controlled trials that ATLS or similar programs impact the outcome for victims of injury, although there is some evidence that educational initiatives improve knowledge of hospital staff of available emergency interventions. Furthermore, there is no evidence that trauma management systems that incorporate ATLS training impact positively on outcome. Future research should concentrate on the evaluation of trauma systems incorporating ATLS, both within hospitals and at the health system level, by using more rigorous research designs. Source

Di Salvo M.L.,University of Rome La Sapienza | Contestabile R.,University of Rome La Sapienza | Safo M.K.,Virginia Commonwealth University
Biochimica et Biophysica Acta - Proteins and Proteomics | Year: 2011

Vitamin B 6 is a generic term referring to pyridoxine, pyridoxamine, pyridoxal and their related phosphorylated forms. Pyridoxal 5′-phosphate is the catalytically active form of vitamin B 6, and acts as cofactor in more than 140 different enzyme reactions. In animals, pyridoxal 5′-phosphate is recycled from food and from degraded B 6-enzymes in a "salvage pathway", which essentially involves two ubiquitous enzymes: an ATP-dependent pyridoxal kinase and an FMN-dependent pyridoxine 5′-phosphate oxidase. Once it is made, pyridoxal 5′-phosphate is targeted to the dozens of different apo-B 6 enzymes that are being synthesized in the cell. The mechanism and regulation of the salvage pathway and the mechanism of addition of pyridoxal 5′-phosphate to the apo-B 6-enzymes are poorly understood and represent a very challenging research field. Pyridoxal kinase and pyridoxine 5′-phosphate oxidase play kinetic roles in regulating the level of pyridoxal 5′-phosphate formation. Deficiency of pyridoxal 5′-phosphate due to inborn defects of these enzymes seems to be involved in several neurological pathologies. In addition, inhibition of pyridoxal kinase activity by several pharmaceutical and natural compounds is known to lead to pyridoxal 5′-phosphate deficiency. Understanding the exact role of vitamin B 6 in these pathologies requires a better knowledge on the metabolism and homeostasis of the vitamin. This article summarizes the current knowledge on structural, kinetic and regulation features of the two enzymes involved in the PLP salvage pathway. We also discuss the proposal that newly formed PLP may be transferred from either enzyme to apo-B 6-enzymes by direct channeling, an efficient, exclusive, and protected means of delivery of the highly reactive PLP. This new perspective may lead to novel and interesting findings, as well as serve as a model system for the study of macromolecular channeling. This article is part of a Special Issue entitled: Pyridoxal Phosphate Enzymology. © 2010 Elsevier B.V. All rights reserved. Source

Moxley G.,Virginia Commonwealth University
Clinical Breast Cancer | Year: 2010

Background: Aromatase inhibitor therapy is often effective for breast cancer, yet it can be accompanied by musculoskeletal pain and stiffness. This prevalence assessment aimed to characterize a rheumatologist's view of frequency and clinical features, including associated disability, within a breast cancer clinic panel of 77 patients. Patients and Methods: The "aromatase inhibitor arthralgia" frequency was estimated at 50%, including both those with new and worsened discomfort. Substantial functional disability was associated, whether measured by individual functional disability (frequencies ranging from 39% to 61%) or composite score of 7 functional disability areas (median score 5 compared with median 0 in the comparison group; P = .00003). Results: The frequency of clinical hand osteoarthritis appeared somewhat increased in the aromatase inhibitor arthralgia group (28% vs. 14%; not statistically significant). Yet the distribution of aromatase inhibitor-related symptoms and functional disabilities appeared to parallel those joint regions commonly affected by osteoarthritis. Using clinical criteria to assess 5 common rheumatic disorders (hand osteoarthritis, trigger finger, carpal tunnel syndrome, Raynaud's phenomenon, and sicca syndrome), the aromatase inhibitor arthralgia group tended to have more common rheumatic disorders (P < .05), consistent with nociceptive mechanisms making latent disorders symptomatic. Conclusion: Aromatase inhibitor therapy for postmenopausal breast cancer might be associated with common musculoskeletal symptoms and with substantial functional disability and should prompt patient education. In view of the potential relevance of estrogen deprivation to osteoarthritis onset and severity, future studies of natural history should include systematic assessment of osteoarthritis frequency and severity. Source

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

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

Kendler K.S.,Virginia Commonwealth University
Molecular Psychiatry | Year: 2013

In influencing risk for psychiatric and substance use disorders, genes are typically conceptualized as working in silent physiological pathways in the bowels of our biology, far from the influences of human desires. I here argue that this model of gene action is too restricted. At the individual, family and societal level, humans can, through their decision-making capacity, intervene in causal pathways from genes to behavior. At the individual level, I present four paradigmatic cases involving alcohol dependence, major depression, general externalizing behaviors and animal phobia showing how human decisions can inhibit the expression of risk genes. I review the literatures demonstrating that parental behaviors can suppress or augment the heritability of traits in their children, and social attitudes can alter and even create causal pathways from genes to phenotypes. We evolved from organisms whose nervous systems were networks of reflexes that then developed simple cognitive systems and finally self-reflection. Just as our cognitions have gone 'meta,' we are now nearing a time when we can go 'meta' about our genetic risk. For many psychiatric disorders, our risk genes are not entirely cordoned off in our silent, purposeless biological substrate. Rather, we are able to make decisions that impact on the expression of our own genomes, those of our loved ones and those of our friends and neighbors. Our actions and our genes are often weaved together, integrated into the fabric of our lives. © 2013 Macmillan Publishers Limited. All rights reserved 1359-4184/13. Source

Sanyal A.J.,Virginia Commonwealth University
Liver International | Year: 2011

Hepatitis C is a common cause of chronic viral infection of the liver. It is associated with insulin resistance and the development of type 2 diabetes mellitus. It is also associated with the development of hepatic steatosis. The presence of hepatic steatosis is associated with an increased risk of having hepatic fibrosis. This is also associated with the severity of insulin resistance. These findings are specifically germane for those with genotype1 infection. Genotype 3 infection independently causes steatosis and successful treatment of the virus is followed by resolution of steatosis. In genotype 1 infection, the presence of hepatic steatosis is also a risk factor for failure to respond to pegylated interferon and ribavirin therapy. Unfortunately efforts to treat insulin resistance prior to antiviral therapy have not been very successful. Newer efforts focused on the role of specific micro RNAs in mediating the metabolic effects of hepatitis C virus infection may provide to ameliorate the metabolic risks of HCV infection. © 2011 John Wiley & Sons A/S. Source

de Wit M.,Virginia Commonwealth University
Respiratory Care | Year: 2011

Monitoring of patient-ventilator interactions at the bedside involves evaluation of patient breathing pattern on ventilator settings. One goal of mechanical ventilation is to have ventilator-assisted breathing coincide with patient breathing. The objectives of this goal are to have patient breath initiation result in ventilator triggering without undue patient effort, to match assisted-breath delivery with patient inspiratory effort, and to have assisted breathing cease when the patient terminates inspiration, thus avoiding ventilator-assisted inspiration during patient exhalation. Asynchrony can occur throughout the respiratory cycle, and this paper describes common asynchronies. The types of asynchronies discussed are trigger asynchrony (ie, breath initiation that may manifest as ineffective triggering, double-triggering, or auto-triggering); flow asynchrony (ie, breath-delivery asynchrony, which may manifest as assisted-breath delivery being faster or slower than what patient desires); and cycling asynchronies (ie, termination of assisted inspiration does not coincide with patient breath termination, which may manifest as delayed cycling or premature cycling). Various waveforms are displayed and graphically demonstrate asynchronies; basic principles of waveform interpretation are discussed. © 2011 Daedalus Enterprises. Source

Meredith M.A.,Virginia Commonwealth University | Allman B.L.,University of Western Ontario
European Journal of Neuroscience | Year: 2015

The recent findings in several species that the primary auditory cortex processes non-auditory information have largely overlooked the possibility of somatosensory effects. Therefore, the present investigation examined the core auditory cortices (anterior auditory field and primary auditory cortex) for tactile responsivity. Multiple single-unit recordings from anesthetised ferret cortex yielded histologically verified neurons (n = 311) tested with electronically controlled auditory, visual and tactile stimuli, and their combinations. Of the auditory neurons tested, a small proportion (17%) was influenced by visual cues, but a somewhat larger number (23%) was affected by tactile stimulation. Tactile effects rarely occurred alone and spiking responses were observed in bimodal auditory-tactile neurons. However, the broadest tactile effect that was observed, which occurred in all neuron types, was that of suppression of the response to a concurrent auditory cue. The presence of tactile effects in the core auditory cortices was supported by a substantial anatomical projection from the rostral suprasylvian sulcal somatosensory area. Collectively, these results demonstrate that crossmodal effects in the auditory cortex are not exclusively visual and that somatosensation plays a significant role in modulation of acoustic processing, and indicate that crossmodal plasticity following deafness may unmask these existing non-auditory functions. © 2015 Federation of European Neuroscience Societies and John Wiley and Sons Ltd. Source

Fauber T.L.,Virginia Commonwealth University
Radiologic technology | Year: 2011

To explore digital exposure techniques during pelvic imaging on patient dosimetry, exposure indicator (EXI) values and image quality. An experimental design was used to study the effect of varying kilovoltage peak (kVp) and milliampere-seconds (mAs) on a male phantom pelvis when using a direct digital radiography (DR) flat panel detector. The radiation intensity was varied by increasing the kVp and reducing mAs. Image quality was evaluated by assessing density, density differences, quantum noise and overall diagnostic quality. When the kVp was increased in 15% increments and mAs divided by half, the radiation dose to the gonads significantly decreased. The lowest and highest kVp exposure groups produced the lowest EXI values. There was no correlation between the thermoluminescent dosimeter milliroentgen (mR) measurements and the EXI values. The results indicate that a pelvic DR image produced at 93 kVp and 12.5 mAs will reduce the gonadal dose while maintaining an image of diagnostic quality. Source

Ginder G.D.,Virginia Commonwealth University
Translational Research | Year: 2015

The developmental regulation of globin gene expression has served as an important model for understanding higher eukaryotic transcriptional control mechanisms. During human erythroid development, there is a sequential switch from expression of the embryonic ε-globin gene to the fetal É£-globin gene in utero, and postpartum the É£-globin gene is silenced, as the β-globin gene becomes the predominantly expressed locus. Because the expression of normally silenced fetal É£-type globin genes and resultant production of fetal hemoglobin (HbF) in adult erythroid cells can ameliorate the pathophysiological consequences of both abnormal β-globin chains in sickle cell anemia and deficient β-globin chain production in β-thalassemia, understanding the complex mechanisms of this developmental switch has direct translational clinical relevance. Of particular interest for translational research are the factors that mediate silencing of the É£-globin gene in adult stage erythroid cells. In addition to the regulatory roles of transcription factors and their cognate DNA sequence motifs, there has been a growing appreciation of the role of epigenetic signals and their cognate factors in gene regulation, and in particular in gene silencing through chromatin. Much of the information about epigenetic silencing stems from studies of globin gene regulation. As discussed here, the term epigenetics refers to postsynthetic modifications of DNA and chromosomal histone proteins that affect gene expression and can be inherited through somatic cell replication. A full understanding of the molecular mechanisms of epigenetic silencing of HbF expression should facilitate the development of more effective treatment of β-globin chain hemoglobinopathies. © 2015 Elsevier Inc. Source

Wu W.,Virginia Commonwealth University
Journal of Technology Transfer | Year: 2010

Research shows that there are important institutional underpinnings for building university-industry linkages. This paper aims to understand how China is developing the relevant organizational structures and incentives in its universities. What academic institutions shape the scope and channels of university-industry linkages? What incentives do universities provide to encourage and facilitate faculty engagement with industry? My analysis is accomplished through content analysis of university documents and in-depth interviews with personnel in two top institutions-Fudan University and Shanghai Jiaotong University, supplemented by official statistics. It shows that the hybrid organizational structure to manage technology transfer is a product of historical legacy and institutional learning-parts uniquely Chinese and parts adapted from the West. Faculty incentives also have varied effects. In spite of being enticed to disclose inventions and pursue commercialization, faculty remains keener on scholarly publications. © 2009 Springer Science+Business Media, LLC. Source

Budanov A.V.,Virginia Commonwealth University
Sub-Cellular Biochemistry | Year: 2014

Tumor suppressor p53 is inactivated in most cancers and the critical role of p53 in the suppression of carcinogenesis has been confirmed in many mouse models. The protein product of the tumor suppressor p53 gene works as a transcriptional regulator, activating expression of numerous genes involved in cell death, cell cycle arrest, senescence, DNA-repair and many other processes. In spite of the multiple efforts to characterize the functions of p53, the mechanisms of tumor suppression by p53 are still elusive. Recently, new activities of p53 such as regulation of reactive oxygen species (ROS) and metabolism have been described and the p53-regulated genes responsible for these functions have been identified. Metabolic derangements and accumulation of ROS are features of carcinogenesis, supporting the idea that many tumor suppressive effects of p53 can be mediated by regulation of metabolism and/or ROS. Mutations in the p53 gene can not only inactivate wild type function of p53 but also endow p53 with new functions such as activation of new metabolic pathways contributing to carcinogenesis. Understanding the metabolic and antioxidant functions of p53 allows us to develop approaches to restore p53 function in cancers, where p53 is inactivated, in other to ensure the best outcome of anti-cancer treatment. © Springer Science+Business Media Dordrecht 2014. Source

To report a case of subtherapeutic linezolid concentrations in a patient with morbid obesity. A 34-year-old male with morbid obesity (265 kg, body mass index 82 kg/m(2)) was admitted for severe sepsis due to respiratory failure requiring emergent intubation and treatment of community-acquired pneumonia. Admission tracheal aspirate culture revealed methicillin-resistant Staphylococcus aureus (MRSA) for which vancomycin was prescribed. Therapy subsequently was changed to linezolid, because the patient's clinical status worsened, with significant hypoxia (partial pressure of arterial oxygen/fraction of inspired oxygen [PaO2/FiO2] ratio 145), increasing leukocytosis (white blood cell count from 10,800/μL on admission to 15,400/μL on hospital day 6), and persistent fever (38.3 °C). After 48 hours of linezolid monotherapy, the patient remained febrile with continued leukocytosis, worsening hypoxemia, and a persistently positive MRSA culture from a repeat endotracheal aspirate. Linezolid serum concentrations were obtained and vancomycin was reinstituted, after which the patient began to improve (afebrile, improving PaO2/FiO2 ratio, decreasing leukocytosis). On hospital day 12, the patient removed his endotracheal tube, and a sputum sample was obtained for culture. The patient's clinical status subsequently declined, prompting addition of cefepime to his antibiotic regimen. This sputum culture revealed not only MRSA, but also quinolone-resistant Escherichia coli. After completing treatment for both organisms the patient was discharged home. Limited data on linezolid dosing in the morbidly obese population show lower serum drug concentrations than those in nonobese patients, but no clinical failure has been reported when treating MRSA skin and soft tissue infections or MRSA tracheitis. In our patient, low steady-state linezolid serum concentrations (peak 4.13 μg/mL [reference 15-27] and trough 1.27 μg/mL [reference 2-9]) were thought to contribute to his poor clinical response. To our knowledge, this is the first report of subtherapeutic linezolid concentrations correlated with decreased clinical effectiveness when during treatment of MRSA pneumonia in a patient with morbid obesity. Source

The incidence of hepatocellular carcinoma (HCC) is increasing worldwide. This is largely to do with the epidemic of chronic hepatitis C virus (HCV) in the USA and other developed countries and an increasing prevalence of cirrhosis. The current treatment for chronic HCV is peginterferon (Peg-IFN) and ribavirin. Unfortunately, response rates are limited especially in patients with cirrhosis. Several observations have led to the hypothesis that continuing Peg-IFN as maintenance therapy in patients with chronic HCV and cirrhosis could reduce the risk of developing complications including HCC. However, three large prospective controlled trials of maintenance therapy have now failed to demonstrate that Peg-IFN maintenance therapy reduces complications of cirrhosis, HCC and liver-related mortality. In the HALT-C trial, the only one of these three studies for which HCV RNA data is available during maintenance therapy, only a minimal reduction in serum HCV RNA level was observed during maintenance therapy. It therefore remains uncertain if profound and persistent virologic suppression to undetectable levels of HCV RNA impacts the risk of developing HCC in patients with chronic HCV and advanced fibrosis or cirrhosis. Based upon the available data, there appears to be no rationale for utilizing Peg-IFN maintenance therapy in patients with cirrhosis and this approach does not reduce the risk of HCC. Copyright © 2010 S. Karger AG. Source

Thomson R.M.,Carleton University | Tedgren A.C.,Linkoping University | Williamson J.F.,Virginia Commonwealth University
Physics in Medicine and Biology | Year: 2013

The purpose of this work is to investigate how alternative macroscopic dose descriptors track absorbed dose to biologically relevant subcellular targets via Monte Carlo (MC) analysis of cellular models for a variety of cancerous and normal soft tissues for kilovoltage radiation. The relative mass distributions of water, light inorganic elements, and protein components of nuclear and cytoplasm compartments for various tissues are determined from a literature review. These data are used to develop representative cell models to demonstrate the range of mass elemental compositions of these subcellular structures encountered in the literature from which radiological quantities (energy absorption and attenuation coefficients; stopping powers) are computed. Using representative models of cell clusters, doses to subcellular targets are computed using MC simulation for photon sources of energies between 20 and 370 keV and are compared to bulk medium dose descriptors. It is found that cells contain significant and varying mass fractions of protein and inorganic elements, leading to variations in mass energy absorption coefficients for cytoplasm and nuclear media as large as 10% compared to water for sub-50 keV photons. Doses to subcellular structures vary by as much as 23% compared to doses to the corresponding average bulk medium or to small water cavities embedded in the bulk medium. Relationships between cellular target doses and doses to the bulk medium or to a small water cavity embedded in the bulk medium are sensitive to source energy and cell morphology, particularly for lower energy sources, e.g., low energy brachytherapy (<50 keV). Results suggest that cells in cancerous and normal soft tissues are generally not radiologically equivalent to either water or the corresponding average bulk tissue. For kilovoltage photon sources, neither dose to bulk medium nor dose to water quantitatively tracks energy imparted to biologically relevant subcellular targets for the range of cellular morphologies and tissues considered. © 2013 Institute of Physics and Engineering in Medicine. Source

Samaha M.A.,Princeton University | Gad-el-Hak M.,Virginia Commonwealth University
Polymers | Year: 2014

We review recent developments in nature-inspired superhydrophobic and omniphobic surfaces. Water droplets beading on a surface at significantly high static contact angles and low contact-angle hystereses characterize superhydrophobicity. Microscopically, rough hydrophobic surfaces could entrap air in their pores resulting in a portion of a submerged surface with air-water interface, which is responsible for the slip effect. Suberhydrophobicity enhances the mobility of droplets on lotus leaves for self-cleaning purposes, so-called lotus effect. Amongst other applications, superhydrophobicity could be used to design slippery surfaces with minimal skin-friction drag for energy conservation. Another kind of slippery coatings is the recently invented slippery liquid-infused porous surfaces (SLIPS), which are one type of omniphobic surfaces. Certain plants such as the carnivorous Nepenthes pitcher inspired SLIPS. Their interior surfaces have microstructural roughness, which can lock in place an infused lubricating liquid. The lubricant is then utilized as a repellent surface for other liquids such as water, blood, crude oil, and alcohol. In this review, we discuss the concepts of both lotus effect and Nepenthes slippery mechanism. We then present a review of recent advances in manufacturing polymeric and non-polymeric slippery surfaces with ordered and disordered micro/nanostructures. Furthermore, we discuss the performance and longevity of such surfaces. Techniques used to characterize the surfaces are also detailed. We conclude the article with an overview of the latest advances in characterizing and using slippery surfaces for different applications. © 2014 by the authors; licensee MDPI, Basel, Switzerland. Source

Ratziu V.,University Pierre and Marie Curie | Goodman Z.,Center for Liver Diseases | Sanyal A.,Virginia Commonwealth University
Journal of Hepatology | Year: 2015

Of all the aspects of non-alcoholic fatty liver disease (NAFLD), the slowest advances have occurred in the therapeutic field. Thirty-five years after its formal description and after 15 years of intense scrutiny from researchers worldwide, there is still no approved drug for the treatment of non-alcoholic steatohepatits (NASH). In the meantime, progress in the understanding of pathophysiology, diagnosis - both invasive and non-invasive, epidemiology and even natural history have been substantial or, at times, spectacular. In contrast, hepatitis C virus (HCV) therapy underwent constant improvement and even before the great acceleration of the past few years, patients were already being offered approved therapies that were increasingly more efficient. What then explains such a slow pace of therapeutic advances in NASH, and will this change in the near future? Here we will review commonly-held myths that have diverted attention from therapy of NASH, obstacles that have slowed down industrial development of drugs for this indication, and recent achievements that will create better conditions for drug development programs. We will also briefly review current knowledge of non-pharmacological and pharmacological management in this early era of NASH therapies. © 2015 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. Source

Maron E.,University of Tartu | Maron E.,Imperial College London | Hettema J.M.,Virginia Commonwealth University | Shlik J.,University of Ottawa | Shlik J.,Royal Ottawa Mental Health Center
Molecular Psychiatry | Year: 2010

The molecular genetic research on panic disorder (PD) has grown tremendously in the past decade. Although the data from twin and family studies suggest an involvement of genetic factors in the familial transmission of PD with the heritability estimate near 40%, the genetic substrate underlying panicogenesis is not yet understood. The linkage studies so far have suggested that chromosomal regions 13q, 14q, 22q, 4q31-q34, and probably 9q31 are associated with the transmission of PD phenotypes. To date, more than 350 candidate genes have been examined in association studies of PD, but most of these results remain inconsistent, negative, or not clearly replicated. Only Val158Met polymorphism of the catechol-O-methyltransferase gene has been implicated in susceptibility to PD by several studies in independent samples and confirmed in a recent meta-analysis. However, the specific role of this genetic variation in PD requires additional analysis considering its gender-and ethnicity-dependent effect and putative impact on cognitive functions. The recent advantages in bioinformatics and genotyping technologies, including genome-wide association and gene expression methods, provide the means for far more comprehensive discovery in PD. The progress in clinical and neurobiological concepts of PD may further guide genetic research through the current controversies to more definitive findings. © 2010 Macmillan Publishers Limited All rights reserved. Source

Harwich Jr. M.D.,Virginia Commonwealth University
BMC genomics | Year: 2012

Bacteria of the genus Sneathia are emerging as potential pathogens of the female reproductive tract. Species of Sneathia, which were formerly grouped with Leptotrichia, can be part of the normal microbiota of the genitourinary tracts of men and women, but they are also associated with a variety of clinical conditions including bacterial vaginosis, preeclampsia, preterm labor, spontaneous abortion, post-partum bacteremia and other invasive infections. Sneathia species also exhibit a significant correlation with sexually transmitted diseases and cervical cancer. Because Sneathia species are fastidious and rarely cultured successfully in vitro; and the genomes of members of the genus had until now not been characterized, very little is known about the physiology or the virulence of these organisms. Here, we describe a novel species, Sneathia amnii sp. nov, which closely resembles bacteria previously designated "Leptotrichia amnionii". As part of the Vaginal Human Microbiome Project at VCU, a vaginal isolate of S. amnii sp. nov. was identified, successfully cultured and bacteriologically cloned. The biochemical characteristics and virulence properties of the organism were examined in vitro, and the genome of the organism was sequenced, annotated and analyzed. The analysis revealed a reduced circular genome of ~1.34 Mbp, containing ~1,282 protein-coding genes. Metabolic reconstruction of the bacterium reflected its biochemical phenotype, and several genes potentially associated with pathogenicity were identified. Bacteria with complex growth requirements frequently remain poorly characterized and, as a consequence, their roles in health and disease are unclear. Elucidation of the physiology and identification of genes putatively involved in the metabolism and virulence of S. amnii may lead to a better understanding of the role of this potential pathogen in bacterial vaginosis, preterm birth, and other issues associated with vaginal and reproductive health. Source

Fettweis J.M.,Virginia Commonwealth University
BMC genomics | Year: 2012

The application of next-generation sequencing to the study of the vaginal microbiome is revealing the spectrum of microbial communities that inhabit the human vagina. High-resolution identification of bacterial taxa, minimally to the species level, is necessary to fully understand the association of the vaginal microbiome with bacterial vaginosis, sexually transmitted infections, pregnancy complications, menopause, and other physiological and infectious conditions. However, most current taxonomic assignment strategies based on metagenomic 16S rDNA sequence analysis provide at best a genus-level resolution. While surveys of 16S rRNA gene sequences are common in microbiome studies, few well-curated, body-site-specific reference databases of 16S rRNA gene sequences are available, and no such resource is available for vaginal microbiome studies. We constructed the Vaginal 16S rDNA Reference Database, a comprehensive and non-redundant database of 16S rDNA reference sequences for bacterial taxa likely to be associated with vaginal health, and we developed STIRRUPS, a new method that employs the USEARCH algorithm with a curated reference database for rapid species-level classification of 16S rDNA partial sequences. The method was applied to two datasets of V1-V3 16S rDNA reads: one generated from a mock community containing DNA from six bacterial strains associated with vaginal health, and a second generated from over 1,000 mid-vaginal samples collected as part of the Vaginal Human Microbiome Project at Virginia Commonwealth University. In both datasets, STIRRUPS, used in conjunction with the Vaginal 16S rDNA Reference Database, classified more than 95% of processed reads to a species-level taxon using a 97% global identity threshold for assignment. This database and method provide accurate species-level classifications of metagenomic 16S rDNA sequence reads that will be useful for analysis and comparison of microbiome profiles from vaginal samples. STIRRUPS can be used to classify 16S rDNA sequence reads from other ecological niches if an appropriate reference database of 16S rDNA sequences is available. Source

Powers J.C.,Virginia Commonwealth University
Osiris | Year: 2014

This essay examines Herman Boerhaave’s work with the instrument maker, Daniel Gabriel Fahrenheit, on integrating the thermometer into the practice of eighteenth- century chemistry. Boerhaave utilized the thermometer to generate empirical evidence for the existence and actions of his instrument, “fire,” by incorporating the instrument into pedagogical demonstrations, chemical research on heat, and, finally, the performing of operations. I examine how the use of the thermometer altered the chemists’ traditional approach to heat, based on skilled sense perception and experiential judgment, and suggest that the threat to traditional practice posed by the instrument explains some of the resistance to it among some chemists in the mid- eighteenth century. © 2014 by The History of Science Society. All rights reserved. Source

Green T.L.,Virginia Commonwealth University
Economics and Human Biology | Year: 2014

Childhood obesity has become an issue of increasing concern to health researchers and policymakers in the United States. One important chronic health condition linked to obesity is pediatric asthma. Although researchers have speculated that both conditions may have common origins, the majority of research in this area has focused on a unidirectional relationship between obesity and later asthma. However, much of the literature is limited by its reliance on cross-sectional data and its failure to examine the possibility that asthma may influence weight fluctuations through changes in physical and sedentary activity. Using data from the Early Childhood Longitudinal Study-Kindergarten Cohort (ECLS-K), I explore the bidirectional relationships between childhood obesity and asthma. The results in this paper suggest that past asthma levels are positively correlated with changes in BMI and the onset of obesity. However, only new onset asthma is positively correlated with subsequent changes in BMI. The potential mechanisms are unclear, as I find little evidence that asthma is structurally related to changes in physical or sedentary activity over time. When testing the prevailing hypothesis that obesity is related to subsequent asthma, I find that lagged weight status is strongly related to asthma prevalence levels but that the onset of overweight or obesity is not associated with the subsequent onset of asthma. These results suggest that the onset of asthma may be related to subsequent weight gain over time. Source

Carnes B.A.,The University of Oklahoma Health Sciences Center | Witten T.M.,Virginia Commonwealth University
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2014

Species are defined by biological criteria. This characterization, however, misses the most unique aspect of our species; namely, an ability to invent technologies that reduce mortality risks. Old animals are rare in nature, but survival to old age has become commonplace in humans. Science now asks how long can humans live, but we suggest a more appropriate question is: How long must humans live? Three lines of evidence are used to identify the biological equivalent of a warranty period for humans and why it exists. The effective end of reproduction, the age when the sex ratio is unity, and the acceleration of mortality reveal that approximately 50-55 years is sufficient time for our species to achieve its biological mandate-Darwinian fitness. Identifying this boundary is biomedically important because it represents a transition from expected health and vigor to a period when health and vigor become progressively harder to maintain. © 2013 The Author. Source

Gronert S.,Virginia Commonwealth University | Keeffe J.R.,San Francisco State University | More O'Ferrall R.A.,University College Dublin
Journal of the American Chemical Society | Year: 2011

Thermodynamic stabilities of 92 carbenes, singlets and triplets, have been evaluated on the basis of hydrogenation enthalpies calculated at the G3MP2 level. The carbenes include alkyl-, aryl-, and heteroatom-substituted structures as well as cyclic 1,3-diheteroatom carbenes. Over a wide energy range, a good correlation is seen between the singlet-triplet gaps and the hydrogenation enthalpies of the singlets, but there are some clear outliers, which represent cases where the triplet has unusual stability or instability. By use of hydrogenation enthalpies, separate carbene stabilization enthalpy scales (CSEs) have been developed for singlets and triplets, and these highlight structural features that affect the stability of each. The treatment also allows estimates of aromaticity in cyclic carbenes. In this way, imidazol-2-ylidene is estimated to have an aromatic stabilization energy of about 20 kcal/mol. © 2011 American Chemical Society. Source

McLeod B.D.,Virginia Commonwealth University | Weisz J.R.,Harvard University
Journal of Clinical Child and Adolescent Psychology | Year: 2010

Most everyday child and adolescent psychotherapy does not follow manuals that document the procedures. Consequently, usual clinical care has remained poorly understood and rarely studied. The Therapy Process Observational Coding System for Child Psychotherapy-Strategies scale (TPOCS-S) is an observational measure of youth psychotherapy procedures designed to support the study of usual clinical care by providing a means of characterizing it. Coders independently rated usual care therapy sessions conducted with 43 children (aged 8-15 years) diagnosed with anxiety and depressive disorders. The TPOCS-S showed good interrater reliability, its 5 subscales (e.g., Behavioral, Cognitive, Psychodynamic, Client-Centered, Family) showed good internal consistency, and analyses supported TPOCS-S validity. © Taylor & Francis Group, LLC. Source

Ghosh S.,Virginia Commonwealth University
Current Opinion in Endocrinology, Diabetes and Obesity | Year: 2012

PURPOSE OF REVIEW: Several controversies exist related to the molecular identity and subcellular localization of the enzyme catalyzing macrophage cholesteryl ester hydrolysis. Some of these issues have been reviewed earlier and this review summarizes new developments that describe effects of overexpression or gene ablation. The main objective is to highlight the disagreement between lack of gene expression and incomplete abolition of macrophage cholesteryl ester hydrolytic activity and to emphasize the importance of redundancy. RECENT FINDINGS: New information resulting from the continuing characterization of the various cholesteryl ester hydrolases (hormone-sensitive lipase, HSL; cholesteryl ester hydrolase, CEH; and KIAA1363/NCEH1) is reviewed. Whereas CEH overexpression leads to beneficial effects such as decreased inflammation, improved glucose tolerance/insulin sensitivity, and attenuation of atherosclerotic lesion progression, deficiency/ablation of HSL or KIAA1363/NCEH1 results in incomplete loss of macrophage cholesteryl ester hydrolysis/turnover. New paradigms challenging the classical view of cytoplasmic cholesteryl ester hydrolysis and reverse cholesterol transport are also presented. SUMMARY: The observed beneficial effects of CEH overexpression identify macrophage cholesteryl ester hydrolysis as an important therapeutic target and future studies will determine whether similar effects are obtained with overexpression of HSL or KIAA1363/NCEH1. It is imperative that, for clinical benefit, mechanisms to enhance endogenous cholesteryl ester hydrolase(s) are established. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Pickett J.T.,University at Albany | Baker T.,Virginia Commonwealth University
Criminology | Year: 2014

Scholars widely agree that the public is pragmatic about criminal justice. The empirical basis for this conclusion is the failure in several previous studies to find a sizable negative relationship between dispositional and situational crime attributions, or between support for punitive and rehabilitative crime policies. We suggest, however, that public pragmatism may be an artifact of the use of unidirectional question batteries in prior research to measure attribution styles and policy support. When such questions are used, acquiescent responding can introduce systematic error that is positively correlated across items and scales. Drawing on data from an experiment with a national sample (N = 826) of Internet panelists, we examine how this methodological approach impacts the bivariate correlations and multivariate relationships between attribution styles and between support for punitive and rehabilitative crime policies. The findings reveal that using unidirectional sets of questions to measure these concepts likely results in 1) inflated alpha reliability coefficients, 2) an underestimation of the magnitude of the negative relationships between attribution styles and between punitiveness and support for rehabilitation, and 3) an underestimation of the extent to which punitiveness and support for rehabilitation are driven by the same factors, working in opposite directions. © 2014 American Society of Criminology. Source

Falco Metcalfe C.,Florida State University | Baker T.,Virginia Commonwealth University
Criminal Justice and Behavior | Year: 2014

This article conceptualizes intermittency in the form of Matza's drift and assesses the relationship between co-offending and intermittency to determine whether the gap between offenses is influenced by a situation of company. Using the 1958 Philadelphia Birth Cohort, we explore the age/intermittency curve for the entire sample and lifetime co-, solo-, and mixed offenders to determine whether co-offending during the life-course influences intermittency. We devote particular attention to lifetime mixed offenders, who exhibit variation between co-offending and solo-offending, by using survival analysis to predict the risk of re-offending (i.e., time to re-offense) when the immediately prior offense was a co-offense. Findings suggest that lifetime mixed offenders have the shortest average gaps between offenses. Among mixed offenders, an immediately prior co-offense is related to a significantly lower risk of re-offending (longer time between offenses). The results do not support a relationship between a situation of company and persistent offending behavior. © 2013 International Association for Correctional and Forensic Psychology. Source

Faircloth A.,Virginia Commonwealth University
AANA Journal | Year: 2015

Acupuncture and acupressure are components of Oriental medicine that have been in existence for thousands of years. These practices have transcended from Asia into Western culture. In the context of anesthesia practice, acupuncture and acupressure have demonstrated clinical usefulness in the perioperative setting. Acupuncture and acupressure can successfully decrease preoperative anxiety, decrease intraoperative anesthetic requirements, assuage postoperative pain, decrease the incidence of postoperative nausea and vomiting, and support chronic pain management. Source

Dyer R.J.,Virginia Commonwealth University | Nason J.D.,Iowa State University | Garrick R.C.,Yale University
Molecular Ecology | Year: 2010

Landscape genetics is a burgeoning field of interest that focuses on how site-specific factors influence the distribution of genetic variation and the genetic connectivity of individuals and populations. In this manuscript, we focus on two methodological extensions for landscape genetic analyses: the use of conditional genetic distance (cGD) derived from population networks and the utility of extracting potentially confounding effects caused by correlations between phylogeographic history and contemporary ecological factors. Individual-based simulations show that when describing the spatial distribution of genetic variation, cGD consistently outperforms the traditional genetic distance measure of linearized FST under both 1- and 2-dimensional stepping stone models and Cavalli-Sforza and Edward's chord distance D c in 1-dimensional landscapes. To show how to identify and extract the effects of phylogeographic history prior to embarking on landscape genetic analyses, we use nuclear genotypic data from the Sonoran desert succulent Euphorbia lomelii (Euphrobiaceae), for which a detailed phylogeographic history has previously been determined. For E. lomelii, removing the effect of phylogeographic history significantly influences our ability to infer both the identity and the relative importance of spatial and bio-climatic variables in subsequent landscape genetic analyses. We close by discussing the utility of cGD in landscape genetic analyses. © 2010 Blackwell Publishing Ltd. Source

Ghosh S.,Virginia Commonwealth University
Expert Review of Cardiovascular Therapy | Year: 2011

Atherogenic dyslipidemia, including low HDL levels, is the major contributor of residual risk of cardiovascular disease that remains even after aggressive statin therapy to reduce LDL-cholesterol. Currently, distinction is not made between HDL-cholesterol and HDL, which is a lipoprotein consisting of several proteins and a core containing cholesteryl esters (CEs). The importance of assessing HDL functionality, specifically its role in facilitating cholesterol efflux from foam cells, is relevant to atherogenesis. Since HDLs can only remove unesterified cholesterol from macrophages while cholesterol is stored as CEs within foam cells, intracellular CE hydrolysis by CE hydrolase is vital. Reduction in macrophage lipid burden not only attenuates atherosclerosis but also reduces inflammation and linked pathologies such as Type 2 diabetes and chronic kidney disease. Targeting reduction in macrophage CE levels and focusing on enhancing cholesterol flux from peripheral tissues to liver for final elimination is proposed. © 2011 Expert Reviews Ltd. Source

Neeland I.J.,University of Texas Southwestern Medical Center | Kontos M.C.,Virginia Commonwealth University | De Lemos J.A.,University of Texas Southwestern Medical Center
Journal of the American College of Cardiology | Year: 2012

Patients with a suspected acute coronary syndrome and left bundle branch block (LBBB) present a unique diagnostic and therapeutic challenge to the clinician. Although current guidelines recommend that patients with new or presumed new LBBB undergo early reperfusion therapy, data suggest that only a minority of patients with LBBB are ultimately diagnosed with acute myocardial infarction, regardless of LBBB chronicity, and that a significant proportion of patients will not have an occluded culprit artery at cardiac catheterization. The current treatment approach exposes a significant proportion of patients to the risks of fibrinolytic therapy without the likelihood of significant benefit and leads to increased rates of false-positive cardiac catheterization laboratory activation, unnecessary risks, and costs. Therefore, alternative strategies to those for patients with ST-segment elevation myocardial infarction are needed to guide selection of appropriate patients with a suspected acute coronary syndrome and LBBB for urgent reperfusion therapy. In this article, we describe the evolving epidemiology of LBBB in acute coronary syndromes and discuss controversies related to current clinical practice. We propose a more judicious diagnostic approach among clinically stable patients with LBBB who do not have electrocardiographic findings highly specific for ST-segment elevation myocardial infarction. © 2012 American College of Cardiology Foundation. Source

Rubin B.K.,Virginia Commonwealth University
Paediatric Respiratory Reviews | Year: 2014

As a student I recall being told that half of what we would learn in medical school would be proven to be wrong. The challenges were to identify the incorrect half and, often more challenging, be willing to give up our entrenched ideas. Myths have been defined as traditional concepts or practice with no basis in fact. A misunderstanding is a mistaken approach or incomplete knowledge that can be resolved with better evidence, while firmly established misunderstandings can become dogma; a point of view put forth as authoritative without basis in fact. In this paper, I explore a number of myths, mistakes, and dogma related to cystic fibrosis disease and care. Many of these are myths that have long been vanquished and even forgotten, while others are controversial. In the future, many things taken as either fact or "clinical experience" today will be proven wrong. Let us examine these myths with an open mind and willingness to change our beliefs when justified. © 2013 Elsevier Ltd. Source

Wood A.C.,University of Alabama at Birmingham | Neale M.C.,Virginia Commonwealth University
Journal of the American Academy of Child and Adolescent Psychiatry | Year: 2010

Objective: To describe the utility of twin studies for attention-deficit/ hyperactivity disorder (ADHD) research and demonstrate their potential for the identification of alternative phenotypes suitable for genomewide association, developmental risk assessment, treatment response, and intervention targets. Method: Brief descriptions of the classic twin study and genetic association study methods are provided, with illustrative findings from ADHD research. Biometrical genetics refers to the statistical modeling of data gathered from one or more group of known biological relation; it was apparently coined by Francis Galton in the 1860s and led to the "Biometrical School" at the University of London. Twin studies use genetic correlations between pairs of relatives, derived using this theoretical framework, to parse the individual differences in a trait into latent (unmeasured) genetic and environmental influences. This method enables the estimation of heritability, i.e., the percentage of variance due to genetic influences. It is usually implemented with a method called structural equation modeling, which is a statistical technique for fitting models to data, typically using maximum likelihood estimation. Genetic association studies aim to identify those genetic variants that account for the heritability estimated in twin studies. Measurements other than those used for the clinical diagnosis of the disorder are popular phenotype choices in current ADHD research. It is argued that twin studies have great potential to refine phenotypes relevant to ADHD. Results: Prior studies have consistently found that the majority of the variance in ADHD symptoms is due to genetic factors. To date, genomewide association studies of ADHD have not identified replicable associations that account for the heritable variation. Possibly, the application of genomewide association studies to these alternative phenotypic measurements will assist in identifying the pathways from genetic variants to ADHD. Conclusion: Power to detect associations should be improved by the study of highly heritable endophenotypes for ADHD and by reducing the number of phenotypes to be considered. Therefore, twin studies are an important research tool in the development of endophenotypes, defined as alternative, more highly heritable traits that act at earlier stages of the pathway from genes to behavior. Although genetic variation in liability to ADHD is likely polygenic, the proposed approach should help to identify improved alternative measurements for genetic association studies. © 2010 American Academy of Child and Adolescent Psychiatry. Source

Bajaj J.S.,Virginia Commonwealth University
Alimentary Pharmacology and Therapeutics | Year: 2010

Aliment Pharmacol Ther 31, 537-547 SummaryBackground Hepatic encephalopathy, both overt and minimal, forms a continuum of cognitive change in cirrhosis. Strategies to diagnose and treat hepatic encephalopathy have evolved considerably. Aim To examine the updated diagnostic and treatment strategies for hepatic encephalopathy. Methods Techniques for the clinical, psychometric and neurophysiological evaluation of hepatic encephalopathy are reviewed. The methods reviewed include pure clinical scales (West-Haven), psychometric tests (PSE-syndrome test), neurophysiological tests (EEG, Critical flicker frequency, CFF) and computerized tests (Inhibitory control test, ICT). Results Clinical scales are limited, whereas psychometric tests (specifically PSE-syndrome test), CFF and ICT can be used to diagnose minimal hepatic encephalopathy. However, there is no single test that can capture the entire spectrum of cognitive impairment. Treatment options and goals depend on the acuity of hepatic encephalopathy. In-patient management should concentrate on supportive care, precipitating factor reversal and lactulose and/or rifaximin therapy. Out-patient therapy should aim to prevent recurrences, and both lactulose and rifaximin have evidence to support their use. Conclusions Diagnostic techniques for hepatic encephalopathy range from simple scales to sophisticated tools. Treatment options depend on the stage of hepatic encephalopathy. The future challenge is to evaluate cognitive function as a continuum with clinically relevant outcomes and to develop well-tolerated and inexpensive treatments for hepatic encephalopathy. © 2010 Blackwell Publishing Ltd. Source

Del Fabbro E.,Virginia Commonwealth University
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting | Year: 2015

Many important advances have occurred in the field of cancer cachexia over the past decade, including progress in understanding the mechanisms of the cancer anorexia-cachexia syndrome (CACS) and the development of promising pharmacologic and supportive care interventions. However, no approved agents for cancer cachexia currently exist, emphasizing the unmet need for an effective pharmacologic therapy. This article reviews the key elements of CACS assessment in daily practice, the contribution of nutritional impact symptoms (NIS), the evidence for current pharmacologic options, and promising anticachexia agents in perclinical and clinical trials. It also proposes a model for multimodality therapy and highlights issues pertinent to CACS in patients with pancreatic, gastric, and esophageal cancer. Source

Pittman R.N.,Virginia Commonwealth University
Microcirculation | Year: 2013

Objective: Cells require energy to carry out their functions and they typically use oxidative phosphorylation to generate the needed ATP. Thus, cells have a continuous need for oxygen, which they receive by diffusion from the blood through the interstitial fluid. The circulatory system pumps oxygen-rich blood through a network of increasingly minute vessels, the microcirculation. The structure of the microcirculation is such that all cells have at least one nearby capillary for diffusive exchange of oxygen and red blood cells release the oxygen bound to hemoglobin as they traverse capillaries. Methods: This review focuses first on the historical development of techniques to measure oxygen at various sites in the microcirculation, including the blood, interstitium, and cells. Results: Next, approaches are described as to how these techniques have been employed to make discoveries about different aspects of oxygen transport. Finally, ways in which oxygen might participate in the regulation of blood flow toward matching oxygen supply to oxygen demand is discussed. Conclusions: Overall, the transport of oxygen to the cells of the body is one of the most critical functions of the cardiovascular system and it is in the microcirculation where the final local determinants of oxygen supply, oxygen demand, and their regulation are decided. © 2012 John Wiley & Sons Ltd. Source

Witten T.M.,Virginia Commonwealth University
Journal of Social Work in End-of-Life and Palliative Care | Year: 2014

In this study, the experiences and needs of a sample of 1,963 current, global, English-speaking, transgender-identified adults responding to the Transgender MetLife Survey (TMLS) as related to a number of later-life and end-of-life (EOL) preparations and concerns were examined. EOL concerns are integrated with concerns and challenges around chronic illness and disability. Overall, this population was significantly ill-prepared for the major legalities and events that occur in the later to EOL time periods. The population was found to harbor significant fears around the future. Drawing on the author's decades of survey research in transgender aging and case data along with current scientific and online literature, illustrative quotations and case examples are provided. © 2014 Copyright Taylor & Francis Group, LLC. Source

Rubin B.K.,Virginia Commonwealth University
Respiratory Care | Year: 2015

Airway mucus hypersecretion and secretion retention can result from inflammation, irritation, stimulation, or mucus-producing tumors. Secretion clearance can be furthered hampered by ciliary dysfunction and by weakness or restrictive lung disease, leading to an ineffective cough. There are a number of different mucoactive medications that have been used to reduce hypersecretion, make secretions easier to transport, or increase the efficiency of cough or mucus clearance. In this paper, I review the pathophysiology of secretory hyper-responsiveness and mucus hypersecretion and discuss the different aerosol medications that can be used to augment secretion clearance. © 2015 Daedalus Enterprises. Source

Szabo C.M.,Virginia Commonwealth University
Journal of Neuroscience Nursing | Year: 2011

Neuroscience intensive care unit nurses routinely perform oral care on patients with intracranial pressure (ICP) monitoring. When the ICP is elevated or rises in response to oral care, this intervention may be withheld despite the lack of evidence linking the two. To appraise the best evidence for providing oral care to patients with ICP monitoring, articles published in English from 1978 to 2009 and indexed in CINHAL, PubMed/MEDLINE, Cochran Library, and BioSys were searched using the key terms ICP monitoring, intracranial hypertension, oral care, mouth care, hygiene, nursing interventions, nursing care, intensive care, and critical care. Reference lists of retrieved articles were reviewed for articles missed during the initial search. The search yielded 65 articles: 16 experimental or quasi-experimental studies, 24 descriptive studies, and 25 review articles. Of these, only four specifically tested or described the effect of oral care on ICP. There is a need for more knowledge about the effect of oral care on ICP so that evidence-based oral care practices in this patient population can be defined. © 2011American Association of Neuroscience Nurses. Source

Brunzell D.H.,Virginia Commonwealth University | McIntosh J.M.,University of Utah
Neuropsychopharmacology | Year: 2012

Individuals diagnosed with schizophrenia have an exceptionally high risk for tobacco dependence. Postmortem studies show that these individuals have significant reductions in α7 nicotinic acetylcholine receptors (nAChRs) in several brain areas. Decreased α7-mediated function might not only be linked to schizophrenia but also to increased tobacco consumption. The purpose of this study was to determine whether pharmacological blockade of α7 nAChRs would increase motivation of rats to intravenously self-administer nicotine (NIC) during a progressive ratio schedule of reinforcement (PR). Before PR, rats received local infusions of 0, 10, or 20 pmol of a selective α7 nAChR antagonist, α-conotoxin ArIB V11L,V16D (ArIB) into the nucleus accumbens (NAc) shell or the anterior cingulate cortex, brain areas that contribute to motivation for drug reward. We additionally sought to determine whether local infusion of 0, 10, or 40 nmol of a selective α7 nAChR agonist, PNU 282987, into these brain areas would decrease motivation for NIC use. Infusion of ArIB into the NAc shell and anterior cingulate cortex resulted in a significant increase in active lever pressing, breakpoints, and NIC intake, suggesting that a decrease in α7 nAChR function increases motivation to work for NIC. In contrast, PNU 282987 infusion resulted in reductions in these measures when administered into the NAc shell, but had no effect after administration into the anterior cingulate cortex. These data identify reduction of α7 nAChR function as a potential mechanism for elevated tobacco use in schizophrenia and also identify activation of α7 nAChRs as a potential strategy for tobacco cessation therapy. © 2012 American College of Neuropsychopharmacology. All rights reserved. Source

Negus S.S.,Virginia Commonwealth University
Methods in molecular biology (Clifton, N.J.) | Year: 2010

Pain-depressed behavior can be defined as any behavior that decreases in rate, frequency, duration, or intensity in response to a putative pain state. Common examples include pain-related decreases in feeding, locomotion and expression of positively reinforced operant behavior. In humans, depression of behavior is often accompanied by a comorbid depression of mood. Measurements of pain-depressed behaviors are used to diagnose pain in both human and veterinary medicine, and restoration of pain-depressed behavior is often a priority of treatment. This article describes two strategies for integrating measures of pain-depressed behaviors into preclinical assays of pain and analgesia. Assays of pain-depressed behaviors may contribute both to improved translational efficiency in analgesic drug development and to new insights regarding the mechanisms and determinants of pain and analgesia. Source

Autism now affects a significant number of students in schools. The purpose of this study was to survey special education teachers who serve students with autism to 1) determine teacher, environmental, and student related characteristics; 2) identify the self-reported knowledge of effective teaching practices; and 3) identify the self-reported implementation of effective teaching practices. The study was conducted with special education teachers employed in Virginia using a web-based survey titled the Needs Assessment of Special Educators who Serve Students with Autism. Respondents included 498 special education teachers with a wide array of qualifications and experience including licensure status, years of teaching and area of endorsement. Results provide a description of teacher characteristics that directly impact instructional delivery as well as information regarding self-rated knowledge and implementation of efficacious strategies. Information from this study can be used to improve service delivery to students with autism by informing policy and directing and enhancing teacher professional development initiatives at the preservice and inservice levels. © 2011 - IOS Press and the authors. All rights reserved. Source

Kollef M.H.,University of Washington | Hamilton C.W.,Virginia Commonwealth University | Montgomery A.B.,Cardeas Pharma
Current Opinion in Infectious Diseases | Year: 2013

PURPOSE OF REVIEW: The increasing rate of ventilator-associated pneumonia (VAP) caused by multidrug-resistant pathogens warrants the development of new treatment strategies. Carefully engineered delivery systems are undergoing evaluation to test the hypothesis that aerosolized administration of antibiotics will provide high local concentrations and fast clearance, which in turn may improve efficacy and decrease the risk of microbial resistance. RECENT FINDINGS: Recent studies indicate that aerosolized delivery systems for specially formulated antibiotics yield high local concentrations with rapid clearance and low systemic exposure. Preliminary clinical studies reveal that aerosolized delivery of antibiotics is well tolerated and active, when combined with intravenous antibiotics. No single aerosolized antibiotic is likely to provide broad-spectrum activity against both Gram-negative and Gram-positive bacteria. SUMMARY: Large multicenter trials are needed to determine whether preliminary findings will translate to improved clinical activity and decreased microbial resistance in VAP patients, and to optimize the use of aerosolized antibiotics. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

McVoy M.A.,Virginia Commonwealth University
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | Year: 2013

An effective cytomegalovirus (CMV) vaccine could prevent the majority of birth defects caused by congenital CMV infections. Candidate vaccines in clinical evaluation include live attenuated, protein subunit, DNA, and viral-vectored approaches. Subunit approaches have focused on the CMV proteins pp65 and IE1 as important inducers of cytotoxic T cells and glycoprotein B (gB) as an important inducer of neutralizing antibodies. A vaccine comprised of recombinant gB protein with MF59 adjuvant reduced the incidence of primary infection by 50%. Recent revelations regarding CMV entry pathways into different cell types suggest a possible course for improvement. A 5-subunit pentameric complex is uniquely required for endothelial and epithelial cell entry. Sera from naturally infected subjects contain high-potency neutralizing activities specific for this complex, whereas the gB/MF59 vaccine fails to induce comparable neutralizing activities. A vaccine's ability to induce salivary antibodies that neutralize epithelial cell entry may be especially important for preventing oral transmission as the first cells infected are presumably epithelial cells of the oral mucosa. In addition, recent evidence suggests that antibodies can inhibit postentry CMV spread between endothelial and epithelial cells. Such activities may serve to limit viral replication in tissues or impair dissemination to the placenta and fetus. Thus, inclusion of epitopes derived from the pentameric complex may provide enhanced efficacy by inducing potent neutralizing/spread-inhibiting antibodies that target virus replication in a broad spectrum of cell types. Next-generation vaccine candidates in preclinical development incorporate peptides, subunits, or multisubunit complexes representing parts or all of the pentameric complex. Approaches include peptides, recombinant proteins, DNA, replication-defective viral vectors, genetically disabled CMV, and inactivated CMV virions. The diversity of novel strategies under development engenders optimism that a successful candidate will emerge. Source

Hughes L.C.,Virginia Commonwealth University
Policy, Politics, and Nursing Practice | Year: 2012

Delayed access to physicians has been identified as a factor in preventable adverse patient events during hospitalization. Nurses as front-line providers are well positioned to provide a timely response to the needs of patients. Yet legal regulations and hospital policies limit the actions nurses can initiate without physician authorization. The purpose of this qualitative study was to describe what experienced critical care nurses do when they recognize a problem that warrants treatment but lack physician authorization to intervene. The 13 nurses who participated in this study bridged the gap between problem recognition and treatment by communicating proactively, being persistent, running interference for other nurses, and, in some situations, acting without physician authorization. Revising legal regulations and hospital policies to incorporate greater acknowledgment of the overlapping functions between medicine and nursing and recognition of the knowledge and expertise of experienced nurses may be important in reducing unnecessary treatment delays during hospitalization. © The Author(s) 2012. Source

Hook J.N.,Virginia Commonwealth University
Journal of sex & marital therapy | Year: 2010

Research has proliferated on sexual addiction in recent years, and this has led to an increase in the instruments created to measure this construct. The authors review 17 instruments that have been created to assess sexual addiction, including self-report rating scales, self-report checklists, and clinician rating scales measuring symptoms of sexual addiction, as well as self-report rating scales measuring consequences associated with sexual addiction. For each instrument, the authors describe its structure, conceptual basis, and samples studied. They also evaluate the evidence for the reliability and validity of each instrument. The instruments vary widely in their psychometric properties. Many have been created recently, and others have only been studied in specific populations. For each group of instruments, the authors make recommendations for researchers and clinicians. Source

Corona R.,Virginia Commonwealth University | Klein D.J.,Childrens Hospital Boston | Schuster M.A.,Harvard University
Pediatrics | Year: 2010

OBJECTIVE: To examine timing of parent-child discussions about sexual topics relative to child-reported sexual behavior. METHODS: Longitudinal study of employed parents and their children, with an initial survey followed by subsequent surveys 3, 6, and 12 months later. Participants were 141 parents, along with their children (13-17 years), who were control participants in a randomized, controlled trial to evaluate a worksite-based intervention to improve parent-adolescent communication. Main outcomes were parent and child reports of discussion of up to 24 sexual topics and presexual and sexual acts (ranging from handholding to vaginal intercourse) that occurred before the first survey and in the intervals between subsequent pairs of surveys. RESULTS: Sexual topics tend to group into 3 sets. The first set includes topics such as girls' bodies and menstruation and typically coincides with children's presexual stage (handholding, kissing). The second set includes topics such as birth control efficacy and refusing sex and typically coincides with the precoital stage (genital touching and oral sex). The third set typically occurs when children have initiated intercourse. Over half of children engage in genital touching before discussing birth control efficacy, resisting partner pressure for sex, sexually transmitted disease symptoms, condom use, choosing birth control, or partner condom refusal; >40% of children have intercourse before any discussion about sexually transmitted disease symptoms, condom use, choosing birth control, or partner condom refusal. CONCLUSIONS: Many parents and adolescents do not talk about important sexual topics before adolescents' sexual debut. Clinicians can facilitate this communication by providing parents with information about sexual behavior of adolescents. Copyright © 2009 by the American Academy of Pediatrics. Source

McLeod B.D.,Virginia Commonwealth University
Clinical Psychology Review | Year: 2011

The goal of this meta-analytic review was to provide a reliable estimate of the alliance-outcome relation in youth psychotherapy. Previous meta-analyses focused upon the alliance-outcome association in youth and adult psychotherapy have produced effect size (ES) estimates above r = .20. In the current study, meta-analytic methods were applied to the largest study sample collected (N = 38) to date in the youth psychotherapy field and the mean weighted ES estimate was r = .14, which is smaller than previous estimates. The child- and parent-therapist alliances were not differentially associated with outcomes. However, the alliance-outcome association did vary across theoretical (i.e., child age, problem type, referral source, and mode of treatment) and methodological (i.e., source and timing of alliance assessment; domain, technology, and source of outcome assessment; single vs. multiple informants) variables. Existing client-, therapist-, and observer-report alliance measures evidenced adequate reliability; however, substantial variability exists in how the alliance is conceptualized and measured. Though the magnitude of the ES estimate raises questions about the role that the alliance may play in youth psychotherapy, the findings also suggest that the extant literature represents a heterogeneous group of studies whose effects vary according to theoretical and methodological factors. Addressing existing knowledge and measurement gaps in the field may therefore lead to a more robust estimate of the alliance-outcome association in youth psychotherapy. © 2011 Elsevier Ltd. Source

Sabo R.T.,Virginia Commonwealth University | Chaganty N.R.,Old Dominion University
Statistics in Medicine | Year: 2010

The analysis of repeated measure or clustered data is often complicated by the presence of correlation. Further complications arise for discrete responses, where the marginal probability-dependent Fr'echet bounds impose feasibility limits on the correlation that are often more restrictive than the positive definite range. Some popular statistical methods, such as generalized estimating equations (GEE), ignore these bounds, and as such can generate erroneous estimates and lead to incorrect inferential results. In this paper, we discuss two alternative strategies: (i) using QIC to select a data-driven correlation value within the Fréchet bounds, and (ii) the use of likelihood-based latent variable modeling, such as multivariate probit, to get around the problem all together. We provide two examples of the repercussions of incorrectly using existing GEE software in the presence of correlated binary responses. Copyright © 2010 John Wiley & Sons, Ltd. Source

Adler R.A.,Virginia Commonwealth University
Endocrine | Year: 2013

As osteoporosis in men has been recognized as an important clinical problem, new information is being accumulated on its scope, pathophysiology, evaluation, and treatment. Fracture risk calculators, such as FRAX, identify a large proportion of the older male population to be at heightened risk for fracture. The classification of osteoporosis into primary and secondary forms, while still useful, is affected by the fact that many men have multiple contributing factors to their fracture risk. The role of sex steroids is being better defined as other risk factors for fracture are delineated. As longevity continues to increase in men and until osteoporotic fracture is truly recognized as a potentially fatal disorder, many men will be undiagnosed and untreated. Two recent studies provide more evidence that treatments which decrease fracture risk in women do the same in men. With the publication of guidelines and increasing strength of evidence for treatment efficacy, it is hoped that more men will be evaluated and treated for this often neglected disorder. © 2013 Springer Science+Business Media New York (outside the USA). Source

Bezanilla F.,University of Chicago | Villalba-Galea C.A.,Virginia Commonwealth University
Journal of General Physiology | Year: 2013

The voltage dependence of charges in voltage-sensitive proteins, typically displayed as charge versus voltage (Q-V) curves, is often quantified by fitting it to a simple two-state Boltzmann function. This procedure overlooks the fact that the fitted parameters, including the total charge, may be incorrect if the charge is moving in multiple steps. We present here the derivation of a general formulation for Q-V curves from multistate sequential models, including the case of infinite number of states. We demonstrate that the commonly used method to estimate the charge per molecule using a simple Boltzmann fit is not only inadequate, but in most cases, it underestimates the moving charge times the fraction of the field. © 2013 Bezanilla and Villalba-Galea. Source

Villalba-Galea C.A.,Virginia Commonwealth University
Cellular Signalling | Year: 2012

The Ciona intestinalis voltage sensitive phosphatase (Ci-VSP) was the first proven enzyme to be under direct control of the membrane potential. Ci-VSP belongs to a family of proteins known as Protein Tyrosine Phosphatases (PTP), which are a group of enzymes that catalyze the removal of phosphate groups from phosphatidylinositides and phosphorylated tyrosine residues on proteins. What makes Ci-VSP and similar phosphatases unique is the presence of a Voltage Sensing Domain (VSD) in their N-terminus. The VSD of Ci-VSP shares high homology with those from voltage-gated channels and confers voltage sensitivity to these enzymes. The catalytic domain of Ci-VSP displays extraordinary structural and functional similarities to PTEN. This latter protein is encoded by the Phosphatase and Tensin homolog deleted from chromosome 10 gene, thus its name, and it is known as a tumor suppressor. The resemblance between these proteins has prompted the use of PTEN as a template for the study of Ci-VSP and produced a rapid advance in our understanding of the mechanism of activity of Ci-VSP. This review will be focused on discussing recent advances in the understanding of the activation mechanism for these molecules known as electrochemical coupling. © 2012 Elsevier Inc. Source

McKenney J.M.,Virginia Commonwealth University | Koren M.J.,Jacksonville Center for Clinical Research | Kereiakes D.J.,Christ Hospital Heart and Vascular Center | Hanotin C.,Sanofi S.A. | And 2 more authors.
Journal of the American College of Cardiology | Year: 2012

Objectives: The primary objective of this study was to evaluate the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of 5 SAR236553/REGN727 (SAR236553) dosing regimens versus placebo at week 12 in patients with LDL-C <100 mg/dl on stable atorvastatin therapy. Secondary objectives included evaluation of effects on other lipid parameters and the attainment of LDL-C treatment goals of <100 mg/dl (2.59 mmol/l) and <70 mg/dl (1.81 mmol/l). Background: Serum proprotein convertase subtilisin kexin 9 (PCSK9) binds to low-density lipoprotein receptors, increasing serum LDL-C. SAR236553 is a fully human monoclonal antibody to PCSK9. Methods: This double-blind, parallel-group, placebo-controlled trial randomized 183 patients with LDL-C <100 mg/dl (2.59 mmol/l) on stable-dose atorvastatin 10, 20, or 40 mg for <6 weeks to: subcutaneous placebo every 2 weeks (Q2W); SAR236553 50, 100, or 150 mg Q2W; or SAR236553 200 or 300 mg every 4 weeks (Q4W), alternating with placebo for a total treatment period of 12 weeks. Results: SAR236553 demonstrated a clear dose-response relationship with respect to percentage LDL-C lowering for both Q2W and Q4W administration: 40%, 64%, and 72% with 50, 100, and 150 mg Q2W, respectively, and 43% and 48% with 200 and 300 mg Q4W. LDL-C reduction with placebo at week 12 was 5%. SAR236553 also substantially reduced non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). SAR236553 was generally well tolerated. One patient on SAR236553 experienced a serious adverse event of leukocytoclastic vasculitis. Conclusions: When added to atorvastatin, PCSK9 inhibition with SAR236553 further reduces LDL-C by 40% to 72%. These additional reductions are both dose- and dosing frequency-dependent. © 2012 American College of Cardiology Foundation. Source

Godwin-Jones R.,Virginia Commonwealth University
Language Learning and Technology | Year: 2014

With today's rapid developments in digital technologies, technical obsolescence can occur much faster than in the past. Who would have predicted five years ago that Adobe's Flash would have seen the rapid decline it has experienced as a development environment? Using open, internationally accepted standards for materials development is no absolute guarantee of longevity, but it does increase the likelihood that content will continue to be usable and that, if needed, conversion tools will be available. In this column I will be discussing approaches to the development of electronically delivered language learning materials that I believe are the least likely to face short-term obsolescence. I will be arguing in favor of multilaterally developed, open standards, supported by major industry players and educational standards bodies. Specifically, I will be looking at approaches for delivering learning materials through Web browsers or e-book readers (e-readers), so that created content works seamlessly across devices and platforms © Robert Godwin-Jones. Source

Kier L.B.,Virginia Commonwealth University
Current Computer-Aided Drug Design | Year: 2012

Models of water in the presence of amino acid side chains have revealed significant variability in the local water structure, reflecting the variations in the hydropathic states of the side chains. These models also reveal patterns of water cavities, termed chreodes, that may exist near the surface of a protein. These patterns have been invoked to explain the facilitated diffusion of ligands to an active site on the protein surface. The action of a volatile, general anesthetic agent has been proposed to occur from the interruption of these chreodes producing some loss of function from the receptor. The many similarities reported between the effects of a general anesthetic agent and sleep have produced a proposal of a common mechanism. In the case of sleep, it has been proposed that inhaled elemental nitrogen accumulates to produce a mild anesthesia. Sleep is the process of reversal of this accumulation. It is proposed that over a lifetime there is a continued accumulation of nitrogen with accompanying influences on many processes, leading to a gradual decline of many functions, called aging. The sequence of these concepts is reviewed here. © 2012 Bentham Science Publishers. Source

Traino H.M.,Virginia Commonwealth University
Patient Education and Counseling | Year: 2014

Objective: Many patients with chronic and end-stage renal disease (ESRD) have reported difficulties initiating and managing discussions about kidney transplantation, particularly live donor transplantation (LDT). Limited communication has demonstrable impact on patients' access to transplantation, the duration of dialysis treatments, and the length of time awaiting a transplantable kidney. This formative study sought to identify the specific communicative and conversational elements impeding ESRD patients' discussions about transplantation to inform the design of an educational program facilitating transplant-related discussions. Methods: From March to July 2012, semi-structured telephone interviews ( n= 63) were conducted with ESRD patients waitlisted for kidney transplantation at one mid-Atlantic transplant center. Results: Although 85.7% ( n= 54) of patients reported holding discussions about transplantation, qualitative analyses of open-ended responses revealed that the majority (66.7%) had limited conversations. Patients reported difficulties managing a variety of logistical and content-related aspects of LDT discussions. Moderate levels of communication self-efficacy were also found (mean = 19.2 out of 28); self-efficacy was highest among respondents having held discussions and was significantly related to perceived magnitude of difficulty handling conversational aspects. Conclusion: Results support comprehensive communication skills training for ESRD patients awaiting kidney transplantation. Practice implications: Potential topics to be included in such training are discussed. © 2013 Elsevier Ireland Ltd. Source

Smith D.H.,University of Pennsylvania | Hicks R.,U.S. National Institutes of Health | Povlishock J.T.,Virginia Commonwealth University
Journal of Neurotrauma | Year: 2013

Diffuse axonal injury (DAI) remains a prominent feature of human traumatic brain injury (TBI) and a major player in its subsequent morbidity. The importance of this widespread axonal damage has been confirmed by multiple approaches including routine postmortem neuropathology as well as advanced imaging, which is now capable of detecting the signatures of traumatically induced axonal injury across a spectrum of traumatically brain-injured persons. Despite the increased interest in DAI and its overall implications for brain-injured patients, many questions remain about this component of TBI and its potential therapeutic targeting. To address these deficiencies and to identify future directions needed to fill critical gaps in our understanding of this component of TBI, the National Institute of Neurological Disorders and Stroke hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in the human clinical setting. The workshop also addressed new tools to aid in the identification of this axonal injury while also identifying more rational therapeutic targets linked to DAI for continued preclinical investigation and, ultimately, clinical translation. This report encapsulates the oral and written components of this workshop addressing key features regarding the pathobiology of DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including, but not limited to, advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better used and integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes with a thorough review of the targets linked to the pathogenesis of DAI, while also presenting a detailed report of those target-based therapies that have been used, to date, with a consideration of their overall implications for future preclinical discovery and subsequent translation to the clinic. Although all participants realize that various research gaps remained in our understanding and treatment of this complex component of TBI, this workshop refines these issues providing, for the first time, a comprehensive appreciation of what has been done and what critical needs remain unfulfilled. © 2013, Mary Ann Liebert, Inc. 2013. Source

Riddle D.L.,Virginia Commonwealth University | Stratford P.W.,McMaster University
Arthritis Care and Research | Year: 2013

Objective To determine if a dose-response relationship exists between percentage changes in body weight in persons with symptomatic knee osteoarthritis (OA) and self-reported pain and function. Methods Data from persons in the Osteoarthritis Initiative (OAI) and the Multicenter Osteoarthritis (MOST) study data sets (n = 1,410) with symptomatic function-limiting knee OA were studied. For the OAI, we used baseline and 3-year followup data, while for the MOST study, baseline and 30-month data were used. Key outcome variables were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function and pain change scores. In addition to covariates, the predictor variable of interest was the extent of weight change over the study period divided into 5 categories representing different percentages of body weight change. Results A significant dose-response relationship (P < 0.003) was found between the extent of percentage change in body weight and the extent of change in WOMAC physical function and WOMAC pain scores. For example, persons who gained ≥10% of body weight had WOMAC physical function score changes of -5.4 (95% confidence interval -8.7, -2.00) points, indicating worsening physical function relative to the reference group of persons with weight changes between <5% weight gain and <5% weight reduction. Conclusion Our data suggest a dose-response relationship exists between changes in body weight and corresponding changes in pain and function. The threshold for this response gradient appears to be body weight shifts of ≥10%. Weight changes of ≥10% have the potential to lead to important changes in pain and function for patient groups as well as individual patients. Copyright © 2013 by the American College of Rheumatology. Source

Sanyal A.J.,Virginia Commonwealth University
Hepatology Research | Year: 2011

Non-alcoholic fatty liver disease (NAFLD) is a major public health problem both in the Western world and in the East. This is mainly due to the high prevalence of the disease and its effects on the individual with NAFLD. In the USA, it is estimated that approximately a third of the general population has NAFLD. Increasing age, obesity and the presence of multiple features of metabolic syndrome, especially diabetes, are associated with a higher probability of having non-alcoholic steatohepatitis (NASH). In the individual with NAFLD, excess hepatic fat is associated with an increased risk of developing diabetes, hypertension, cardiovascular events, abnormal resting electrocardiography and endothelial dysfunction. These findings have been corroborated in studies in teenagers as well as adults. There is also an increase in cardiovascular mortality, especially in those with NASH. In addition, there is an increased risk of death from a variety of non-hepatocellular cancers. From a liver perspective, NAFLD is associated with a 15-20% risk of progression to cirrhosis. The disease progresses more rapidly in those with diabetes, increasing age and obesity. The PNPLA3 gene mutation at position 148 is associated with not only steatosis, but with the likelihood of having steatohepatitis and increased inflammation and fibrosis. Once cirrhosis develops, the liver disease decompensates at the rate of 3-4% per year. NASH-related cirrhosis is a risk factor for hepatocellular cancer. All of these factors indicate that NAFLD is a common condition that has significant adverse health consequences for those who are afflicted. It is therefore a major public health hazard throughout the world. © 2011 The Japan Society of Hepatology. Source

Fong S.S.,Virginia Commonwealth University
Computational and Structural Biotechnology Journal | Year: 2014

Metabolic engineering modifies cellular function to address various biochemical applications. Underlying metabolic engineering efforts are a host of tools and knowledge that are integrated to enable successful outcomes. Concurrent development of computational and experimental tools has enabled different approaches to metabolic engineering. One approach is to leverage knowledge and computational tools to prospectively predict designs to achieve the desired outcome. An alternative approach is to utilize combinatorial experimental tools to empirically explore the range of cellular function and to screen for desired traits. This mini-review focuses on computational systems biology and synthetic biology tools that can be used in combination for prospective in silico strain design. © 2014 Elsevier B.V. Source

Adler S.P.,Virginia Commonwealth University
Infectious Diseases in Obstetrics and Gynecology | Year: 2011

The epidemiology and pathogenesis of CMV infections among pregnant women have been intensely studied over the last three decades. This paper highlights recent developments that make either universal or limited serologic screening for CMV during pregnancy potentially attractive. The developments include an understanding of the pathogenesis of CMV infections, a knowledge of high-risk women, the availability of accurate methods for the serologic diagnosis of a primary CMV infection using either single or serial blood samples, accurate methods for the diagnosis of fetal infection via amniotic fluid, sensitive fetal and placental indicators for neonatal outcomes, and the availability of potentially effective interventions. © 2011 Stuart P. Adler. Source

Calderwood C.,Virginia Commonwealth University | Ackerman P.L.,Georgia Institute of Technology | Conklin E.M.,Georgia Institute of Technology
Computers and Education | Year: 2014

We investigated the frequency and duration of distractions and media multitasking among college students engaged in a 3-h solitary study/homework session. Participant distractions were assessed with three different kinds of apparatus with increasing levels of potential intrusiveness: remote surveillance cameras, a head-mounted point-of-view video camera, and a mobile eyetracker. No evidence was obtained to indicate that method of assessment impacted multitasking behaviors. On average, students spent 73 min of the session listening to music while studying. In addition, students engaged with an average of 35 distractions of 6 s or longer over the course of 3 h, with an aggregated mean duration of 25 min. Higher homework task motivation and self-efficacy to concentrate on homework were associated with less frequent and shorter duration multitasking behaviors, while greater negative affect was linked to longer duration multitasking behaviors during the session. We discuss the implications of these data for assessment and for understanding the nature of distractions and media multitasking during solitary studying. © 2014 Elsevier Ltd. All rights reserved. Source

Zhang W.-J.,Virginia Commonwealth University
Journal of the Electrochemical Society | Year: 2010

In this paper, the specific capacities as a function of discharge rate of over 40 different LiFePO4 materials reported were reviewed and analyzed. The influence of synthesis route, particle size, doping, carbon coating, and conductive carbon loading on the rate performance was discussed. The capacity distribution of the existing LiFePO4 materials over a wide discharge rate (0.1-60C) was constructed. Analysis of the experimental data indicates that carbon coating has a more significant effect in improving the rate performance as compared to doping and particle size reduction. With highly conductive carbon coating, some of the LiFePO4 materials with a large particle size (150-300 nm) exhibited better performance than the materials of nanosize (30-100 nm). In terms of synthesis method, excellent high rate performance was achieved in the LiFePO4 materials prepared by direct precipitation, sol-gel, polyol, and ballmilling techniques. © 2010 The Electrochemical Society. Source

Farrar J.S.,University of Utah | Farrar J.S.,Virginia Commonwealth University | Wittwer C.T.,University of Utah
Clinical Chemistry | Year: 2015

BACKGROUND: PCR is a key technology in molecular biology and diagnostics that typically amplifies and quantifies specific DNA fragments in about an hour. However, the kinetic limits of PCR are unknown. METHODS: We developed prototype instruments to temperaturecycle 1- to 5-L samples in 0.4 -2.0 s at annealing/extension temperatures of 62 °-76 ° and denaturation temperatures of 85 °-92 °. Primer and polymerase concentrations were increased 10- to 20-fold above typical concentrations to match the kinetics of primer annealing and polymerase extension to the faster temperature cycling. We assessed analytical specificity and yield on agarose gels and by high-resolution melting analysis. Amplification efficiency and analytical sensitivity were demonstrated by realtime optical monitoring. RESULTS: Using single-copy genes from human genomic DNA, we amplified 45- to 102-bp targets in 15-60 s. Agarose gels showed bright single bands at the expected size, and high-resolution melting curves revealed singl products without using any "hot start" technique. Amplification efficiencies were 91.7%-95.8% by use of 0.8-to 1.9-s cycles with single-molecule sensitivity. A 60-bp genomic target was amplified in 14.7 s by use of 35 cycles. CONCLUSIONS: The time required for PCR is inversely related to the concentration of critical reactants. By increasing primer and polymerase concentrations 10- to 20-fold with temperature cycles of 0.4-2.0 s, efficient (>90%), specific, high-yield PCR from human DNA is possible in <15 s. ExtremePCRdemonstrates the feasibility of while-you-wait testing for infectious disease, forensics, and any application where immediate results may be critical. © 2014 American Association for Clinical Chemistry. Source

Thomas S.,Virginia Commonwealth University
Human genomics | Year: 2010

Software for network motifs and modules is briefly reviewed, along with programs for network comparison. The three major software packages for network analysis, CYTOSCAPE, INGENUITY and PATHWAY STUDIO, and their associated databases, are compared in detail. A comparative test evaluated how these software packages perform the search for key terms and the creation of network from those terms and from experimental expression data. Source

Ross D.E.,Virginia Institute of Neuropsychiatry | Ross D.E.,Virginia Commonwealth University
Brain Injury | Year: 2011

Introduction: Structural brain imaging in patients with traumatic brain injury (TBI) has progressed remarkably over the years with respect to technology and study design. Methods: Published studies of patients with TBI which used magnetic resonance imaging (MRI), volumetric measures and a longitudinal designthat is, one in which data were collected at more than one point in timewere reviewed. Some of these studies also included analyses using a cross-sectional (one point in time) approach. Results: Ten studies met the review criteria. Although methods varied, these studies showed a consistent pattern of brain atrophy which progressed over the months after injury. Effect sizes (brain size differences) between patients and normal control subjects generally were much larger for comparisons using the longitudinal approach than for those using a cross-sectional approach. Furthermore, atrophy correlated significantly with important clinical variables. Conclusion: In comparison with the cross-sectional design, the longitudinal design may be preferable for understanding the progression of brain atrophy after injury and understanding its association with important clinical variables. © 2011 Informa UK Ltd All rights reserved. Source

Langberg J.M.,Virginia Commonwealth University | Langberg J.M.,Cincinnati Childrens Hospital Medical Center | Becker S.P.,Miami University Ohio
Clinical Child and Family Psychology Review | Year: 2012

Youth with Attention-Deficit/Hyperactivity Disorder (ADHD) frequently experience academic impairment, including lower grades than their peers and elevated risk for grade retention and school dropout. Medication is the most commonly used treatment for youth with ADHD, and it is therefore essential to understand the extent to which medication use improves long-term academic functioning. This paper reviews the literature on the relation between long-term medication use and the academic outcomes of youth with ADHD. A systematic literature search was conducted to identify pertinent studies published since 2000 that followed youth with ADHD for 3 or more years. Academic outcomes of interest included school grades, achievement test scores, and grade retention. Nine studies were identified reporting on eight distinct longitudinal samples (N across studies = 8,721). These studies demonstrate that long-term medication use is associated with improvements in standardized achievement scores. However, the magnitude of these improvements is small and the clinical or educational significance is questionable. Evidence for long-term improvements in school grades and grade retention is less compelling. This review highlights methodological considerations in providing directions for future research. The importance of using multiple sources to gather information about medication adherence is discussed, including use of methodologies such as electronic monitors, rather than relying solely on parent report or chart review. Future research should also examine a range of medication adherence definitions in order to determine whether age of onset, duration of use, dose, and/or consistency of use moderates the relation between long-term medication use and academic outcomes. © 2012 Springer Science+Business Media, LLC. Source

McClish D.K.,Virginia Commonwealth University
Academic Radiology | Year: 2012

Rationale and Objectives: The accuracy of medical tests is often assessed using the area under the entire receiver-operating characteristic (ROC) curve. However, this includes values that might be of no clinical importance. Evaluation of a portion of the curve, or a single point, requires identifying a range of clinical interest, which may not be obvious. The author suggests evaluating the accuracy of medical tests in the vicinity of the optimal point. Materials and Methods: Assuming binormality, the author estimated the optimal threshold as the value that maximizes the generalized Youden index. The confidence interval around the optimal point defined a region of clinical interest; the accuracy of the medical test was assessed using the partial area index (PAI) and standardized partial area (sPA). Bootstrapping was used to estimate variances and construct confidence intervals. Coverage probabilities for the PAI and sPA were assessed, as was the size of the test to compare measures. An example using biomechanical measures from radiographic images of the pelvis and lumbar spine to detect disk hernia and spondylolisthesis is presented. Results: Coverage probabilities of confidence intervals for the partial area measures were good. The size of the test to compare partial area measures was appropriate. Values of PAI and sPA varied with the cost/prevalence ratio. In the example, the biomechanical measures were not found to have significantly different accuracy around the optimal point. Conclusions: The PAI and sPA associated with the optimal point were found to be reasonable and useful measures of accuracy. © 2012 AUR. Source

Noinaj N.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Buchanan S.K.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Cornelissen C.N.,Virginia Commonwealth University
Molecular Microbiology | Year: 2012

Two pathogenic species within the genus Neisseria cause the diseases gonorrhoea and meningitis. While vaccines are available to protect against four N.meningitidis serogroups, there is currently no commercial vaccine to protect against serogroup B or against N.gonorrhoeae. Moreover, the available vaccines have significant limitations and with antibiotic resistance becoming an alarming issue, the search for effective vaccine targets to elicit long-lasting protection against Neisseria species is becoming more urgent. One strategy for vaccine development has targeted the neisserial iron import systems. Without iron, the Neisseriae cannot survive and, therefore, these iron import systems tend to be relatively well conserved and are promising vaccine targets, having the potential to offer broad protection against both gonococcal and meningococcal infections. These efforts have been boosted by recent reports of the crystal structures of the neisserial receptor proteins TbpA and TbpB, each solved in complex with human transferrin, an iron binding protein normally responsible for delivering iron to human cells. Here, we review the recent structural reports and put them into perspective with available functional studies in order to derive the mechanism(s) for how the pathogenic Neisseriae are able to hijack human iron transport systems for their own survival and pathogenesis. © 2012 Blackwell Publishing Ltd. Source

Schry A.R.,Virginia Polytechnic Institute and State University | Roberson-Nay R.,Virginia Commonwealth University | White S.W.,Virginia Polytechnic Institute and State University
Psychological Assessment | Year: 2012

Social anxiety disorder (SAD) is 1 of the most prevalent psychological disorders, and among college students in particular, social anxiety has been associated with other problems such as substance use problems and increased vulnerability to other psychiatric disorders. The Social Phobia and Anxiety Inventory-23 (SPAI-23; Roberson-Nay, Strong, Nay, Beidel, & Turner, 2007) may be a useful, brief measure of problematic social anxiety in college students. Results from 4 studies (total n = 2,436) using the SPAI-23 with college student samples are presented. Scores on the SPAI-23 demonstrated strong convergent validity with other measures of social anxiety and discriminant validity as evidenced by lower correlations with measures of dissimilar constructs. Difference scores on the SPAI-23 also demonstrated adequate test-retest reliability over 5 1/2 weeks (r = .72). Exploratory factor analysis suggested a two-factor structure: social anxiety and agoraphobia. Finally, differential item function analyses suggested that the items function similarly in men and women. In conclusion, the SPAI-23 demonstrated strong psychometric properties for use with college students. © 2012 American Psychological Association. Source

Goncy E.A.,Virginia Commonwealth University | Mrug S.,University of Alabama at Birmingham
Journal of Studies on Alcohol and Drugs | Year: 2013

Objective: This study examined the location and time of adolescent use of cigarettes, alcohol, and marijuana. Age, gender, and racial differences in location and time of use were studied for each substance. Method: Using cross-sectional data collected through the school-wide Pride Survey, 20,055 students between the ages of 10 and 19 years (53.6% female, 55.1% Black, 44.9% White) in one metropolitan area reported on their frequency of cigarette, alcohol, and marijuana use, as well as the location and time of use of each substance. Chi-square tests compared the rates, locations, and times for each substance across boys and girls; Black and White students; and early, middle, and late adolescents. Results: Older adolescents reported higher rates of substance use at friends' homes, at school, and in cars and lower rates of alcohol use at home compared with younger youth. Males were more likely to report alcohol and marijuana use at school and on weeknights and alcohol use in cars, whereas females were more likely to report alcohol and marijuana use on the weekends. No gender differences emerged for times and locations of cigarette use. Compared with Black youth, White adolescents were more likely to use all substances at friends' homes and on weekends; to smoke cigarettes at school, in the car, and on week-nights; and to use alcohol at home. Black adolescents were more likely to report using alcohol at home, at school, in cars, during and after school, and on weeknights and were more likely to report using marijuana at school. Conclusions: The location and time of adolescent substance use vary substantially by age, gender, and race. These differences may help tailor substance use prevention and intervention programs to specific subgroups of youth to improve program effectiveness. Source

Oh Y.,Virginia Commonwealth University
Kidney Research and Clinical Practice | Year: 2012

The growth hormone-insulin-like growth factor-insulin-like growth factor binding protein (GH-IGF-IGFBP) axis plays a critical role in the maintenance of normal renal function and the pathogenesis and progression of chronic kidney disease (CKD). Serum IGF-I and IGFBPs are altered with different stages of CKD, the speed of onset, the amount of proteinuria, and the potential of remission. Recent studies demonstrate that growth failure in children with CKD is due to a relative GH insensitivity and functional IGF deficiency. The functional IGF deficiency in CKD results from either IGF resistance due to increased circulating levels of IGFBPs or IGF deficiency due to increased urinary excretion of serum IGF-IGFBP complexes. In addition, not only GH and IGFs in circulation, but locally produced IGFs, the high-affinity IGFBPs, and low-affinity insulin-like growth factor binding protein-related proteins (IGFBP-rPs) may also affect the kidney. With respect to diabetic kidney disease, there is growing evidence suggesting that GH, IGF-I, and IGFBPs are involved in the pathogenesis of diabetic nephropathy (DN). Thus, prevention of GH action by blockade either at the receptor level or along its signal transduction pathway offers the potential for effective therapeutic opportunities. Similarly, interrupting IGF-I and IGFBP actions also may offer a way to inhibit the development or progression of DN. Furthermore, it is well accepted that the systemic inflammatory response is a key player for progression of CKD, and how to prevent and treat this response is currently of great interest. Recent studies demonstrate existence of IGF-independent actions of high-affinity and low-affinity-IGFBPs, in particular, antiinflammatory action of IGFBP-3 and profibrotic action of IGFBP-rP2/CTGF. These findings reinforce the concept in support of the clinical significance of the IGF-independent action of IGFBPs in the assessment of pathophysiology of kidney disease and its therapeutic potential for CKD. Further understanding of GH-IGF-IGFBP etiopathophysiology in CKD may lead to the development of therapeutic strategies for this devastating disease. It would hold promise to use of GH, somatostatin analogs, IGFs, IGF agonists, GHR and insulin-like growth factor-I receptor (IGF-IR) antagonists, IGFBP displacer, and IGFBP antagonists as well as a combination treatment as therapeutic agents for CKD. © 2012. The Korean Society of Nephrology. Published by Elsevier. All rights reserved. Source

Rubin B.K.,Virginia Commonwealth University
Paediatric Respiratory Reviews | Year: 2012

A highlight of many journals is a review of pertinent literature in a specific field that has been published in the preceding year. Although such " Year in Review" presentations are important, at PRR we are pleased to present the news that has not yet happened. In this manuscript, which is a combination of science and fiction, I will present the very best research that has not yet been conducted but will be published sometime in 2012 or 2013. This will cover all aspects of paediatric pulmonary disease. Any resemblance to real research that is actually published during this time period is strictly coincidental and the product of a fertile imagination. However, if these ideas inspire you to do these studies and publish the results it would make this science fiction even more interesting. To quote the famous baseball player, Yogi Berra, " It's difficult to make predictions, especially about the future." 1. © 2011 Elsevier Ltd. Source

Chatterjee A.,Johns Hopkins University | Dasgupta S.,Johns Hopkins University | Dasgupta S.,Virginia Commonwealth University | Sidransky D.,Johns Hopkins University
Cancer Prevention Research | Year: 2011

Mitochondria control essential cellular activities including generation of ATP via oxidative phosphorylation. Mitochondrial DNA (mtDNA) mutations in the regulatory D-loop region and somatic mtDNA mutations are common in primary human cancers. The biological impact of a given mutation may vary, depending on the nature of the mutation and the proportion of mutant mtDNAs carried by the cell. Identification of mtDNA mutations in precancerous lesions supports their early contribution to cell transformation and cancer progression. Introduction of mtDNA mutations in transformed cells has been associated with increased ROS production and tumor growth. Studies reveal that increased and altered mtDNA plays a role in the development of cancer but further work is required to establish the functional significance of specific mitochondrialmutations in cancer and disease progression. This reviewoffers some insight into the extent of mtDNA mutations, their functional consequences in tumorigenesis, mitochondrial therapeutics, and future clinical application. ©2011 AACR. Source

Osei-Bryson K.-M.,Virginia Commonwealth University
Expert Systems with Applications | Year: 2012

The knowledge discovery via data mining process (KDDM) is a multiple phase that aims to at a minimum semi-automatically extract new knowledge from existing datasets. For many data mining tasks, the evaluation phase is a challenging one for various reasons. Given this challenge several studies have presented techniques that could be used for the semi-automated evaluation of data mining results. When taken together, these studies suggest the possibility of a common multi-criteria evaluation framework. The use of such a multi-criteria evaluation framework, however, requires that relevant objectives, measures and preference function be identified. This implies that the context of the DM problem is particularly important for the evaluation phase of the KDDM process. Our framework utilizes and integrates a pair of established tightly coupled techniques (i.e. Value Focused Thinking (VFT) and the Goal-Question-Metric (GQM) methods) as well as established techniques from multi-criteria decision analysis in order to explicate and utilize context information in order to facilitate semi-automated evaluation. © 2011 Elsevier Ltd. All rights reserved. Source

Mueller T.F.,University of Alberta | Solez K.,University of Alberta | Mas V.,Virginia Commonwealth University
Seminars in Immunopathology | Year: 2011

The critical importance of donor organ quality, i.e., number of surviving nephrons, ability to withstand injury, and capacity for repair in determining short- and long-term outcomes is becoming increasingly clear. This review provides an overview of studies to assess donor kidney quality and subsequent transplant outcomes based on clinical pathology and transcriptome-based variables available at time of transplantation. Prediction scores using clinical variables function when applied to large data sets but perform poorly for the individual patient. Histopathology findings in pre-implantation or post-reperfusion biopsies help to assess structural integrity of the donor kidney, provide information on pre-existing donor disease, and can serve as a baseline for tracking changes over time. However, more validated approaches of analysis and prospective studies are needed to reduce the number of discarded organs, improve allocation, and allow prediction of outcomes. Molecular profiling detects changes not seen by morphology or captured by clinical markers. In particular, molecular profiles provide a quantitative measurement of inflammatory burden or immune activation and reflect coordinated changes in pathways associated with injury and repair. However, description of transcriptome patterns is not an end in itself. The identification of predictive gene sets and the application to an individualized patient management needs the integration of clinical and pathology-based variables, as well as more objective reference markers of transplant function, post-transplant events, and long-term outcomes. © 2011 Springer-Verlag. Source

Chen X.,Virginia Commonwealth University | Ankenman B.E.,Northwestern University | Nelson B.L.,Northwestern University
Operations Research | Year: 2013

Stochastic kriging is a new metamodeling technique for effectively representing the mean response surface implied by a stochastic simulation; it takes into account both stochastic simulation noise and uncertainty about the underlying response surface of interest. We show theoretically, through some simplified models, that incorporating gradient estimators into stochastic kriging tends to significantly improve surface prediction. To address the issue of which type of gradient estimator to use, when there is a choice, we briefly review stochastic gradient estimation techniques; we then focus on the properties of infinitesimal perturbation analysis and likelihood ratio/score function gradient estimators and make recommendations. To conclude, we use simulation experiments with no simplifying assumptions to demonstrate that the use of stochastic kriging with gradient estimators provides more reliable prediction results than stochastic kriging alone. © 2013 INFORMS. Source

Moradi H.,University of California at Irvine | Sica D.A.,Virginia Commonwealth University | Kalantar-Zadeh K.,University of California at Irvine
American Journal of Nephrology | Year: 2013

Background: Retention of uremic toxins in patients with chronic kidney disease (CKD) negatively affects multiple organ systems, including the cardiovascular system, resulting in significant morbidity and mortality. Alleviation of the adverse effects of uremic toxins is an important priority in the management of CKD. Scope: This review focuses on the evidence for the influence of uremic toxins on cardiovascular morbidity and mortality among patients with CKD and slowly developing uremia. The cardiovascular effects of acute kidney injury and rapidly developing azotemia are beyond the scope of this review and will not be discussed. Data on potential treatment options aimed at ameliorating the toxic effects of uremic toxins are summarized. Findings: Uremic toxins are associated with significant cardiovascular morbidity and mortality in patients with CKD. While a number of preclinical studies have detailed these effects, clinical studies directly evaluating cardiovascular outcomes consequent to the presence of uremic toxins have only recently become available. Conclusion: Uremic toxins play an important role in the progression of cardiovascular disease in patients with CKD. Further studies are needed to better characterize the impact of these compounds on cardiovascular outcomes. Beneficial treatments are currently available that, in preliminary studies, appear to neutralize some of the adverse effects of uremic toxins. Large randomized clinical trials are needed to further determine the utility of these varied therapeutic agents. Copyright © 2013 S. Karger AG, Basel. Source

Pittman R.N.,Virginia Commonwealth University
Acta physiologica (Oxford, England) | Year: 2011

Early in the last century August Krogh embarked on a series of seminal studies to understand the connection between tissue metabolism and mechanisms by which the cardiovascular system supplied oxygen to meet those needs. Krogh recognized that oxygen was supplied from blood to the tissues by passive diffusion and that the most likely site for oxygen exchange was the capillary network. Studies of tissue oxygen consumption and diffusion coefficient, coupled with anatomical studies of capillarity in various tissues, led him to formulate a model of oxygen diffusion from a single capillary. Fifty years after the publication of this work, new methods were developed which allowed the direct measurement of oxygen in and around microvessels. These direct measurements have confirmed the predictions by Krogh and have led to extensions of his ideas resulting in our current understanding of oxygenation within the microcirculation. Developments during the last 40 years are reviewed, including studies of oxygen gradients in arterioles, capillaries, venules, microvessel wall and surrounding tissue. These measurements were made possible by the development and use of new methods to investigate oxygen in the microcirculation, so mention is made of oxygen microelectrodes, microspectrophotometry of haemoglobin and phosphorescence quenching microscopy. Our understanding of oxygen transport from the perspective of the microcirculation has gone from a consideration of oxygen gradients in capillaries and tissue to the realization that oxygen has the ability to diffuse from any microvessel to another location under the conditions that there exists a large enough PO(2) gradient and that the permeability for oxygen along the intervening pathway is sufficient. © 2011 The Author. Acta Physiologica © 2011 Scandinavian Physiological Society. Source

Bowers M.S.,Virginia Commonwealth University
Behavioural Pharmacology | Year: 2010

Drug addiction is marked by continued drug-seeking behavior despite deleterious consequences and a heightened propensity to relapse not withstanding long, drug-free periods. The enduring nature of addiction has been hypothesized to arise from perturbations in intracellular signaling, gene expression, and brain circuitry induced by substance abuse. Ameliorating some of these aberrations should abate behavioral and neurochemical markers associated with an 'addiction phenotype'. This review summarizes data showing that protein expression and signaling through the nonreceptor activator of G-protein signaling 3 (AGS3) are altered by commonly abused substances in rat and in in-vitro addiction models. AGS3 structure and function are unrelated to the more broadly studied regulator of G-protein signaling family. Thus, the unique role of AGS3 is the focus of this review. Intriguingly, AGS3 protein changes persist into drug abstinence. Accordingly, studies probing the role of AGS3 in the neurochemistry of drug-seeking behavior and relapse are studied in detail. To illuminate this study, AGS3 structure, cellular localization, and function are covered so that an idealized AGS3-targeted pharmacotherapy can be proposed. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Lister J.A.,Virginia Commonwealth University
Genesis | Year: 2010

Summary: Genome engineering strategies employing site-specific recombinases (SSRs) have become invaluable to the study of gene function in model organisms. One such SSR, the integrase encoded by the Streptomyces bacteriophage phiC31, promotes recombination between heterotypic attP and attB sites. In the present study I have examined the feasibility of the use of phiC31 integrase for intramolecular recombination strategies in zebrafish embryos. I report here that (1) phiC31 integrase is functional in zebrafish cells, (2) phiC31 integrase can excise a transgene cassette flanked by an attB and an attP site, analogous to a common use of the Cre/lox SSR system, (3) phiC31 integrase functions in the zebrafish germline, and (4) a phiC31 integrase-estrogen receptor hormone-binding domain variant fusion protein catalyzes attB-attP recombination in zebrafish embryos in a 4-hydroxytamoxifen-dependent manner, albeit less efficiently than phiC31 alone. These features should make this a useful approach for genome manipulations in the zebrafish. © 2010 Wiley-Liss, Inc. Source

Godwin-Jones R.,Virginia Commonwealth University
Language Learning and Technology | Year: 2014

There has been a substantial increase in recent years in the interest in using digital games for language learning. This coincides with the explosive growth in multiplayer online gaming and with the proliferation of mobile games for smart phones. It also reflects the growing recognition among educators of the importance of extramural, informal learning and the interest in finding ways to connect learning to students' real lives. Given the important role that gaming currently plays in the everyday lives of adolescents and young adults in developed countries, this spike in interest is not surprising. However, there are a number of practical and pedagogical obstacles in the way of incorporating gaming into instructed language learning. Among those issues are: what kind of games to choose or to create; how to find the opportunities for language learning within gameplay; and how to integrate gameplay and its associated activities into the curriculum. In order to address these issues, we need research-generated data, which is crucial not only for learning how to make gaming more effective in classroom practice, but also in informing future game development. Collecting, analyzing, and sharing data collected from digital games is a major challenge, but some recent technical developments may present new opportunities. This column will not provide answers to the complex set of issues raised in the integration of gaming into language learning, but will identify and discuss some recent developments and point to possible future directions. © Robert Godwin-Jones. Source

Dula J.H.,Virginia Commonwealth University
INFORMS Journal on Computing | Year: 2011

The standard approach to process a data envelopment analysis (DEA) data set, and the one in widespread use, consists of solving as many linear programs (LPs) as there are entities. The dimensions of these LPs are determined by the size of the data sets, and they keep their dimensions as each decision-making unit is scored. This approach can be computationally demanding, especially with large data sets. We present an algorithm for DEA based on a two-phase procedure. The first phase identifies the extreme efficient entities, the frame, of the production possibility set. The frame is then used in a second phase to score the rest of the entities. The new procedure applies to any of the four standard DEA returns to scale. It also imparts flexibility to a DEA study because it postpones the decision about orientation, benchmarking measurements, etc., until after the frame has been identified. Extensive computational testing on large data sets verifies and validates the procedure and demonstrates that it is computationally fast. © 2011 INFORMS. Source

Brooks J.P.,Virginia Commonwealth University
Operations Research | Year: 2011

In the interest of deriving classifiers that are robust to outlier observations, we present integer programming formulations of Vapnik's support vector machine (SVM) with the ramp loss and hard margin loss. The ramp loss allows a maximum error of 2 for each training observation, while the hard margin loss calculates error by counting the number of training observations that are in the margin or misclassified outside of the margin. SVM with these loss functions is shown to be a consistent estimator when used with certain kernel functions. In computational studies with simulated and real-world data, SVM with the robust loss functions ignores outlier observations effectively, providing an advantage over SVM with the traditional hinge loss when using the linear kernel. Despite the fact that training SVM with the robust loss functions requires the solution of a quadratic mixed-integer program (QMIP) and is NP-hard, while traditional SVM requires only the solution of a continuous quadratic program (QP), we are able to find good solutions and prove optimality for instances with up to 500 observations. Solution methods are presented for the new formulations that improve computational performance over industry-standard integer programming solvers alone. © 2011 INFORMS. Source

Sisson E.M.,Virginia Commonwealth University
Pharmacotherapy | Year: 2011

Liraglutide is a United States Food and Drug Administration (FDA)-approved glucagon-like peptide-1 (GLP-1) analog that is 97% homologous to native human GLP-1. The additional 16-carbon fatty acid chain causes noncovalent binding to albumin, which slows absorption from the injection site and protects the molecule from degradation by the enzyme dipeptidyl peptidase-4, allowing for protraction of action. Albumin binding and an elimination halflife of 13 hours combine to allow for once-daily dosing. Liraglutide 1.2 and 1.8 mg/day given as monotherapy for up to 52 weeks produced mean reductions in hemoglobin A1c (A1C) of 0.6-1.6%; combination therapy of liraglutide with oral antidiabetic agents demonstrated mean A1C reductions up to 1.5%. The satiety effect of GLP-1 receptor agonists and documented weight loss as great as 3.38 kg in clinical trials may make liraglutide ideal for obese patients with type 2 diabetes mellitus. Like other incretin-based agents, preliminary studies suggest liraglutide may also increase β-cell mass and function. Hypoglycemia is rare with liraglutide and tends to occur when used in combination with sulfonylureas; liraglutide in combination with insulin is not yet FDA approved. The pharmacokinetic parameters of liraglutide are unaffected by age, sex, race, or ethnicity, and no special recommendations for altered dosing of liraglutide need apply to populations with hepatic or renal impairment. Results from clinical trials have not shown an increased risk of medullary thyroid cancer, pancreatitis, or poor cardiovascular outcomes with liraglutide treatment. Ongoing, long-term monitoring studies continue to evaluate the safety of liraglutide treatment in these outcomes. Source

Sanyal A.J.,Virginia Commonwealth University
The oncologist | Year: 2010

Most patients with hepatocellular carcinoma (HCC) have liver cirrhosis, which develops following long periods of chronic liver disease. Cirrhosis is characterized by a decrease in hepatocyte proliferation, indicating an exhaustion of the regenerative capacity of the liver, and results in an increase in fibrous tissue and a destruction of liver cells, which may ultimately lead to the development of cancerous nodules. Half of all cases of HCC are associated with hepatitis B virus infection, with a further 25% associated with hepatitis C virus. Other risk factors for developing HCC include alcoholic liver disease, nonalcoholic steatohepatitis, intake of aflatoxin-contaminated food, diabetes, and obesity. There are multiple factors involved in the etiology of HCC, all of which have a direct impact on patient characteristics and disease course, and although a causative agent can often be identified, HCC remains an extremely complex condition associated with a poor prognosis. Additionally, the geographic variation in etiology means that information from different countries is needed in order to optimize surveillance methods and develop effective chemoprevention strategies. Unfortunately, there are still many gaps in our current understanding, and further research efforts are needed to fully elucidate the diverse mechanisms involved in the pathogenesis of HCC and offer optimal prevention strategies for those at risk. Source

Strauss III J.F.,Virginia Commonwealth University
Reproductive Sciences | Year: 2013

The extracellular matrix (ECM) plays an important role in determining cell and organ function: (1) it is an organizing substrate that provides tissue tensile strength; (2) it anchors cells and influences cell morphology and function via interaction with cell surface receptors; and (3) it is a reservoir for growth factors. Alterations in the content and the composition of the ECM determine its physical and biological properties, including strength and susceptibility to degradation. The ECM components themselves also harbor cryptic matrikines, which when exposed by conformational change or proteolysis have potent effects on cell function, including stimulating the production of cytokines and matrix metalloproteinases (MMPs). Collectively, these properties of the ECM reflect a dynamic tissue component that influences both tissue form and function. This review illustrates how defects in ECM synthesis and metabolism and the physiological process of ECM turnover contribute to changes in the fetal membranes that precede normal parturition and contribute to the pathological events leading to preterm premature rupture of membranes (PPROM). © 2013 The Author(s). Source

Cunningham P.,Virginia Commonwealth University
JAMA Internal Medicine | Year: 2014

IMPORTANCE Increased patient engagement with health and health care is considered crucial to increasing the quality of health care and patient self-management of health. OBJECTIVE To examine whether patients with high levels of engagement during medical encounters are more likely to receive advice and counseling about smoking compared with less engaged patients. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional survey using multivariate regression analysis of 8656 current and retired autoworkers and their spouses younger than 65 years who are or were employed by the 3 major US auto companies. MAIN OUTCOMES AND MEASURES Clinician advice and counseling about smoking; patients who tried to quit smoking. RESULTS Among 1904 current smokers, 58.5%of those who were more highly engaged during medical encounters were counseled by clinicians about specific strategies and methods to stop smoking, compared with 45.4%of patients who were less engaged. Patient engagement and being advised by clinicians to stop smoking had independent effects on smoking cessation efforts by patients. Accounting for differences in other patient characteristics, patients with high engagement levels were more likely to try to stop smoking compared with patients with lower engagement (odds ratio, 1.62; P < .01). Patients who were both highly engaged and had received counseling from clinicians were the most likely to try to stop smoking (74.6%) while patients with low engagement who did not receive counseling were the least likely (46.0%). Nevertheless, counseling is still effective among even less engaged patients; 60.4%of smokers with low engagement who received counseling tried to quit smoking in the past year compared with 46.0%who did not receive counseling. CONCLUSIONS AND RELEVANCE The study results provide evidence that clinicians respond differently to patients who are highly engaged during medical encounters than they do to less engaged patients in terms of smoking cessation advice. Clinicians should not assume that low patient engagement and greater passivity during medical encounters is evidence of unwillingness to quit. The results show that smoking cessation counseling is associated with a higher likelihood of quit attempts even for patients who are less engaged during medical encounters. © 2014 American Medical Association. Source

Shepherd R.W.,Virginia Commonwealth University
Current Opinion in Pulmonary Medicine | Year: 2016

Purpose of review Peripheral pulmonary lesions (PPL) are being diagnosed with increasing frequency, especially with the increased use of chest computed tomography (CT). Depending on the location and size, these lesions often present a diagnostic challenge in terms of the low yield of traditional bronchoscopic biopsy techniques or the risks of a percutaneous biopsy approach. Recent findings Over the last several years, several different image-guided bronchoscopy techniques have emerged, including virtual bronchoscopic navigation, electromagnetic navigation bronchoscopy, radial endobronchial ultrasound, and ultrathin bronchoscopy. These technologies seek to improve both access and the diagnostic yield of PPL compared with traditional bronchoscopy and to perform with a lower complication rate than percutaneous techniques such as CT-guided trans-thoracic needle aspiration. Summary These advanced bronchoscopic techniques play an increasingly common role in the evaluation and biopsy of PPL. Electromagnetic navigation bronchoscopy and radial endobronchial ultrasound are the most commonly used guided techniques either in isolation or in combination and have the most published data regarding clinical experience and diagnostic yield; however, none of the techniques have consistently matched the yield of CT-guided trans-thoracic needle biopsy for PPL. Overall the complication rate of image-guided bronchoscopy techniques is low with pneumothorax being the most common adverse event. © 2016 Wolters Kluwer Health, Inc. All rights reserved. Source

Doern C.D.,Virginia Commonwealth University
Journal of Clinical Microbiology | Year: 2014

In this age of emerging antibiotic resistance, limited therapeutic options exist for treating multidrug-resistant organisms. Combination therapy is commonly employed to manage these infections despite little laboratory guidance as to the efficacy of this approach. Synergy testing methods have been used to assess the interaction of antibiotic combinations in vitro. This review will discuss the four primary methods used to assess synergy, as well as the data that exist for testing of cystic fibrosis. In the final analysis, this review concludes that there is not enough evidence to endorse synergy testing for routine clinical use. Copyright © 2014, American Society for Microbiology. All Rights Reserved. Source

Herbers J.E.,University of Minnesota | Reynolds A.J.,University of Minnesota | Chen C.-C.,Virginia Commonwealth University
Development and Psychopathology | Year: 2013

School mobility has been shown to increase the risk of poor achievement, behavior problems, grade retention, and high school dropout. Using data over 25 years from the Chicago Longitudinal Study, we investigated the unique risk of school moves on a variety of young adult outcomes including educational attainment, occupational prestige, depression symptoms, and criminal arrests. We also investigated how the timing of school mobility, whether earlier or later in the academic career, may differentially predict these outcomes over and above associated risks. Results indicate that students who experience more school changes between kindergarten and 12th grade are less likely to complete high school on time, complete fewer years of school, attain lower levels of occupational prestige, experience more symptoms of depression, and are more likely to be arrested as adults. Furthermore, the number of school moves predicted outcomes above and beyond associated risks such as residential mobility and family poverty. When timing of school mobility was examined, results indicated more negative outcomes associated with moves later in the grade school career, particularly between 4th and 8th grades. Copyright © Cambridge University Press 2013. Source

Krist A.H.,Virginia Commonwealth University
Journal of the American Board of Family Medicine | Year: 2015

This special issue explores a range of health information technology (HIT) issues that can help primary care practices and patients. Findings address the design of HIT systems, primarily electronic health records (EHRs), the utility of various functionalities, and implementation strategies that ensure the greatest value. The articles also remind us that, while HIT can support the delivery of care, it is not a panacea. To be effective, functionality needs to be relevant and timely for both the clinician and patient. Prompts and better documentation can improve care, and "prompt fatigue" is not inevitable. Information presented within EHRs needs to be actionable. There is an ongoing tension between information overload and the right - and helpful - information. Even the order of presentation of information can make a difference in the outcome. Whether supported by HIT or not, basic tenants of care, such as including the whole care team in trainings, communicating with other providers, and engaging patients, remain essential. The studies in this issue will prove useful for informatics developers, practices and health systems making HIT decisions, and care teams refining HIT to support the needs of their patients. © 2015, American Board of Family Medicine. All rights reserved. Source

The soft medical model for psychiatric illness, which was operationalized in DSM-III, defines psychiatric disorders as syndromes with shared symptoms, signs, course of illness and response to treatment. Many in our field want to move to a hard medical model based on etiological mechanisms. This essay explores the feasibility of this move and asks whether psychiatric disorders have the needed single clear level of explanation for an etiologically based nosology. I propose seven criteria for a good explanation: (i) strength, (ii) causal confidence, (iii) generalizability, (iv) specificity, (v) manipulability, (vi) proximity and (vii) generativity. Applying them to cystic fibrosis, a gene-level approach to etiology performs well across the board. By contrast, a detailed review of alcohol dependence and a briefer review of major depression suggests that psychiatric disorders have multiple explanatory perspectives no one of which can be privileged over others using scientific data alone. Therefore, a move toward an etiologically based diagnostic system cannot assume that one level of explanation will stand out as the obvious candidate on which to base the nosology. This leaves two options. Either a hard medical model will be implemented that will require a consensus about a preferred level of explanation which must reflect value judgments as well as science. To take this approach, we need to agree on what we most want from our explanations. Alternatively, we will need to move away from the traditional hard medical model that requires that we ground our diagnoses in single biological essences, and focus instead on fuzzy, cross-level mechanisms, which may more realistically capture the true nature of psychiatric disorders. © 2012 Macmillan Publishers Limited All rights reserved. Source

Miller W.G.,Virginia Commonwealth University | Jones G.R.D.,University of New South Wales | Horowitz G.L.,Harvard University | Weykamp C.,Queen Beatrix Hospital
Clinical Chemistry | Year: 2011

BACKGROUND: Proficiency testing (PT), or external quality assessment (EQA), is intended to verify on a recurring basis that laboratory results conform to expectations for the quality required for patient care. CONTENT: Key factors for interpreting PT/EQA results are knowledge of the commutability of the samples used and the process used for target value assignment. A commutable PT/EQA sample demonstrates the same numeric relationship between different measurement procedures as that expected for patients' samples. Noncommutable PT/EQA samples frequently have a matrix-related bias of unknown magnitude that limits interpretation of results. PT/EQA results for commutable samples can be used to assess accuracy against a reference measurement procedure or a designated comparison method. In addition, the agreement of the results between different measurement procedures for commutable samples reflects that which would be seen for patients' samples. PT/EQA results for noncommutable samples must be compared to a peer group mean/median of results from participants who use measurement procedures that are expected to have the same or very similar matrix-related bias. Peer group evaluation is used to asses whether a laboratory is using a measurement procedure in conformance to the manufacturer's specifications and/or in conformance to other laboratories using the same technology. A noncommutable PT/EQA sample does not give meaningful information about the relationship of results for patients' samples between different measurement procedures. SUMMARY: PT/EQA provides substantial value to the practice of laboratory medicine by assessing the performance of individual laboratories and, when commutable samples are used, the status of standardization or harmonization among different measurement procedures. © 2011 American Association for Clinical Chemistry. Source

Meredith M.A.,Virginia Commonwealth University | Allman B.L.,State University of New York at Buffalo
Neural Plasticity | Year: 2012

Numerous investigations of cortical crossmodal plasticity, most often in congenital or early-deaf subjects, have indicated that secondary auditory cortical areas reorganize to exhibit visual responsiveness while the core auditory regions are largely spared. However, a recent study of adult-deafened ferrets demonstrated that core auditory cortex was reorganized by the somatosensory modality. Because adult animals have matured beyond their critical period of sensory Development and plasticity, it was not known if adult-deafening and early-deafening would generate the same crossmodal results. The present study used young, ototoxically-lesioned ferrets (n = 3) that, after maturation (avg. =173 days old), showed significant hearing Deficits (avg. threshold=72dB SPL). Recordings from single-units (n = 132) in core auditory cortex showed that 72 were activated by somatosensory stimulation (compared to 1 in hearing controls). In addition, tracer injection into early hearing-impaired core auditory cortex labeled essentially the same auditory cortical and thalamic projection sources as seen for injections in the hearing controls, indicating that the functional reorganization was not the result of new or latent projections to the cortex. These data, along with similar observations from adult-deafened and adult hearing-impaired animals, support the recently proposed brainstem theory for crossmodal plasticity induced by hearing loss. © Copyright 2012 M. Alex Meredith and Brian L. Allman. Source

Background: Preclinical drug vs. food choice is an emerging group of drug self-administration procedures that have shown predictive validity to clinical drug addiction. Emerging data suggest that serotonin (5-HT)2A receptors modulate mesolimbic dopamine function, such that 5-HT2A antagonists blunt the abuse-related neurochemical effects of monoamine transporter substrates, such as amphetamine or methamphetamine. Whether subchronic 5-HT2A antagonist treatment attenuates methamphetamine reinforcement in any preclinical drug self-administration procedure is unknown. The study aim was therefore to determine 7-day treatment effects with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in monkeys. Methods: Behavior was maintained under a concurrent schedule of food delivery (1. g pellets, fixed-ratio 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n = 3). Methamphetamine choice dose-effect functions were determined daily before and during 7-day repeated pimavanserin (1.0-10. mg/kg/day, intramuscular) treatment periods. Results: Under control conditions, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Repeated pimavanserin administration failed to attenuate methamphetamine choice and produce a reciprocal increase in food choice in any monkey up to doses (3.2-10. mg/kg) that suppressed rates of operant responding primarily during components where behavior was maintained by food pellets. Conclusions: Repeated 5-HT2A receptor inverse agonist/antagonist treatment did not attenuate methamphetamine reinforcement under a concurrent schedule of intravenous methamphetamine and food presentation in nonhuman primates. Overall, these results do not support the therapeutic potential of 5-HT2A inverse agonists/antagonists as candidate medications for methamphetamine addiction. © 2016 The Author(s). Source

Song B.-M.,University of Texas Southwestern Medical Center | Avery L.,Virginia Commonwealth University
Journal of Neuroscience | Year: 2012

Food intake in the nematode Caenorhabditis elegans requires two distinct feeding motions, pharyngeal pumping and isthmus peristalsis. Bacteria, the natural food of C. elegans, activate both feeding motions (Croll, 1978; Horvitz et al., 1982; Chiang et al., 2006). The mechanisms by which bacteria activate the feeding motions are largely unknown. To understand the process, we studied how serotonin, an endogenous pharyngeal pumping activator whose action is triggered by bacteria, activates feeding motions. Here,weshow that serotonin, like bacteria, activates overall feeding by activating isthmus peristalsis as well as pharyngeal pumping. During active feeding, the frequencies and the timing of onset of the two motions were distinct, but each isthmus peristalsis was coupled to the preceding pump.We found that serotonin activates the two feeding motions mainly by activating two separate neural pathways in response to bacteria. For activating pumping, the SER-7 serotonin receptor in the MC motor neurons in the feeding organ activated cholinergic transmission from MCto the pharyngeal muscles by activating the Gsα signaling pathway. For activating isthmus peristalsis, SER-7 in the M4 (and possibly M2) motor neuron in the feeding organ activated the G 12α signaling pathway in a cell-autonomous manner, which presumably activates neurotransmission from M4 to the pharyngeal muscles. Based on our results and previous calcium imaging of pharyngeal muscles (Shimozono et al., 2004), we propose a model that explains how the two feeding motions are separately regulated yet coupled. The feeding organ may have evolved this way to support efficient feeding. © 2012 the authors. Source

McQuiston A.R.,Virginia Commonwealth University
Journal of Physiology | Year: 2010

During theta rhythm, the timing of inputs to hippocampal CA1 from the perforant path (PP) of the entorhinal cortex and the Schaffer collaterals (SCs) from individual CA3 pyramidal neurons can vary within an individual theta period. Importantly, during theta rhythms these interactions occur during elevated acetylcholine concentrations. Thus, I examined the effect that PP inputs have on SC inputs in hippocampal CA1 during cholinergic receptor activation. To do this I measured the impact that a single electrical stimulus of the stratum lacunosum-moleculare (SLM, which contains the PP) had on excitation evoked by stimulation of the stratum radiatum (SR, which contains the SC) using voltage-sensitive dye imaging, field excitatory postsynaptic potentials and whole cell patch clamping in rat hippocampal brain slices. My data showed that SLM stimulation one half a theta cycle or less (25-75 ms) before SR stimulation resulted in the summation of excitatory events in SR and SP of hippocampal CA1. The summation was unaffected by cholinergic receptor activation by carbachol. SLM stimulation one theta cycle (150-225 ms) preceding SR stimulation significantly suppressed excitatory events measured in SR and SP. This SLM stimulus inhibition of SR-driven excitatory events was augmented by carbachol application. The carbachol effect was blocked by atropine and SLM-driven suppression of excitatory events was blocked by the GABAB receptor antagonist CGP 54626. SR field EPSP slopes were unaffected by SLM prepulses. Carbachol increased the probability of SR input to drive action potential firing in CA1 pyramidal neurons, which was inhibited by SLM prepulses (150-225 ms). Together these data provide important information regarding the integration of inputs in hippocampal CA1 during theta rhythms. More specifically, SR inputs can be differentially gated by SLM feedforward inhibition at varying temporal intervals within a theta cycle. © 2010 The Author. Journal compilation © 2010 The Physiological Society. Source

Abbate A.,Virginia Commonwealth University | Narula J.,Mount Sinai School of Medicine
Heart Failure Clinics | Year: 2012

Apoptosis is a key feature in the progression of heart disease. Stage B heart failure is characterized by a structurally abnormal heart in which the remodeled myocardium is prone to apoptosis. Elimination of the proapoptotic stimuli or inhibition of the apoptotic cascade could presumably rescue the myocardium and halt the progression of adverse remodeling and heart failure. In this article, the authors review the role of apoptosis (or programmed cell death) in determining the evolution of symptomatic heart failure and particularly the adverse remodeling in the aftermath of acute myocardial infarction. © 2012 Elsevier Inc. Source

Guillen Schlippe Y.V.,Massachusetts General Hospital | Hartman M.C.T.,Massachusetts General Hospital | Hartman M.C.T.,Virginia Commonwealth University | Josephson K.,Massachusetts General Hospital | And 2 more authors.
Journal of the American Chemical Society | Year: 2012

There is a great demand for the discovery of new therapeutic molecules that combine the high specificity and affinity of biologic drugs with the bioavailability and lower cost of small molecules. Small, natural-product-like peptides hold great promise in bridging this gap; however, access to libraries of these compounds has been a limitation. Since ribosomal peptides may be subjected to in vitro selection techniques, the generation of extremely large libraries (>10 13) of highly modified macrocyclic peptides may provide a powerful alternative for the generation and selection of new useful bioactive molecules. Moreover, the incorporation of many non-proteinogenic amino acids into ribosomal peptides in conjunction with macrocyclization should enhance the drug-like features of these libraries. Here we show that mRNA-display, a technique that allows the in vitro selection of peptides, can be applied to the evolution of macrocyclic peptides that contain a majority of unnatural amino acids. We describe the isolation and characterization of two such unnatural cyclic peptides that bind the protease thrombin with low nanomolar affinity, and we show that the unnatural residues in these peptides are essential for the observed high-affinity binding. We demonstrate that the selected peptides are tight-binding inhibitors of thrombin, with K i app values in the low nanomolar range. The ability to evolve highly modified macrocyclic peptides in the laboratory is the first crucial step toward the facile generation of useful molecular reagents and therapeutic lead molecules that combine the advantageous features of biologics with those of small-molecule drugs. © 2012 American Chemical Society. Source

Brunzell D.H.,Virginia Commonwealth University | Mcintosh J.M.,University of Utah | Papke R.L.,Florida College
Annals of the New York Academy of Sciences | Year: 2014

Preclinical studies suggest that a diversity of nicotinic acetylcholine receptors (nAChRs) with different sensitivities to nicotine may contribute to tobacco addiction. Using rodent intravenous nicotine self-administration as a preclinical model with good predictive validity for therapeutic efficacy for tobacco cessation, investigators have identified heteromeric α6β2* and homomeric α7 nAChRs as promising novel therapeutic targets to promote smoking abstinence (*denotes possible assembly with other subunits). The data suggest that diverse strategies that target these subclasses of nAChRs, namely inhibition of α6β2* nAChRs and stimulation of α7 nAChRs, will support tobacco cessation. α6β2* nAChRs, members of the high-affinity family of β2* nAChRs, function similarly to α4β2* nAChRs, the primary target of the FDA-approved drug varenicline, but have a much more selective neuroanatomical pattern of expression in catecholaminergic nuclei. Although activation of β2* nAChRs facilitates nicotine self-administration, stimulation of α7 nAChRs appears to negatively modulate both nicotine reinforcement and β2* nAChR function in the mesolimbic dopamine system. Although challenges and caveats must be considered in the development of therapeutics that target these nAChR subpopulations, an accumulation of data suggests that α7 nAChR agonists, partial agonists, or positive allosteric modulators and α6β2* nAChR antagonists, partial agonists, or negative allosteric modulators may prove to be effective therapeutics for tobacco cessation. © 2014 New York Academy of Sciences. Source

Bledowski J.,Virginia Commonwealth University
Psychosomatics | Year: 2012

The prevalence of delirium has been estimated at anywhere between 10% and 30% in general medical patients and in upwards of 80% in patients who are admitted to an intensive care unit (ICU). Given the high prevalence of delirium in the ICU population, it should not be surprising that a large percentage of psychiatric consults arise from this setting. While the mainstay of pharmacologic management of delirium centers on neuroleptic medications, such as haloperidol, recent studies using alternate agents have shown varying levels of promise. Our purpose is to outline the major prospective studies looking at the efficacy of pharmacologic management and prevention strategies for delirium exclusively in adult ICU patients. Both conventional and novel pharmacotherapeutic interventions are discussed. Articles were obtained using the MEDLINE/PUBMED database looking specifically at pharmacologic interventions for delirium in the intensive care unit. A search was performed using the key words"delirium," "intensive care unit," "treatment," and "prophylaxis." The authors limited their search to prospective studies, specifically randomized trials (both placebo-controlled and non-controlled) in the adult ICU population, and eliminated retrospective and observational studies. Relevant citations from the previously mentioned articles were also included in the review. There is a plethora of studies on pharmacologic management strategies in general medical patients with delirium. Findings from these studies are often extrapolated to the ICU population; however, when looking at studies limited to ICU patients with delirium, there are far fewer credible prospective studies. Copyright © 2012 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved. Source

Bajaj J.S.,Virginia Commonwealth University
Gut Microbes | Year: 2014

Hepatic encephalopathy (HE), which consists of minimal (MHE) and overt (OHE) stages, is a model for impaired gut-liver-brain axis in cirrhosis. Microbiota changes in both stages have been associated with impaired cognition, endotoxemia, and inflammation. There is dysbiosis (reduced autochthonous taxa [Lachnospiraceae, Ruminococcaceae, and Clostridiales XIV] and increased Enterobacteriaceae and Streptococcaceae) with disease progression. In MHE, there is an increased abundance of Streptococcus salivarius linked to cognition and ammonia. In OHE, stool Alcaligenaceae and Porphyromonadaceae are associated with poor cognition. Colonic mucosal microbiome in cirrhosis is significantly different compared with stool and independently related to cognition. HE treatment can affect microbial composition and function; cognitive improvement in MHE after rifaximin, a non-absorbable antibiotic, occurred without significant stool microbiota composition change but improved metabolic linkages. Similarly, there are only modest lactulose and rifaximin-associated changes on microbiota composition in OHE. HE represents an important model to study microbiome-brain interactions. © 2014 Landes Bioscience. Source

Baumann M.H.,U.S. National Institute on Drug Abuse | Solis E.,Virginia Commonwealth University | Watterson L.R.,Arizona State University | Marusich J.A.,Rti International | And 2 more authors.
Journal of Neuroscience | Year: 2014

The abuse of synthetic psychoactive substances known as “designer drugs,” or “new psychoactive substances” (NPS), is increasing at an alarming rate. NPS are purchased as alternatives to traditional illicit drugs of abuse and are manufactured to circumvent laws regulating the sale and use of controlled substances. Synthetic cathinones (i.e., “bath salts”) and synthetic cannabinoids (i.e., “spice”) are two types of NPS that have received substantial media attention. Although low recreational doses of bath salts or spice compounds can produce desirable effects, high doses or chronic exposure often leads to dangerous medical consequences, including psychosis, violent behaviors, tachycardia, hyperthermia, and even death. Despite the popularity of NPS, there is a paucity of scientific data about these drugs. Here we provide a brief up-to-date review describing the mechanisms of action and neurobiological effects of synthetic cathinones and cannabinoids. © 2014 the authors. Source

Prostate cancer is the second leading cause of cancer-related deaths in men in the U.S. At present, no single or combination therapy has shown efficacy in decreasing disease progression in patients with metastatic disease. A potentially viable approach for treating late-stage prostate cancer is gene therapy. Adenoviruses (Ad) are the most commonly used mode of gene delivery, but progress using this vector has been hampered by concerns over the safety and practicality of viruses including conditionally replicating Ads (CRAds), particularly for intravenous delivery, and the inefficiency of non-viral transfection techniques. Major challenges for effective gene therapy using Ads are the limited infectivity of regular Ad serotype 5 (Ad5) and the inability to specifically deliver the therapeutic directly into diseased tissue without trapping in the liver or elimination by the immune system. The shortcoming in using Ad5 is mostly attributed to a reduction in Coxsackie-adenovirus receptors (CAR) on the surface of cancer cells, which can be mitigated by generating tropism-modified Ads permitting CAR-independent infection of tumor cells. The limitations of systemic gene delivery can now be overcome by using a novel targeted-delivery approach such as ultrasound (US) contrast agents (microbubbles) to deliver effective therapeutic reagents, Ads, or recombinant proteins, combined with ultrasound-targeted microbubble destruction (UTMD), to develop a site-specific therapy in immune competent transgenic mouse models. These unique strategies for enhancing the efficacy of gene therapy provide a direct path to translation from the laboratory into the clinic for developing an effective gene therapy of prostate cancer. Source

Holdford D.A.,Virginia Commonwealth University
American journal of pharmaceutical education | Year: 2011

This paper provides baseline information on integrating the science of safety into the professional degree curriculum at colleges and schools of pharmacy. A multi-method examination was conducted that included a literature review, key informant interviews of 30 individuals, and in-depth case studies of 5 colleges and schools of pharmacy. Educators believe that they are devoting adequate time to science of safety topics and doing a good job teaching students to identify, understand, report, manage, and communicate medication risk. Areas perceived to be in need of improvement include educating pharmacy students about the Food and Drug Administration's (FDA's) role in product safety, how to work with the FDA in post-marketing surveillance and other FDA safety initiatives, teaching students methods to improve safety, and educating students to practice in interprofessional teams. The report makes 10 recommendations to help pharmacy school graduates be more effective in protecting patients from preventable drug-related problems. Source

Nader M.A.,Wake forest University | Banks M.L.,Virginia Commonwealth University
Neuropharmacology | Year: 2014

The current review highlights the importance of environmental variables on cocaine self-administration in nonhuman primate models of drug abuse. In addition to describing the behavioral consequences, potential mechanisms of action are discussed, based on imaging results using the non-invasive and translational technique of positron emission tomography (PET). In this review, the role of three environmental variables - both positive and negative - are described: alternative non-drug reinforcers; social rank (as an independent variable) and punishment of cocaine self-administration. These environmental stimuli can profoundly influence brain function and drug self-administration. We focus on environmental manipulations involving non-drug alternatives (e.g., food reinforcement) using choice paradigms. Manipulations such as response cost and social variables (e.g., social rank, social stress) also influence the behavioral effects of drugs. Importantly, these manipulations are amenable to brain imaging studies. Taken together, these studies emphasize the profound impact environmental variables can have on drug taking, which should provide important information related to individual-subject variability in treatment responsiveness, and the imaging work may highlight pharmacological targets for medications related to treating drug abuse. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue. © 2013 Elsevier Ltd. All rights reserved. Source

Becker S.P.,Miami University Ohio | Langberg J.M.,Virginia Commonwealth University | Langberg J.M.,Cincinnati Childrens Hospital Medical Center
Child Psychiatry and Human Development | Year: 2014

Previous research has failed to find a consistent relation between Sluggish Cognitive Tempo (SCT) and executive function (EF) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD) when laboratory-based neuropsychological tasks of EF are used, whereas recent research with youth and adults suggests a significant relation between SCT and ratings of EF. The purpose of this study was to examine ADHD dimensions and SCT symptoms in relation to ratings of EF in adolescents with ADHD. Fifty-two adolescents (ages 12-16; 70 % male) participated in this study. Parents and teachers completed validated measures of SCT, ADHD symptoms, and EF in daily life. Adolescents' intelligence and academic achievement were also assessed. ADHD and SCT symptoms were significantly correlated with ratings of EF. Regression analyses demonstrated that, as hypothesized, ADHD hyperactive-impulsive symptoms were strongly associated with behavioral regulation EF deficits, with ADHD inattentive and SCT symptoms unrelated to behavioral regulation EF when hyperactive-impulsivity symptoms were included in the model. The parent-reported SCT Slow scale measuring motivation, initiative, and apathy predicted both parent- and teacher-reported metacognitive EF deficits above and beyond youth characteristics and ADHD symptoms. In contrast, teacher-reported ADHD inattention was most clearly associated with teacher-reported metacognitive EF deficits. This study provides preliminary evidence for the importance of SCT symptoms in relation to metacognitive EF deficits among adolescents with ADHD and the need to further investigate the overlap and distinctiveness of SCT/ADHD. Further research is needed to replicate and extend these findings. © 2013 Springer Science+Business Media New York. Source

Paduani C.,Federal University of Santa Catarina | Jena P.,Virginia Commonwealth University
Chemical Physics Letters | Year: 2013

First-principles calculations based on the density functional theory (DFT) are performed to study the structure, stability and electron affinity of sodium and magnesium borohydrides. With successive attachments of BH4 complexes to the metal atom a superhalogen behavior is identified for the Na(BH4)2 and Mg(BH4)3 clusters, whose electron affinities reach 5.07 eV and 5.13 eV, respectively. As Mg(BH 4)3 cluster is used as a building block to decorate the Mg atom the electron affinity is pushed up to a higher level (6.18 eV) which classifies the Mg[Mg(BH4)3]3 moiety as a hyperhalogen. © 2012 Elsevier B.V. All rights reserved. Source

Excipient enhanced growth (EEG) of inhaled submicrometer pharmaceutical aerosols is a recently proposed method intended to significantly reduce extrathoracic deposition and improve lung delivery. The objective of this study was to evaluate the size increase of combination drug and hygroscopic excipient particles in a characteristic model of the airways during inhalation using both in vitro experiments and computational fluid dynamic (CFD) simulations. The airway model included a characteristic mouth-throat (MT) and upper tracheobronchial (TB) region through the third bifurcation and was enclosed in a chamber geometry used to simulate the thermodynamic conditions of the lungs. Both in vitro results and CFD simulations were in close agreement and indicated that EEG delivery of combination submicrometer particles could nearly eliminate MT deposition for inhaled pharmaceutical aerosols. Compared with current inhalers, the proposed delivery approach represents a 1-2 order of magnitude reduction in MT deposition. Transient inhalation was found to influence the final size of the aerosol based on changes in residence times and relative humidity values. Aerosol sizes following EEG when exiting the chamber (2.75-4.61 μm) for all cases of initial submicrometer combination particles were equivalent to or larger than many conventional pharmaceutical aerosols that frequently have MMADs in the range of 2-3 μm. Source

Background: Immigrant and refugee populations and people with disabilities are known to have inequitable access to a range of health services. Very little study has been undertaken, however, about immigrants who have disabilities and their experience of the American health care system.Research Design: This qualitative study seeks to discover the particular challenges that immigrants with disabilities face when accessing health care, and the facilitating factors that assist them in this process. A complex multicase study design was utilized, and included purposively sampled individuals from 3 different immigrant communities, having an array of developmental disabilities. Interviews and participant observation provided the data that were analyzed in NVivo9 using a conventional content analysis approach.Results: Findings from this study suggest strong resilience among immigrant families with a member with a disability, as they continue to seek help despite experiencing confusion in navigating a complex health care system. Factors challenging access included difficulty finding accurate information on insurance and service providers, troubles with coordinating multiple specialist services, and a lack of cultural competence in all levels of health service provision. Access to health care services was facilitated by linguistically and culturally sensitive practitioners, favorable comparisons to the country or origin, and systems such as schools that helped to coordinate care.Conclusions: Much can be done to integrate and improve health services to immigrants with developmental disabilities. Emerging models such as medical home may assist with coordination, and improvements in communication patterns could help to improve service access and outcomes. Copyright © 2014 by Lippincott Williams & Wilkins. Source

Witten T.M.,Virginia Commonwealth University
Journal of Lesbian Studies | Year: 2015

This study is the first to examine the experiences and needs of an international sample of current, English-speaking, lesbian, transgender-identified (trans-lesbian) adults around a number of later life and end-of-life perceptions, preparations, and concerns. I analyzed a subset (n = 276) of the cross-sectional data collected from the online Trans MetLife Survey on Later-Life Preparedness and Perceptions in Transgender-Identified Individuals (N = 1,963). I assessed perceptions and fears around aging, preparation for later life, and end-of-life as well as numerous demographic and psycho-social variables. Despite the overall feeling that they have aged successfully, the respondent trans-lesbian population harbors significant fears about later life. I found that this population, while better-prepared than the overall respondent trans-identified population, is still ill-prepared for the major legalities and events that occur in the later to end-of-life time periods. © 2015, Copyright © Taylor & Francis Group, LLC. Source

Daviskas E.,E11 West | Rubin B.K.,Virginia Commonwealth University
Expert Review of Respiratory Medicine | Year: 2013

Insufficient hydration at the airway surface can make mucus adherent and poorly cleared. Cough, the major mechanism of mucus clearance in disease, is ineffective when mucus is adhesive. Inhaled mannitol creates an osmotic drive for water to move into the airway lumen. The consequent increased hydration of the airway surface decreases the adherence of mucus to the epithelium, facilitates the coupling of mucus and cilia thereby increasing mucus clearance. Inhaled mannitol also promotes effective coughing and stimulates mucociliary clearance. The beneficial effect of mannitol on mucus and its clearance has been demonstrated in patients with asthma, bronchiectasis and cystic fibrosis. Inhaled dry powder mannitol (Bronchitol™) is promising to be an effective treatment for the clearance of retained airway secretions. © 2013 2013 Expert Reviews Ltd. Source

Elhai J.,Virginia Commonwealth University
Life | Year: 2015

The sequence GCGATCGC (Highly Iterated Palindrome, HIP1) is commonly found in high frequency in cyanobacterial genomes. An important clue to its function may be the presence of two orphan DNA methyltransferases that recognize internal sequences GATC and CGATCG. An examination of genomes from 97 cyanobacteria, both free-living and obligate symbionts, showed that there are exceptional cases in which HIP1 is at a low frequency or nearly absent. In some of these cases, it appears to have been replaced by a different GC-rich palindromic sequence, alternate HIPs. When HIP1 is at a high frequency, GATC-and CGATCG-specific methyltransferases are generally present in the genome. When an alternate HIP is at high frequency, a methyltransferase specific for that sequence is present. The pattern of 1-nt deviations from HIP1 sequences is biased towards the first and last nucleotides, i.e., those distinguish CGATCG from HIP1. Taken together, the results point to a role of DNA methylation in the creation or functioning of HIP sites. A model is presented that postulates the existence of a GmeC-dependent mismatch repair system whose activity creates and maintains HIP sequences. © 2015 by the authors; licensee MDPI, Basel, Switzerland. Source

Gewirtz D.A.,Virginia Commonwealth University
Autophagy | Year: 2013

Two primary forms of autophagy have been identified in the field of cancer therapy based on their apparent functions in the tumor cell; these are the cytoprotective form that could, in theory, be inhibited for the purpose of sensitization to radiation and chemotherapeutic drugs and the "cytotoxic" form that either mediates or contributes to the actions of these treatment modalities. Surprisingly, to date, no clear-cut biochemical or molecular characteristics have been identified that might serve to distinguish between these two forms. In this commentary, we develop the concept of an additional form of autophagy that is nonprotective in that its inhibition neither sensitizes the tumor cell to exogenous stress (again, chemotherapy or radiation) nor protects the cell from the impact of these treatments. This form of autophagy also fails to exhibit any characteristics that might distinguish it from the cytoprotective and/or cytotoxic forms of autophagy. However, the existence of nonprotective autophagy is of potential significance in that it contributes to the challenge of predicting when the strategy of autophagy suppression might prove to have therapeutic benefit in the clinical treatment of cancer. © 2013 Landes Bioscience. Source

Adler R.A.,Virginia Commonwealth University
Clinical Biochemistry | Year: 2012

Osteoporosis has been classified into primary and secondary forms. All patients with osteoporosis should have measurements of 25-hydroxyvitamin D, serum and urine calcium, and some estimation of renal function. There are a wide variety of disorders that lead to secondary osteoporosis, and the tests that confirm these diagnoses are described herein. Making the specific diagnosis is important because treatment of the underlying condition may be sufficient to lessen fracture risk, although some patients may also need usual treatment for osteoporosis. Laboratory testing in addition to a careful history and physical examination will often lead to diagnoses of treatable conditions. © 2012. Source

Albrecht T.A.,Virginia Commonwealth University
Oncology Nursing Forum | Year: 2014

Purpose/Objectives: To evaluate the current knowledge of symptoms experienced by adults with acute leukemia (AL) and provide evidence to inform practice and research. Data Sources: Literature review using an electronic search supplemented by a hand search of current literature re-porting the physiologic and/or psychological symptoms of patients with AL was conducted. Data Synthesis: Because of the variability found in the methods and specific aims of the articles, a rating system was applied to score how strongly the findings contributed to meeting the aims of the research. This rating system was applied to assist the authors in analyzing the findings. Therefore, the articles that scored lower ultimately contributed less during the analysis phase. Conclusions: Knowledge regarding the symptoms experienced by adults undergoing treatment is being slowly evaluated. However, to better understand and subsequently manage these symptoms, longitudinal research examining the symptom trajectories in this population is needed. Implications for Nursing: Additional investigation into symptom characteristics will facilitate the development of tailored interventions to manage the temporal characteristics of symptoms for this population. Source

Brown T.H.,Vanderbilt University | O'Rand A.M.,Duke University | Adkins D.E.,Virginia Commonwealth University
Journal of Health and Social Behavior | Year: 2012

Racial-ethnic disparities in static levels of health are well documented. Less is known about racial-ethnic differences in age trajectories of health. The few studies on this topic have examined only single health outcomes and focused on black-white disparities. This study extends prior research by using a life course perspective, panel data from the Health and Retirement Study, and multilevel growth curve models to investigate racial-ethnic differences in the trajectories of serious conditions and functional limitations among blacks, Mexican Americans, and whites. We test three hypotheses on the nature of racial-ethnic disparities in health across the life course (aging-as-leveler, persistent inequality, and cumulative disadvantage). Results controlling for mortality selection reveal that support for the hypotheses varies by health outcome, racial-ethnic group, and life stage. Controlling for childhood socioeconomic status, adult social and economic resources, and health behaviors reduces but does not eliminate racial-ethnic disparities in health trajectories. © American Sociological Association 2012. Source

Biskobing D.M.,Virginia Commonwealth University
Endocrine Practice | Year: 2010

Objective: To review the prevalence of parathyroid hormone elevation after parathyroidectomy for primary hyperparathyroidism and to discuss possible mechanisms. Methods: A Medline search of the English-language literature published between 1990 and 2009 was performed using the search terms "elevated PTH after parathyroidectomy." All of the identified articles reported either prospective or retrospective studies without control groups. Studies that included patients with secondary or tertiary hyperparathyroidism were not reviewed. Results: Within 1 week to 5 years after parathyroidectomy, 9% to 62% of patients with a normal serum calcium concentration are reported to have an elevated parathyroid hormone concentration. No evidence suggests that postoperative normocalcemic parathyroid hormone elevation is an indication of surgical failure and recurrent hypercalcemia. Preoperative findings in patients with postoperative parathyroid hormone elevation include lower vitamin D concentration, higher concentrations of bone turnover markers, and higher parathyroid hormone concentration. Potential mechanisms for parathyroid hormone elevation in the setting of normocalcemia include vitamin D deficiency, hungry bone syndrome, and parathyroid hormone resistance. Study findings suggest a possible benefit of postoperative calcium and vitamin D supplementation, but no randomized trials have been done. Conclusion: Elevation of parathyroid hormone commonly occurs after parathyroidectomy for primary hyperparathyroidism, although the underlying mechanism remains unclear. © 2010 AACE. Source

Schubert M.L.,Virginia Commonwealth University | Schubert M.L.,Hunter Holmes ire Veterans Affairs Medical Center
Current Opinion in Gastroenterology | Year: 2014

Purpose of review: This review summarizes the past year's literature regarding the neural, paracrine, hormonal, and intracellular regulation of gastric acid secretion. Recent findings: Gastric acid facilitates the digestion of protein as well as the absorption of iron, calcium, vitamin B12, and certain medications. High gastric acidity, in combination with pepsin and lipase, kills ingested microorganisms and may play a role in preventing bacterial overgrowth, enteric infection, and possibly spontaneous bacterial peritonitis, community-acquired pneumonia, and infection with Mycobacterium tuberculosis. Stimulants of acid secretion include histamine, gastrin, acetylcholine, and ghrelin. Inhibitors include somatostatin, gastric inhibitory polypeptide, calcitonin gene-related peptide, and adrenomedullin. Helicobacter pylori stimulates or inhibits depending upon the time course of infection and the area of the stomach predominantly infected. Proteins implicated in H-K-ATPase membrane trafficking include myosin IIB, F-actin, ezrin, and Rab GTPases. Summary: Our understanding of the regulation of gastric acid secretion continues to advance. Such knowledge is crucial for the management of acid-peptic disorders and the development of novel medications, such as cholecystokinin-2 receptor antagonists. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Reshchikov M.A.,Virginia Commonwealth University
Journal of Applied Physics | Year: 2014

Mechanisms of thermal quenching of photoluminescence (PL) related to defects in semiconductors are analyzed. We conclude that the Schön-Klasens (multi-center) mechanism of the thermal quenching of PL is much more common for defects in III-V and II-VI semiconductors as compared to the Seitz-Mott (one-center) mechanism. The temperature dependencies of PL are simulated with a phenomenological model. In its simplest version, three types of defects are included: a shallow donor, an acceptor responsible for the PL, and a nonradiative center that has the highest recombination efficiency. The case of abrupt and tunable thermal quenching of PL is considered in more detail. This phenomenon is predicted to occur in high-resistivity semiconductors. It is caused by a sudden redirection of the recombination flow from a radiative acceptor to a nonradiative defect. © 2014 AIP Publishing LLC. Source

Zhang C.,U.S. National Institutes of Health | Ning Y.,Virginia Commonwealth University
American Journal of Clinical Nutrition | Year: 2011

Gestational diabetes mellitus (GDM), defined as glucose intolerance with onset or first recognition in pregnancy, is a common pregnancy complication and a growing health concern. GDM has been related to significant short-term and long-term adverse health outcomes for both mothers and offspring. Importantly, this number is increasing with the increasing burden of obesity among women of reproductive age. Collectively, these data highlight the significance of understanding risk factors, in particular modifiable factors, for GDM and of preventing GDM among high-risk populations. Research in the past decade has identified a few diet and lifestyle factors that are associated with GDM risk. This review provides an overview of emerging diet and lifestyle factors that may contribute to the prevention of GDM. It also discusses major methodologic concerns about the available epidemiologic studies of GDM risk factors. © 2011 American Society for Nutrition. Source

Kuemmerle J.F.,Virginia Commonwealth University
Gastroenterology | Year: 2014

The ABIM's mission is to enhance the quality of healthcare. This goal is met by certifying physicians who demonstrate the knowledge, skills, and attitudes needed to deliver safe, quality patient care in the rapidly changing world of medical practice.5 This mission resonates also with that of gastroenterologists and with the AGA, and can be a practical and necessary component of our practice as we move into a value-based health care delivery world. All the partner stakeholders in health care delivery-physicians, ABIM, and the public-seek to ensure the safe care of patients and provide demonstrably high-quality gastroenterology and hepatology care. © 2014 by the AGA Institute. Source

Malina J.,Academy of Sciences of the Czech Republic | Farrell N.P.,Virginia Commonwealth University | Brabec V.,Academy of Sciences of the Czech Republic
Inorganic Chemistry | Year: 2014

The noncovalent analogues of antitumor polynuclear platinum complexes represent a structurally discrete class of platinum drugs. Their chemical and biological properties differ significantly from those of most platinum chemotherapeutics, which bind to DNA in a covalent manner by formation of Pt-DNA adducts. In spite of the fact that these noncovalent polynuclear platinum complexes contain no leaving groups, they have been shown to bind to DNA with high affinity. We report here on the DNA condensation properties of a series of noncovalent analogues of antitumor polynuclear platinum complexes described by biophysical and biochemical methods. The results demonstrate that these polynuclear platinum compounds are capable of inducing DNA condensation at more than 1 order of magnitude lower concentrations than conventional spermine. Atomic force microscopy studies of DNA condensation confined to a mica substrate have revealed that the DNA morphologies become more compact with increasing concentration of the platinum complexes. Moreover, we also found that the noncovalent polynuclear platinum complex [{Pt(NH3)3} 2-μ-{trans-Pt(NH3)2(NH2(CH 2)6NH2)2}]6+ (TriplatinNC-A) binds to DNA in a sequence-dependent manner, namely, to A/T-rich sequences and A-tract regions, and that noncovalent polynuclear platinum complexes protect DNA from enzymatic cleavage by DNase I. The results suggest that mechanisms of antitumor and cytotoxic activities of these complexes may be associated with their unique ability to condense DNA along with their sequence-specific DNA binding. Owing to their high cellular accumulation, it is also reasonable to suggest that their mechanism of action is based on the competition with naturally occurring DNA condensing agents, such as polyamines spermine, spermidine, and putrescine, for intracellular binding sites, resulting in the disturbance of the correct binding of regulatory proteins initiating the onset of apoptosis. © 2014 American Chemical Society. Source

Two articles in this issue seek to further the goal of NIMH's Research Domain Criteria (RDoC) initiative to develop new approaches for investigating mental disorders, using fundamental dimensions that cut across traditional disorder categories and align more closely with mechanisms that underlie psychopathology. One article, by Lang, McTeague, and Bradley, describes the construction of such a disorder cross-crossing dimension of fear response. The other, by Kozak and Cuthbert, expounds upon the basis and conceptualization of research targets under RDoC. Possible implications of these developments for psychiatric genetics research are discussed. © 2016 Society for Psychophysiological Research. Source

George M.,Virginia Commonwealth University
Clinical Social Work Journal | Year: 2012

Each step of the refugee migratory journey has its own unique characteristics and mental health consequences, which require much attention from social work service providers. In an effort to provide quality service delivery for refugees, their premigration, migration and post-migration traumatic experiences need to be examined and understood beyond current narrow formulations. Integrating the concepts derived from refugee trauma and psychological distress literature, the author presents in this paper group-based interventions grounded in cultural competency, spirituality and strengths which will enable social workers to provide efficient service delivery and adopt a leadership role among service providers as advocates for refugees. © 2012 Springer Science+Business Media, LLC. Source

Negus S.S.,Virginia Commonwealth University
Life Sciences | Year: 2014

This mini-review summarizes the history of cathinone and its synthesized derivatives from early records to the present day, including the appearance of synthetic cathinones in the drug combination known as bath salts. Bath salts may consist of one compound (MDPV) or combinations of MDPV and one or more other synthetic cathinones, which may also appear alone without MDPV. We briefly review recent in vitro studies of bath salts components alone or in combination, focusing on pharmacological and biophysical studies. Finally we summarize new data from in vivo procedures that characterize the abuse-related neurochemical and behavioral effects of synthetic cathinones in rats. © 2013 Elsevier Inc. All rights reserved. Source

Sugerman H.J.,Virginia Commonwealth University
Medical Hypotheses | Year: 2011

It is hypothesized that in some women an excessively high intra-abdominal pressure (IAP) compresses the inferior vena cava, uterine veins, portal vein, hepatic veins, splenic vein and renal veins which lead to a decreased flow in these vascular beds, producing lower extremity edema, fetal-placental ischemia, a glomerulopathy with proteinuria and hypertension, hepatic ischemia and thrombocytopenia, increased uric acid, and hemolysis/elevated liver enzymes/low platelet known as the HELLP syndrome. There can be variability in the expression of these components. Placental-fetal ischemia could lead to expression of soluble fms-like tyrosine kinase1 (sFLT) and endoglin which have been shown to cause additional diffuse endovascular damage. A further increase in IAP pushes the diaphragm cephalad, increasing intrathoracic pressure leading to upper extremity edema, decreased internal jugular venous flow, cerebral vascular engorgement, raised intracranial pressure, and if unresolved, seizures. Placental/fetal ischemia and hepatic ischemic necrosis may lead to diffuse inflammation and a septic inflammatory response syndrome (SIRS) which may become a vicious cycle, perpetuating the ischemia. It is further hypothesized that application of an externally applied negative abdominal pressure device will lower IAP and possibly reverse the pathophysiology of preeclampsia. As the abnormal placental proteins develop weeks before clinical preeclampsia, early application of external negative abdominal pressure may prevent development of the syndrome. © 2011 Elsevier Ltd. Source

Eissenberg T.,Virginia Commonwealth University
AANA Journal | Year: 2013

Smoking tobacco using a waterpipe (hookah) is increasing worldwide and is remarkably common among adolescents and young adults in the United States. Contrary to misperceptions that waterpipe tobacco smoking presents fewer health risks than cigarette smoking, recent data demonstrate clearly that the smoke from a waterpipe contains many of the same toxicants that are in cigarettes, including the dependence-producing drug nicotine, cancer-causing polycyclic aromatic hydrocarbons, pulmonary disease-causing volatile aldehydes, and cardiovascular disease-causing carbon monoxide that can also lead to acute intoxication in waterpipe users. Because many anesthesia providers are likely treating waterpipe tobacco smokers, the goal ofthis AANA Journal Course is to describe a waterpipe, who uses a waterpipe to smoketobacco, and the toxicants found in waterpipe smoke and waterpipe smokers. Based on available evidence, there is no indication that waterpipe tobacco smoking is anyless risky to patient health than cigarette smoking. Anesthesia providers should begin to assess patients for this form of tobacco use explicitly and should consider addressing it as they do cigarette smoking, with the additional precaution of presurgery carboxyhemoglobin measurement. Source

Dasgupta S.,Virginia Commonwealth University
Journal of molecular medicine (Berlin, Germany) | Year: 2013

The purpose of this study was to identify key genetic pathways involved in non-small cell lung cancer (NSCLC) and understand their role in tumor progression. We performed a genome wide scanning using paired tumors and corresponding 16 mucosal biopsies from four follow-up lung cancer patients on Affymetrix 250K-NSpI array platform. We found that a single gene SH3GL2 located on human chromosome 9p22 was most frequently deleted in all the tumors and corresponding mucosal biopsies. We further validated the alteration pattern of SH3GL2 in a substantial number of primary NSCLC tumors at DNA and protein level. We also overexpressed wild-type SH3GL2 in three NSCLC cell lines to understand its role in NSCLC progression. Validation in 116 primary NSCLC tumors confirmed frequent loss of heterozygosity of SH3GL2 in overall 51 % (49/97) of the informative cases. We found significantly low (p = 0.0015) SH3GL2 protein expression in 71 % (43/60) primary tumors. Forced overexpression of wild-type (wt) SH3GL2 in three NSCLC cell lines resulted in a marked reduction of active epidermal growth factor receptor (EGFR) expression and an increase in EGFR internalization and degradation. Significantly decreased in vitro (p = 0.0015-0.030) and in vivo (p = 0.016) cellular growth, invasion (p = 0.029-0.049), and colony formation (p = 0.023-0.039) were also evident in the wt-SH3GL2-transfected cells accompanied by markedly low expression of activated AKT(Ser(473)), STAT3 (Tyr(705)), and PI3K. Downregulation of SH3GL2 interactor USP9X and activated ß-catenin was also evident in the SH3GL2-transfected cells. Our results indicate that SH3GL2 is frequently deleted in NSCLC and regulates cellular growth and invasion by modulating EGFR function. Source

Hanumegowda C.,McMaster University | Farkas L.,McMaster University | Farkas L.,Virginia Commonwealth University | Kolb M.,McMaster University
Chest | Year: 2012

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal disease, based on a multifaceted and incompletely understood pathogenesis. Some of the cellular and molecular mechanisms of vascular remodeling have been experimentally explored, and it is obvious that alterations of microvessels are involved in IPF. These can, among others, lead to the development of pulmonary hypertension. In order to understand the process of vascular integrity and repair, it is necessary to identify the factors associated with angiogenesis in IPF. A delicate balance of angiogenic and angiostatic factors regulates vessel homeostasis in normal physiologic conditions in the lungs. Although earlier studies have proposed that IPF is associated with an increase of angiogenesis, there is some more recent evidence that angiogenesis in fibrotic lungs may actually be decreased, causing some controversy in the literature in this area. This review, therefore, discusses the concept of angiogenesis in pulmonary fibrosis and speculates on how the spatial and temporal heterogeneity of IPF might explain the controversial findings about vessel density in fibrotic lungs. © 2012 American College of Chest Physicians. Source

Dash A.,Hershey Medical Center | Brinster D.R.,Virginia Commonwealth University
Annals of Thoracic Surgery | Year: 2011

We describe a 73-year-old woman who had a right atrial-inferior vena caval thrombus and pulmonary thromboembolism develop after percutaneous vertebroplasty with methylmethacrylate. Our patient subsequently underwent open-heart surgery to effectively remove the bulk of the foreign material. This case illustrates the need for close monitoring of patients undergoing percutaneous vertebroplasty and emphasizes the importance of prompt diagnosis and treatment. © 2011 The Society of Thoracic Surgeons. Source

Linde C.,Karolinska University Hospital | Ellenbogen K.,Virginia Commonwealth University | McAlister F.A.,University of Alberta
Heart Rhythm | Year: 2012

Over the last 10 years, several large, well-designed clinical trials have firmly established the role of cardiac resynchronization therapy (CRT) as a recommended treatment strategy for moderate-to-severe heart failure (HF). A review of the relevant results from the MUSTIC, MIRACLE, CONAK-CD, and MIRACLE ICD trials reveals that in patients with New York Heart Association (NYHA) class III-IV HF, CRT produces consistent improvements in quality of life, functional status, and exercise capacity while also providing strong evidence for reverse remodeling and diminished functional mitral regurgitation, resulting in reductions in both HF hospitalizations and all-cause morbidity and mortality. In patients with earlier NYHA class I-II HF, the benefit of CRT has been more controversial. The principal ongoing challenges addressed in this article include the substantial 30% of patients who receive a CRT device but fail to respond, the wide variations in how to define "response" vs "nonresponse," and how to identify patients who will benefit from CRT, especially narrow QRS (<120 ms), those with right bundle branch block, and those with mild-to-moderate (NYHA class I-II) HF. An important result of this uncertainty is the lack of a good sense of the optimal rate of CRT implantation, making consideration of the data reviewed in this article crucial for identifying important gaps of knowledge and mechanisms of action that need to be studied in the near future. © 2012 Heart Rhythm Society. Source

Estabrook R.,Virginia Commonwealth University | Grimm K.J.,University of California at Davis | Bowles R.P.,Michigan State University
Psychology and Aging | Year: 2012

Recent research has seen intraindividual variability become a useful technique to incorporate trial-to-trial variability into many types of psychological studies. Intraindividual variability, as measured by individual standard deviations (ISDs), has shown unique prediction to several types of positive and negative outcomes (Ram, Rabbit, Stollery, & Nesselroade, 2005). One unanswered question regarding measuring intraindividual variability is its reliability and the conditions under which optimal reliability is achieved. Monte Carlo simulation studies were conducted to determine the reliability of the ISD as compared with the intraindividual mean. The results indicate that ISDs generally have poor reliability and are sensitive to insufficient measurement occasions, poor test reliability, and unfavorable amounts and distributions of variability in the population. Secondary analysis of psychological data shows that use of individual standard deviations in unfavorable conditions leads to a marked reduction in statistical power, although careful adherence to underlying statistical assumptions allows their use as a basic research tool. Source

Gewirtz D.A.,Virginia Commonwealth University
Biochemical Pharmacology | Year: 2014

Four different functional forms of autophagy have been observed to occur in tumor cells in response to chemotherapeutic drugs and radiation. Currently the different forms of autophagy are distinguished almost exclusively by determining the impact of autophagy inhibition on drug and radiation sensitivity. That is, it cannot otherwise be predicted whether the autophagy induced by radiation or chemotherapy is associated with resistance and the circumstances under which autophagy inhibition might be a useful strategy for enhancing sensitivity to therapy. This commentary highlights an additional level of complexity in the autophagy landscape, specifically that autophagy can switch its function even within the context of a specific external stress and/or a biological cancer model. © 2014 Elsevier B.V. All rights reserved. Source

Dent P.,Virginia Commonwealth University
Cancer Biology and Therapy | Year: 2014

It is historically well known that signaling by the PI3K-AKT and MEK1/2-ERK1/2 pathways in a cell type-dependent fashion can collaborate to maintain cell viability.1-3 Signaling pathways can also crosstalk with each other wherein one pathway can signal to either enhance or suppress signaling by another.4 Signaling by the ERK1/2 pathway can also stimulate release of growth factors which can feed back onto tumor cells to re-energize signaling pathways.5 The studies described by Toulany et al. add to this knowledge base by examining the relationship between PI3K-AKT and MEK1/2-ERK1/2 pathway signaling, EGF receptor signaling, K-RAS function, and tumor cell survival.6 © 2014 Landes Bioscience. Source

Adler S.P.,Virginia Commonwealth University
British Medical Bulletin | Year: 2013

Introduction: A primary maternal cytomegalovirus (CMV) during pregnancy causes newborn disease that includes hearing deficit and/or mental retardation. Sources of data: Relevant published literature. Areas of agreement: There are no biologic obstacles to immunization against fetal/ placental infection with CMV. Areas of uncertainty: CMV vaccine trials may be difficult due to a lack of public awareness of CMV. Vaccine trials that use fetal infection as an endpoint will be prolonged, since vaccination will need to occur preconception. Areas timely for developing research: Vaccines in preclinical development include antigens of the CMV gB glycoprotein and the gH/gL UL128, 130 and 131 pentameric complex. These antigens induce antibodies that block viral entry into fibroblasts and endothelial/epithelial cells. Vaccines immunogenic in animals include an inactivated virus with a wild-type UL131 gene, a DNAvaccine using a wild-type UL130 gene and peptide vaccines using peptides from UL130 and 131. Conclusions: In spite of these potential obstacles, successful evaluation of CMV vaccines is possible. © The Author 2013. Published by Oxford University Press. All rights reserved. Source

Teves M.E.,Virginia Commonwealth University
Andrology | Year: 2013

Meiosis expressed gene 1 (Meig1) was originally identified in a search for mammalian genes potentially involved in meiosis. Seven mouse Meig1 transcripts with the same coding region, but different 5'-UTRs, have been identified. These transcripts have different tissue distributions, two are only present in the testis. In the testis, Meig1 is present in germ cells and Sertoli cells. A Meig1 conditional knockout model has been generated. When Meig1 was inactivated globally by crossing with Cmv-Cre transgenic mice, the Meig1-deficient males were sterile due to severe spermiogenic defects, and had no obvious defects in meiosis. To further study its role in individual cell types in the testis, the Meig1(flox) mice were crossed with Hsp2a-Cre, Prm-Cre, and Amh-Cre mice, in which the Cre recombinase is driven by the heat shock protein 2 (Hsp2a) gene promoter (expressed in spermatocytes), the protamine 1 gene promoter (expressed in post-meiotic spermatids) and the anti-Mullerian hormone (Amh) gene promoter (expressed in Sertoli cells) respectively. Both Meig1 mRNA and protein were undetectable in testis of the Hsp2a-Cre; Meig1(flox/flox) mice and all the mutant adult males tested were sterile. This phenotype mirrors that of the Cmv-Cre; Meig1(flox/flox) mice. Even though the total testicular Meig1 mRNA and protein expression levels were dramatically reduced in testis of the Prm-Cre; Meig1(flox/flox) males, all the mice tested were fertile, and there was no significant difference in sperm count and sperm motility compared with age-matched Meig1(flox/flox) male mice. Disruption of Meig1 in the Sertoli cells did not affect the MEIG1 protein expression. Amh-Cre; Meig1(flox/flox) males were fertile, and produced the same amount of spermatozoa as age-matched Meig1(flox/flox) mice. The testicular histology was also normal. Our results indicate that MEIG1 regulates spermiogenesis through effects in germ cells alone, and that the Meig1 gene must be active during a discrete period in spermatogenesis after which it is dispensable. © 2012 American Society of Andrology and European Academy of Andrology. Source

Nigro G.,University of LAquila | Adler S.P.,Virginia Commonwealth University
Current Opinion in Obstetrics and Gynecology | Year: 2011

PURPOSE OF REVIEW: To review current prenatal diagnosis and management of congenital cytomegalovirus (CMV) infections with emphasis on maternal screening and available interventions. RECENT FINDINGS: Recent findings include an enhanced understanding of the epidemiology, pathogenesis, and treatment of CMV infections; a knowledge of high-risk women particularly those with chronic exposure to a young child in the home; the availability of accurate methods for the serologic diagnosis of a primary CMV infection using either single or serial blood samples; accurate methods for the diagnosis of fetal infection via amniotic fluid; sensitive fetal and placental indicators for neonatal outcomes, and the availability of potentially effective interventions such as hygienic intervention and CMV hyperimmune globulin. SUMMARY: These findings suggest that serologic testing for CMV during pregnancy may be appropriate either using one-time testing or serial serologic testing throughout the first two trimesters of pregnancy and that education of pregnant women about CMV is necessary so that they can asses their risk and make informed choices about serologic screening. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Shapiro S.M.,Virginia Commonwealth University
Seminars in Fetal and Neonatal Medicine | Year: 2010

Chronic bilirubin encephalopathy (kernicterus) can be diagnosed using semi-objective criteria based on history, physical and neurological examination and laboratory findings including auditory brainstem responses and magnetic resonance imaging. Classical kernicterus is a well-described clinical tetrad of (i) abnormal motor control, movements and muscle tone, (ii) an auditory processing disturbance with or without hearing loss, (iii) oculomotor impairments, especially impairment of upward vertical gaze, and (iv) dysplasia of the enamel of deciduous teeth. Subtle kernicterus or bilirubin-induced neurologic dysfunction (BIND) refers to individuals with subtle neurodevelopmental disabilities without classical findings of kernicterus that, after careful evaluation and consideration, appear to be due to bilirubin neurotoxicity. Kernicterus can be further classified as auditory predominant or motor predominant and characterized based on the severity of clinical sequelae. Proposed research definitions for kernicterus diagnosis in infants from 3 to 18 months are reviewed, as are treatments of auditory and motor deficits and other complications of bilirubin encephalopathy. © 2010 Elsevier Ltd. All rights reserved. Source

Reynolds S.,Virginia Commonwealth University | Urruela M.,University of Florida | Devine D.P.,University of Florida
Autism Research | Year: 2013

Lower order and higher order repetitive behaviors have been documented in the BTBR T+tf/J (BTBR) mouse strain, a mouse model that exhibits all three core behavioral domains that define autism. The purpose of this study was to evaluate the effectiveness of environmental enrichment for reducing repetitive behaviors in BTBR mice. Lower order behaviors were captured by assaying the time and sequence of grooming, while higher order behaviors were measured using pattern analysis of an object exploration task from digital recordings. Baseline scores were established at 7 weeks of age, followed by 30 days of housing in either a standard or enriched cage. As expected, BTBR mice spent significantly more time grooming and had a more rigid grooming sequence than control C57BL/6J mice did at baseline. After 30 days of enrichment housing, BTBR mice demonstrated a significant reduction in time spent grooming, resulting in levels that were lower than those exhibited by BTBR mice in standard housing. However, no changes were noted in the rigidity of their grooming sequence. In contrast to previous findings, there was no difference in repetitive patterns of exploration at baseline between BTBR and C57BL/6J mice in the object exploration test. Subsequently, enrichment did not significantly alter the number of repetitive patterns at posttest. Overall, the results suggest that environmental enrichment may be beneficial for reducing the time spent engaging in lower order repetitive behaviors, but may not change the overall quality of the behaviors when they do manifest. © 2013 International Society for Autism Research, Wiley Periodicals, Inc. Source

Hajek P.,Queen Mary, University of London | Etter J.-F.,University of Geneva | Benowitz N.,University of California at San Francisco | Eissenberg T.,Virginia Commonwealth University | Mcrobbie H.,Queen Mary, University of London
Addiction | Year: 2014

Aims: We reviewed available research on the use, content and safety of electronic cigarettes (EC), and on their effects on users, to assess their potential for harm or benefit and to extract evidence that can guide future policy. Methods: Studies were identified by systematic database searches and screening references to February 2014. Results: EC aerosol can contain some of the toxicants present in tobacco smoke, but at levels which are much lower. Long-term health effects of EC use are unknown but compared with cigarettes, EC are likely to be much less, if at all, harmful to users or bystanders. EC are increasingly popular among smokers, but to date there is no evidence of regular use by never-smokers or by non-smoking children. EC enable some users to reduce or quit smoking. Conclusions: Allowing EC to compete with cigarettes in the market-place might decrease smoking-related morbidity and mortality. Regulating EC as strictly as cigarettes, or even more strictly as some regulators propose, is not warranted on current evidence. Health professionals may consider advising smokers unable or unwilling to quit through other routes to switch to EC as a safer alternative to smoking and a possible pathway to complete cessation of nicotine use. © 2014 Society for the Study of Addiction. Source

Meachen J.A.,National Evolutionary Synthesis Center | Sakai S.A.,Virginia Commonwealth University
Journal of Morphology | Year: 2013

Members of the order Carnivora display a broad range of locomotor habits, including cursorial, scansorial, arboreal, semiaquatic, aquatic, and semifossorial species from multiple families. Ecomorphological analyses from osteological measurements have been used successfully in prior studies of carnivorans and rodents to accurately infer the locomotor habits of extinct species. This study uses 20 postcranial measurements that have been shown to be effective indicators of locomotor habits in rodents and incorporates an extensive sample of over 300 individuals from more than 100 living carnivoran species. We performed statistical analyses, including analysis of variance (ANOVA) and stepwise discriminant function analysis, using a set of 16 functional indices (ratios). Our ANOVA results reveal consistent differences in postcranial skeletal morphology among locomotor groups. Cursorial species display distal elongation of the limbs, gracile limb elements, and relatively narrow humeral and femoral epicondyles. Aquatic and semiaquatic species display relatively robust, shortened femora and elongate metatarsals. Semifossorial species display relatively short, robust limbs with enlarged muscular attachment sites and elongate claws. Both semiaquatic and semifossorial species have relatively elongate olecranon process of the ulna and enlarged humeral and femoral epicondyles. Terrestrial, scansorial, and arboreal species are characterized by having primarily intermediate features, but arboreal species do show relatively elongate manual digits. Morphological indices effectively discriminate locomotor groups, with cursorial and arboreal species more accurately classified than terrestrial, scansorial, or semiaquatic species. Both within and between families, species with similar locomotor habits converge toward similar postcranial morphology despite their independent evolutionary histories. The discriminant analysis worked particularly well to correctly classify members of the Canidae, but not as well for members of the Mustelidae or Ursidae. Results are used to infer the locomotor habits of extinct carnivorans, including members of several extinct families, and also 12 species from the Pleistocene of Rancho La Brea. © 2012 Wiley Periodicals, Inc. Source

Lux V.,Free University of Berlin | Kendler K.S.,Virginia Commonwealth University
Psychological Medicine | Year: 2010

Background The DSM-IV symptomatic criteria for major depression (MD) derive primarily from clinical experience with modest empirical support. Method The sample studied included 1015 (518 males, 497 females) Caucasian twins from a population-based registry who met criteria for MD in the year prior to the interview. Logistic regression analyses were conducted to compare the associations of: (1) single symptomatic criterion, (2) two groups of criteria reflecting cognitive and neurovegetative symptoms, with a wide range of potential validators including demographic factors, risk for future episodes, risk of MD in the co-twin, characteristics of the depressive episode, the pattern of co-morbidity and personality traits. Results The individual symptomatic criteria showed widely varying associations with the pattern of co-morbidity, personality traits, features of the depressive episode and demographic characteristics. When examined separately, these two criteria groups showed robust differences in their patterns of association, with the validators with the cognitive criteria generally producing stronger associations than the neurovegetative. Conclusions Among depressed individuals, individual DSM-IV symptomatic criteria differ substantially in their predictive relationship with a range of clinical validators. These results challenge the equivalence assumption for the symptomatic criteria for MD and suggest a more than expected degree of covert heterogeneity among these criteria. Part of this heterogeneity is captured by the distinction between cognitive versus neurovegetative symptoms, with cognitive symptoms being more strongly associated with most clinically relevant characteristics. Detailed psychometric evaluation of DSM-IV criteria is overdue. © Cambridge University Press 2010. Source

Community-based participatory research (CBPR) is a collaborative partnership approach to research that combines the efforts of researchers and stakeholders. CBPR can effectively be used to target local community populations in increasing knowledge and improving behaviors in cancer prevention as participants have a voice and active role in the research process. This article describes how CBPR was used in the development, implementation, and evaluation of a pilot intervention for breast and cervical cancer screening among a Vietnamese female population. The authors outline the use of CBPR in three phases: (a) the identification of preventive health topics important in the local Vietnamese community, (b) the development and administration of a survey to gain a deeper understanding of barriers to breast and cancer screening among Vietnamese women, and (c) the development of a culturally appropriate pilot intervention to promote cancer screening behavior among a local Vietnamese population. In Study 1, it was found that Vietnamese women experienced disparities in breast and cervical cancer screening. In Study 2, it was found that having health insurance and a regular physician were predictive of breast and cervical cancer screening. It was also found that participants had low levels of acculturation and lacked cancer screening knowledge. In Study 3, it was found that the culturally relevant intervention used in this study improved cancer screening-related outcomes in knowledge, self-efficacy, intention, and behavior. Source

Zonta M.M.,Virginia Commonwealth University
Environment and Planning A | Year: 2012

In this paper it is argued that the spatial segmentation of financial services in urban areas, generated by a combination of financial market characteristics, transnational movements of people and capital, cultural practices, ethnic resources, and social networks may produce, at the early stages of the home mortgage application process, a sorting of Asian borrowers into mortgage channels that may differ from those of other minority groups and may have, in the long run, a different impact on the exposure and vulnerability of borrowers to adverse lending practices and products. The study employs multinomial logistic regression and GIS analysis of annual Home Mortgage Disclosure Data and explores trends in home mortgage loan applications to different types of lenders by Asian, white, and other minority prospective borrowers in the Los Angeles Metropolitan Area. Findings indicate that Asian applicants feature a greater propensity to apply for mortgage loans at very large mainstream banks and Asian-owned banks than at subprime lenders compared with other minority prospective borrowers. The larger presence of competing financial institutions in Asian immigrant markets may result in a greater access by Asian prospective borrowers to more options and, possibly, to higher quality and affordable mortgage products than other pools of minority applicants. At the same time, some of the social and cultural resources typically found in ethnic enclaves may affect how Asian applicants react to the outreach practices, sorting procedures, and products offered by different lenders. © 2012 Pion Ltd and its Licensors. Source

Al-Horani R.A.,Virginia Commonwealth University
Cardiovascular and Hematological Agents in Medicinal Chemistry | Year: 2014

Fibrinolysis is the ultimate outcome of a cascade of enzymatic reactions in which serine proteases such as plasmin, tissue plasminogen activator (tPA), and urokinase plasminogen activator (uPA) are the key players. Plasmin degrades fibrin into soluble fibrin degradation products. The tPA-mediated plasminogen activation is mainly involved in the dissolution of fibrin in the circulating blood whereas the uPA binds to a specific cellular receptor, resulting in an enhanced activation of cell membrane bound plasminogen. These proteases are regulated by serine protease inhibitors (serpins). Serpin-mediated regulation may occur either at the level of plasmin, mainly by α2-antiplasmin (α2-AP) or at the level of the PAs, mainly by plasminogen activator inhibitor -1 (PAI-1). Other serpins may also be involved including plasminogen activator inhibitor -2 and -3 (PAI-2 and PAI-3), protease nexin-1 (PN-1), C1-inhibitor (C1-INH), placental thrombin inhibitor (PTI), neuroserpin, and yukopin. The serpin-protease reactions serve as potential platforms to develop therapeutics for the treatment and prevention of cardiovascular diseases such as thrombosis and hemorrhage. This review will describe key serpins involved in the regulation of fibrinolytic system, particularly α2-AP and PAI-1, with the focus on their biochemical and biophysical aspects, the pathologies related to their dysfunction or deficiency, their therapeutic roles, and their reported cofactors or modulators. © 2014 Bentham Science Publishers. Source

The integrity of the intestinal epithelial barrier plays a crucial role in maintaining symbiotic homeostasis between microbes in the gut lumen and eukaryotic cells. Disruption of intestinal epithelial barrier function occurs commonly under various pathological conditions, including trauma, inflammatory bowel disease, and drug-induced gastrointestinal toxicity, exhibiting increased intestinal epithelial paracellular permeability or "leakiness" of the intestinal mucosa. Endoplasmic reticulum (ER) stress has recently been linked to various pathological conditions, including intestinal inflammation. Our previous studies have shown that HIV protease inhibitors (PIs) induce ER stress and activate the unfolded protein response (UPR) in different types of cells, and HIV PI-induced UPR activation contributes to the disruption of barrier function in intestinal epithelial cells and the increase of intestinal permeability. This chapter will discuss the commonly used methods for analysis of ER stress activation and epithelial barrier function. Both in vitro cell culture models and in vivo animal models are useful tools to examine general drug-induced ER stress and intestinal barrier dysfunction. © 2011 Elsevier Inc. Source

Qiao L.-Y.,Virginia Commonwealth University
Frontiers in Biology | Year: 2014

Neurotrophin family are traditionally recognized for their nerve growth promoting function and are recently identified as crucial factors in regulating neuronal activity in the central and peripheral nervous systems. The family members including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) are reported to have distinct roles in the development and maintenance of sensory phenotypes in normal states and in the modulation of sensory activity in disease. This paper highlights receptor tyrosine kinase (Trk) -mediated signal transduction by which neurotrophins regulate neuronal activity in the visceral sensory reflex pathways with emphasis on the distinct roles of NGF and BDNF signaling in physiologic and pathophysiological processes. Viscero-visceral cross-organ sensitization exists widely in human diseases. The role of neurotrophins in mediating neural cross talk and interaction in primary afferent neurons in the dorsal root ganglia (DRG) and neurotrophin signal transduction in the context of cross-organ sensitization are also discussed. © 2014, Higher Education Press and Springer-Verlag Berlin Heidelberg. Source

Lee M.,Virginia Commonwealth University
Molecular Psychiatry | Year: 2016

Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat–response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case–control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10-8); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10-9). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.Molecular Psychiatry advance online publication, 12 January 2016; doi:10.1038/mp.2015.197. © 2016 Macmillan Publishers Limited Source