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Vanderbilt University is a private research university located in Nashville, Tennessee, United States. Founded in 1873, the university is named in honor of shipping and rail magnate "Commodore" Cornelius Vanderbilt, who provided the school its initial $1 million endowment despite having never been to the South. The Commodore hoped that his gift and the greater work of the university would help to heal the sectional wounds inflicted by the Civil War.Today Vanderbilt enrolls approximately 12,000 students from all 50 U.S. states and over 90 foreign countries in four undergraduate and six graduate and professional schools. Several research centers and institutes are affiliated with the university, including the Vanderbilt Institute for Public Policy Studies, Freedom Forum First Amendment Center, Dyer Observatory, and Vanderbilt University Medical Center, the only Level I trauma center in Middle Tennessee. With the exception of the off-campus observatory and satellite medical clinics, all of university's facilities are situated on its 330-acre campus in the heart of Nashville, 1.5 miles from downtown. Despite its urban surroundings, the campus itself is a national arboretum and features over 300 different species of trees and shrubs. Wikipedia.

Niswender K.D.,Vanderbilt University
Postgraduate Medicine | Year: 2011

Primary goals in the treatment of type 2 diabetes mellitus (T2DM) include lowering blood glucose levels sufficiently to prevent micro- and macrovascular complications while limiting side effects, such as hypoglycemia and excessive weight gain. Patients with T2DM are typically treated initially with oral antidiabetes agents; however, as the disease progresses, most will require insulin to maintain glycemic control. Often insulin therapy is initiated with basal insulin, and the objective of this article is to present the conceptual aspects of basal insulin therapy and use these concepts to illustrate important clinical aspects. This will be accomplished within a broader contextual discussion of the normal physiologic patterns of insulin secretion, which consist of sustained levels of basal insulin production throughout the day, superimposed with bursts of insulin secretion following a meal (termed bolus or prandial insulin secretion) that slowly decay over 1 to 3 hours. Long-acting basal insulin analogs form a key component of basal-bolus therapy and provide basal support for patients with T2DM. Insulin therapy is often initiated with basal insulin, and newer long-acting analogs, such as insulin glargine and insulin detemir, provide steady, reliable basal insulin coverage in addition to significant advantages over traditional long-acting insulins. This article will integrate conceptual aspects of basal insulin therapy in the context of physiology, molecular pharmacology, and clinical implications of modern basal insulin analogs to provide a foundational understanding of basal insulin biology and physiology. © Postgraduate Medicine.

Zhao Z.,Vanderbilt University
BMC genomics | Year: 2012

We present a report of the 2012 International Conference on Intelligent Biology and Medicine (ICIBM 2012) and the editorial report of the supplement to BMC Genomics that includes 22 research papers selected from ICIBM 2012, which was held on April 22-24, 2012 in Nashville, Tennessee, USA. The conference covered a variety of research areas, including bioinformatics, systems biology, and intelligent computing. It included six sessions, a tutorial - Introduction to Proteome Informatics, a workshop - Next Generation Sequencing, and a poster session. The selected papers in this Supplement issue represent the genomic focus in ICIBM 2012.

BACKGROUND: In subsets of pediatric cardiac surgery patients, red blood cells (RBCs) are often washed to reduce extracellular potassium (K) to avoid hyperkalemia, but mechanical manipulation and time delay in issuing washed products may increase hemolysis and K. This study's purpose was to evaluate the quality of washed RBCs with regard to hemolysis and extracellular K using different cell washers as a function of postprocessing time. STUDY DESIGN AND METHODS: Fresh (<4 days old) RBCs were washed on COBE 2991 blood cell processors (Model 1 and Model 2) or the Fresenius Continuous AutoTransfusion System (CATS), and K and hemolysis index (HI) were analyzed. Academic pediatric hospitals were surveyed to ascertain practice trends regarding indications for washing, washing device, and expiration time for washed RBCs. RESULTS: K concentration at 24 hours for units washed with the COBE devices met or exceeded prewash values. At 12 hours, there was a significant difference (p < 0.001) in K concentration between all devices, with the CATS maintaining the lowest K concentration. HI increased immediately after wash on all devices and showed a significant difference between the COBE devices and CATS at times of more than 6 hours (p < 0.01). At storage times beyond 4 hours, hemoglobin exceeded 100 mg/dL on the COBE Model 1. Survey of pediatric hospitals indicated that COBE devices are commonly used, and storage time after washing was 12 hours or more in blood banks queried. CONCLUSIONS: Hemolysis levels vary among different cell washers. Decreasing the expiration time of units after washing may be warranted. © 2010 American Association of Blood Banks.

Seegmiller A.C.,Vanderbilt University
International Journal of Molecular Sciences | Year: 2014

Cystic fibrosis is an inherited multi-organ disorder caused by mutations in the CFTR gene. Patients with this disease exhibit characteristic abnormalities in the levels of unsaturated fatty acids in blood and tissue. Recent studies have uncovered an underlying biochemical mechanism for some of these changes, namely increased expression and activity of fatty acid desaturases. Among other effects, this drives metabolism of linoeate to arachidonate. Increased desaturase expression appears to be linked to cystic fibrosis mutations via stimulation of the AMP-activated protein kinase in the absence of functional CFTR protein. There is evidence that these abnormalities may contribute to disease pathophysiology by increasing production of eicosanoids, such as prostaglandins and leukotrienes, of which arachidonate is a key substrate. Understanding these underlying mechanisms provides key insights that could potentially impact the diagnosis, clinical monitoring, nutrition, and therapy of patients suffering from this deadly disease. © 2014 by the authors; licensee MDPI, Basel, Switzerland.

Song L.,Vanderbilt University
Journal of Health and Social Behavior | Year: 2011

The author proposes a conceptual model to explain the diverse roles of social capital-resources embedded in social networks-in the social production of health. Using a unique national U.S. sample, the author estimated a path analysis model to examine the direct and indirect effects of social capital on psychological distress and its intervening effects on the relationships between other structural antecedents and psychological distress. The results show that social capital is inversely associated with psychological distress, and part of that effect is indirect through subjective social status. Social capital also acts as an intervening mechanism to link seven social factors (age, gender, race-ethnicity, education, occupational prestige, annual family income, and voluntary participation) with psychological distress. This study develops the theory of social capital as network resources and demonstrates the complex functions of social capital as a distinct social determinant of health. © American Sociological Association 2011.

Zienkiewicz J.,Vanderbilt University
Journal of the American Heart Association | Year: 2013

We recently reported that a bifunctional nuclear transport modifier (NTM), cSN50.1 peptide, reduced atherosclerosis, plasma cholesterol, triglycerides, and glucose along with liver fat and inflammatory markers, in a murine model of familial hypercholesterolemia. We determined that cSN50.1 improved lipid homeostasis by modulating nuclear transport of sterol regulatory element-binding proteins through interaction with importin β. Previous studies established that cSN50.1 and related NTMs also modulate nuclear transport of proinflammatory transcription factors mediated by binding of their nuclear localization sequences (NLSs) to importins/karyopherins α. However, selectivity and specificity of NTMs for importins/karyopherins α were undetermined. We analyzed interaction of the NTM hydrophilic module, N50 peptide, derived from the NLS of NFκB1/p50, with endogenous human importins/karyopherins α to determine the mechanism of NTM modulation of importin α-mediated nuclear transport. We show that N50 peptide forms stable complexes with multiple importins/karyopherins α. However, only interaction with importin α5 (Imp α5) displayed specific, high-affinity binding. The 2:1 stoichiometry of the N50-Imp α5 interaction (KD1 = 73 nmol/L, KD2 = 140 nmol/L) indicated occupancy of both major and minor NLS binding pockets. Utilizing in silico 3-dimensional (3-D) docking models and comparative structural analysis, we identified a structural component of the Imp α5 major NLS binding pocket that may stabilize N50 binding. Imp α5 also displayed rapid stimulus-induced turnover, which could influence its availability for nuclear transport during the inflammatory response. These results provide direct evidence that N50 peptide selectively targets Imp α5, encouraging further refinement of NLS-derived peptides as new tools to modulate inflammatory disorders.

Mutations that arose in bacille Calmette-Guérin (BCG) daughter strains during decades of in vitro cultivation have long been suspected of reducing the efficacy of the BCG vaccine against pulmonary tuberculosis. Although concern was raised 6 decades ago that BCG had become overattenuated, preferential use of relatively virulent BCG vaccines has not restored efficacy. The recent discovery that as BCG evolved its production of antioxidants increased as a consequence of genomic duplications and other mutations suggests the alternative hypothesis that BCG became better at suppressing oxidant-dependent immune responses. This new model of BCG evolution is supported by evidence indicating that reducing BCG antioxidants enhances immunogenicity. Furthermore, some previously unexplained aspects of the performance of the BCG vaccine in clinical trials now make sense in the context of the new model. Finally, the model suggests that the risk of developing pulmonary tuberculosis is influenced by the balance between host-generated oxidants and microbial antioxidants that activate and suppress, respectively, the antigen-presentation pathways that protect the lungs. © 2010 by the Infectious Diseases Society of America. All rights reserved.

Stenvinkel P.,Karolinska Institutet | Zoccali C.,National Research Council Italy | Ikizler T.A.,Vanderbilt University
Journal of the American Society of Nephrology | Year: 2013

Obesity, the epidemic of the 21st century, carries a markedly increased risk for comorbid complications, such as type 2 diabetes, cancer, hypertension, dyslipidemia, cardiovascular disease, and sleep apnea. In addition, obesity increases the risk for CKD and its progression to ESRD. Paradoxically, even morbid obesity associates with better outcomes in studies of ESRD patients on maintenance dialysis. Because the number ofobese CKD and maintenance dialysis patients is projected to increase markedly in developed as well as low- and middle-income countries, obesity is a rapidly emerging problem for the international renal community. Targeting the obesity epidemic represents an unprecedented opportunity for health officials to ameliorate the current worldwide increase in CKD prevalence. Nephrologists need more information about assessing and managing obesity in the setting of CKD. Specifically, more precise estimation of regional fat distribution and the amount of musclemass should be introduced into regular clinical practice to complement more commonly used practical markers, such as body mass index. Studies examining the effects of obesity on kidney disease progression and other clinical outcomes along with weight management strategies are much needed in this orphan area of research. Copyright © 2013 by the American Society of Nephrology.

Light R.W.,Vanderbilt University
Seminars in Respiratory and Critical Care Medicine | Year: 2010

An estimated 300,000 to 500,000 patients develop a pleural effusion secondary to pulmonary embolism each year in the United States. The pleural effusions due to pulmonary embolism are usually small. They occupy less than one third of the hemithorax in 90% and are frequently manifest only as blunting of the costophrenic angle. The pleural fluid with pulmonary embolism is almost always an exudate. When pulmonary embolism is considered a diagnostic possibility, the clinical probability of pulmonary embolism should be assessed. If the probability is low, measurement of D-dimers is useful. If the D-dimer test is negative, the diagnosis is virtually excluded. If the D-dimer test is positive or if there is a high clinical probability of pulmonary embolism, the best test to assess the possibility of pulmonary embolism is probably the computed tomographic angiogram (CTA). Patients who have a high probability of pulmonary embolism should be anticoagulated while the definitive test is being performed. The presence of a pleural effusion does not alter the standard treatment for pulmonary embolism. The two complications of pleural effusions in patients with pulmonary embolism are hemothorax and pleural infection. If the pleural effusion increases in size while a patient is being treated for pulmonary embolism, a diagnostic thoracentesis should be performed to rule out these complications. Copyright © 2010 by Thieme Medical Publishers, Inc.

Zhang X.-G.,Oak Ridge National Laboratory | Pantelides S.T.,Oak Ridge National Laboratory | Pantelides S.T.,Vanderbilt University
Physical Review Letters | Year: 2012

Space-charge-limited currents are important in energy devices such as solar cells and light-emitting diodes, but the available theory from the 1950s finds it necessary to postulate defect states that are distributed in energy in order to match data. Here, we show that this postulate is not warranted. Instead, we demonstrate that dopants and the concomitant Frenkel effect, which have been neglected, control the shape of measured current-voltage characteristics. We also account for the observed peak in the noise power. The new theory can anchor efforts to develop experimental techniques to measure deep-trap levels. © 2012 American Physical Society.

Oskay C.,Vanderbilt University
Computer Methods in Applied Mechanics and Engineering | Year: 2013

This manuscript presents the formulation and implementation of the variational multiscale enrichment (VME) method using canopy-shaped microscale enrichment functions obtained through the use of a new family of microscale boundary conditions. The purpose of the new enrichment functions and the new boundary condition is to relax the overconstraint imposed by the homogeneous microscale boundary condition (e.g., residual free bubbles) commonly employed in the variational multiscale literature. The formulation and implementation of the method are presented for diffusion and elasticity problems. The performance of the proposed method is assessed by comparing with direct numerical simulations on diffusion and deformation problems. A boundary parameter identification approach is proposed to obtain near-optimal boundary conditions. The identification approach is verified in the context of the deformation response of particle-reinforced composites. © 2013 Elsevier B.V.

Auerbach D.I.,RAND Health | Buerhaus P.I.,Vanderbilt University | Staiger D.O.,Dartmouth College
Health Affairs | Year: 2011

The vast preponderance of the nation's registered nurses are women. In the 1980s and 1990s, a decline in the number of women ages 23-26 who were choosing nursing as a career led to concerns that there would be future nurse shortages unless the trend was reversed. Between 2002 and 2009, however, the number of full-time-equivalent registered nurses ages 23-26 increased by 62 percent. If these young nurses follow the same life-cycle employment patterns as those who preceded them-as they appear to be thus far- then they will be the largest cohort of registered nurses ever observed. Because of this surge in the number of young people entering nursing during the past decade, the nurse workforce is projected to grow faster during the next two decades than previously anticipated. However, it is uncertain whether interest in nursing will continue to grow in the future.

Song Y.,State University of New York at Stony Brook | Washington M.K.,Vanderbilt University | Crawford H.C.,State University of New York at Stony Brook
Cancer Research | Year: 2010

FOXA1 and FOXA2, members of the forkhead transcription factor family, are critical for epithelial differentiation in many endoderm-derived organs, including the pancreas. However, their role in tumor progression is largely unknown. Here, we identified FOXA1 and FOXA2 as important antagonists of the epithelial-to-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDA) through their positive regulation of E-cadherin and maintenance of the epithelial phenotype. In human PDA samples, FOXA1/2 are expressed in all epithelia from normal to well-differentiated cancer cells, but are lost in undifferentiated cancer cells. In PDA cell lines, FOXA1/2 expression is consistently suppressed in experimental EMT models and RNAi silencing of FOXA1/2 alone is sufficient to induce EMT. Conversely, ectopic FOXA1/2 expression can potently neutralize several EMT-related E-cadherin repressive mechanisms. Finally, ectopic FOXA2 expression could reactivate E-cadherin expression in a PDA cell line with extensive promoter hypermethylation. In fact, demethylation-mediated reactivation of E-cadherin expression in these cells required concurrent reactivation of endogenous FOXA2 expression. We conclude that suppression of FOXA1/2 expression is both necessary and sufficient for EMT during PDA malignant progression. ©2010 AACR.

Auerbach D.I.,RAND Corporation in Boston | Buerhaus P.I.,Vanderbilt University | Staiger D.O.,Dartmouth College
Health Affairs | Year: 2014

The size of the registered nurse (RN) workforce has surpassed forecasts from a decade ago, growing to 2.7 million in 2012 instead of peaking at 2.2 million. Much of the difference is the result of a surge in new nursing graduates. However, the size of the RN workforce is particularly sensitive to changes in retirement age, given the large number of baby-boomer RNs now in the workforce. We found that in the period 1969-90, for a given number of RNs working at age fifty, 47 percent were still working at age sixty-two and 9 percent were working at age sixty-nine. In contrast, in the period 1991-2012 the proportions were 74 percent at age sixty-two and 24 percent at age sixty-nine. This trend, which largely predates the recent recession, extended nursing careers by 2.5 years after age fifty and increased the 2012 RN workforce by 136,000 people. Because many RNs tend to shift out of hospital settings as they age, employers seeking RNs for nonhospital roles may welcome (and seek to capitalize on) the growing numbers of experienced RNs potentially able to fill these positions.© 2014 by Project HOPE - The People-to-People Health Foundation.

Harris R.C.,Vanderbilt University
Kidney International | Year: 2012

As new components of the renin-angiotensin system (RAS) are elucidated, our understanding of the complexities of their interactions also advances. Previous studies have determined that podocytes possess a local RAS that can generate angiotensin II. Podocytes have also been shown to express angiotensin-converting enzyme 2 (ACE2), which can decrease angiotensin II levels by generation of angiotensin-(1-7). Nadarajah et al. now show that increased podocyte ACE2 activity can attenuate the development of diabetic nephropathy.

Ritchie M.D.,Vanderbilt University
Annals of Human Genetics | Year: 2011

The search for the missing heritability in genome-wide association studies (GWAS) has become an important focus for the human genetics community. One suspected location of these genetic effects is in gene-gene interactions, or epistasis. The computational burden of exploring gene-gene interactions in the wealth of data generated in GWAS, along with small to moderate sample sizes, have led to epistasis being an afterthought, rather than a primary focus of GWAS analyses. In this review, I discuss some potential approaches to filter a GWAS dataset to a smaller, more manageable dataset where searching for epistasis is considerably more feasible. I describe a number of alternative approaches, but primarily focus on the use of prior biological knowledge from databases in the public domain to guide the search for epistasis. The manner in which prior knowledge is incorporated into a GWA study can be many and these data can be extracted from a variety of database sources. I discuss a number of these approaches and propose that a comprehensive approach will likely be most fruitful for searching for epistasis in large-scale genomic studies of the current state-of-the-art and into the future. © 2010 The Author Annals of Human Genetics © 2010 Blackwell Publishing Ltd/University College London.

Penson D.F.,Vanderbilt University
Journal of the National Cancer Institute - Monographs | Year: 2012

Clinical decision making in localized prostate cancer is a complicated, multidimensional process in which men often consider their own personal preferences, the advice of their healthcare providers, the opinions of their family and friends, and outside information sources. They synthesize all of this within the framework of their own unique socioeconomic situation, their social support network, and their preconceived impressions of their health and the health-care system. This is particularly germane when considering factors that influence a patient's acceptance of and adherence to active surveillance (AS). We propose a conceptual framework based on a previously described systematic-heuristic theoretical model of decision making in this setting. We identify a number of factors that patients systematically prioritize when considering AS. These include desire for cancer control or cure, age at diagnosis, and concern regarding side effects of treatment. The way patients value these factors and effectively decide on treatment is influenced by more heuristic factors, including physician recommendation, opinion of friends and family members, and overall decision uncertainty. These heuristic factors also play an important role in adherence when a patient elects AS. Finally, some of the factors, particularly the heuristic ones, are potentially modifiable and may serve as targets for future interventions to increase acceptance of and adherence to AS.

Steyer R.,Friedrich - Schiller University of Jena | Mayer A.,Ghent University | Geiser C.,Utah State University | Cole D.A.,Vanderbilt University
Annual Review of Clinical Psychology | Year: 2015

We present a revision of latent state-trait (LST-R) theory with new definitions of states and traits. This theory applies whenever we study the consistency of behavior, its variability, and its change over time. States and traits are defined in terms of probability theory. This allows for a seamless transition from theory to statistical modeling of empirical data. LST-R theory not only gives insights into the nature of latent variables but it also takes into account four fundamental facts: Observations are fallible, they never happen in a situational vacuum, they are always made using a specific method of observations, and there is no person without a past. Although the first fact necessitates considering measurement error, the second fact requires allowances for situational fluctuations. The third fact implies that, in the first place, states and traits are method specific. Furthermore, compared to the previous version of LST theory (see, e.g., Steyer et al. 1992, 1999), our revision is based on the notion of a person-at-time-t. The new definitions in LST-R theory have far-reaching implications that not only concern the properties of states, traits, and the associated concepts of measurement errors and state residuals, but also are related to the analysis of states and traits in longitudinal observational and intervention studies. © 2015 by Annual Reviews. All rights reserved.

Catania K.C.,Vanderbilt University
Journal of Comparative Physiology A: Neuroethology, Sensory, Neural, and Behavioral Physiology | Year: 2013

American water shrews (Sorex palustris) are aggressive predators that dive into streams and ponds to find prey at night. They do not use eyesight for capturing fish or for discriminating shapes. Instead they make use of vibrissae to detect and attack water movements generated by active prey and to detect the form of stationary prey. Tactile investigations are supplemented with underwater sniffing. This remarkable behavior consists of exhalation of air bubbles that spread onto objects and are then re-inhaled. Recordings for ultrasound both above and below water provide no evidence for echolocation or sonar, and presentation of electric fields and anatomical investigations provide no evidence for electroreception. Counts of myelinated fibers show by far the largest volume of sensory information comes from the trigeminal nerve compared to optic and cochlear nerves. This is in turn reflected in the organization of the water shrew's neocortex, which contains two large somatosensory areas and much smaller visual and auditory areas. The shrew's small brain with few cortical areas may allow exceptional speed in processing sensory information and producing motor output. Water shrews can accurately attack the source of a water disturbance in only 50 ms, perhaps outpacing any other mammalian predator. © 2013 Springer-Verlag Berlin Heidelberg.

Bruehl S.,Vanderbilt University
BMJ (Online) | Year: 2015

Complex regional pain syndrome is a chronic pain condition characterized by autonomic and inflammatory features. It occurs acutely in about 7% of patients who have limb fractures, limb surgery, or other injuries. Many cases resolve within the first year, with a smaller subset progressing to the chronic form. This transition is often paralleled by a change from "warm complex regional pain syndrome," with inflammatory characteristics dominant, to "cold complex regional pain syndrome" in which autonomic features dominate. Multiple peripheral and central mechanisms seem to be involved, the relative contributions of which may differ between individuals and over time. Possible contributors include peripheral and central sensitization, autonomic changes and sympatho-afferent coupling, inflammatory and immune alterations, brain changes, and genetic and psychological factors. The syndrome is diagnosed purely on the basis of clinical signs and symptoms. Effective management of the chronic form of the syndrome is often challenging. Few high quality randomized controlled trials are available to support the efficacy of the most commonly used interventions. Reviews of available randomized trials suggest that physical and occupational therapy (including graded motor imagery and mirror therapy), bisphosphonates, calcitonin, subanesthetic intravenous ketamine, free radical scavengers, oral corticosteroids, and spinal cord stimulation may be effective treatments. Multidisciplinary clinical care, which centers around functionally focused therapies is recommended. Other interventions are used to facilitate engagement in functional therapies and to improve quality of life.

Johnson C.H.,Vanderbilt University
Cell Cycle | Year: 2010

Evolution has selected a system of two intertwined cell cycles: the cell division cycle (CDC) and the daily (circadian) biological clock. The circadian clock keeps track of solar time and programs biological processes to occur at environmentally appropriate times. One of these processes is the CDC, which is often gated by the circadian clock. The intermeshing of these two cell cycles is probably responsible for the observation that disruption of the circadian system enhances susceptibility to some kinds of cancer. The core mechanism underlying the circadian clockwork has been thought to be a transcription & translation feedback loop (TTFL), but recent evidence from studies with cyanobacteria, synthetic oscillators and immortalized cell lines suggests that the core circadian pacemaking mechanism that gates cell division in mammalian cells could be a post-translational oscillator (PTO). © 2010 Landes Bioscience.

Elevated serum free fatty acid levels are associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. Macrophages are recruited to atherosclerotic plaques and metabolic tissues during obesity and accumulate lipids, including free fatty acids. We investigated the molecular consequences of intracellular saturated free fatty acid accumulation in macrophages. Previously, we demonstrated that cotreatment of mouse peritoneal macrophages (MPMs) with stearic acid and triacsin C (an inhibitor of long-chain acyl coenzyme A synthetases) results in intracellular free fatty acid accumulation and apoptosis. Here, we used Western blotting analysis, real-time reverse transcription polymerase chain reaction, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining to assess endoplasmic reticulum (ER) stress, inflammation, and apoptosis in MPMs. Intracellular stearic acid accumulation induces Toll-like receptor 4/2-independent inflammation that results in ER stress-mediated apoptosis of MPMs. Polarization of MPMs to a proinflammatory M1 phenotype increases their susceptibility to inflammation and ER stress, but not apoptosis, in response to cotreatment with stearic acid and triacsin C. Intracellular accumulation of stearic acid in MPMs activates inflammatory signaling, leading to ER stress-mediated apoptosis. M1 macrophages are more prone to stearic acid-induced inflammation and ER stress. These same pathways may be activated in macrophages residing in atherosclerotic plaques and metabolic tissues during conditions of obesity and hyperlipidemia.

Taylor W.D.,Vanderbilt University | Aizenstein H.J.,University of Pittsburgh | Alexopoulos G.S.,New York Medical College
Molecular Psychiatry | Year: 2013

The 'Vascular Depression' hypothesis posits that cerebrovascular disease may predispose, precipitate or perpetuate some geriatric depressive syndromes. This hypothesis stimulated much research that has improved our understanding of the complex relationships between late-life depression (LLD), vascular risk factors, and cognition. Succinctly, there are well-established relationships between LLD, vascular risk factors and cerebral hyperintensities, the radiological hallmark of vascular depression. Cognitive dysfunction is common in LLD, particularly executive dysfunction, a finding predictive of poor antidepressant response. Over time, progression of hyperintensities and cognitive deficits predicts a poor course of depression and may reflect underlying worsening of vascular disease. This work laid the foundation for examining the mechanisms by which vascular disease influences brain circuits and influences the development and course of depression. We review data testing the vascular depression hypothesis with a focus on identifying potential underlying vascular mechanisms. We propose a disconnection hypothesis, wherein focal vascular damage and white matter lesion location is a crucial factor, influencing neural connectivity that contributes to clinical symptomatology. We also propose inflammatory and hypoperfusion hypotheses, concepts that link underlying vascular processes with adverse effects on brain function that influence the development of depression. Testing such hypotheses will not only inform the relationship between vascular disease and depression, but also provide guidance on the potential repurposing of pharmacological agents that may improve LLD outcomes. © 2013 Macmillan Publishers Limited.

Liu Y.,Vanderbilt University
Journal of the American Heart Association | Year: 2013

Elevated cholesterol and triglycerides in blood lead to atherosclerosis and fatty liver, contributing to rising cardiovascular and hepatobiliary morbidity and mortality worldwide. A cell-penetrating nuclear transport modifier (NTM) reduced hyperlipidemia, atherosclerosis, and fatty liver in low-density lipoprotein receptor-deficient mice fed a Western diet. NTM treatment led to lower cholesterol and triglyceride levels in blood compared with control animals (36% and 53%, respectively; P<0.005) and liver (41% and 34%, respectively; P<0.05) after 8 weeks. Atherosclerosis was reduced by 63% (P<0.0005), and liver function improved compared with saline-treated controls. In addition, fasting blood glucose levels were reduced from 209 to 138 mg/dL (P<0.005), and body weight gain was ameliorated (P<0.005) in NTM-treated mice, although food intake remained the same as that in control animals. The NTM used in this study, cSN50.1 peptide, is known to modulate nuclear transport of stress-responsive transcription factors such as nuclear factor kappa B, the master regulator of inflammation. This NTM has now been demonstrated to also modulate nuclear transport of sterol regulatory element-binding protein (SREBP) transcription factors, the master regulators of cholesterol, triglyceride, and fatty acid synthesis. NTM-modulated translocation of SREBPs to the nucleus was associated with attenuated transactivation of their cognate genes that contribute to hyperlipidemia. Two-pronged control of inflammation and dyslipidemia by modulating nuclear transport of their critical regulators offers a new approach to comprehensive amelioration of hyperlipidemia, atherosclerosis, fatty liver, and their potential complications.

Pitz R.W.,Vanderbilt University | Hu S.,Babcock and Wilcox Research Center | Wang P.,Xiamen University
Progress in Energy and Combustion Science | Year: 2014

Tubular flames are ideal for the study of stretch and curvature effects on flame structure, extinction, and instabilities. Tubular flames have uniform stretch and curvature and each parameter can be varied independently. Curvature strengthens or weakens preferential diffusion effects on the tubular flame and the strengthening or weakening is proportional to the ratio of the flame thickness to the flame radius. Premixed flames can be studied in the standard tubular burner where a single premixed gas stream flows radially inward to the cylindrical flame surface and products exit as opposed jets. Premixed, diffusion and partially premixed flames can be studied in the opposed tubular flame where opposed radial flows meet at a cylindrical stagnation surface and products exit as opposed jets. The tubular flame flow configurations can be mathematically reduced to a two-point boundary value solution along the single radial coordinate. Non-intrusive measurements of temperature and major species concentrations have been made with laser-induced Raman scattering in an optically accessible tubular burner for both premixed and diffusion flames. The laser measurements of the flame structure are in good agreement with numerical simulations of the tubular flame. Due to the strong enhancement of preferential diffusion effects in tubular flames, the theory-data comparison can be very sensitive to the molecular transport model and the chemical kinetic mechanism. The strengthening or weakening of the tubular flame with curvature can increase or decrease the extinction strain rate of tubular flames. For lean H 2-air mixtures, the tubular flame can have an extinction strain rate many times higher than the corresponding opposed jet flame. More complex cellular tubular flames with highly curved flame cells surrounded by local extinction can be formed under both premixed and non-premixed conditions. In the hydrogen fueled premixed tubular flames, thermal-diffusive flame instabilities result in the formation of a uniform symmetric petal flames far from extinction. In opposed-flow tubular diffusion flames, thermal-diffusive flame instabilities result in cellular flames very close to extinction. Both of these flames are candidates for further study of flame curvature and extinction. © 2014 Elsevier Ltd. All rights reserved.

Stokes Peebles R.,Vanderbilt University
Journal of Leukocyte Biology | Year: 2015

ILC2s have been primarily identified at environmentalmucosal interfaces and can be activated quickly by environmental antigens and pathogens to produce large quantities of IL-5 and IL-13. As a result of the production of these cytokines, ILC2s have been implicated in the host response to allergens, viruses, and parasites. However, the exact role of ILC2s in any human disease state is presently unknown, as specifically eliminating these cells is not possible, given that potentially targetable cell-surface markers are shared with other immune cells. Likewise, selectively and completely inhibiting ILC2 activation is also not currently possible, as several activating cytokines, IL-25, IL-33, and TSLP, act in redundancy or are not specific for ILC2 stimulation. Therefore, at this point, we can only identify the relative abundance of ILC2s in organs and tissue identified as being involved in specific diseases, and the contribution of ILC2s in human disease can only be inferred from mouse studies. Given these limitations, in this article, we will review the studies that have examined the presence of ILC2s in human disease states and speculate on their possible role in disease pathogenesis. The intent of the review is to identify priority areas for basic research based on clinical research insights. © Society for Leukocyte Biology.

Kim S.,Yonsei University | Richards W.O.,Vanderbilt University
Annals of Surgery | Year: 2010

Objective: The goal of this study was to evaluate the effect of Roux-en-Y gastric bypass (RYGBP) on 2 metabolic disorders, diabetes and dyslipidemia, in obese type 2 diabetes mellitus (T2DM) patients. Summary background data: Little is known about the long-term change in metabolic and lipid profiles of T2DM patients after RYGBP. Methods: This is a retrospective review of prospectively collected data about glucose metabolism and lipid profiles of morbidly obese patients with T2DM on antidiabetic medications who underwent laparoscopic RYGBP. Results: A total 219 patients with mean (±SD) duration of follow-up of 26.4 (±12.8) months were included in the study. At one year postoperative mean serum fasting plasma glucose fell from 152.8 to 106.0 mg/dL, HGBA1c (glycated hemoglobin) fell from 7.6% to 6.1%, TC (total cholesterol) went from 180.9 to 172.0 mg/dL, TG (triglyceride) fell from 208.0 to 117.4 mg/dL, and HDL-C (HDL-cholesterol) levels increased from 48.7 to 58.7 mg/dL. These improvements were maintained 2 to 4 years after surgery. Older age, longer duration of T2DM, and insulin use were important preoperative factors associated with failure to resolve T2DM. Postoperatively, the amount of total weight loss was associated with the improvement or resolution of T2DM (P = 0.053). Conclusion: Laparoscopic RYGBP has a beneficial effect on glucose metabolism and serum lipid composition in obese T2DM patients. Sustained weight loss was associated with maintenance of euglycemia in postoperative obese T2DM patients. © 2010 Lippincott Williams & Wilkins.

Veter N.M.,Vanderbilt University
Biology letters | Year: 2013

Macroecology strives to identify ecological patterns on broad spatial and temporal scales. One such pattern, Rapoport's rule, describes the tendency of species' latitudinal ranges to increase with increasing latitude. Several mechanisms have been proposed to explain this rule. Some invoke climate, either through glaciation driving differential extinction of northern species or through increased seasonal variability at higher latitudes causing higher thermal tolerances and subsequently larger ranges. Alternatively, continental tapering or higher interspecific competition at lower latitudes may be responsible. Assessing the incidence of Rapoport's rule through deep time can help to distinguish between competing explanations. Using fossil occurrence data from the Palaeobiology Database, we test these hypotheses by evaluating mammalian compliance with the rule throughout the Caenozoic of North America. Adherence to Rapoport's rule primarily coincides with periods of intense cooling and increased seasonality, suggesting that extinctions caused by changing climate may have played an important role in erecting the latitudinal gradients in range sizes seen today.

Koppel R.,University of Pennsylvania | Lehmann C.U.,Vanderbilt University
Journal of the American Medical Informatics Association : JAMIA | Year: 2015

In many hospitals and health systems, a 'new' electronic health record means a shift to one vendor: Epic, a vendor that dominates in large and medium hospital markets and continues its success with smaller institutions and ambulatory practices. Our paper examines the implications of this emerging monoculture: its advantages and disadvantages for physicians and hospitals and its role in innovation, professional autonomy, implementation difficulties, workflow, flexibility, cost, data standards, interoperability, and interactions with other information technology (IT) systems. © The Author 2014. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Fine J.-D.,Vanderbilt University
Annals of the New York Academy of Sciences | Year: 2010

Inherited epidermolysis bullosa encompasses dozens of diseases characterized by mechanical fragility of the skin, blister formation, and abnormal wound healing. Most of the more severe subtypes are associated with clinically significant extracutaneous complications. Some subtypes may lead to death, even in early infancy. Over the past two decades substantial advances have been made to our understanding of the underlying molecular basis for each member of this protean group of diseases. Research has now shifted toward the identification of therapeutic interventions, to include gene therapy, recombinant protein infusions, intradermal injection of allogeneic fibroblasts, and stem cell transplantation, that might eventually lead to a definitive cure for this disease. Other developing therapies being explored are directed toward the enhancement of wound healing and the prevention of potentially life-threatening skin cancers in these patients. © 2010 New York Academy of Sciences.

Fougnie D.,Vanderbilt University
Journal of vision | Year: 2010

An influential theory suggests that integrated objects, rather than individual features, are the fundamental units that limit our capacity to temporarily store visual information (S. J. Luck & E. K. Vogel, 1997). Using a paradigm that independently estimates the number and precision of items stored in working memory (W. Zhang & S. J. Luck, 2008), here we show that the storage of features is not cost-free. The precision and number of objects held in working memory was estimated when observers had to remember either the color, the orientation, or both the color and orientation of simple objects. We found that while the quantity of stored objects was largely unaffected by increasing the number of features, the precision of these representations dramatically decreased. Moreover, this selective deterioration in object precision depended on the multiple features being contained within the same objects. Such fidelity costs were even observed with change detection paradigms when those paradigms placed demands on the precision of the stored visual representations. Taken together, these findings not only demonstrate that the maintenance of integrated features is costly; they also suggest that objects and features affect visual working memory capacity differently.

This paper evaluates the ability to detect three forms of methicillin-resistant Staphylococcus aureus (MRSA) in a microfluidic system. The MRSA was prepared off-chip by varying levels of sample preparation: one containing purified genomic DNA, another containing the supernatant of a crude preparation using simple reagents, and a third through boiled culture preparation without any additional reagents. Polydimethylsiloxane (PDMS) microfluidic chips were fabricated using soft lithography and then bonded to a 22mmx22mmx0.1mm glass cover slip. A lid fabricated in a similar manner was used during compression to prevent bubble formation and evaporation in the stationary well-based chip. A miniature thermal cycler based on a resistive heater and a small fan were used to cycle through desired temperatures for polymerase chain reaction and fluorescent intensity measurements were taken at each cycle. Each form of template provided positive results utilizing the developed micro-PCR system (verified with gel electrophoresis). A serial dilution of the purified genomic DNA provided a standard curve with an efficiency of 1.77. The lowest concentration that provided clear positive results came from a 3microL sample containing 11.2pg of DNA. The ability to detect MRSA in a sample having undergone minimal sample preparation is a necessary step in the development of a point-of-care detection system capable of identifying infectious organisms.

Patterson E.J.,Vanderbilt University
Demography | Year: 2010

Using data from the U.S. Bureau of Justice Statistics and Census Bureau, I estimate death rates of working-age prisoners and nonprisoners by sex and race. Incarceration was more detrimental to females in comparison to their male counterparts in the period covered by this study. White male prisoners had higher death rates than white males who were not in prison. Black male prisoners, however, consistently exhibited lower death rates than black male nonprisoners did. Additionally, the findings indicate that while the relative difference in mortality levels of white and black males was quite high outside of prison, it essentially disappeared in prison. Notably, removing deaths caused by firearms and motor vehicles in the nonprison population accounted for some of the mortality differential between black prisoners and nonprisoners. The death rates of the other groups analyzed suggest that prison is an unhealthy environment; yet, prison appears to be a healthier place than the typical environment of the nonincarcerated black male population. These findings suggest that firearms and motor vehicle accidents do not sufficiently explain the higher death rates of black males, and they indicate that a lack of basic healthcare may be implicated in the death rates of black males not incarcerated.

Schaffner W.,Vanderbilt University
New England Journal of Medicine | Year: 2014

A 23-year-old man sustained abdominal trauma in a motorcycle accident that required a surgical splenectomy. He received the 23-valent pneumococcal polysaccharide vaccine (PPSV23) after surgery. Six months after his surgery, he calls his primary care provider because he has fever. What is the appropriate management? Are other prophylactic measures available and indicated? Copyright © 2014 Massachusetts Medical Society.

Beckman J.A.,Vanderbilt University | Creager M.A.,Dartmouth Hitchcock Medical Center
Circulation Research | Year: 2016

Over the last several decades, the global incidence and prevalence of diabetes mellitus has increased significantly. The raised incidence rate is projected to continue as greater numbers of persons adopt a Western lifestyle and diet. Patients with diabetes mellitus are at heightened risk of both adverse microvascular and cardiovascular events. Moreover, once cardiovascular disease develops, diabetes mellitus exacerbates progression and worsens outcomes. The medical management of patients with diabetes mellitus mandates comprehensive risk factor modification and antiplatelet therapy. Recent clinical trials of new medical therapies continue to inform the care of patients with diabetes mellitus to reduce both cardiovascular morbidity and mortality. © 2016 American Heart Association, Inc.

Moses H.,Vanderbilt University
Cold Spring Harbor perspectives in biology | Year: 2011

Transforming growth factor-β1 (TGF-β) was first implicated in mammary epithelial development by Daniel and Silberstein in 1987 and in breast cancer cells and hormone resistance by Lippman and colleagues in 1988. TGF-β is critically important for mammary morphogenesis and secretory function through specific regulation of epithelial proliferation, apoptosis, and extracellular matrix. Differential TGF-β effects on distinct cell types are compounded by regulation at multiple levels and the influence of context on cellular responses. Studies using controlled expression and conditional-deletion mouse models underscore the complexity of TGF-β biology across the cycle of mammary development and differentiation. Early loss of TGF-β growth regulation in breast cancer evolves into fundamental deregulation that mediates cell interactions and phenotypes driving invasive disease. Two outstanding issues are to understand the mechanisms of biological control in situ and the circumstances by which TGF-β regulation is subverted in neoplastic progression.

Clayton E.W.,Vanderbilt University | McGuire A.L.,Baylor College of Medicine
Genetics in Medicine | Year: 2012

Published guidelines suggest that research results and incidental findings should be offered to study participants under some circumstances. Although some have argued against the return of results in research, many cite an emerging consensus that there is an ethical obligation to return at least some results; the debate quickly turns to issues of mechanics (e.g., which results? who discloses? for how long does the obligation exist?). Although commentators are careful to distinguish this as an ethical rather than legal obligation, we worry that return of results may unjustifiably become standard of care based on this growing "consensus," which could quickly lead to a legal (negligence-based) duty to offer and return individualized genetic research results. We caution against this and argue in this essay that the debate to date has failed to give adequate weight to a number of fundamental ethical and policy issues that should undergird policy on return of research results in the first instance, many of which go to the fundamental differences between research and clinical care. We confine our comments to research using data from large biobanks, the topic of the guidelines proposed in this symposium issue. ©American College of Medical Genetics and Genomics.

Tian F.-B.,Vanderbilt University
Applied Physics Letters | Year: 2013

The interaction between flag/flags and fluid is studied numerically and the time-average flow in the wake is analyzed. It is found that a zero-mass flag in uniform flow can not exhibit sustained flapping which only occurs when the mass is involved, while multiple zero-mass flags with small separation settle into sustained flapping state. Furthermore, the nonzero mass is an essential condition for flag/flags to establish the sustained flapping in the case of convectively instable wake, while it is an unnecessary condition for the case of the absolutely instable wake. © 2013 AIP Publishing LLC.

Wang J.,Vanderbilt University
Nucleic acids research | Year: 2013

Functional enrichment analysis is an essential task for the interpretation of gene lists derived from large-scale genetic, transcriptomic and proteomic studies. WebGestalt (WEB-based GEne SeT AnaLysis Toolkit) has become one of the popular software tools in this field since its publication in 2005. For the last 7 years, WebGestalt data holdings have grown substantially to satisfy the requirements of users from different research areas. The current version of WebGestalt supports 8 organisms and 201 gene identifiers from various databases and different technology platforms, making it directly available to the fast growing omics community. Meanwhile, by integrating functional categories derived from centrally and publicly curated databases as well as computational analyses, WebGestalt has significantly increased the coverage of functional categories in various biological contexts including Gene Ontology, pathway, network module, gene-phenotype association, gene-disease association, gene-drug association and chromosomal location, leading to a total of 78 612 functional categories. Finally, new interactive features, such as pathway map, hierarchical network visualization and phenotype ontology visualization have been added to WebGestalt to help users better understand the enrichment results. WebGestalt can be freely accessed through http://www.webgestalt.org or http://bioinfo.vanderbilt.edu/webgestalt/.

McDonnell T.E.,Vanderbilt University
American Journal of Sociology | Year: 2010

AIDS media lead unexpected lives once distributed through urban space: billboards fade, posters go missing, bumper stickers travel to other cities. The materiality of AIDS campaign objects and of the urban settings in which they are displayed structures how the public interprets their messages. Ethnographic observation of AIDS media in situ and interview data reveal how the materiality of objects and places shapes the availability of AIDS knowledge in Accra, Ghana. Significantly for AIDS organizations, these material conditions often systematically obstruct access to AIDS knowledge for particular groups. Attending to materiality rethinks how scholars assess the cultural power of media. © 2010 by The University of Chicago.

Wikswo J.P.,Vanderbilt University
Experimental Biology and Medicine | Year: 2014

Microphysiological systems (MPS), consisting of interacting organs-on-chips or tissue-engineered, 3D organ constructs that use human cells, present an opportunity to bring new tools to biology, medicine, pharmacology, physiology, and toxicology. This issue of Experimental Biology and Medicine describes the ongoing development of MPS that can serve as in-vitro models for bone and cartilage, brain, gastrointestinal tract, lung, liver, microvasculature, reproductive tract, skeletal muscle, and skin. Related topics addressed here are the interconnection of organs-on-chips to support physiologically based pharmacokinetics and drug discovery and screening, and the microscale technologies that regulate stem cell differentiation. The initial motivation for creating MPS was to increase the speed, efficiency, and safety of pharmaceutical development and testing, paying particular regard to the fact that neither monolayer monocultures of immortal or primary cell lines nor animal studies can adequately recapitulate the dynamics of drug–organ, drug–drug, and drug–organ–organ interactions in humans. Other applications include studies of the effect of environmental toxins on humans, identification, characterization, and neutralization of chemical and biological weapons, controlled studies of the microbiome and infectious disease that cannot be conducted in humans, controlled differentiation of induced pluripotent stem cells into specific adult cellular phenotypes, and studies of the dynamics of metabolism and signaling within and between human organs. The technical challenges are being addressed by many investigators, and in the process, it seems highly likely that significant progress will be made toward providing more physiologically realistic alternatives to monolayer monocultures or whole animal studies. The effectiveness of this effort will be determined in part by how easy the constructs are to use, how well they function, how accurately they recapitulate and report human pharmacology and toxicology, whether they can be generated in large numbers to enable parallel studies, and if their use can be standardized consistent with the practices of regulatory science. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Guo Y.,Vanderbilt University
Bioinformatics (Oxford, England) | Year: 2013

Exome capture kits have capture efficiencies that range from 40 to 60%. A significant amount of off-target reads are from the mitochondrial genome. These unintentionally sequenced mitochondrial reads provide unique opportunities to study the mitochondria genome. MitoSeek is an open-source software tool that can reliably and easily extract mitochondrial genome information from exome and whole genome sequencing data. MitoSeek evaluates mitochondrial genome alignment quality, estimates relative mitochondrial copy numbers and detects heteroplasmy, somatic mutation and structural variants of the mitochondrial genome. MitoSeek can be set up to run in parallel or serial on large exome sequencing datasets. https://github.com/riverlee/MitoSeek

Hackett T.A.,Vanderbilt University
Handbook of Clinical Neurology | Year: 2015

The auditory cortex is a network of areas in the part of the brain that receives inputs from the subcortical auditory pathways in the brainstem and thalamus. Through an elaborate network of intrinsic and extrinsic connections, the auditory cortex is thought to bring about the conscious perception of sound and provide a basis for the comprehension and production of meaningful utterances. In this chapter, the organization of auditory cortex is described with an emphasis on its anatomic features and the flow of information within the network. These features are then used to introduce key neurophysiologic concepts that are being intensively studied in humans and animal models. The discussion is presented in the context of our working model of the primate auditory cortex and extensions to humans. The material is presented in the context of six underlying principles, which reflect distinct, but related, aspects of anatomic and physiologic organization: (1) the division of auditory cortex into regions; (2) the subdivision of regions into areas; (3) tonotopic organization of areas; (4) thalamocortical connections; (5) serial and parallel organization of connections; and (6) topographic relationships between auditory and auditory-related areas. Although the functional roles of the various components of this network remain poorly defined, a more complete understanding is emerging from ongoing studies that link auditory behavior to its anatomic and physiologic substrates. © 2015 Elsevier B.V.

Blakely R.D.,Vanderbilt University | Edwards R.H.,University of California at San Francisco
Cold Spring Harbor Perspectives in Biology | Year: 2012

The regulated exocytosis that mediates chemical signaling at synapses requires mechanisms to coordinate the immediate response to stimulation with the recycling needed to sustain release. Two general classes of transporter contribute to release, one located on synaptic vesicles that loads them with transmitter, and a second at the plasma membrane that both terminates signaling and serves to recycle transmitter for subsequent rounds of release. Originally identified as the target of psychoactive drugs, these transport systems have important roles in transmitter release, but we are only beginning to understand their contribution to synaptic transmission, plasticity, behavior, and disease. Recentwork has started to provide a structural basis for their activity, to characterize their trafficking and potential for regulation. The results indicate that far from the passive target of psychoactive drugs, neurotransmitter transporters undergo regulation that contributes to synaptic plasticity. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.

Miller E.K.,Vanderbilt University
Immunology and Allergy Clinics of North America | Year: 2010

Asthma is the most common chronic disease of childhood, affecting 10% to 15% of all children. Several different stimuli including allergens, tobacco smoke, certain drugs, and viral or bacterial infections are known to exacerbate asthma symptoms. Among these triggers, viruses are frequent inducers of asthma exacerbations, with human rhinoviruses being the most common in children and adults. This article describes the different species of this virus and their roles as major triggers of asthma exacerbations. © 2010 Elsevier Inc.

Bagai K.,Vanderbilt University
Neurologist | Year: 2010

Background: Obstructive sleep apnea (OSA) is gaining recognition as a cardiovascular and cerebrovascular risk factor. Sleep apnea is now implicated in the etiopathogenesis of stroke, coronary artery disease, hypertension, and congestive heart failure. Review Summary: OSA exerts its negative cardiovascular consequences through its unique pattern of intermittent hypoxia and arousals. The putative mechanisms involved in the pathogenesis of cardiovascular disease in OSA include fibrinolytic imbalance, endothelial dysfunction, oxidative stress, and inflammation. This study discusses the known cellular and molecular processes that promote atherogenesis and vascular dysfunction in patients with OSA, and their implications for cardiovascular disease and prevention in that patient population. Conclusion: Neurologists should familiarize themselves with the symptoms and signs of OSA and the pathophysiology of the association between untreated OSA and cardiovascular disease, including stroke. OSA should be ruled out in patients with cardiovascular disease and be regarded as an important modifiable risk factor. Knowledge of this association is of prime public health importance and can result in primary and secondary prevention of cardiovascular events. This study will also help neurologists in providing patient education and treatment. Copyright © 2010 by Lippincott Williams & Wilkins.

Aschner M.,Vanderbilt University
Metal ions in life sciences | Year: 2010

Methylmercury is a global pollutant and potent neurotoxin whose abundance in the food chain mandates additional studies on the consequences and mechanisms of its toxicity to the central nervous system. Formulation of our new hypotheses was predicated on our appreciation for (a) the remarkable affinity of mercurials for the anionic form of sulfhydryl (-SH) groups, and (b) the essential role of thiols in protein biochemistry. The present chapter addresses pathways to human exposure of various mercury compounds, highlighting their neurotoxicity and potential involvement in neurotoxic injury and neurodegenerative changes, both in the developing and senescent brain. Mechanisms that trigger these effects are discussed in detail.

Lee D.,Vanderbilt University
The journal of knee surgery | Year: 2013

The diagnosis of quadriceps and patellar tendon ruptures requires a high index of suspicion and thorough history-taking to assess for medical comorbidities that may predispose patients to tendon degeneration. Radiographic assessment with plain films supplemented by ultrasound and magnetic resonance imaging when the work-up is equivocal further aids diagnosis; however, advanced imaging is often unnecessary in patients with functional extensor mechanism deficits. Acute repair is preferred, and transpatellar bone tunnels serve as the primary form of fixation when the tendon rupture occurs at the patellar insertion, with or without augmentation depending on surgeon preference. Chronic tears and disruptions following total knee arthroplasty are special cases requiring reconstructions with allograft, synthetic mesh, or autograft. Rehabilitation protocols generally allow immediate weight-bearing with the knee locked in extension and crutch support. Limited arc motion is started early with active flexion and passive extension and then advanced progressively, followed by full active range of motion and strengthening. Complications are few but include quadriceps atrophy, knee stiffness, and rerupture. Outcomes are excellent if repair is done acutely, with poorer outcomes associated with delayed repair. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Niswender K.D.,Vanderbilt University
Postgraduate Medicine | Year: 2011

Insulin is a pleiotropic hormone with numerous effects at the cellular, tissue, and organismal levels. Clinicians are familiar with physiological effects of insulin on carbohydrate metabolism, including stimulation of glucose uptake in skeletal muscle and the suppression of glucose production from the liver. Other metabolic effects of insulin include inhibiting the release of free fatty acids from adipose tissue and stimulating the incorporation of amino acids into proteins. Indeed, every organ in the body, including the brain, is a target for insulin action. Insulin resistance, typically defined with respect to glucose metabolism, is a condition in which normal levels of insulin do not trigger the signal for glucose disposition. The effects of insulin resistance and impaired insulin signaling have profound pathophysiologic effects, such as hyperglycemia-induced tissue damage, hypertension, dyslipidemia, metabolic syndrome, and cardiovascular and renal disease. An integrated view of insulin action in all of these tissues may yield improved therapeutic insight and possibly even illuminate new therapeutic opportunities. With the increase in the number of patients diagnosed with prediabetes and diabetes, an updated understanding of the disease and the pharmacologic armamentarium used to treat it is needed to improve outcomes. To help expand the clinical care provider's perspective, this article will provide a provocative discussion about the pathophysiology of diabetes, the role of insulin and insulin resistance, and the clinical efficacy potential of insulin. Understanding the cellular and molecular mechanisms underlying the effects of insulin and how these translate into clinical consequences beyond glycemia will assist primary care physicians in the care of their patients with diabetes and metabolic syndrome. © Postgraduate Medicine.

Genome-wide association studies (GWAS) have generated a wealth of valuable genotyping data for complex diseases/traits. A large proportion of these data are embedded with many weakly associated markers that have been missed in traditional single marker analyses, but they may provide valuable insights in dissecting the genetic components of diseases. Gene set analysis (GSA) augmented by protein-protein interaction network data provides a promising way to examine GWAS data by analyzing the combined effects of multiple genes/markers, each of which may have only individually weak to moderate association effects. A critical issue in GSA of GWAS data is the definition of gene-wise P values based on multiple SNPs mapped to a gene. In this study, we proposed an alternative restricted search approach based on our previously developed dense module search algorithm, and we demonstrated it in the CATIE GWAS dataset for schizophrenia. Specifically, we explored three ways of computing gene-wise P values and examined their effects on the resultant module genes. These methods calculate gene-wise P values based on all the SNPs, the top ranked SNPs, or the most significant SNP among all the SNPs mapped to a gene. We applied the restricted search approach and identified a module gene set for each of the gene-wise P value data set. In our evaluation using an independent method, ALIGATOR, we showed that although each of these input datasets generated a unique set of module genes, all of them were significant in the GWAS dataset. Further functional enrichment analysis of these module genes showed that at the pathway level, they were all consistently related to neuro- and immune-related pathways. Finally, we compared our method with a previously reported method. Our results showed that the approaches to computing gene-wise P values in GWAS data are critical in GSA. This work is useful for evaluating key factors in GSA of GWAS data.

Bretz C.A.,Vanderbilt University
Investigative ophthalmology & visual science | Year: 2013

The purpose of the present study was to investigate the role of nuclear factor of activated T cells (NFAT), a transcription factor downstream of VEGF, in angiogenic cell behaviors of human retinal microvascular endothelial cells (HRMEC), and to assess the efficacy of NFAT signaling inhibitors in a rat model of oxygen-induced retinopathy (OIR). Human retinal microvascular endothelial cells were treated with VEGF in the presence or absence of the NFAT inhibitor of NFAT-calcineurin association-6 (INCA-6), and NFAT translocation was evaluated using immunocytochemistry (ICC). Human retinal microvascular endothelial cells were treated with increasing doses of INCA-6, and cell proliferation and tube formation were assessed. Rats subjected to OIR were administered increasing doses of INCA-6 or the CN inhibitor FK-506, and the retinal neovascular area was measured. Nuclear factor of activated T-cells c1 was translocated to the nucleus of HRMEC treated with VEGF, and INCA-6 treatment blocked translocation. Inhibitor of NFAT-calcineurin association-6inhibited HRMEC proliferation and tube formation in a dose-dependent manner. Both INCA-6 and FK-506 treatment significantly reduced pathologic neovascularization in OIR. This investigation has demonstrated that in HRMEC, NFATc1 is activated downstream of VEGF signaling and NFAT signaling plays a key role in angiogenic cell behaviors. In addition, NFAT inhibition is shown to be highly efficacious in an OIR model. These findings indicate that the NFAT signaling pathway may serve as a suitable therapeutic target for the treatment of neovascular eye disease.

Objective: In lower-income countries rates of AIDS-defining events (ADEs) and death are high during the first year of combination antiretroviral therapy (ART). We investigated differences between foreign-born (migrant) and native-born (nonmigrant) patients initiating ART in Europe, the US and Canada, and examined rates of the most common ADEs and mortality during the first year of ART. Design: Observational cohort study. Methods: We studied HIV-positive adults participating in one of 12 cohorts in the Antiretroviral Therapy Cohort Collaboration (ART-CC). Results: Of 48 854 patients, 25.6% were migrants: 16.1% from sub-Saharan Africa, 5.6% Latin America, 2.3% North Africa/Middle East, and 1.6% Asia. Incidence of ADEs during the first year of ART was 60.8 per 1000 person-years: 69.9 for migrants and 57.7 for nonmigrants [crude hazard ratio (HR) 1.18; 95% confidence interval (CI) 1.08-1.29], adjusted HR (for sex, age, CD4, HIV-1 RNA, ART regimen, prior ADE, probable route of infection and year of initiation, and stratified by cohort) 1.21 (95% CI 1.09-1.34). Rates of tuberculosis were substantially higher in migrants than nonmigrants (14.3 vs. 6.3; adjusted HR 1.94; 95% CI 1.53-2.46). In contrast, mortality was higher among nonmigrants than migrants (crude HR0.71; 95% CI 0.61-0.84), although excess mortality was partially explained by patient characteristics at start of ART (adjusted HR 0.91; 95% CI 0.76-1.09). Conclusions: During the first year of ART, HIV-positive migrants had higher rates of ADEs than nonmigrants. Tuberculosis was the most common ADE among migrants, highlighting the importance of screening for tuberculosis prior to ART initiation in this population. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Hopkins C.R.,Vanderbilt University
ACS Chemical Neuroscience | Year: 2013

Two recent Phase II results show opposing outcomes for the potential of activators of mGlu2 in the treatment of schizophrenia. The first outcome revealed that Eli Lilly's mGlu2/3 agonist, pomaglumetad methionil (LY2140023), failed to meet the primary efficacy end point. The second report showed the mGlu2 positive allosteric modulator (PAM) from Addex (ADX71149) in conjunction with Janssen Research & Development met the primary objectives of safety, tolerability and demonstrated an effect on negative symptoms in patients. © 2013 American Chemical Society.

A variety of species and experimental designs have been used to study genetic influences on alcohol dependence, ethanol response, and related traits. Integration of these heterogeneous data can be used to produce a ranked target gene list for additional investigation. In this study, we performed a unique multi-species evidence-based data integration using three microarray experiments in mice or humans that generated an initial alcohol dependence (AD) related genes list, human linkage and association results, and gene sets implicated in C. elegans and Drosophila. We then used permutation and false discovery rate (FDR) analyses on the genome-wide association studies (GWAS) dataset from the Collaborative Study on the Genetics of Alcoholism (COGA) to evaluate the ranking results and weighting matrices. We found one weighting score matrix could increase FDR based q-values for a list of 47 genes with a score greater than 2. Our follow up functional enrichment tests revealed these genes were primarily involved in brain responses to ethanol and neural adaptations occurring with alcoholism. These results, along with our experimental validation of specific genes in mice, C. elegans and Drosophila, suggest that a cross-species evidence-based approach is useful to identify candidate genes contributing to alcoholism.

DNA methylation, which mainly occurs at CpG dinucleotides, is a dynamic epigenetic regulation mechanism in most eukaryotic genomes. It is already known that methylated CpG dinucleotides can lead to a high rate of C to T mutation at these sites. However, less is known about whether and how the methylation level causes a different mutation rate, especially at the single-base resolution. In this study, we used genome-wide single-base resolution methylation data to perform a comprehensive analysis of the mutation rate of methylated cytosines from human embryonic stem cell. Through the analysis of the density of single nucleotide polymorphisms, we first confirmed that the mutation rate in methylated CpG sites is greater than that in unmethylated CpG sites. Then, we showed that among methylated CpG sites, the mutation rate is markedly increased in low-intermediately (20-40% methylation level) to intermediately methylated CpG sites (40-60% methylation level) of the human genome. This mutation pattern was observed regardless of DNA strand direction and the sequence coverage over the site on which the methylation level was calculated. Moreover, this highly non-random mutation pattern was found more apparent in intergenic and intronic regions than in promoter regions and CpG islands. Our investigation suggested this pattern appears primarily in autosomes rather than sex chromosomes. Further analysis based on human-chimpanzee divergence confirmed these observations. Finally, we observed a significant correlation between the methylation level and cytosine allele frequency. Our results showed a high mutation rate in low-intermediately to intermediately methylated CpG sites at different scales, from the categorized genomic region, whole chromosome, to the whole genome level, thereby providing the first supporting evidence of mutation rate variation at human methylated CpG sites using the genome-wide sing-base resolution methylation data.

McCaffrey L.M.,McGill University | Montalbano J.,University of Virginia | Mihai C.,McGill University | Macara I.G.,Vanderbilt University
Cancer Cell | Year: 2012

Loss of epithelial organization is a hallmark of carcinomas, but whether polarity regulates tumor growth and metastasis is poorly understood. To address this issue, we depleted the Par3 polarity gene by RNAi in combination with oncogenic Notch or Ras61L expression in the murine mammary gland. Par3 silencing dramatically reduced tumor latency in both models and produced invasive and metastatic tumors that retained epithelial marker expression. Par3 depletion was associated with induction of MMP9, destruction of the extracellular matrix, and invasion, all mediated by atypical PKC-dependant JAK/Stat3 activation. Importantly, Par3 expression is significantly reduced in human breast cancers, which correlates with active aPKC and Stat3. These data identify Par3 as a regulator of signaling pathways relevant to invasive breast cancer. © 2012 Elsevier Inc.

Shay G.,H. Lee Moffitt Cancer Center and Research Institute | Lynch C.C.,H. Lee Moffitt Cancer Center and Research Institute | Fingleton B.,Vanderbilt University
Matrix Biology | Year: 2015

Matrix metalloproteinases have long been associated with cancer. Clinical trials of small molecule inhibitors for this family of enzymes however, were spectacularly unsuccessful in a variety of tumor types. Here, we discuss some of the newer roles that have been uncovered for MMPs in cancer that would not have been targeted with those initial inhibitors or in the patient populations analyzed. We also consider novel ways of using cancer-associated MMP activity for clinical benefit. © 2015 International Society of Matrix Biology.

Asselbergs F.W.,University of Groningen | Williams S.M.,Vanderbilt University
Bioinformatics | Year: 2010

Motivation: The sequencing of the human genome has made it possible to identify an informative set of >1 million single nucleotide polymorphisms (SNPs) across the genome that can be used to carry out genome-wide association studies (GWASs). The availability of massive amounts of GWAS data has necessitated the development of new biostatistical methods for quality control, imputation and analysis issues including multiple testing. This work has been successful and has enabled the discovery of new associations that have been replicated in multiple studies. However, it is now recognized that most SNPs discovered via GWAS have small effects on disease susceptibility and thus may not be suitable for improving health care through genetic testing. One likely explanation for the mixed results of GWAS is that the current biostatistical analysis paradigm is by design agnostic or unbiased in that it ignores all prior knowledge about disease pathobiology. Further, the linear modeling framework that is employed in GWAS often considers only one SNP at a time thus ignoring their genomic and environmental context. There is now a shift away from the biostatistical approach toward a more holistic approach that recognizes the complexity of the genotype-phenotype relationship that is characterized by significant heterogeneity and gene-gene and gene-environment interaction. We argue here that bioinformatics has an important role to play in addressing the complexity of the underlying genetic basis of common human diseases. The goal of this review is to identify and discuss those GWAS challenges that will require computational methods. Contact: jason.h.moore@dartmouth.edu © The Author(s) 2010. Published by Oxford University Press.

Seger D.,Vanderbilt University
Clinical Toxicology | Year: 2010

Introduction. This article reviews the role and clinical importance of specific neuroadaptations that may occur following use of cocaine, metamfetamine, and 3,4,methylenedioxymetamfetamine (MDMA). Methods. A literature search was performed using OVID MEDLINE and PubMed for all years to the present date, which identified 250 papers of which 154 were considered relevant. Mechanisms of action of cocaine and metamfetamine. Cocaine and metamfetamine increase central nervous system synaptic dopamine primarily by increasing the release of dopamine into the synapse and binding to the dopamine reuptake transporter, which prevents the reuptake of dopamine from the synapse back into the nerve cell. Synaptic dopamine then stimulates post synaptic receptors. The continued release of dopamine and prevention of reuptake results in a supraphysiological concentration of dopamine, which causes euphoria or a "high." The greater the concentration of dopamine, the greater the high. Continued supraphysiological concentrations of dopamine and postsynaptic receptor stimulation may cause physiological and anatomical changes (neuroadaptations) in the central nervous system (CNS) synapse that attempt to maintain homeostasis. An example of a dopaminergic neuroadaptation is the decrease in number of post synaptic D2 receptors that occurs when synaptic dopamine concentrations remain supraphysiological. This neuroadaptation attempts to maintain homeostasis, that is, the decreased number of D2 receptors provides fewer receptors to be constantly stimulated by increased synaptic dopamine. Although metamfetamine also increases synaptic dopamine similarly to cocaine, metamfetamine also increases cytoplasmic dopamine, which causes CNS oxidative stress and neurotoxicity. The clinical impact of the oxidative stress is unknown. Mechanisms of action of MDMA. MDMA increases concentrations of synaptic serotonin by increasing the release of serotonin and binding to the serotonin reuptake transporter, preventing the reuptake of serotonin from the synapse back into the nerve cell. An example of a serotonergic neuroadaptation is a decrease in the number of serotonin presynaptic autoreceptors (one of the regulators of synaptic serotonin concentration) to maintain homeostasis. MDMA also causes a decrease in serotonergic biochemical markers and neuronal axotomy in rats and nonhuman primates. Abstinence may allow reinnervation, but the axonal regrowth pattern is abnormal. Whether axotomy and reinnervation also occur in humans is unknown. Pharmacogenomics may play a role in the varied response of the individual to MDMA. Conclusions. Neuroadaptations may be transient or permanent. The duration of drug use or drug concentration needed to cause neuroadaptations is unknown, but some neuroadaptations begin shortly after initiation of drug use and are dependent on variables such as genetics and age at the initiation of use. Understanding the concept of neuroadaptation and some specific neuroadaptations that occur will allow clinicians to better understand the interindividual variability in response to drugs of abuse. © 2010 Informa UK, Ltd.

Background: Studies involving samples of children with life-threatening illnesses and their families face significant challenges, including inadequate sample sizes and limited diversity. Social media recruitment and Web-based research methods may help address such challenges yet have not been explored in pediatric cancer populations. Objective: This study examined the feasibility of using Facebook advertisements to recruit parent caregivers of children and teenagers with cancer. We also explored the feasibility of Web-based video recording in pediatric palliative care populations by surveying parents of children with cancer regarding (a) their preferences for research methods and (b) technological capabilities of their computers and phones. Methods: Facebook's paid advertising program was used to recruit parent caregivers of children currently living with cancer to complete an electronic survey about research preferences and technological capabilities. Results: The advertising campaign generated 3 897 981 impressions, which resulted in 1050 clicks at a total cost of $1129.88. Of 284 screened individuals, 106 were eligible. Forty-five caregivers of children with cancer completed the entire electronic survey. Parents preferred and had technological capabilities for Web-based and electronic research methods. Participant survey responses are reported. Conclusion: Facebook was a useful, cost-effective method to recruit a diverse sample of parent caregivers of children with cancer. Web-based video recording and data collection may be feasible and desirable in samples of children with cancer and their families. Implications for Practice: Web-based methods (eg, Facebook, Skype) may enhance communication and access between nurses and pediatric oncology patients and their families. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Noto J.M.,Vanderbilt University
Methods in molecular biology (Clifton, N.J.) | Year: 2012

Infection with Helicobacter pylori is directly responsible for substantial morbidity and mortality worldwide. This ubiquitous organism causes disease through the interaction of multiple factors including bacterial factors, host immune responses, and environmental factors. The following chapters address the bacterial specific contributions to disease.

Grace A.A.,University of Cambridge | Roden D.M.,Vanderbilt University
The Lancet | Year: 2012

During the past few years, the development of effective, empirical technologies for treatment of cardiac arrhythmias has exceeded the pace at which detailed knowledge of the underlying biology has accumulated. As a result, although some clinical arrhythmias can be cured with techniques such as catheter ablation, drug treatment and prediction of the risk of sudden death remain fairly primitive. The identification of key candidate genes for monogenic arrhythmia syndromes shows that to bring basic biology to the clinic is a powerful approach. Increasingly sophisticated experimental models and methods of measurement, including stem cell-based models of human cardiac arrhythmias, are being deployed to study how perturbations in several biologic pathways can result in an arrhythmia-prone heart. The biology of arrhythmia is largely quantifiable, which allows for systematic analysis that could transform treatment strategies that are often still empirical into management based on molecular evidence.

Wills T.A.,Vanderbilt University
Cold Spring Harbor perspectives in medicine | Year: 2013

The extended amygdala is a series of interconnected, embryologically similar series of nuclei in the brain that are thought to play key roles in aspects of alcohol dependence, specifically in stress-induced increases in alcohol-seeking behaviors. Plasticity of excitatory transmission in these and other brain regions is currently an intense area of scrutiny as a mechanism underlying aspects of addiction. N-methyl-D-aspartate (NMDA) receptors (NMDARs) play a critical role in plasticity at excitatory synapses and have been identified as major molecular targets of ethanol. Thus, this article will explore alcohol and NMDAR interactions first at a general level and then focusing within the extended amygdala, in particular on the bed nucleus of the stria terminalis (BNST).

Bruehl S.,Vanderbilt University
Anesthesiology | Year: 2010

Complex regional pain syndrome (CRPS) is a neuropathic pain disorder with significant autonomic features. Few treatments have proven effective, in part, because of a historically poor understanding of the mechanisms underlying the disorder. CRPS research largely conducted during the past decade has substantially increased knowledge regarding its pathophysiologic mechanisms, indicating that they are multifactorial. Both peripheral and central nervous system mechanisms are involved. These include peripheral and central sensitization, inflammation, altered sympathetic and catecholaminergic function, altered somatosensory representation in the brain, genetic factors, and psychophysiologic interactions. Relative contributions of the mechanisms underlying CRPS may differ across patients and even within a patient over time, particularly in the transition from "warm CRPS" (acute) to "cold CRPS" (chronic). Enhanced knowledge regarding the pathophysiology of CRPS increases the possibility of eventually achieving the goal of mechanismbased CRPS diagnosis and treatment. Copyright © 2010, the American Society of Anesthesiologists, Inc.

Van der Sloot H.A.,Hans van der Sloot Consultancy | Kosson D.S.,Vanderbilt University
Journal of Hazardous Materials | Year: 2012

The evaluation of the hazardous nature of a waste is frequently based on total composition in many jurisdictions, while for most cases the chemical form of the constituents and the release pathways that may result in exposure of man and organisms under conditions of handling, transport, disposal or beneficial use are the most important factors controlling potential environmental impact. Thus, leaching assessment related to possible management scenarios rather than total content can provide a much more robust basis for evaluating health risks and environmental risks for waterborne pathways. Standardized characterisation leaching tests based on intrinsic characteristics of a material provide a new foundation for needed decisions. Chemical speciation modelling using characterisation testing results provides a means to identify mechanisms controlling constituent release, including mineral or sorptive phases, and thus insights into the long-term release behaviour of the material and approaches to reducing potential impacts. © 2011 Elsevier B.V..

Cates J.M.M.,Vanderbilt University
European Journal of Surgical Oncology | Year: 2016

Aim Recently published meta-analyses have concluded that pathologic fracture is a negative prognostic factor in osteosarcoma. But several confounding variables were not accounted for in the index studies, thereby compromising internal validity. Methods A multivariable survival analysis of a retrospective cohort of 131 patients with conventional, high-grade osteosarcoma of the extremity long bones treated with neoadjuvant chemotherapy and surgical resection was performed. Results There were no significant differences in clinicopathologic variables between the 21 patients who suffered pathologic fracture and the 110 patients who did not in standard bivariable statistical tests. Hazard ratios for decreased overall and disease-free survival of patients with pathologic fracture failed to reach statistical significance in univariable Cox proportional hazard regression. Furthermore, pathologic fracture did not significantly affect patient outcome (hazard ratio for overall survival, 1.15 [95% CI 0.56–2.38], P = 0.71 or disease-free survival, 1.01 [95% CI 0.53–1.91], P = 0.98) after controlling for confounding factors not accounted for in prior meta-analyses, such as tumor size, chemotherapy response, and proximal tumor location. Conclusions Pathologic fracture is not a significant prognostic factor for extremity osteosarcoma after controlling for other established prognostic factors. Although a useful statistical method, meta-analysis can generate false conclusions if important confounding factors are ignored. Analysis of individual patient data, which would require collaboration among different groups, would circumvent this limitation of meta-analysis. © 2016 Elsevier Ltd

Graves C.R.,Vanderbilt University
Clinical Obstetrics and Gynecology | Year: 2010

Recent attention to H1N1 influenza has increased awareness in the lay community of the seriousness of respiratory complications in the gravid patient. Historically, pneumonia during pregnancy has been associated with increased maternal morbidity and mortality. Similarly, the increased number of pregnant patients with chronic medical illnesses, including diabetes, HIV, cardiac disease, and obesity may further complicate the clinical outcome in this population. Although data suggest that infants born to mother whose pregnancies have been complicated by pneumonia are more likely to be born preterm and to have a lower birth weight, care must be taken to balance treatment to serve both the mother and the fetus. © 2010, Lippincott Williams & Wilkins.

Saritas Yuksel E.,Vanderbilt University
Swiss medical weekly | Year: 2012

GER is a common condition affecting many patients in different parts of the world. It usually presents with the classic manifestations of heartburn and regurgitation; however, in some it can also present with extraesophageal manifestations such as chronic cough, laryngitis, asthma or chest pain. Commonly employed diagnostic tests such as EGD and ambulatory pH or impedance monitoring in GER, are less useful in extraesophageal syndromes due to their poor sensitivity and specificity. In contrast, empiric trials of PPI's are shown to be cost effective; however, patients may require long-term treatment to establish effectiveness. Diagnostic testing with pH and impedance monitoring are commonly reserved for patients with partial or poor response to the initial treatment with PPI's. Poor response to PPI therapy may be an important indicator for non-GER causes for patients' symptoms and should initiate a search for other potential causes.

Myers M.V.,Vanderbilt University
Molecular & cellular proteomics : MCP | Year: 2012

Analysis of cellular signaling networks typically involves targeted measurements of phosphorylated protein intermediates. However, phosphoproteomic analyses usually require affinity enrichment of phosphopeptides and can be complicated by artifactual changes in phosphorylation caused by uncontrolled preanalytical variables, particularly in the analysis of tissue specimens. We asked whether changes in protein expression, which are more stable and easily analyzed, could reflect network stimulation and inhibition. We employed this approach to analyze stimulation and inhibition of the epidermal growth factor receptor (EGFR) by EGF and selective EGFR inhibitors. Shotgun analysis of proteomes from proliferating A431 cells, EGF-stimulated cells, and cells co-treated with the EGFR inhibitors cetuximab or gefitinib identified groups of differentially expressed proteins. Comparisons of these protein groups identified 13 proteins whose EGF-induced expression changes were reversed by both EGFR inhibitors. Targeted multiple reaction monitoring analysis verified differential expression of 12 of these proteins, which comprise a candidate EGFR inhibition signature. We then tested these 12 proteins by multiple reaction monitoring analysis in three other models: 1) a comparison of DiFi (EGFR inhibitor-sensitive) and HCT116 (EGFR-insensitive) cell lines, 2) in formalin-fixed, paraffin-embedded mouse xenograft DiFi and HCT116 tumors, and 3) in tissue biopsies from a patient with the gastric hyperproliferative disorder Ménétrier's disease who was treated with cetuximab. Of the proteins in the candidate signature, a core group, including c-Jun, Jagged-1, and Claudin 4, were decreased by EGFR inhibitors in all three models. Although the goal of these studies was not to validate a clinically useful EGFR inhibition signature, the results confirm the hypothesis that clinically used EGFR inhibitors generate characteristic protein expression changes. This work further outlines a prototypical approach to derive and test protein expression signatures for drug action on signaling networks.

Schulman G.,Vanderbilt University
Journal of Renal Nutrition | Year: 2012

Fibrosis plays a major role in the pathogenesis of progressive chronic kidney disease (CKD). The inhibition of the renin-angiotensin system, which promotes fibrosis, has become the standard of care in the treatment of patients with CKD. The use of alternative agents capable of blocking the actions of profibrotic cytokines such as transforming growth factor-beta (TGF-β) is also an important strategy that is in its early stages of development. An example of such a drug is AST-120, a charcoal compound that ultimately inhibits the synthesis of TGF-β in the kidney. The inhibition is mediated by blocking the intestinal absorption of tryptophan-derived indole by AST-120. This reduces the hepatic conversion of indole to indoxyl sulfate (IS). IS stimulates the production of TGF-β in the renal parenchyma, and lowering the level of IS with AST-120 appears to slow progression of CKD. The status of recent trials examining the safety and efficacy of AST-120 has been described, including a multicenter, randomized, placebo-controlled, phase III trial of approximately 2,000 subjects being conducted to gain approval of this drug by the U.S. Food and Drug Administration. © 2012 National Kidney Foundation, Inc.

Cascio C.J.,Vanderbilt University
Journal of Neurodevelopmental Disorders | Year: 2010

The purpose of this article is to review the role of somatosensory perception in typical development, its aberration in a range of neurodevelopmental disorders, and the potential relations between tactile processing abnormalities and central features of each disorder such as motor, communication, and social development. Neurodevelopmental disorders that represent a range of symptoms and etiologies, and for which multiple peer-reviewed articles on somatosensory differences have been published, were chosen to include in the review. Relevant studies in animal models, as well as conditions of early sensory deprivation, are also included. Somatosensory processing plays an important, yet often overlooked, role in typical development and is aberrant in various neurodevelopmental disorders. This is demonstrated in studies of behavior, sensory thresholds, neuroanatomy, and neurophysiology in samples of children with Fragile X syndrome, autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and cerebral palsy (CP). Impaired somatosensory processing is found in a range of neurodevelopmental disorders and is associated with deficits in communication, motor ability, and social skills in these disorders. Given the central role of touch in early development, both experimental and clinical approaches should take into consideration the role of somatosensory processing in the etiology and treatment of neurodevelopmental disorders. © 2010 Springer Science+Business Media, LLC.

Chen S.,University of Dundee | Wasserman D.H.,Vanderbilt University | MacKintosh C.,University of Dundee | Sakamoto K.,University of Dundee
Cell Metabolism | Year: 2011

AS160 has emerged as a key player in insulin-mediated glucose transport through controlling GLUT4 trafficking, which is thought to be regulated by insulin-stimulated phosphorylation of sites including the 14-3-3 binding phospho-Thr649 (equivalent to Thr642 in human AS160). To define physiological roles of AS160-Thr649 phosphorylation and 14-3-3 binding in glucose homeostasis, we substituted this residue by a nonphosphorylatable alanine by knockin mutation in mice. The mutant protein was expressed at normal levels, while insulin-stimulated AS160 binding to 14-3-3s was abolished in homozygous knockin mice. These animals displayed impaired glucose disposal and insulin sensitivity, which were associated with decreased glucose uptake in vivo. Insulin-stimulated glucose transport and cell surface GLUT4 content were reduced in isolated muscles, but not in adipocytes. These results provide genetic evidence that insulin-induced AS160-Thr649 phosphorylation and/or its binding to 14-3-3 play an important role in regulating whole-body glucose homeostasis, at least in part through regulating GLUT4 trafficking in muscle. © 2011 Elsevier Inc.

Zic J.A.,Vanderbilt University
Current opinion in oncology | Year: 2012

Cutaneous T-cell lymphoma is the overall name for a group of malignancies in which malignant T-lymphocytes localize at the skin. Of the current 20 recognized subtypes of the disease, the most common are mycosis fungoides and Sézary syndrome. Extracorporeal photopheresis (ECP), an immunomodulating procedure that treats pheresed blood with a photoactive agent, received US Food and Drug Administration approval in 1988 as a medical device for the treatment of CTCL patients, one of many treatment options for such patients. This was followed in 2003 by guidelines in the United Kingdom that recommended ECP for patients with advanced CTCL, particularly after skin-directed treatment options have failed. ECP is now under investigation for use in patients with earlier stages of CTCL. This article reviews the evolution of the ECP technique--for example, the most recent generation of the device requires a lower extracorporeal volume of blood than the previous version did, thus making it possible for more patients to be candidates for the procedure. In addition, there has been progress in understanding how ECP works at the cellular level.

Shinn M.,Vanderbilt University
American Journal of Community Psychology | Year: 2015

What makes for a good life? The capabilities approach to this question has much to offer community psychology, particularly with respect to marginalized groups. Capabilities are freedoms to engage in valued social activities and roles—what people can do and be given both their capacities, and environmental opportunities and constraints. Economist Amartya Sen’s focus on freedoms and agency resonates with psychological calls for empowerment, and philosopher Martha Nussbaum’s specification of requirements for a life that is fully human provides an important guide for social programs. Community psychology’s focus on mediating structures has much to offer the capabilities approach. Parallels between capabilities, as enumerated by Nussbaum, and settings that foster positive youth development, as described in a National Research Council Report (Eccles and Gootman (Eds) in Community programs to promote youth development. National Academy Press, Washington, 2002) suggest extensions of the approach to children. Community psychologists can contribute to theory about ways to create and modify settings to enhance capabilities as well as empowerment and positive youth development. Finally, capabilities are difficult to measure, because they involve freedoms to choose but only choices actually made or enacted can be observed. The variation in activities or goals across members of a setting provides a measure of the capabilities that the setting fosters. © 2015, Society for Community Research and Action.

Debaun M.R.,Vanderbilt University
Expert Review of Hematology | Year: 2014

Hydroxyurea therapy, a chemotherapeutic agent, is the only US FDA approved therapy for the prevention of vaso-occlusive pain in sickle cell disease (SCD). The National Institutes of Health has sponsored two Phase III randomized, placebo-controlled trials, initially in adults, and subsequently in children with sickle cell anemia (SCA). Despite the overwhelming evidence that hydroxyurea therapy is beneficial to children and adults with SCA, individuals with SCA and their families express reservations about its use, in part because of the concerns about fertility, particularly in men. As adolescent boys with SCD are now expected to reach their reproductive years, a new concern is emerging about the role of hydroxyurea therapy as a barrier to their progeny. This review will systemically evaluate compromised fertility in men with SCD, and the evidence that hydroxyurea therapy is associated with further decreasing fertility in men with SCD. © Informa UK, Ltd.

Osteoplastic laminoplasty is a well-described technique that may decrease the incidence of progressive kyphosis when used in the setting of intradural spinal cord tumor resection. The BoneScalpel by Aesculap (Central Valley, Pennsylvania) is an ultrasonic osteotome that precisely cuts bone while preserving the underlying soft tissues, potentially reducing the risk of dural laceration during laminoplasty. By producing osteotomies as narrow as 0.5 mm, the device may also facilitate postoperative osteointegration. A retrospective analysis was conducted of 40 patients (mean age, 38.0 years; range, 4.0-79.7 years) who underwent osteoplastic laminoplasty using the BoneScalpel for the treatment of intradural spinal pathology at the Johns Hopkins Hospital between January 2009 and December 2011. After lesion resection, titanium plates were used to reconstruct the lamina in all cases. The technical results and procedure-related complications were subsequently noted. Successful laminoplasty was carried out in all 40 patients. Intraoperatively, 1 case of incidental durotomy was noted after use of the device, which was repaired primarily without neurological or clinical sequelae. During the follow-up period (mean, 195 days; median, 144 days), there were 2 complications (1 cerebrospinal fluid leak, 1 seroma) and no cases of immediate postoperative instability. The BoneScalpel is a safe and technically feasible device for performing osteoplastic laminoplasty.

Ghiorso M.S.,OFM Research | Gualda G.A.R.,Vanderbilt University
Contributions to Mineralogy and Petrology | Year: 2013

A method is described for estimating the activity of titania (TiO2) in a magmatic liquid from the compositions of coexisting cubic oxide (spinel) and rhombohedral oxide (ilmenite). These estimates are derived from the thermodynamic models of Ghiorso and Evans (Am J Sci 308:957-1039, 2008; see also Sack and Ghiorso in Contrib Mineral Petrol 106:474-505, 1991a; Am Mineral 76:827-847, 1991b) and may be computed self consistently along with temperature and oxygen fugacity for an assumed pressure. The method is applied to a collection of 729 naturally occurring oxide pairs from rhyolites and dacites. For this suite of oxides, values of titania activity relative to rutile saturation range from 0. 3 to 0. 9. Genetically related groups of oxide pairs display activity-temperature trends with negative slopes at higher activities (0. 6-0. 9) or positive slopes at lower activities (0. 3-0. 7). Thermodynamic analysis supports the assumption of two-oxide, liquid equilibrium for the former group, but suggests that such an interpretation for oxide sequences with positive activity-temperature trends may be problematic. Application of the estimation method to oxide pairs from the Shiveluch Volcano and the Bishop Tuff reveals that the former are consistent with having equilibrated with known matrix glass compositions, whereas the latter pairs are inconsistent with equilibration with pre-eruptive liquids trapped in quartz inclusions. © 2012 Springer-Verlag.

Ye J.,Louisiana State University | McGuinness O.P.,Vanderbilt University
American Journal of Physiology - Endocrinology and Metabolism | Year: 2013

Chronic inflammation is a characteristic of obesity and is associated with accompanying insulin resistance, a hallmark of type 2 diabetes mellitus (T2DM). Although proinflammatory cytokines are known for their detrimental effects on adipose tissue function and insulin sensitivity, their beneficial effects in the regulation of metabolism have not drawn sufficient attention. In obesity, inflammation is initiated by a local hypoxia to augment angiogenesis and improve adipose tissue blood supply. A growing body of evidence suggests that macrophages and proinflammatory cytokines are essential for adipose remodeling and adipocyte differentiation. Phenotypes of multiple lines of transgenic mice consistently suggest that proinflammatory cytokines increase energy expenditure and act to prevent obesity. Removal of proinflammatory cytokines by gene knockout decreases energy expenditure and induces adult-onset obesity. In contrast, elevation of proinflammatory cytokines augments energy expenditure and decreases the risk for obesity. Anti-inflammatory therapies have been tested in more than a dozen clinical trials to improve insulin sensitivity and glucose homeostasis in patients with T2DM, and the results are not encouraging. One possible explanation is that anti-inflammatory therapies also attenuate the beneficial effects of inflammation in stimulating energy expenditure, which may have limited the efficacy of the treatment by promoting energy accumulation. Thus, the positive effects of proinflammatory events should be considered in evaluating the impact of inflammation in obesity and type 2 diabetes. © 2013 the American Physiological Society.

Although several studies have implicated disgust in contamination-based obsessive-compulsive disorder (OCD), there remains a paucity of research examining this relationship prospectively. To address this gap in the literature, undergraduate students (n=177) participated in a 12-week prospective study for which they completed measures of contamination-based OCD symptoms, disgust, and negative affect. Change in disgust levels over the 12-week period predicted change in symptoms of contamination-based OCD, even when controlling for age, gender, and change in negative affect. However, this association was driven by change in the perceived negative impact of experiencing disgust (disgust sensitivity) rather than change in the intensity that disgust is generally experienced (disgust propensity). Subsequent analyses also revealed that change in disgust sensitivity fully mediated the association between change in disgust propensity and change in symptoms of contamination-based OCD. The implications of these findings for further delineating the causal role of disgust-related vulnerabilities in contamination-based OCD are discussed. © 2010 Elsevier Ltd.

Fogo A.B.,Vanderbilt University
Nature Reviews Nephrology | Year: 2015

Focal segmental glomerulosclerosis (FSGS) describes both a common lesion in progressive kidney disease, and a disease characterized by marked proteinuria and podocyte injury. The initial injuries vary widely. Monogenetic forms of FSGS are largely due to alterations in structural genes of the podocyte, many of which result in early onset of disease. Genetic risk alleles in apolipoprotein L1 are especially prevalent in African Americans, and are linked not only to adult-onset FSGS but also to progression of some other kidney diseases. The recurrence of FSGS in some transplant recipients whose end-stage renal disease was caused by FSGS points to circulating factors in disease pathogenesis, which remain incompletely understood. In addition, infection, drug use, and secondary maladaptive responses after loss of nephrons from any cause may also cause FSGS. Varying phenotypes of the sclerosis are also manifest, with varying prognosis. The so-called tip lesion has the best prognosis, whereas the collapsing type of FSGS has the worst prognosis. New insights into glomerular cell injury response and repair may pave the way for possible therapeutic strategies. © 2015 Macmillan Publishers Limited. All rights reserved.

Roden D.M.,Vanderbilt University
Canadian Journal of Cardiology | Year: 2013

Responses to drug therapy vary from benefit to no effect to adverse effects which can be serious or occasionally fatal. Increasing evidence supports the idea that genetic variants can play a major role in this spectrum of responses. Well-studied examples in cardiovascular therapeutics include predictors of steady-state warfarin dosage, predictors of reduced efficacy among patients receiving clopidogrel for drug eluting stents, and predictors of some serious adverse drug effects. This review summarizes contemporary approaches to identifying and validating genetic predictors of variability in response to drug treatment. Approaches to incorporating this new knowledge into clinical care, and the barriers to this concept, are addressed. © 2013 Canadian Cardiovascular Society.

This article reviews the pharmacological profile and published efficacy and tolerability/safety data of iloperidone, asenapine and lurasidone, the most recent atypical antipsychotics to be approved in the USA for the treatment of schizophrenia. All three agents are similar in terms of overall efficacy and low propensity for clinically significant weight gain or adverse changes in glycemic or lipid profile. However, these agents differ from one another in terms of formulations, pharmacokinetics, and dosing and nonmetabolic adverse effect profile. For each drug, comparative and real-world effectiveness studies are lacking, as are effectiveness and safety data in elderly, young and pregnant/nursing patients. As such, the exact place of iloperidone, asenapine and lurasidone within the broader antipsychotic armamentarium is currently difficult to establish. © 2013 Expert Reviews Ltd.

1. Outstanding issues in evolutionary ecology include: (1) the prevalence of host-associated ecological specialisation among herbivorous insects, and (2) the speciation processes contributing to the tremendous species-level diversity of herbivores. 2. Neochlamisus leaf beetle species are generally monophagous, but cumulatively employ a disparate array of host plants. These patterns occur in microcosm within the putatively oligophagous Neochlamisus bebbianae, which uses specific host species within each of six plant genera representing five families. I refer to all beetle populations associated with any one of these hosts as a particular 'host form'. 3. This paper describes aspects of Neochlamisus biology and some experimental findings relevant to both host-use evolution and host specialisation in Neochlamisus, and to ecological divergence, reproductive isolation, and genetic differentiation among N. bebbianae host forms. It thereby reviews a research programme focused on ecological speciation. 4. With respect to these host forms, our findings include: (1) ubiquitous host specialisation, (2) constraints on 'multitasking' that select for host specialisation, (3) ubiquitous ecological divergence, (4) pre- and post-mating reproductive barriers, (5) genetic and environmental contributions to ecological divergence and reproductive isolation, (6) positive statistical associations between ecological divergence and reproductive isolation, (7) strongly differentiated loci despite gene flow, reflecting divergent host-related selection, and (8) possible host race formation. We additionally describe a unique example of intimate host adaptation in another species, Neochlamisus platani. 5. The intimate and discrete nature of herbivore-host associations may generate unusually strong (host-related) selection that could simultaneous explain pronounced rates of herbivore specialisation and speciation. © 2010 The Royal Entomological Society.

Odiete O.,Vanderbilt University
Circulation research | Year: 2012

Studies in genetically modified mice have demonstrated that neuregulin-1 (NRG-1), along with the erythroblastic leukemia viral oncogene homolog (ErbB) 2, 3, and 4 receptor tyrosine kinases, is necessary for multiple aspects of cardiovascular development. These observations stimulated in vitro and in vivo animal studies, implicating NRG-1/ErbB signaling in the regulation of cardiac cell biology throughout life. Cardiovascular effects of ErbB2-targeted cancer therapies provide evidence in humans that ErbB signaling plays a role in the maintenance of cardiac function. These and other studies suggest a conceptual model in which a key function of NRG-1/ErbB signaling is to mediate adaptations of the heart to physiological and pathological stimuli through activation of intracellular kinase cascades that regulate tissue plasticity. Recent work implicates NRG-1/ErbB signaling in the regulation of multiple aspects of cardiovascular biology, including angiogenesis, blood pressure, and skeletal muscle responses to exercise. The therapeutic potential of recombinant NRG-1 as a potential treatment for heart failure has been demonstrated in animal models and is now being explored in clinical studies. NRG-1 is found in human serum and plasma, and it correlates with some clinical parameters, suggesting that it may have value as an indicator of prognosis. In this review, we bring together this growing literature on NRG-1 and its significance in cardiovascular development and disease.

Niswender K.,Vanderbilt University
Diabetes, Obesity and Metabolism | Year: 2010

Obesity is a major risk factor for the development of diabetes and predisposes individuals to hypertension and dyslipidaemia. Together these pathologies increase the risk for cardiovascular disease (CVD), the major cause of morbidity and mortality in type 2 diabetes mellitus (T2DM). Worsening trends in obesity and T2DM raise a serious conundrum, namely, how to control blood glucose, blood pressure, and lipids when many antidiabetic agents cause weight gain and thereby exacerbate other cardiovascular risk factors associated with T2DM. Further, evidence suggests that some established antihypertensive agents may worsen glucose intolerance. Many patients who are obese, hypertensive, and/or hyperlipidaemic fail to achieve blood pressure, lipid and glycaemic goals, and this failure may in part be explained by physician reluctance to utilize complex combination regimens for fear of off-target effects. Thus, a clear need exists for clinicians to understand the risks and benefits of different pharmacologic, and indeed non-pharmacologic, options in order to maximize treatment outcomes. While intensive lifestyle modification remains an elusive gold standard, newer diabetes targets, including the incretin axis, may offer greater cardiovascular risk reduction than other antidiabetes therapies, although definitive clinical trial data are needed. The glucagon-like peptide-1 (GLP-1) receptor agonists exenatide and liraglutide and the dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin and vildagliptin effectively lower HbA1c; exenatide and liraglutide reduce weight and blood pressure and improve lipid profiles. Sitagliptin and vildagliptin are weight neutral but also appear to improve lipid profiles. Integration of incretin therapies into the therapeutic armamentarium is a promising approach to improving outcomes in T2DM, and perhaps even in reducing complications of T2DM, such as co-morbid hypertension and dyslipidaemia. Additional long-term studies, including CVD end-point studies, will be necessary to determine the appropriate places for incretin-based therapies in treatment algorithms. © 2010 Blackwell Publishing Ltd.

Hartmann K.E.,Vanderbilt University
American Journal of Epidemiology | Year: 2013

Many adverse pregnancy outcomes differ by race. We examined the association between self-reported race and miscarriage (pregnancy loss at <20 weeks) in a community-based pregnancy cohort. Women from the southeastern United States (North Carolina, Texas, and Tennessee) were enrolled in "Right from the Start" from 2000 to 2009. They were recruited while trying to conceive or during early pregnancy. Participants completed study ultrasound examinations, interviews, and consent forms for review of medical records. We used proportional hazard models to examine miscarriage risk among black women compared with white women, adjusted for confounders. There were 537 observed miscarriages among 4,070 women, 23% of whom self-identified as black (n = 932). The life table-adjusted cumulative risk of loss after gestational week 5 was 21.3%. With adjustment for age and alcohol use, blacks had increased risk of miscarriage compared with whites (adjusted hazard ratio = 1.57, 95% confidence interval: 1.27, 1.93). When risk of loss before gestational week 10 was dichotomized at the median gestational age, there was little difference, but black women had a greater risk thereafter compared with white women (adjusted hazard ratio = 1.93, 95% confidence interval: 1.48, 2.51). Early pregnancy ultrasound examinations did not differ by race. In summary, self-reported race is independently associated with risk of miscarriage, and the higher risk for black women is concentrated in gestational weeks 10-20. © 2013 © The Author 2013. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

DeBaun M.R.,Vanderbilt University
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2011

Overt strokes, previously one of the most common neurological complications in sickle cell disease (SCD), have become far less frequent with routine transcranial Doppler (TCD) assessment followed by regular blood transfusion therapy. Nevertheless, children and adults with SCD continue to have overt strokes, and in the foreseeable future will continue to require secondary prevention of strokes. With the exception of the most recently completed "Stroke With Transfusions Changing to Hydroxyurea" Trial (SWiTCH; NCT00122980), randomized trials providing best evidence for long-term management of overt strokes in SCD is lacking. Instead of randomized clinical trials, a series of observational and single-arm studies have predominated. This review assesses the best available evidence for acute and chronic management of overt stroke and the efficacy of regular blood transfusion therapy, hydroxyurea therapy, and hematopoietic stem cell transplantation (HSCT), including matched sibling donor and unrelated HSCT.

Hess D.J.,Vanderbilt University
Health, Risk and Society | Year: 2014

Although smart meters for electricity have received widespread acclaim as a means to achieve more resilient and sustainable electricity consumption, public opposition has emerged in several countries. In this article, I examine the reasons for public opposition in North America and the role of concern with health risks. The article provides an analysis of reasons given for opposing smart meters by 75 US and Canadian organisations listed in the 2013 EMF (electromagnetic field) Safety Network, a review of all news reports (499) in the Lexis-Nexis database relating to smart meters in seven US states and one Canadian province from 2010 to 2013 and case studies of policy responses in the same seven states and province. Thirty-one of the organisations in the EMF network focused mainly on health concerns about EMFs, and 44 organisations identified broader concerns as well as health risks. The more politically conservative groups focused on issues relating to privacy and government intrusion. Newspaper reports also identified health risks, although they also identified issues relating to cost overruns and privacy. The study of newspaper reporting in the seven US states and one Canadian province indicated that relevant agencies had responded to public concerns by developing opt-out provisions for meter installation, in some cases after protracted public campaigns. I consider possible patterns of opposition for future investigation: opposition may be higher where the roll-out of smart meters is rapid and without an opt-out provision; technological differences (for example, wired versus wireless) may contribute to levels of public opposition; and challengers to incumbent parties of either the right or left may also contribute to public opposition. In the 'Conclusion' section, I compare two policy strategies, one of which views public opposition as a lack of good communication from utilities, and the other which views it as an opportunity for innovation in systems design and improvements in governance policies. © 2014 © 2014 Taylor & Francis.

May A.K.,Vanderbilt University
Surgical Infections | Year: 2011

Background: The Surgical Infection Society Guidelines for the treatment of complicated skin and soft tissue infections (SSTIs) were published in October 2009 in Surgical Infections, and an overview of these guidelines was provided at the Thirtieth Annual Meeting of the Society. A summary of this overview is provided. Methods: Review of relevant papers related to complicated SSTIs published between 1966 and 2008 with graded recommendations and summations of general epidemiology and recommendations. Results: The frequency of SSTI has increased over the past decade, predominately because of an increase in infections caused by community-acquired methicillin-resistant Staphylococcus aureus. Drug resistance is increasing among all pathogens. A total of 61 graded recommendations were made in the complete guidelines, 28 of which are presented here, separated into those for non-necrotizing and necrotizing infections. Conclusions: Appropriate antibiotic therapy should be provided in complicated SSTIs. Early diagnosis and treatment of necrotizing infections is paramount, as time to therapy alters morbidity and mortality rates. © Copyright 2011, Mary Ann Liebert, Inc.

Li J.,Vanderbilt University
Seminars in Neurology | Year: 2012

With a prevalence of 1 in 2500 people, inherited peripheral nerve diseases, collectively called Charcot-Marie-Tooth disease (CMT), are among the most common inherited neurologic disorders. Patients with CMT typically present with chronic muscle weakness and atrophy in limbs, sensory loss in the feet and hands, and foot deformities. Clinical similarities between patients often require genetic testing to achieve a precise diagnosis. In this article, the author reviews the clinical and pathologic features of CMT, and demonstrates how electrodiagnostic and genetic tools are used to assist in the diagnosis and symptomatic management of the diseases. Several cases are presented to illustrate the diagnostic processes. Copyright © 2012 by Thieme Medical Publishers, Inc.

Lindegren M.L.,Vanderbilt University
Cochrane database of systematic reviews (Online) | Year: 2012

The integration of HIV/AIDS and maternal, neonatal, child health and nutrition services (MNCHN), including family planning (FP) is recognized as a key strategy to reduce maternal and child mortality and control the HIV/AIDS epidemic. However, limited evidence exists on the effectiveness of service integration. To evaluate the impact of integrating MNCHN-FP and HIV/AIDS services on health, behavioral, and economic outcomes and to identify research gaps. Using the Cochrane Collaboration's validated search strategies for identifying reports of HIV interventions, along with appropriate keywords and MeSH terms, we searched a range of electronic databases, including the Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, MEDLINE (via PubMed), and Web of Science / Web of Social Science. The date range was from 01 January 1990 to 15 October 2010. There were no limits to language. Included studies were published in peer-reviewed journals, and provided intervention evaluation data (pre-post or multi-arm study design).The interventions described were organizational strategies or change, process modifications or introductions of technologies aimed at integrating MNCHN-FP and HIV/AIDS service delivery. We identified 10,619 citations from the electronic database searches and 101 citations from hand searching, cross-reference searching and interpersonal communication. After initial screenings for relevance by pairs of authors working independently, a total of 121 full-text articles were obtained for closer examination. Twenty peer-reviewed articles representing 19 interventions met inclusion criteria. There were no randomized controlled trials. One study utilized a stepped wedge design, while the rest were non-randomized trials, cohort studies, time series studies, cross-sectional studies, serial cross-sectional studies, and before-after studies. It was not possible to perform meta-analysis. Risk of bias was generally high. We found high between-study heterogeneity in terms of intervention types, study objectives, settings and designs, and reported outcomes. Most studies integrated FP with HIV testing (n=7) or HIV care and treatment (n=4). Overall, HIV and MNCHN-FP service integration was found to be feasible across a variety of integration models, settings and target populations. Nearly all studies reported positive post-integration effects on key outcomes including contraceptive use, antiretroviral therapy initiation in pregnancy, HIV testing, and quality of services. This systematic review's findings show that integrated HIV/AIDS and MNCHN-FP services are feasible to implement and show promise towards improving a variety of health and behavioral outcomes. However, significant evidence gaps remain. Rigorous research comparing outcomes of integrated with non-integrated services, including cost, cost-effectiveness, and health outcomes such as HIV and STI incidence, morbidity and mortality are greatly needed to inform programs and policy.

Wente S.R.,Vanderbilt University
Cold Spring Harbor perspectives in biology | Year: 2010

Internal membrane bound structures sequester all genetic material in eukaryotic cells. The most prominent of these structures is the nucleus, which is bounded by a double membrane termed the nuclear envelope (NE). Though this NE separates the nucleoplasm and genetic material within the nucleus from the surrounding cytoplasm, it is studded throughout with portals called nuclear pore complexes (NPCs). The NPC is a highly selective, bidirectional transporter for a tremendous range of protein and ribonucleoprotein cargoes. All the while the NPC must prevent the passage of nonspecific macromolecules, yet allow the free diffusion of water, sugars, and ions. These many types of nuclear transport are regulated at multiple stages, and the NPC carries binding sites for many of the proteins that modulate and modify the cargoes as they pass across the NE. Assembly, maintenance, and repair of the NPC must somehow occur while maintaining the integrity of the NE. Finally, the NPC appears to be an anchor for localization of many nuclear processes, including gene activation and cell cycle regulation. All these requirements demonstrate the complex design of the NPC and the integral role it plays in key cellular processes.

Blakely R.D.,Vanderbilt University
Cold Spring Harbor perspectives in biology | Year: 2012

The regulated exocytosis that mediates chemical signaling at synapses requires mechanisms to coordinate the immediate response to stimulation with the recycling needed to sustain release. Two general classes of transporter contribute to release, one located on synaptic vesicles that loads them with transmitter, and a second at the plasma membrane that both terminates signaling and serves to recycle transmitter for subsequent rounds of release. Originally identified as the target of psychoactive drugs, these transport systems have important roles in transmitter release, but we are only beginning to understand their contribution to synaptic transmission, plasticity, behavior, and disease. Recent work has started to provide a structural basis for their activity, to characterize their trafficking and potential for regulation. The results indicate that far from the passive target of psychoactive drugs, neurotransmitter transporters undergo regulation that contributes to synaptic plasticity.

Hopkins C.R.,Vanderbilt University
ACS Chemical Neuroscience | Year: 2012

A "second generation" γ-secretase, Begacestat (GSI-953), which is more selective against Notch-signaling, has shown promise in recent Phase I clinical trials. Begacestat, a novel, 2,5-disubsitituted thiophene sulfonamide from Wyeth (now Pfizer) is under evaluation for the treatment of Alzheimer's disease. © 2012 American Chemical Society.

Hopkins C.R.,Vanderbilt University
ACS Chemical Neuroscience | Year: 2012

BMS-708163 is a novel, sulfonamide containing γ-secretase inhibitor from Bristol-Myers Squibb Co. currently in Phase II clinical trials for the treatment of Alzheimer's disease (AD). © 2012 American Chemical Society.

Hess D.J.,Vanderbilt University
Research Policy | Year: 2014

In the case of technology transitions to low-carbon sources of energy, there is growing evidence that even in countries with a strong political consensus in favor of a transition, the pace has been slow in comparison with the need to reduce greenhouse gases. One factor that affects the slowness of the transition is political resistance from the incumbent industrial regime. Using data on the mobilization of resistance from the fossil-fuel industry in the United States, the study builds on the growing literature on the political dimensions of sustainability transitions by drawing attention to the role of incumbent regime coalitions, grassroots coalitions in support of green transition policies, and countervailing industrial power. Case studies of political coalitions for ballot propositions in the U.S. are used to show how countervailing industrial power, especially from the technology and financial sector, can tip the balance of electoral spending in favor of grassroots organizations. © 2013 Elsevier B.V. All rights reserved.

Catania K.C.,Vanderbilt University
Current Opinion in Neurobiology | Year: 2012

A number of predators depend heavily on tactile cues for pursuing and capturing prey. Here I describe and discuss the whiskers of carnivorous grasshopper mice and shrews, the sensory rays of the star-nosed mole, and the tactile appendages of the tentacled snake. These diverse sensors are accompanied by remarkable corresponding specializations in the central nervous system. But understanding their function and the significance of the central nervous system correlates requires the careful documentation of behavior inherent to a neuroethological approach. © 2011.

Previous studies from our and other groups have demonstrated that the majority of γ-aminobutyric acid (GABA)(A) receptor subunit mutations produce mutant subunits with impaired biogenesis and trafficking. These GABA(A) receptor mutations include missense, nonsense, deletion, or insertion mutations that result in a frameshift with premature translation-termination codons (PTCs) and splice-site mutations. Frameshift or splice-site mutations produce mutant proteins with PTCs, thus generating nonfunctional truncated proteins. All of these mutant GABA(A) receptor subunits are subject to cellular quality control at the messenger RNA (mRNA) or protein level. These quality-control checkpoints shape the cell's response to the presence of the mutant subunits and attempt to reduce the impact of the mutant subunit on GABA(A) receptor expression and function. The check points prevent nonfunctioning or malfunctioning GABA(A) receptor subunits from trafficking to the cell surface or to synapses, and help to ensure that the receptor channels trafficked to the membrane and synapses are indeed functional. However, if and how these quality control or check points impact the posttranslational modifications of functional GABA(A) receptor channels such as receptor phosphorylation and ubiquitination and their involvement in mediating GABAergic inhibitory synaptic strength needs to be investigated in the near future. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Foster D.J.,Vanderbilt University
Discovery medicine | Year: 2012

Currently available therapeutic agents for treatment of schizophrenia target signaling by monoaminergic neurotransmitters; however, these treatments do not adequately treat the range of symptoms observed in patients. While these therapies treat the positive symptoms, they do not have efficacy in treating the negative symptoms and cognitive deficits that are associated with the disease. Evidence suggests that molecules that modulate signaling by the neurotransmitter acetylcholine (ACh) could provide a more comprehensive treatment of schizophrenia than currently prescribed antipsychotics. Molecules that broadly increase ACh-signaling have been demonstrated to have efficacy in treating numerous symptom clusters in schizophrenia patients. Unfortunately, these compounds induce adverse effects via activation of peripheral receptors that limit their clinical utility. One proposed strategy for retaining the efficacy of cholinergic treatments, without the adverse effects, is to target specific cholinergic receptor subtypes in the brain. Several cholinergic receptors are able to modulate brain circuits that are dysregulated in schizophrenia patients including receptors belonging to both the muscarinic family (i.e., M1, M4, and M5), and the nicotinic family (i.e., α7, α4β2). Recently, great strides have been made in developing small molecules with high specificity for these receptors, and several of these novel molecules have robust efficacy in several preclinical models predictive of both anti-psychotic and pro-cognitive effectiveness. Promising studies suggest that targeting M1 and α7 may be beneficial for pro-cognitive effects, while molecules that target M4 may be ideally suited to address the positive symptoms. Since these receptor subtypes are distinct from those responsible for the adverse effects observed with non-selective cholinergic treatments, there is hope that molecules targeting these receptors could provide novel therapeutics. Further research is needed to examine the utility of such compounds as therapeutics that could be used either alone, or in combination with existing medications, to better treat schizophrenia.

Hopkins C.R.,Vanderbilt University
ACS Chemical Neuroscience | Year: 2012

Suvorexant is a dual orexin antagonist currently in Phase III clinical trials for the modulation of sleep and is being developed by Merck. Recent Phase III results showed that patients taking the drug fell asleep faster and slept longer than those on placebo. © 2012 American Chemical Society.

Shi C.,Vanderbilt University | Hruban R.H.,Johns Hopkins University
Human Pathology | Year: 2012

Intraductal papillary mucinous neoplasm (IPMN) is a grossly visible (≥1 cm), mucin-producing neoplasm that arises in the main pancreatic duct and/or its branches. Patients with intraductal papillary mucinous neoplasm can present with symptoms caused by obstruction of the pancreatic duct system, or they can be asymptomatic. There are 3 clinical subtypes of intraductal papillary mucinous neoplasm: main duct, branch duct, and mixed. Five histologic types of intraductal papillary mucinous neoplasm are recognized: gastric foveolar type, intestinal type, pancreatobiliary type, intraductal oncocytic papillary neoplasm, and intraductal tubulopapillary neoplasm. Noninvasive intraductal papillary mucinous neoplasms are classified into 3 grades based on the degree of cytoarchitectural atypia: low-, intermediate-, and high-grade dysplasia. The most important prognosticator, however, is the presence or absence of an associated invasive carcinoma. Some main duct-intraductal papillary mucinous neoplasms progress into invasive carcinoma, mainly tubular adenocarcinoma (conventional pancreatic ductal adenocarcinoma) and colloid carcinoma. Branch duct-intraductal papillary mucinous neoplasms have a low risk for malignant transformation. Preoperative prediction of the malignant potential of an intraductal papillary mucinous neoplasm is of growing importance because pancreatic surgery has its complications, and many small intraductal papillary mucinous neoplasms, especially branch duct-intraductal papillary mucinous neoplasms, have an extremely low risk of progressing to an invasive cancer. Although most clinical decision making relies on imaging, a better understanding of the molecular genetics of intraductal papillary mucinous neoplasm could help identify molecular markers of high-risk lesions. When surgery is performed, intraoperative frozen section assessment of the pancreatic resection margin can guide the extent of resection. Intraductal papillary mucinous neoplasms are often multifocal, and surgically resected patients should be followed for metachronous disease. © 2012 Elsevier Inc. All rights reserved.

Drolet B.C.,Brown University | Lorenzi N.M.,Vanderbilt University
Translational Research | Year: 2011

The process of translating basic scientific discoveries to clinical applications, and ultimately to public health improvements, has emerged as an important, but difficult, objective in biomedical research. The process is best described as a "translation continuum" because various resources and actions are involved in this progression of knowledge, which advances discoveries from the bench to the bedside. The current model of this continuum focuses primarily on translational research, which is merely one component of the overall translation process. This approach is ineffective. A revised model to address the entire continuum would provide a methodology to identify and describe all translational activities (eg, implementation, adoption translational research, etc) as well their place within the continuum. This manuscript reviews and synthesizes the literature to provide an overview of the current terminology and model for translation. A modification of the existing model is proposed to create a framework called the Biomedical Research Translation Continuum, which defines the translation process and describes the progression of knowledge from laboratory to health gains. This framework clarifies translation for readers who have not followed the evolving and complicated models currently described. Authors and researchers may use the continuum to understand and describe their research better as well as the translational activities within a conceptual framework. Additionally, the framework may increase the advancement of knowledge by refining discussions of translation and allowing more precise identification of barriers to progress.

Desai S.V.,Duke University | McClave S.A.,University of Louisville | Rice T.W.,Vanderbilt University
Chest | Year: 2014

Providing artifi cial nutrition is an important part of caring for critically ill patients. However, because of a paucity of robust data, the practice has been highly variable and often based more on dogma than evidence. A number of studies have been published investigating many different aspects of critical care nutrition. Although the infl ux of data has better informed the practice, the results have often been confl icting or counter to prevailing thought, resulting in discordant opinions and different interpretations by experts in the fi eld. In this article, we review and summarize the data from a number of the published studies, including studies investigating enteral vs parenteral nutrition, supplementing enteral with parenteral nutrition, and use of immunonutrition. In addition, published studies informing the practice of how best to provide enteral nutrition will be reviewed, including the use of trophic feedings, gastric residual volumes, and gastric vs postpyloric tube placement. © 2014 American College of Chest Physicians.

Kirshner H.S.,Vanderbilt University
Current Neurology and Neuroscience Reports | Year: 2012

Primary progressive aphasia (PPA) has been recognized as a syndrome distinct from the usual pattern of language deterioration in Alzheimer's disease and typically more related to the pathology of frontotemporal dementia (FTD). In recent years, however, the syndromes of primary progressive aphasia have become more complex, divided into the three subtypes of progressive nonfluent aphasia (PNFA), semantic dementia (SD), and logopenic/phonological progressive aphasia (LPA). These syndromes have not only made the linguistic analysis more complex, but the associated pathologies have also become more variable. In particular, PNFA is usually, but not always, associated with FTD pathology and often evidence of a tau mutation, but rarely AD; SD is usually associated with FTD of the ubiquitin staining or progranulin (TAR-DNA) mutation type, but, again, occasionally AD; LPA is typically associated with AD pathology. Patterns of atrophy on magnetic resonance imaging (MRI) generally conform to these subtypes, with PNFA associated with left frontal and insular atophy, SD associated with bilateral temporal atrophy, and LPA associated with L superior-posterior temporal and parietal atrophy. These patterns can also be seen on positron emission (PET) scanning with fluorodeoxyglucose. The newer amyloid binding ligand PET technologies are less useful for detecting regional atrophy patterns but more useful for indication of the underlying pathology. We can thus speak of syndromes of PPA or underlying pathological bases of PPA. © Springer Science+Business Media, LLC 2012.

Brown N.J.,Vanderbilt University
Nature Reviews Nephrology | Year: 2013

The steroid hormone aldosterone regulates sodium and potassium homeostasis. Aldosterone and activation of the mineralocorticoid receptor also causes inflammation and fibrosis of the heart, fibrosis and remodelling of blood vessels and tubulointerstitial fibrosis and glomerular injury in the kidney. Aldosterone and mineralocorticoid-receptor activation initiate an inflammatory response by increasing the generation of reactive oxygen species by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondria. High salt intake potentiates these effects, in part by activating the Rho family member Rac1, a regulatory subunit of reduced NADPH oxidase that activates the mineralocorticoid receptor. Studies in mice in which the mineralocorticoid receptor has been deleted from specific cell types suggest a key role for macrophages in promoting inflammation and fibrosis. Aldosterone can exert mineralocorticoid-receptor-independent effects via the angiotensin II receptor and via G-protein-coupled receptor 30. Mineralocorticoid-receptor antagonists are associated with decreased mortality in patients with heart disease and show promise in patients with kidney injury, but can elevate serum potassium concentration. Studies in rodents genetically deficient in aldosterone synthase or treated with a pharmacological aldosterone-synthase inhibitor are providing insight into the relative contribution of aldosterone compared with the contribution of mineralocorticoid-receptor activation in inflammation, fibrosis, and injury. Aldosterone-synthase inhibitors are under development in humans. © 2013 Macmillan Publishers Limited. All rights reserved.

Henninger N.A.,Vanderbilt University
Autism : the international journal of research and practice | Year: 2013

In this review, we examine the ways in which researchers have defined successful adult outcomes for individuals with autism spectrum disorders (ASDs) from the first systematic follow-up reports to the present day. The earliest outcome studies used vague and unreliable outcome criteria, and institutionalization was a common marker of poor outcomes. In the past decade, researchers have begun to standardize the measurement of adult outcomes with specific criteria based on friendships, employment, and living arrangements. Although nearly all of these studies have agreed that the majority of adults with ASD have poor outcomes, evolving concepts of what it means to be an adult could have an impact on outcomes measured. For example, some researchers have suggested that taking into account the person-environment fit could reveal a more optimistic picture of outcomes for these adults. Suggestions for future research are discussed.

Objective: In 2013, the American College of Critical Care Medicine published a revised version of the pain, agitation, and delirium guidelines. The guidelines included an ICU pain, agitation, and delirium care bundle designed to facilitate implementation of the pain, agitation, and delirium guidelines. Design: Review article. Setting: Multispecialty critical care units. Patients: Adult ICU patients. Interventions: This article describes: 1) the ICU pain, agitation, and delirium care bundle in more detail, linking pain, sedation/agitation, and delirium management in an integrated and interdisciplinary fashion; 2) pain, agitation, and delirium implementation strategies; and 3) the potential synergistic benefits of linking pain, agitation, and delirium management strategies to other evidence-based ICU practices, including spontaneous breathing trials, ICU early mobility programs, and ICU sleep hygiene programs, in order to improve ICU patient outcomes and to reduce costs of care. Results: Linking the ICU pain, agitation, and delirium management strategies with spontaneous awakening trials, spontaneous breathing trials, and early mobility and sleep hygiene programs is associated with significant improvements in ICU patient outcomes and reductions in their costs of care. Conclusions: The 2013 ICU pain, agitation, and delirium guidelines provide critical care providers with an evidence-based, integrated, and interdisciplinary approach to managing pain, agitation/sedation, and delirium. The ICU pain, agitation, and delirium care bundle provides a framework for facilitating implementation of the pain, agitation, and delirium guidelines. Widespread implementation of the ICU pain, agitation, and delirium care bundle is likely to result in large-scale improvements in ICU patient outcomes and significant reductions in costs. © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

Allen D.K.,Plant Genetic Research Unit | Allen D.K.,Donald Danforth Plant Science Center | Young J.D.,Vanderbilt University
Plant Physiology | Year: 2013

Soybean (Glycine max) seeds store significant amounts of their biomass as protein, levels of which reflect the carbon and nitrogen received by the developing embryo. The relationship between carbon and nitrogen supply during filling and seed composition was examined through a series of embryo-culturing experiments. Three distinct ratios of carbon to nitrogen supply were further explored through metabolic flux analysis. Labeling experiments utilizing [U-13C5]glutamine, [U-13C4]asparagine, and [1,2-13C2] glucose were performed to assess embryo metabolism under altered feeding conditions and to create corresponding flux maps. Additionally, [U-14C12]sucrose, [U-14C6]glucose, [U-14C5]glutamine, and [U-14C4]asparagine were used to monitor differences in carbon allocation. The analyses revealed that: (1) protein concentration as a percentage of total soybean embryo biomass coincided with the carbon-to-nitrogen ratio; (2) altered nitrogen supply did not dramatically impact relative amino acid or storage protein subunit profiles; and (3) glutamine supply contributed 10% to 23% of the carbon for biomass production, including 9% to 19% of carbon to fatty acid biosynthesis and 32% to 46% of carbon to amino acids. Seed metabolism accommodated different levels of protein biosynthesis while maintaining a consistent rate of dry weight accumulation. Flux through ATP-citrate lyase, combined with malic enzyme activity, contributed significantly to acetyl-coenzyme A production. These fluxes changed with plastidic pyruvate kinase to maintain a supply of pyruvate for amino and fatty acids. The flux maps were independently validated by nitrogen balancing and highlight the robustness of primary metabolism. © 2013 American Society of Plant Biologists. All Rights Reserved.

Devin J.K.,Vanderbilt University
Neurosurgery Clinics of North America | Year: 2012

Pituitary tumors are a unique class of intracranial neoplasms with the potential to disrupt hormone function and water metabolism. Preoperative and postoperative endocrine assessment is mandatory to recognize and promptly treat new deficiencies and identify those that have resolved. Close collaboration among neurosurgical, endocrine, and anesthetic teams is equally vital during the perioperative period. Appropriate patient education at the time of discharge regarding the symptoms of diabetes insipidus, hyponatremia, and adrenal insufficiency is increasingly important. © 2012 Elsevier Inc.

Benning S.D.,Vanderbilt University
Psychophysiology | Year: 2011

The postauricular reflex is a relatively new psychophysiological measure of appetitive emotional processing during picture viewing. However, the degree to which other auricular (i.e., superior and anterior auricular) muscles might exhibit reflexive activity congruent with that found in the postauricular muscle has not been investigated, nor has the robustness of postauricular reflex modulation across stimulus modality. In this study, postauricular reflexes were the only reflexes that showed consistent emotional modulation across ears and genders. Additionally, postauricular reflexes were significantly modulated for both emotional pictures and sounds; in both cases, postauricular reflexes were greatest during pleasant stimuli. © 2010 Society for Psychophysiological Research.

Peterson T.E.,Vanderbilt University | Furenlid L.R.,University of Arizona
Physics in Medicine and Biology | Year: 2011

The development of radiation detectors capable of delivering spatial information about gamma-ray interactions was one of the key enabling technologies for nuclear medicine imaging and, eventually, single-photon emission computed tomography (SPECT). The continuous sodium iodide scintillator crystal coupled to an array of photomultiplier tubes, almost universally referred to as the Anger Camera after its inventor, has long been the dominant SPECT detector system. Nevertheless, many alternative materials and configurations have been investigated over the years. Technological advances as well as the emerging importance of specialized applications, such as cardiac and preclinical imaging, have spurred innovation such that alternatives to the Anger Camera are now part of commercial imaging systems. Increased computing power has made it practical to apply advanced signal processing and estimation schemes to make better use of the information contained in the detector signals. In this review we discuss the key performance properties of SPECT detectors and survey developments in both scintillator and semiconductor detectors and their readouts with an eye toward some of the practical issues at least in part responsible for the continuing prevalence of the Anger Camera in the clinic. © 2011 Institute of Physics and Engineering in Medicine.

Chacon A.,Vanderbilt University
Journal of mass spectrometry : JMS | Year: 2011

MALDI-imaging mass spectrometry (IMS) has been shown to be a powerful tool to study drug distributions in organ tissue as well as whole animal bodies. Nevertheless, not all drugs are amenable to MALDI while others may be limited by poor sensitivity poor sensitivity. The use of chemical derivatization to improve detection of small molecules by mass spectrometry techniques is well documented. To our knowledge, however, this approach has not been applied to direct tissue analysis of small organic molecules. In this manuscript, we demonstrate the use of on-tissue chemical derivatization of a small organic molecule, 3-methoxysalicylamine (3-MoSA) a scavenger of γ-ketoaldehydes. Derivatization of 3-MoSA with 1,1'-thiocarbonyldiimidazole (TCDI) results in an oxothiazolidine derivative which is detected with much greater sensitivity by MALDI than 3-MoSA itself. TCDI treatment of tissue from mice dosed with 3-MoSA allowed images to be obtained showing its spatial distribution as well as its pharmacokinetic profile in different organs. These images correlated well with results obtained from HPLC-MS/MS analyses of the same tissues. These results provide proof-of-concept that on-tissue chemical derivatization can be used to improve detection of a small organic molecule by MALDI-IMS. Copyright © 2011 John Wiley & Sons, Ltd.

Hu T.,Xiamen University | Li C.,Vanderbilt University
Molecular Cancer | Year: 2010

Wnt and EGFR signaling play key roles in embryonic development and cell proliferation. It is well documented that dysregulation of these two pathways often leads to tumorigenesis with poor prognosis. However, the possible crosstalk between the two pathways in cancer development is largely unknown. Although some reports show that EGFR might antagonize Wnt signaling during development in Drosophila, an increasing body of evidence indicates that Wnt and EGFR signaling crosstalk and transactivate one another in development and cancer. This review summarizes recent studies on the crosstalk between Wnt and EGFR signaling in cancers and points out several possible convergence points. Wnt ligands can activate EGFR signaling through their 7-transmembrane domain receptor Frizzled while EGFR can activate β-catenin via receptor tyrosine kinase-PI3K/Akt pathway; EGFR has been shown to form a complex with β-catenin and increase the invasion and metastasis of cancer cells. NKD2, a Wnt antagonist by interacting with Dishevelled, also escorts TGFα-containing exocytic vesicles to the basolateral membrane of polarized epithelial cells. Down-regulation of NKD2 causes Wnt activation and TGFα misdelivery, suggesting its functions in cell homeostasis and prevention of tumorigenesis.© 2010 Hu and Li; licensee BioMed Central Ltd.

In this paper, new measurements of anisotropic flow (v1,v2) for identified particles such as pions and protons in Cu + Au collisions at sNN=200 GeV and U + U collisions at sNN=193 GeV are reported. The anisotropic flow is studied as a function of p T and centrality in these two collision systems. In ultra-central U + U collisions (0-2% centrality), v2 of protons shows a weak p T dependence for p T < 1.0 GeV/c. A positive v1 for charged pions is observed for p T > 1 GeV/c with respect to the first-order event plane, the angle of which is determined by the Au-going spectators. The scaling of identified particle v2 with the number of valence quarks (n q) has been observed in these two collision systems, with the transverse kinetic energy. © 2013 Elsevier B.V.

Catania K.C.,Vanderbilt University
Nature Communications | Year: 2013

Integration of bilateral sensory information is fundamental to stimulus localization in auditory systems and depth perception in vision, but the role of stereo olfactory cues remains obscure. Here it is shown that blind, eastern American moles combine serial sampling with bilateral nasal cues to localize odorants. Blocking one nostril causes moles to err in the direction of the open nostril with strongest effect within 4-5 cm of the stimulus. Nostril block does not severely disrupt more distant navigation towards odorants in a T-maze nor prevent animals from ultimately locating the odour source. Crossing inputs to the nostrils using plastic tubes causes a local repulsion from the stimulus, whereas uncrossed tubes do not disrupt localization. These findings show that mammals can make use of bilateral chemosensory cues combined with serial sampling to localize odorants and offer insights into the relative contribution of each strategy during different stages of natural search behaviours. © 2013 Macmillan Publishers Limited.

Kaas J.H.,Vanderbilt University
Annals of the New York Academy of Sciences | Year: 2011

Neocortex is an important part of the mammalian brain that is quite different from its homologue of the dorsal cortex in the reptilian brain. Whereas dorsal cortex is small, thin, and composed of a single layer of neurons, neocortex is thick and has six layers, while being variable across species in size, number of functional areas, and architectonic differentiation. Early mammals had little neocortex, with perhaps 20 areas of poor structural differentiation. Many extant mammals continue to have small brains with little neocortex, but they often have sensory specializations reflected in the organization of sensory areas in neocortex. In primates, neocortex is variously enlarged and characterized by structural and other specializations, including those of cortical networks devoted to vision and visuomotor processing. In humans, neocortex occupies 80% of the volume of the brain, where as many as 200 areas may exist. © 2011 New York Academy of Sciences.

Goldenring J.R.,Vanderbilt University | Goldenring J.R.,Nashville Veternas Affairs Medical Center
Nature Reviews Cancer | Year: 2013

Epithelial cell carcinogenesis involves the loss of cell polarity, alteration of polarized protein presentation, dynamic cell morphology changes, increased proliferation, and increased cell motility and invasion. Membrane vesicle trafficking underlies all of these processes. Specific membrane trafficking regulators, including RAB small GTPases, through the coordinated dynamics of intracellular trafficking along cytoskeletal pathways, determine the cell surface presentation of proteins and the overall function of both differentiated and neoplastic cells. Although mutations in vesicle trafficking proteins may not be direct drivers of transformation, components of the machinery of vesicle movement have crucial roles in the phenotypes of neoplastic cells. Therefore, the regulators of membrane vesicle trafficking decisions are essential mediators of the full range of cell physiologies that drive cancer cell biology, including initial loss of cell polarity, invasion and metastasis. Targeting of these fundamental intracellular processes may permit the manipulation of cancer cell behaviour. © 2013 Macmillan Publishers Limited. All rights reserved.

Knollmann B.C.,Vanderbilt University
Circulation Research | Year: 2013

This article reviews the strengths and limitations of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) as models of cardiac arrhythmias. Specifically, the article attempts to answer the following questions: Which clinical arrhythmias can be modeled by iPSC-CM? How well can iPSC-CM model adult ventricular myocytes? What are the strengths and limitations of published iPSC-CM arrhythmia models? What new mechanistic insight has been gained? What is the evidence that would support using iPSC-CM to personalize antiarrhythmic drug therapy? The review also discusses the pros and cons of using the iPSC-CM technology for modeling specific genetic arrhythmia disorders, such as long QT syndrome, Brugada Syndrome, or Catecholaminergic Polymorphic Ventricular Tachycardia. © 2013 American Heart Association, Inc.

Hann S.R.,Vanderbilt University
Cold Spring Harbor Perspectives in Medicine | Year: 2014

The transcription factor MYC has fundamental roles in proliferation, apoptosis, tumorigenesis, and stem cell pluripotency.Over the last 30 years extensive information has been gathered on the numerous cofactors that interact with MYC and the target genes that are regulated by MYC as a means of understanding the molecular mechanisms controlling its diverse roles. Despite significant advances and perhaps because the amount of information learned about MYCis overwhelming, there has been little consensus on the molecular functions ofMYCthat mediate its critical biological roles. In this perspective, the majorMYCcofactors that regulate the various transcriptional activities of MYC, including canonical and noncanonical transactivation and transcriptional repression, will be reviewed and a model of how these transcriptional mechanisms control MYC-mediated proliferation, apoptosis, and tumorigenesis will be presented. The basis of the model is that a variety of cofactors form dynamic MYC transcriptional complexes that can switch the molecular and biological functions of MYC to yield a diverse range of outcomes in a cell-type- and context-dependent fashion. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

Kassim A.A.,Vanderbilt University | DeBaun M.R.,Meharry Center for Excellence in Sickle Cell Disease
Annual Review of Medicine | Year: 2013

Sickle cell disease (SCD) is caused by a mutation in both beta globin genes, resulting in chronic hemolysis and multiorgan disease that ultimately leads to premature death. Although hemoglobin S (HbS) polymerization and vaso-occlusion are central to the pathogenesis of SCD, overlapping pathways implicated in SCD-related endothelial dysfunction include hemolysis, defects in nitric oxide metabolism, ischemiareperfusion injury, oxidative stress, increased cell-to-cell adhesion, and proinflammatory and coagulation mediators. Progression of organspecific vasculopathy often precedes organ dysfunction and may provide targets for therapeutic intervention. SCD-related vasculopathies include, but are not limited to, moyamoya that often precedes cerebral infarcts or hemorrhage, proliferative retinopathy prior to loss of eyesight, pulmonary vasculopathy associated with pulmonary hypertension, and renal vasculopathy prior to the onset of chronic renal disease. This review evaluates evidence that SCD vasculopathy is a harbinger for organ dysfunction and reviews the potential for targeted antivasculopathy therapies. Copyright © 2013 by Annual Reviews.

Heckers S.,Vanderbilt University
Schizophrenia Bulletin | Year: 2011

Schizophrenia remains a major challenge for psychiatry. One hundred years after the publication of Eugen Bleuler's monograph, we are still debating the nosology and mechanisms of schizophrenia. We have stalled in the development of more effective treatments, after success with the introduction of antipsychotic medication. Cure and prevention remain in the distance. This article reviews the importance of Bleuler's monograph for the neuroscientific exploration of schizophrenia. While Bleuler assumed that schizophrenia has a neural basis, he remained agnostic on possible mechanisms and skeptical about the value of pathological diagnosis. He preferred psychological understanding over neural explanation. He gave hope by making schizophrenia dimensional and less predictive of course and outcome. To make progress now, we need to redefine schizophrenia at the level of the brain. © The Author 2010. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.

Vaezi M.F.,Vanderbilt University
American Journal of Gastroenterology | Year: 2011

The role of esophageal pH (or impedance) monitoring in diagnosing gastroesophageal reflux disease (GERD) has evolved over the years. In the era of empiric therapy with potent acid-suppressive agents such as proton pump inhibitors (PPIs), esophageal reflux monitoring is often reserved for patients with PPI-refractory symptoms (1, 2). Given the complexity of patient presentations, technological advancement, and emerging data in the field of GERD, two essential questions need to be addressed: (i) What are the indications for esophageal pH testing in patients suspected to have GERD? (ii) If patients do not respond to aggressive acid suppression, what is the likelihood that they still have reflux; and should the testing be performed at baseline (i.e., off therapy), or is it more important to know whether there is continued reflux despite therapy (i.e., on therapy)? © 2011 by the American College of Gastroenterology.

Vermund S.H.,Vanderbilt University | Vermund S.H.,West Health Institute
Current HIV/AIDS Reports | Year: 2014

Global trends in HIV incidence are estimated typically by serial prevalence surveys in selected sentinel populations or less often in representative population samples. Incidence estimates are often modeled because cohorts are costly to maintain and are rarely representative of larger populations. From global trends, we can see reason for cautious optimism. Downward trends in generalized epidemics in Africa, concentrated epidemics in persons who inject drugs (PWID), some female sex worker cohorts, and among older men who have sex with men (MSM) have been noted. However, younger MSM and those from minority populations, as with black MSM in the United States, show continued transmission at high rates. Among the many HIV prevention strategies, current efforts to expand testing, linkage to effective care, and adherence to antiretroviral therapy are known as "treatment as prevention" (TasP). A concept first forged for the prevention of mother to child transmission, TasP generates high hopes that persons treated early will derive considerable clinical benefits and that lower infectiousness will reduce transmission in communities. With the global successes of risk reduction for PWID, we have learned that reducing marginalization of the at-risk population, implementation of nonjudgmental and pragmatic sterile needle and syringe exchange programs, and offering of opiate substitution therapy to help persons eschew needle use altogether can work to reduce the HIV epidemic. Never has the urgency of stigma reduction and guarantees of human rights been more urgent; a public health approach to at-risk populations requires that to avail themselves of prevention services and they must feel welcomed. © 2014 Springer Science+Business Media.

Jourquin J.,Vanderbilt University
BMC genomics | Year: 2012

Answering questions such as "Which genes are related to breast cancer?" usually requires retrieving relevant publications through the PubMed search engine, reading these publications, and creating gene lists. This process is not only time-consuming, but also prone to errors. We report GLAD4U (Gene List Automatically Derived For You), a new, free web-based gene retrieval and prioritization tool. GLAD4U takes advantage of existing resources of the NCBI to ensure computational efficiency. The quality of gene lists created by GLAD4U for three Gene Ontology (GO) terms and three disease terms was assessed using corresponding "gold standard" lists curated in public databases. For all queries, GLAD4U gene lists showed very high recall but low precision, leading to low F-measure. As a comparison, EBIMed's recall was consistently lower than GLAD4U, but its precision was higher. To present the most relevant genes at the top of a list, we studied two prioritization methods based on publication count and the hypergeometric test, and compared the ranked lists and those generated by EBIMed to the gold standards. Both GLAD4U methods outperformed EBIMed for all queries based on a variety of quality metrics. Moreover, the hypergeometric method allowed for a better performance by thresholding genes with low scores. In addition, manual examination suggests that many false-positives could be explained by the incompleteness of the gold standards. The GLAD4U user interface accepts any valid queries for PubMed, and its output page displays the ranked gene list and information associated with each gene, chronologically-ordered supporting publications, along with a summary of the run and links for file export and functional enrichment and protein interaction network analysis. GLAD4U has a high overall recall. Although precision is generally low, the prioritization methods successfully rank truly relevant genes at the top of the lists to facilitate efficient browsing. GLAD4U is simple to use, and its interface can be found at: http://bioinfo.vanderbilt.edu/glad4u.

Tabb D.L.,Vanderbilt University
Clinical Biochemistry | Year: 2013

Proteomics has emerged from the labs of technologists to enter widespread application in clinical contexts. This transition, however, has been hindered by overstated early claims of accuracy, concerns about reproducibility, and the challenges of handling batch effects properly. New efforts have produced sets of performance metrics and measurements of variability that establish sound expectations for experiments in clinical proteomics. As researchers begin incorporating these metrics in a quality by design paradigm, the variability of individual steps in experimental pipelines will be reduced, regularizing overall outcomes. This review discusses the evolution of quality assessment in 2D gel electrophoresis, mass spectrometry-based proteomic profiling, tandem mass spectrometry-based protein inventories, and proteomic quantitation. Taken together, the advances in each of these technologies are establishing databases that will be increasingly useful for decision-making in clinical experimentation. © 2012 The Canadian Society of Clinical Chemists.

Green E.A.,Vanderbilt University
Journal of the American Heart Association | Year: 2013

Postural tachycardia syndrome (POTS) is a disorder of chronic orthostatic intolerance accompanied by excessive orthostatic tachycardia. Patients with POTS commonly have comorbid conditions such as attention deficit hyperactivity disorder, depression, or fibromyalgia that are treated with medications that inhibit the norepinephrine reuptake transporter (NRI). NRI medications can increase sympathetic nervous system tone, which may increase heart rate (HR) and worsen symptoms in POTS patients. We sought to determine whether NRI with atomoxetine increases standing tachycardia or worsens the symptom burden in POTS patients. Patients with POTS (n = 27) underwent an acute drug trial of atomoxetine 40 mg and placebo on separate mornings in a randomized, crossover design. Blood pressure (BP), HR, and symptoms were assessed while seated and after standing prior to and hourly for 4 hours following study drug administration. Atomoxetine significantly increased standing HR compared with placebo (121 ± 17 beats per minute versus 105 ± 15 beats per minute; P = 0.001) in POTS patients, with a trend toward higher standing systolic BP (P = 0.072). Symptom scores worsened with atomoxetine compared to placebo (+4.2 au versus -3.5 au; P = 0.028) from baseline to 2 hours after study drug administration. Norepinephrine reuptake inhibition with atomoxetine acutely increased standing HR and symptom burden in patients with POTS.

Bai M.,University of Pittsburgh | Bornhop D.J.,Vanderbilt University
Current Medicinal Chemistry | Year: 2012

Receptor-targeted optical imaging of cancer is emerging as an attractive strategy for early cancer diagnosis and surgical guidance. The success of such strategy depends largely upon the development of receptor-targeted fluorescent probes with high specificity and binding affinity to the target receptors. Recently, a host of such probes have been reported to target cancer-specific receptors, such as somatostatin receptors (SSTRs), integrin receptors, cholecystokinin-2 (CCK2) receptor, gastrin-releasing peptide (GRP) receptor, endothelin A (ETA) receptor, translocator protein (TSPO) receptor, epidermal growth factor (EGF) receptor, human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor (VEGF) receptor, folate receptor (FR), transferrin receptor (TFR), low-density lipoprotein (LDL) receptors, type I insulin-like growth factor receptor (IGF1R), vasoactive intestinal peptide (VIP) receptors, urokinase plasminogen activator (uPA) and estrogen receptor (ER). This review will describe the recent advances in synthetic targeting optical imaging probes and demonstrate their in vivo imaging potentials. Moreover, current status of near infrared (NIR) fluorescent dyes, targeting moieties and coupling reactions, as well as strategies for designing targeted probes, will also be discussed. © 2012 Bentham Science Publishers.

Graham T.R.,Vanderbilt University | Burd C.G.,University of Pennsylvania
Trends in Cell Biology | Year: 2011

Phosphatidylinositol 4-kinases (PI4Ks) regulate vesicle-mediated export from the Golgi apparatus via phosphatidylinositol 4-phosphate (PtdIns4. P) binding effector proteins that control vesicle budding reactions and regulate membrane dynamics. Evidence has emerged from the characterization of Golgi PI4K effectors that vesicle budding and lipid dynamics are tightly coupled via a regulatory network that ensures that the appropriate membrane composition is established before a transport vesicle buds from the Golgi. An important hub of this network is protein kinase D, which regulates the activity of PI4K and several PtdIns4. P effectors that control sphingolipid and sterol content of Golgi membranes. Other newly identified PtdIns4. P effectors include Vps74/GOLPH3, a phospholipid flippase called Drs2 and Sec2, a Rab guanine nucleotide exchange factor (GEF). These effectors orchestrate membrane transformation events facilitating vesicle formation and targeting. In this review, we discuss how PtdIns4. P signaling is integrated with membrane biosynthetic and vesicle budding machineries to potentially coordinate these crucial functions of the Golgi apparatus. © 2010 Elsevier Ltd.

Peebles Jr. R.S.,Vanderbilt University
Science Translational Medicine | Year: 2013

Innate lymphoid cells (ILCs) produce cytokines that drive allergic responses in asthma and can be inhibited by lipoxin A4 (Barnig et al., this issue).

Rosado F.G.N.,Mayo Medical School | Kim A.S.,Vanderbilt University
American Journal of Clinical Pathology | Year: 2013

Hemophagocytic lymphohistiocytosis (HLH) is a frequently fatal and likely underdiagnosed disease involving a final common pathway of hypercytokinemia, which can result in end-organ damage and death. Although an early diagnosis is crucial to decrease mortality, the definitive diagnosis is often challenging because of the lack of specificity of currently accepted diagnostic criteria and the absence of confirmatory gold standards. Because of the wide range of laboratory assays involved in the diagnosis of HLH, practicing pathologists from a broad spectrum of clinical specialties need to be aware of the disease so that they may appropriately flag results and convey them to their clinical counterparts. Our article summarizes these new advances in the diagnosis of HLH and includes a review of clinical findings, updated understanding of the pathogenesis, and promising new testing methods. © American Society for Clinical Pathology.

Papai G.,University of Strasbourg | Weil P.A.,Vanderbilt University | Schultz P.,University of Strasbourg
Current Opinion in Genetics and Development | Year: 2011

The general transcription factor IID is a key player in the early events of gene expression. TFIID is a multisubunit complex composed of the TATA binding protein and at least 13 TBP associated factors (TAfs) which recognize the promoter of protein coding genes in an activator dependant way. This review highlights recent findings on the molecular architecture and dynamics of TFIID. The structural analysis of functional transcription complexes formed by TFIID, TFIIA, activators and/or promoter DNA illuminates the faculty of TFIID to adjust to various promoter architectures and highlights its role as a platform for preinitiation complex assembly. © 2011 Elsevier Ltd.

GoldenMerry Y.L.,Vanderbilt University
Molecular Therapy | Year: 2015

Glaucoma, a common cause of blindness, is currently treated by intraocular pressure (IOP)–lowering interventions. However, this approach is insufficient to completely prevent vision loss. Here, we evaluate an IOP-independent gene therapy strategy using a modified erythropoietin, EPO-R76E, which has reduced erythropoietic function. We used two models of glaucoma, the murine microbead occlusion model and the DBA/2J mouse. Systemic recombinant adeno-associated virus–mediated gene delivery of EpoR76E (rAAV.EpoR76E) was performed concurrent with elevation of IOP. Axon structure and active anterograde transport were preserved in both models. Vision, as determined by the flash visual evoked potential, was preserved in the DBA/2J. These results show that systemic EpoR76E gene therapy protects retinal ganglion cells from glaucomatous degeneration in two different models. This suggests that EPO targets a component of the neurodegenerative pathway that is common to both models. The efficacy of rAAV.EpoR76E delivered at onset of IOP elevation supports clinical relevance of this treatment.Molecular Therapy (2015); doi:10.1038/mt.2015.198. © 2015 American Society of Gene & Cell Therapy

Loyd J.E.,Vanderbilt University
Proceedings of the American Thoracic Society | Year: 2011

Familial pulmonary arterial hypertension (FPAH) was described 60 years ago, but real progress in understanding its origins and pathogenesis is just beginning. Germline mutations in bone morphogenetic protein receptor type 2 (BMPR2) are responsible for the disease in most families, and also in many sporadic cases Of idiopathic PAH. Heritable PAH refers to patients with a positive family history, or with a responsible genetic mutation, and is an autosomal dominant disease that affects females disproportionately, may occur at any age, and is characterized by reduced penetrance and variable expressivity. These characteristics suggest that other endogenous or exogenous factors modify its expression. Several different factors have recently been demonstrated to modify the clinical expression of BMPR2 mutation, including estrogen metabolites and functional polymorphismsin transforming growth factor-β1 and CYP1B1. Furthermore, a linkage study recently identified modifier loci for BMPR2 clinical expression, which suggests an oligogenic model. Clinical testing for BMPR2 mutations is available for families with heritable and idiopathic PAH, and is an evolving model of personalized medicine. Variable age of onset and decreased penetrance confound genetic counseling, because the majority of carriers of a BMPR2 mutation will never develop PAH, but often transmit the risk to their progeny.

Keedy V.L.,Vanderbilt University
OncoTargets and Therapy | Year: 2012

Sarcomas of soft tissue and bone are a rare group of cancers hallmarked by relative insensitivity to cytotoxic chemotherapy. The development of targeted therapies in the treatment of sarcoma has been difficult due to the significant heterogeneity and rarity of these diseases. Inhibition of the mammalian target of rapamycin (mTOR) has emerged as an exciting treatment approach and is being studied extensively in sarcoma patients. Ridaforolimus is a second generation mTOR inhibitor that has shown potential benefit in the treatment of sarcoma. Recently a Phase III study demonstrated an improvement in progression-free survival when patients with at least stable disease after treatment with standard chemotherapy received maintenance ridaforolimus compared to placebo. The results of this study show that mTOR is an important pathway in soft tissue and bone sarcomas and represents an exciting opportunity for the improvement in the treatment of our patients. © 2012 Keedy, publisher and licensee Dove Medical Press Ltd.

Brown N.J.,Vanderbilt University
Therapeutic Advances in Cardiovascular Disease | Year: 2010

Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of fibrinolysis and regulates cell migration and fibrosis. Preclinical studies using genetically altered mice and biological or small molecule inhibitors have elucidated a role for PAI-1 in the pathogenesis of thrombosis, vascular remodeling, renal injury, and initiation of diabetes. Inhibition of PAI-1 is a potential therapeutic strategy in these diseases. © The Author(s), 2010.

George Jr. A.L.,Vanderbilt University
Journal of Clinical Investigation | Year: 2013

The abrupt cessation of effective cardiac function due to an aberrant heart rhythm can cause sudden and unexpected death at any age, a syndrome called sudden cardiac death (SCD). Annually, more than 300,000 cases of SCD occur in the United States alone, making this a major public health concern. Our current understanding of the mechanisms responsible for SCD has emerged from decades of basic science investigation into the normal electrophysiology of the heart, the molecular physiology of cardiac ion channels, fundamental cellular and tissue events associated with cardiac arrhythmias, and the molecular genetics of monogenic disorders of heart rhythm. This knowledge has helped shape the current diagnosis and treatment of inherited arrhythmia susceptibility syndromes associated with SCD and has provided a pathophysiological framework for understanding more complex conditions predisposing to this tragic event. This Review presents an overview of the molecular basis of SCD, with a focus on monogenic arrhythmia syndromes.

Eichbaum Q.,Vanderbilt University
Current Medicinal Chemistry | Year: 2011

Programmed death-1 (PD-1) is a negative immunoregulatory cell surface receptor molecule whose interaction with its ligands PD-L1 and PD-L2 downmodulates T-cell immune responses. Originally investigated in the context of self-tolerance, PD-1 has more recently been discovered to be upregulated on T cells of HIV-infected individuals. High levels of PD-1 on HIV-infected T cells are correlated with viral load and with a state of cellular anergy, or 'exhaustion' that results in decreased cellular proliferation, cytotoxic function and cytokine secretion. The finding that interruption of PD-1 with its ligand PD-L1 rescues HIV-infected cells from this state of anergy or 'exhaustion' presents the promise for therapeutic intervention. Understanding the molecular signaling pathway(s) of PD-1 may provide opportunities for therapeutic intervention, that may serve as adjunctive therapies to HIV vaccine development. Evidence to date suggests that PD-1 exerts its regulatory effect by interfering with T cell receptor signaling. While certain molecular signals in the PD-1 pathway have been identified, their precise roles and mechanisms of action remain poorly understood. This article reviews what is currently known about PD-1 signaling in human T cells, and more specifically in T cells of individuals chronically infected with certain viruses such as HIV. © 2011 Bentham Science Publishers Ltd.

Over the past decade, large multicenter trials have unequivocally demonstrated that decreasing low-density lipoprotein (LDL) cholesterol can reduce both primary and secondary cardiovascular events in patients at risk. However, even in the context of maximal LDL lowering, there remains considerable residual cardiovascular risk. Some of this risk can be attributed to variability in high-density lipoprotein (HDL) cholesterol. As such, there is tremendous interest in defining determinants of HDL homeostasis. Risk prediction models are being constructed based upon (1) clinical contributors, (2) known molecular determinants and (3) the genetic architecture underlying HDL cholesterol levels. To date, however, no single resource has combined these factors within the context of a practice-based data set. Recently, a number of academic medical centers have begun constructing DNA biobanks linked to secure encrypted versions of their respective electronic medical record. As these biobanks combine resources, the clinical community is in a position to characterize lipid-related treatment outcome on an unprecedented scale. © 2011 Macmillan Publishers Limited. All rights reserved.

Liu M.,Vanderbilt University
AMIA ... Annual Symposium proceedings / AMIA Symposium. AMIA Symposium | Year: 2012

Electronic Medical Records (EMRs) are valuable resources for clinical observational studies. Smoking status of a patient is one of the key factors for many diseases, but it is often embedded in narrative text. Natural language processing (NLP) systems have been developed for this specific task, such as the smoking status detection module in the clinical Text Analysis and Knowledge Extraction System (cTAKES). This study examined transportability of the smoking module in cTAKES on the Vanderbilt University Hospital's EMR data. Our evaluation demonstrated that modest effort of change is necessary to achieve desirable performance. We modified the system by filtering notes, annotating new data for training the machine learning classifier, and adding rules to the rule-based classifiers. Our results showed that the customized module achieved significantly higher F-measures at all levels of classification (i.e., sentence, document, patient) compared to the direct application of the cTAKES module to the Vanderbilt data.

Peterson J.F.,Vanderbilt University
Pharmacogenomics Journal | Year: 2015

Clinician attitudes toward multiplexed genomic testing may be vital to the success of translational programs. We surveyed clinicians at an academic medical center about their views on a large pharmacogenomics implementation, the PREDICT (Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment) program. Participants were asked about test ordering, major factors influencing use of results, expectations of efficacy and responsibility for applying results to patient care. Virtually all respondents (99%) agreed that pharmacogenomics variants influence patients’ response to drug therapy. The majority (92%) favored immediate, active notification when a clinically significant drug–genome interaction was present. However, clinicians were divided on which providers were responsible for acting on a result when a prescription change was indicated and whether patients should be directly notified of a significant result. We concluded genotype results were valued for tailoring prescriptions, but clinicians do not agree on how to appropriately assign clinical responsibility for actionable results from a multiplexed panel.The Pharmacogenomics Journal advance online publication, 11 August 2015; doi:10.1038/tpj.2015.57. © 2015 Macmillan Publishers Limited

Sun J.,Vanderbilt University
BMC bioinformatics | Year: 2012

Understanding drug bioactivities is crucial for early-stage drug discovery, toxicology studies and clinical trials. Network pharmacology is a promising approach to better understand the molecular mechanisms of drug bioactivities. With a dramatic increase of rich data sources that document drugs' structural, chemical, and biological activities, it is necessary to develop an automated tool to construct a drug-target network for candidate drugs, thus facilitating the drug discovery process. We designed a computational workflow to construct drug-target networks from different knowledge bases including DrugBank, PharmGKB, and the PINA database. To automatically implement the workflow, we created a web-based tool called DTome (Drug-Target interactome tool), which is comprised of a database schema and a user-friendly web interface. The DTome tool utilizes web-based queries to search candidate drugs and then construct a DTome network by extracting and integrating four types of interactions. The four types are adverse drug interactions, drug-target interactions, drug-gene associations, and target-/gene-protein interactions. Additionally, we provided a detailed network analysis and visualization process to illustrate how to analyze and interpret the DTome network. The DTome tool is publicly available at http://bioinfo.mc.vanderbilt.edu/DTome. As demonstrated with the antipsychotic drug clozapine, the DTome tool was effective and promising for the investigation of relationships among drugs, adverse interaction drugs, drug primary targets, drug-associated genes, and proteins directly interacting with targets or genes. The resultant DTome network provides researchers with direct insights into their interest drug(s), such as the molecular mechanisms of drug actions. We believe such a tool can facilitate identification of drug targets and drug adverse interactions.

Ruhl J.B.,Vanderbilt University
Ecology and Society | Year: 2012

Panarchy theory focuses on improving theories of change in natural and social systems to improve the design of policy responses. Its central thesis is that successfully working with the dynamic forces of complex adaptive natural and social systems demands an active adaptive management regime that eschews optimization approaches that seek stability. This is a new approach to resources management, and yet no new theory of how to do things in environmental and natural resources management, particularly one challenging entrenched ways of doing things and the interests aligned around them, is likely to gain traction in practice if it cannot gain traction in the form of endorsement and implementation through specific laws and regulations. At some point, that bridge must be crossed or the enterprise of putting panarchy theory into panarchy practice will stall. Any effort to operationalize panarchy theory through law thus comes up against the mission of law to provide social stability and the nature of law itself as a complex adaptive system. To state the problem in another way, putting panarchy theory into practice will require adaptively managing the complex adaptive legal system to adaptively manage other complex adaptive natural and social systems, all in a way that maintains some level of social order. Panarchy theorists have yet to develop an agenda for doing so. It is time for lawyers to join the team. © 2012 by the author(s).

Koury M.J.,Vanderbilt University
Blood Reviews | Year: 2014

Erythropoiesis, the bone marrow production of erythrocytes by the proliferation and differentiation of hematopoietic cells, replaces the daily loss of 1% of circulating erythrocytes that are senescent. This daily output increases dramatically with hemolysis or hemorrhage. When erythrocyte production rate of erythrocytes is less than the rate of loss, chronic anemia develops. Normal erythropoiesis and specific abnormalities of erythropoiesis that cause chronic anemia are considered during three periods of differentiation: a) multilineage and pre-erythropoietin-dependent hematopoietic progenitors, b) erythropoietin-dependent progenitor cells, and c) terminally differentiating erythroblasts. These erythropoietic abnormalities are discussed in terms of their pathophysiological effects on the bone marrow cells and the resultant changes that can be detected in the peripheral blood using a clinical laboratory test, the complete blood count. © 2014.

Grijalva C.G.,Vanderbilt University
Rheumatology (Oxford, England) | Year: 2010

OBJECTIVE: In clinical trials of RA patients on traditional DMARDs, the addition of TNF-alpha antagonists increased infections compared with addition of placebo. Our objective was to compare serious infections following initiation of different RA regimens. Prior comparative studies of DMARD initiation have yielded conflicting results. METHODS: We estimated hospitalization rates for infections following initiation of TNF-alpha antagonists, other DMARDs and oral glucocorticoids in Tennessee Medicaid-enrolled RA patients (1995-2005). Exposure time was measured using pharmacy information and infections were identified using validated definitions. Initiation of RA regimens was compared using Cox regression models with MTX as the reference. Sensitivity analyses excluded glucocorticoid users, applied a first exposure carried forward approach, restricted observations to 2002-05 and first episodes of use and explored effects of unmeasured confounders. RESULTS: We identified 28 906 new episodes of medication use, including TNF-alpha antagonists (8%), MTX alone (15%) and glucocorticoids alone (57%). Compared with MTX initiation, TNF-alpha antagonist initiation did not significantly increase the risk of hospitalizations for pneumonia [adjusted hazard ratio (aHR) 1.61; 95% CI 0.85, 3.03] or any infection (aHR 1.31; 95% CI 0.78, 2.19). Initiation of LEF, SSZ or HCQ did not increase serious infections, compared with MTX. Both initiation and concurrent glucocorticoid use were associated with a dose-dependent increase in serious infections. Sensitivity analyses showed consistent results. CONCLUSIONS: Compared with initiation of MTX alone, initiation of TNF-alpha antagonists was not associated with a large increase in the risk of serious infections. Glucocorticoid use was associated with a dose-dependent increase in the risk of these infections.

Heitz R.P.,Vanderbilt University
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

The stochastic accumulation framework provides a mechanistic, quantitative account of perceptual decision-making and how task performance changes with experimental manipulations. Importantly, it provides an elegant account of the speed-accuracy trade-off (SAT), which has long been the litmus test for decision models, and also mimics the activity of single neurons in several key respects. Recently, we developed a paradigm whereby macaque monkeys trade speed for accuracy on cue during visual search task. Single-unit activity in frontal eye field (FEF) was not homomorphic with the architecture of models, demonstrating that stochastic accumulators are an incomplete description of neural activity under SAT. This paper summarizes and extends this work, further demonstrating that the SAT leads to extensive, widespread changes in brain activity never before predicted. We will begin by reviewing our recently published work that establishes how spiking activity in FEF accomplishes SAT. Next, we provide two important extensions of this work. First, we report a new chronometric analysis suggesting that increases in perceptual gain with speed stress are evident in FEF synaptic input, implicating afferent sensory-processing sources. Second, we report a new analysis demonstrating selective influence of SAT on frequency coupling between FEF neurons and local field potentials. None of these observations correspond to the mechanics of current accumulator models.

Emmitte K.A.,Vanderbilt University
ACS Chemical Neuroscience | Year: 2011

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu 5) have remained attractive to researchers as potential therapies for a number of central nervous system related diseases, including anxiety, pain, gastresophageal reflux disease (GERD), addiction, Parkinson's disease (PD), and fragile X syndrome (FXS). In addition to the many publications with supportive preclinical data with key tool molecules, recent positive reports from the clinic have bolstered the confidence in this approach. During the 2 year time span from 2009 through 2010, a number of new mGlu 5 NAM chemotypes have been disclosed and discussed in the primary and patent literature. A summary of several efforts representing many diverse chemotypes are presented here, along with a discussion of representative structure-activity relationships (SAR) and synthetic approaches to the templates where possible. © 2011 American Chemical Society.

VanSaun M.N.,Vanderbilt University
Clinical Cancer Research | Year: 2013

The increasing percentage of obese individuals in the population and its independent association of increased risk for the development of cancer have heightened the necessity to understand the molecular mechanisms that underlie this connection. The deregulation of adipokines in the setting of obesity and their impact on cancer progression and metastasis is one such area of research. Adipokines are bioactive proteins that mediate metabolism, inflammation, angiogenesis, and proliferation. Altered levels of adipokines or their cognate receptors in cancers can ultimately lead to an imbalance in downstream molecular pathways. Discovery of adipokine receptors in various cancers has highlighted the potential for novel therapeutic targets. Leptin and adiponectin represent two adipokines that elicit generally opposing molecular effects. Epidemiologic studies have highlighted associations between increased serum leptin levels and increased tumor growth, whereas adiponectin exhibits an inverse correlation with cancer development. This review addresses the current level of understanding of molecular pathways activated by adiponectin and leptin to identify the areas of intervention and facilitate advancement in the field. ©2013 AACR.

Pentassuglia L.,University of Basel | Sawyer D.B.,Vanderbilt University
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2013

Neuregulin (Nrg)/ErbB and integrin signaling pathways are critical for the normal function of the embryonic and adult heart. Both systems activate several downstream signaling pathways, with different physiological outputs: cell survival, fibrosis, excitation-contraction coupling, myofilament structure, cell-cell and cell-matrix interaction. Activation of ErbB2 by Nrg1β in cardiomycytes or its overexpression in cancer cells induces phosphorylation of FAK (Focal Adhesion Kinase) at specific sites with modulation of survival, invasion and cell-cell contacts. FAK is also a critical mediator of integrin receptors, converting extracellular matrix alterations into intracellular signaling. Systemic FAK deletion is lethal and is associated with left ventricular non-compaction whereas cardiac restriction in adult hearts is well tolerated. Nevertheless, these hearts are more susceptible to stress conditions like trans-aortic constriction, hypertrophy, and ischemic injury. As FAK is both downstream and specifically activated by integrins and Nrg-1β, here we will explore the role of FAK in the heart as a protective factor and as possible mediator of the crosstalk between the ErbB and Integrin receptors. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction. © 2012 Elsevier B.V.

Catania K.C.,Vanderbilt University
Current Biology | Year: 2015

Nature is replete with predator venoms that immobilize prey by targeting ion channels. Electric eels (Electrophorus electricus) take a different tactic to accomplish the same end. Striking eels emit electricity in volleys of 1 ms, high-voltage pulses. Each pulse is capable of activating prey motor neuron efferents, and hence muscles. In a typical attack, eel discharges cause brief, immobilizing tetanus, allowing eels to swallow small prey almost immediately. Here I show that when eels struggle with large prey or fish held precariously, they commonly curl to bring their own tail to the opposite side of prey, sandwiching it between the two poles of their powerful electric organ. They then deliver volleys of high-voltage pulses. Shortly thereafter, eels juggle prey into a favorable position for swallowing. Recordings from electrodes placed within prey items show that this curling behavior at least doubles the field strength within shocked prey, most likely ensuring reliable activation of the majority of prey motor neurons. Simulated pulse trains, or pulses from an eel-triggered stimulator, applied to a prey muscle preparations result in profound muscle fatigue and loss of contractile force. Consistent with this result, video recordings show that formerly struggling prey are temporarily immobile after this form of attack, allowing the manipulation of prey that might otherwise escape. These results reveal a unique use of electric organs to a unique end; eels superimpose electric fields from two poles, ensuring maximal remote activation of prey efferents that blocks subsequent prey movement by inducing involuntary muscle fatigue. © 2015 Elsevier Ltd. All rights reserved.

Stauffer S.R.,Vanderbilt University
ACS Chemical Neuroscience | Year: 2011

This Review describes recent trends in the development of small molecule mGlu5 positive allosteric modulators (PAMs). A large body of pharmacological, genetic, electrophysiological, and in vivo behavioral evidence has accumulated over the past decade which continues to support the hypothesis and rationale for the activation of the metabotropic glutamate receptor subtype 5 (mGlu5) as a viable and promising target for the development of novel antipsychotics. Until recently, functionally efficacious and potent mGlu5 PAMs have been somewhat structurally limited in scope and slow to emerge. This Review will discuss efforts since late 2008 which have provided novel mGlu5 PAM chemotypes, offering ligands with a diverse range of pharmacological, physicochemical, and DMPK properties that were previously unavailable. In addition, significant biological studies of importance in the past few years using the well established PAMs known as DFB, CPPHA, CDPPB, and ADX-47273 will be discussed. © 2011 American Chemical Society.

Polavarapu P.L.,Vanderbilt University
Chirality | Year: 2012

Chiroptical spectroscopy is being widely used for determining the three-dimensional molecular structures (i.e., absolute configurations and conformations) of chiral molecules. The general procedure used with any of the chiroptical spectroscopic methods is to analyze the experimental data using corresponding quantum chemical predictions. Such analysis involves multiple steps, including consideration of conformations, solvent effects, electronic transitions, stereoisomers, and experimental artifacts, each of which possesses certain limitations. These limitations, when not recognized or properly taken into account, may lead to incorrect conclusions. This review emphasizes on selected examples that illustrate the potential limitations in utilizing the chiroptical spectroscopic methods. The examples used include hibiscus acid dimethylester, hibiscus acid disodium salt, 3,3'-diphenyl-[2,2'-binaphthalene]- 1,1'-diol, tartaric acid esters, and 6,6'-dibromo-[1,1'-binaphthalene]-2,2'- diol. Chirality 24:909-920, 2012. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc., A Wiley Company.

Milatovic D.,Vanderbilt University
Methods in Molecular Biology | Year: 2011

Oxidative stress results from an imbalance between production of reactive oxygen and nitrogen species (ROS and RNS, respectively) and endogenous antioxidant defense mechanisms. Increased generation of ROS/RNS is implicated in the pathogenesis of a variety of human diseases, including neurodegenerative disease, atherosclerosis, cancer, and aging. However, measuring oxidative stress in biological systems is complex and requires accurate quantification of either free radicals or damaged biomolecules. One method to quantify oxidative injury is to measure lipid peroxidation. Lipids are readily attacked by free radicals, resulting in the formation of a number of peroxidation products. F 2-isoprostanes (F2-IsoPs) are one group of these compounds and they are derived by the free radical peroxidation of arachidonic acid (AA). The F2-IsoPs, prostaglandine F2-like compounds, provide an accurate measure of oxidative stress both in vitro and in vivo. This protocol details current methodology used to quantify these molecules using gas chromatography-mass spectrometry (GC/MS). © 2011 Springer Science+Business Media, LLC.

Dickinson D.K.,Vanderbilt University | Porche M.V.,Wellesley College
Child Development | Year: 2011

Indirect effects of preschool classroom indexes of teacher talk were tested on fourth-grade outcomes for 57 students from low-income families in a longitudinal study of classroom and home influences on reading. Detailed observations and audiotaped teacher and child language data were coded to measure content and quantity of verbal interactions in preschool classrooms. Preschool teachers' use of sophisticated vocabulary during free play predicted fourth-grade reading comprehension and word recognition (mean age=9; 7), with effects mediated by kindergarten child language measures (mean age=5; 6). In large group preschool settings, teachers' attention-getting utterances were directly related to later comprehension. Preschool teachers' correcting utterances and analytic talk about books, and early support in the home for literacy predicted fourth-grade vocabulary, as mediated by kindergarten receptive vocabulary. © 2011 The Authors. Child Development © 2011 Society for Research in Child Development, Inc.

Vaezi M.F.,Vanderbilt University | Pandolfino J.E.,Northwestern University | Vela M.F.,Baylor College of Medicine
American Journal of Gastroenterology | Year: 2013

Achalasia is a primary motor disorder of the esophagus characterized by insufficient lower esophageal sphincter relaxation and loss of esophageal peristalsis. This results in patients' complaints of dysphagia to solids and liquids, regurgitation, and occasional chest pain with or without weight loss. Endoscopic finding of retained saliva with puckered gastroesophageal junction or barium swallow showing dilated esophagus with birds beaking in a symptomatic patient should prompt appropriate diagnostic and therapeutic strategies. In this ACG guideline the authors present an evidence-based approach in patients with achalasia based on a comprehensive review of the pertinent evidence and examination of relevant published data. © 2013 by the American College of Gastroenterology.

Muglia L.J.,Vanderbilt University | Muglia L.J.,Monroe Hospital | Katz M.,March of Dimes Foundation
New England Journal of Medicine | Year: 2010

The world's preterm birth rate continues to increase. In 2006, preterm births accounted for 12.8% of live births in the United States. Only about half the cases of prematurity result from identifiable causes. This review discusses the challenge of understanding the causes of premature birth and finding ways to prevent it. Copyright © 2010 Massachusetts Medical Society.

Guengerich F.P.,Vanderbilt University
Journal of Labelled Compounds and Radiopharmaceuticals | Year: 2013

Cytochrome P450 (P450) enzymes account for 75% of the metabolism of drugs. Most of the reactions catalyzed by P450s are mixed-function oxidations, and a C-H bond is (usually) broken. The rate-limiting nature of this step can be analyzed using the kinetic isotope effect (KIE) approach. The most relevant type of KIE is one termed intermolecular non-competitive, indicative of rate-limiting C-H bond breaking. A plot of KIE versus kcat for several P450s showed a correlation coefficient (r2) of 0.62. Deuterium substitution has been considered as a potential means of slowing drug metabolism or redirecting sites of metabolism in some cases, and several general points can be made regarding the potential for application of deuterium in drug design/ development based on what is known about P450 KIEs. Copyright © 2013 John Wiley & Sons, Ltd.

Myers M.I.,Vanderbilt University
Current neurology and neuroscience reports | Year: 2013

Skin biopsy is a valuable diagnostic tool for small-fiber-predominant neuropathy by the quantification of intraepidermal nerve fiber density (IENFD). It has the unique advantage of being a minimally invasive procedure with the potential for longitudinal evaluation of both sensory and autonomic fibers. Unmyelinated small fibers are not otherwise quantified objectively with such a level of sensitivity as has been reported with IENFD. Recent advances include an expansion of the skin punch biopsy technique to evaluate larger myelinated fibers and mechanoreceptors, and recent work has also focused on additional methods of quantifying dermal fibers and densely innervated autonomic structures. This review discusses current work using skin biopsy for the pathologic analysis of peripheral nerve fibers in neuropathy of various causes as well as its use in clinical trials.

Eisenberg E.,Vanderbilt University
Seminars in Reproductive Medicine | Year: 2012

Millions of children have been born worldwide through assisted reproductive technology (ART), and access is increasing yearly. Our current knowledge and understanding of the long-term risks and/or benefits to the children conceived is incomplete. Investigations of the health, disease, cognitive, developmental, and behavioral outcomes are often confounded by other factors, including multiple gestations, prematurity, and low birthweight. Reports of the long-term health and psychosocial adjustment of children conceived with ART show generally good outcomes. Many of the major long-term problems observed in the children may be associated with multiple gestations, preterm delivery, and low birthweight or with subfertility of the parents. Evidence in the male infants conceived with the aid of intracytoplasmic sperm injection suggests an increased risk of reproductive tract anomalies such as hypospadias. Outcome data on health of children born after cryopreservation of cleavage stage embryos are reassuring. Measuring long-term outcomes is the first step to improving and optimizing health in the offspring conceived with medical and technological assistance. Copyright © 2012 by Thieme Medical Publishers, Inc.

Catania K.,Vanderbilt University
Science | Year: 2014

Electric eels can incapacitate prey with an electric discharge, but the mechanism of the eel's attack is unknown. Through a series of experiments, I show that eel high-voltage discharges can activate prey motor neurons, and hence muscles, allowing eels to remotely control their target. Eels prevent escape in free-swimming prey using high-frequency volleys to induce immobilizing whole-body muscle contraction (tetanus). Further, when prey are hidden, eels can emit periodic volleys of two or three discharges that cause massive involuntary twitch, revealing the prey's location and eliciting the full, tetanus-inducing volley. The temporal patterns of eel electrical discharges resemble motor neuron activity that induces fast muscle contraction, suggesting that eel high-voltage volleys have been selected to most efficiently induce involuntary muscle contraction in nearby animals. ©2014 by the American Association for the Advancement of Science; all rights reserved.

Gagnon K.B.,University of Saskatchewan | Delpire E.,Vanderbilt University
American Journal of Physiology - Cell Physiology | Year: 2013

Among the over 300 members of the solute carrier (SLC) group of integral plasma membrane transport proteins are the nine electroneutral cation-chloride cotransporters belonging to the SLC12 gene family. Seven of these transporters have been functionally described as coupling the electrically silent movement of chloride with sodium and/or potassium. Although in silico analysis has identified two additional SLC12 family members, no physiological role has been ascribed to the proteins encoded by either the SLC12A8 or the SLC12A9 genes. Evolutionary conservation of this gene family from protests to humans confirms their importance. A wealth of physiological, immunohistochemical, and biochemical studies have revealed a great deal of information regarding the importance of this gene family to human health and disease. The sequencing of the human genome has provided investigators with the capability to link several human diseases with mutations in the genes encoding these plasma membrane proteins. The availability of bacterial artificial chromosomes, recombination engineering techniques, and the mouse genome sequence has simplified the creation of targeting constructs to manipulate the expression/function of these cation-chloride cotransporters in the mouse in an attempt to recapitulate some of these human pathologies. This review will summarize the three human disorders that have been linked to the mutation/dysfunction of the Na-Cl, Na-K-2Cl, and K-Cl cotransporters (i.e., Bartter's, Gitleman's, and Andermann's syndromes), examine some additional pathologies arising from genetically modified mouse models of these cotransporters including deafness, blood pressure, hyperexcitability, and epithelial transport deficit phenotypes. © 2013 the American Physiological Society.

Mir H.R.,Vanderbilt University
The Journal of bone and joint surgery. American volume | Year: 2011

The Accreditation Council for Graduate Medical Education (ACGME) established national guidelines for resident duty hours in July 2003. Following an Institute of Medicine report in December 2008, the ACGME recommended further restrictions on resident duty hours that went into effect in July 2011. We conducted a national survey to assess the opinions of orthopaedic residents and of directors of residency and fellowship programs in the U.S. regarding the 2003 and 2011 ACGME resident duty-hour regulations and the effects of these regulations on resident education and patient care. A fifteen-item questionnaire was electronically distributed by the Candidate, Resident, and Fellow Committee of the American Academy of Orthopaedic Surgeons (AAOS) to all U.S. orthopaedic residents (n = 3860) and directors of residency programs (n = 184) and fellowship programs (n = 496) between January and April 2011. Thirty-four percent (1314) of the residents and 27% (185) of the program directors completed the questionnaire. Statistical analyses were performed to detect differences between the responses of residents and program directors and between the responses of junior and senior residents. The responses of orthopaedic residents and program directors differed significantly (p < 0.001) for fourteen of the fifteen survey items. The responses of residents and program directors were divergent for questions regarding the 2003 rules. Overall, 71% of residents thought that the eighty-hour work week was appropriate, whereas only 38% of program directors agreed (p < 0.001). Most program directors (70%) did not think that the 2003 duty-hour rules had improved patient care, whereas only 24% of residents responded in the same way (p < 0.001). The responses of residents and program directors to questions regarding the 2011 duty-hour rules were generally compatible, but the degree to which they perceived the issues was different. Only 18% of residents and 19% of program directors thought that the suggested strategic five-hour evening rest period implemented in July 2011 for on-call residents was appropriate (p > 0.05), and both groups (84% of residents and 74% of program directors) also disagreed with the limitation of intern shifts to sixteen hours (p < 0.001). Seventy percent of residents and 79% of program directors thought that the new duty-hour regulations would result in an increased number of handoffs that would be detrimental to patient care (p < 0.001). The mean responses of junior residents and senior residents differed for eight of the fifteen survey items (p < 0.001), with the responses of senior residents more closely resembling those of program directors on six of these eight questions. The mean responses and percentiles for the survey items did not differ significantly between residency directors and fellowship directors (p > 0.05). This national survey indicated significant differences between the opinions of orthopaedic residents and program (residency and fellowship) directors regarding the 2003 ACGME resident duty-hour regulations and the effects of these regulations on resident education and patient care. However, both residents and program directors agreed that the further reductions in duty hours in the 2011 rules may be detrimental to resident education and patient care.

Donnelly E.F.,Vanderbilt University
Journal of Thoracic Imaging | Year: 2012

Lung cancer screening computed tomographies (CTs) differ from traditional chest CT scans in that they are performed at very low radiation doses, which allow the detection of small nodules but which have a much higher noise content than would be acceptable in a diagnostic chest CT. The technical parameters require a great deal of attention on the part of the user, because inappropriate settings could result in either excess radiation dose to the large population of screened individuals or in low-quality images with impaired nodule detectability. Both situations undermine the main goal of the screening program, which is to detect lung nodules using as low a radiation dose as can reasonably be achieved. Once an image has been obtained, there are unique interpretive issues that must be addressed mainly because of the very high noise content of the images and the high prevalence of incidental findings in the chest unrelated to the sought-after pulmonary nodules. Copyright © 2012 by Lippincott Williams & Wilkins.

Lovly C.M.,Vanderbilt University | Shaw A.T.,Massachusetts General Hospital
Clinical Cancer Research | Year: 2014

The development of targeted therapies has revolutionized the treatment of cancer patients. The identification of "druggable" oncogenic kinases and the creation of small-molecule inhibitors designed to specifically target these mutant kinases have become an important therapeutic paradigm across several different malignancies. Often these inhibitors induce dramatic clinical responses in molecularly defined cohorts. However, resistance to such targeted therapies is an inevitable consequence of this therapeutic approach. Resistance can be either primary (de novo) or acquired. Mechanisms leading to primary resistance may be categorized as tumor intrinsic factors or as patient/drug-specific factors. Acquired resistance may bemediated by target genemodification, activation of "bypass tracks" that serve as compensatory signaling loops, or histologic transformation. This brief review is a snapshot of the complex problem of therapeutic resistance, with a focus on resistance to kinase inhibitors in EGF receptor mutant and ALK rearranged non-small cell lung cancer, BRAF-mutant melanoma, and BCRABL-positive chronic myeloid leukemia. We describe specific mechanisms of primary and acquired resistance and then review emerging strategies to delay or overcome drug resistance. © 2014 AACR.

Kaverina I.,Vanderbilt University | Straube A.,University of Warwick
Seminars in Cell and Developmental Biology | Year: 2011

Microtubules define the architecture and internal organization of cells by positioning organelles and activities, as well as by supporting cell shape and mechanics. One of the major functions of microtubules is the control of polarized cell motility. In order to support the asymmetry of polarized cells, microtubules have to be organized asymmetrically themselves. Asymmetry in microtubule distribution and stability is regulated by multiple molecular factors, most of which are microtubule-associated proteins that locally control microtubule nucleation and dynamics. At the same time, the dynamic state of microtubules is key to the regulatory mechanisms by which microtubules regulate cell polarity, modulate cell adhesion and control force-production by the actin cytoskeleton. Here, we propose that even small alterations in microtubule dynamics can influence cell migration via several different microtubule-dependent pathways. We discuss regulatory factors, potential feedback mechanisms due to functional microtubule-actin crosstalk and implications for cancer cell motility. © 2011 Elsevier Ltd.

Helicobacter pylori (H. pylori) is the strongest identified risk factor for gastric cancer, the third most common cause of cancer-related death worldwide. An H. pylori constituent that augments cancer risk is the strain-specific cag pathogenicity island, which encodes a type IV secretion system (T4SS) that translocates a pro-inflammatory and oncogenic protein, CagA, into epithelial cells. However, the majority of persons colonized with CagA+ H. pylori strains do not develop cancer, suggesting that other microbial effectors also have a role in carcinogenesis. Toll-like receptor 9 (TLR9) is an endosome bound, innate immune receptor that detects and responds to hypo-methylated CpG DNA motifs that are most commonly found in microbial genomes. High-expression tlr9 polymorphisms have been linked to the development of premalignant lesions in the stomach. We now demonstrate that levels of H. pylori-mediated TLR9 activation and expression are directly related to gastric cancer risk in human populations. Mechanistically, we show for the first time that the H. pylori cancer-associated cag T4SS is required for TLR9 activation and that H. pylori DNA is actively translocated by the cag T4SS to engage this host receptor. Activation of TLR9 occurs through a contact-dependent mechanism between pathogen and host, and involves transfer of microbial DNA that is both protected as well as exposed during transport. These results indicate that TLR9 activation via the cag island may modify the risk for malignancy within the context of H. pylori infection and provide an important framework for future studies investigating the microbial–epithelial interface in gastric carcinogenesis.Oncogene advance online publication, 9 May 2016; doi:10.1038/onc.2016.158. © 2016 Macmillan Publishers Limited

Gualda G.A.R.,Vanderbilt University | Ghiorso M.S.,OFM Research West
Contributions to Mineralogy and Petrology | Year: 2013

The Bishop Tuff, one of the most extensively studied high-silica rhyolite bodies in the world, is usually considered as the archetypical example of a deposit formed from a magma body characterized by thermal and compositional vertical stratification-what we call the Standard Model for the Bishop magma body. We present here new geothermometry and geobarometry results derived using a large database of previously published quartz-hosted glass inclusion compositions. Assuming equilibrium between melt and an assemblage composed of quartz, ±plagioclase, ±sanidine, +zircon, ±fluid, we use Zr contents in glass inclusions to derive quartz crystallization temperatures, and we use (1) silica contents in glass, (2) projection of glass compositions onto the haplogranitic (quartz-albite-orthoclase) ternary, and (3) phase equilibria calculations using rhyolite-MELTS, to constrain crystallization pressures. We find crystallization temperatures of ~740-750 °C for all inclusions from both early- and late-erupted pumice. Crystallization pressures for both early- and late-erupted inclusions are also very similar to each other, with averages of ~175-200 MPa. We find no evidence of late-erupted inclusions having been entrapped at higher temperatures or pressures than early-erupted inclusions, as would be expected by the Standard Model. We argue that the thermal gradient inferred from Fe-Ti oxides-the backbone of the Standard Model-does not reflect equilibrium pre-eruptive conditions; we also note that H2O-CO2 systematics of glass inclusions yields overlapping pressure ranges for early- and late-erupted inclusions, similar to the results presented here; and we show that glass inclusion and phenocryst compositions show bimodal distributions, suggestive of compositional separation between early- and late-erupted populations. These findings are inconsistent with the Standard Model. The similarity in crystallization conditions and the compositional separation between early- and late-erupted magmas suggest that two laterally juxtaposed independent magma reservoirs existed in the same region at the same time and co-erupted to form the Long Valley Caldera and the Bishop Tuff. This hypothesis would explain the lack of mixing between early- and late-erupted crystal populations in pumice clasts; it could also explain the inferred eruption pattern-which resulted in early-erupted magmas being deposited only to the south of the caldera-if the early-erupted magma body resided to the south and the late-erupted magma body was located to the north. Our alternative model is consistent with the patchy distribution of thermal anomalies and the inference of co-eruption of distinct magma types in active volcanic areas such as the central Taupo Volcanic Zone. © 2013 Springer-Verlag Berlin Heidelberg.

Brantley-Sieders D.M.,Vanderbilt University
Seminars in Cell and Developmental Biology | Year: 2012

Pre-clinical studies provide compelling evidence that members of the Eph family of receptor tyrosine kinases and their ephrin ligands promote tumor growth, invasion and metastasis, and neovascularization. Tumor suppressive roles have also been reported for the receptors, and ligand-dependent versus ligand-independent signaling has emerged as one key mechanism underlying tumor suppressive function as opposed to oncogenic effects. Determining how these observations relate to clinical outcome is a crucial step for translating the biological and mechanistic data into new molecularly targeted therapies. Expression profiling in human patient samples bridges this gap and provides valuable clinical relevance to laboratory observations. In addition to analyses performed using privately assembled patient tumor samples, publically available microarray datasets and tissue microarrays linked to clinical data have emerged as tractable tools for addressing the clinical relevance of specific molecules and families of related molecules. This review summarizes the clinical relevance of specific Eph and ephrin molecules in human breast, colorectal, and lung cancers. © 2011 Elsevier Ltd.

Approximately 25% of human breast cancers overexpress the HER2 (ErbB2) proto-oncogene, which confers a more aggressive tumor phenotype and associates with a poor prognosis in patients with this disease. Two approved therapies targeting HER2, the monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib, are clinically active against this type of breast cancer. However, a significant fraction of patients with HER2+ breast cancer treated with these agents eventually relapse or develop progressive disease. This suggests that tumors acquire or possess intrinsic mechanisms of resistance that allow escape from HER2 inhibition. This review focuses on mechanisms of intrinsic and/or acquired resistance to HER2-targeted therapies that have been identified in preclinical and clinical studies. These mechanisms involve alterations to HER2 itself, coexpression or acquisition of bypass signaling through other receptor or intracellular signaling pathways, defects in mechanisms of cell cycle regulation or apoptosis, and host factors that may modulate drug response. Emerging clinical evidence already suggests that combinations of therapies targeting HER2 as well as these resistance pathways will be effective in overcoming or preventing resistance.

Patterson E.J.,Vanderbilt University
American Journal of Public Health | Year: 2013

Objectives. I investigated the differential impact of the dose-response of length of stay on postprison mortality among parolees. Methods. Using 1989-2003 New York State parole administrative data from the Bureau of Justice Statistics on state correctional facilities, I employed multinomial logistic regression analyses and formal demographic techniques that used the life table of the populations to deduce changes in life expectancy. Results. Each additional year in prison produced a 15.6% increase in the odds of death for parolees, which translated to a 2-year decline in life expectancy for each year served in prison. The risk was highest upon release from prison and declined over time. The time to recovery, or the lowest risk level, was approximately two thirds of the time served in prison. Conclusions. Incarceration reduces life span. Future research should investigate the pathways to this higher mortality and the possibilities of recovery.

Taylor W.D.,Geriatric Research | Taylor W.D.,Vanderbilt University
New England Journal of Medicine | Year: 2014

A 74-year-old woman with hypertension that is well controlled with hydrochlorothiazide is brought by her daughter for an evaluation. The daughter states that her mother is withdrawn, often tearful, and at times appears to have memory problems but has no history of psychiatric illness. The patient is a retired teacher who is widowed and has lived independently for several years. During the last few months, she has stopped going to church and visiting friends. The patient's symptoms include irritability, anhedonia, fatigue, a 4.5-kg (10-lb) weight loss over a period of 3 months, and difficulty sleeping. She feels like a burden to her family. How should she be treated? Copyright © 2014 Massachusetts Medical Society.

Objectives: To maintain optimal understanding, persons with sensorineural hearing loss (SNHL) often report a need for increased attention, concentration, and "listening effort" compared with persons without hearing loss. It is generally assumed that this increased effort is related to subjective reports of mental fatigue in persons with hearing loss. Although the benefits of hearing aids for improving intelligibility are well documented, their impact on listening effort and mental fatigue are less clear. This study used subjective and objective measures to examine the effects of hearing aid use and advanced hearing aid features on listening effort and mental fatigue in adults with SNHL. DESIGN: Sixteen adults (aged 47-69 years) with mild to severe sloping SNHL participated. A dual-task paradigm assessed word recognition, word recall, and visual reaction times (RTs) to objectively quantify listening effort and fatigue. Mental fatigue was operationally defined as a decrement in performance over the duration of the experiment (approximately 1 hr). Participants were fitted with study hearing aids and tested unaided and in two aided conditions (omnidirectional and with directional processing and digital noise reduction active). Subjective ratings of listening effort experienced during the day and ratings of fatigue and attentiveness immediately before and after the dual-task were also obtained. Results: Word recall was better and dual-task RTs were significantly faster in the aided compared with unaided conditions, suggesting a decrease in listening effort when listening aided. Word recognition and recall in unaided and aided conditions remained relatively stable over the duration of the dual-task, suggesting these processes were resistant to mental fatigue. In contrast, dual-task RTs systematically increased over the duration of the speech task when listening unaided, consistent with development of mental fatigue. However, dual-task RTs remained stable over time in both aided conditions suggesting that hearing aid use reduced susceptibility to mental fatigue. Subjective ratings of fatigue and attentiveness also increased significantly after completion of the dual-task; however, no differences between unaided and aided subjective ratings were observed. Correlation analyses between subjective and objective measures of listening effort and mental fatigue showed no strong or consistent relationship. Likewise, subject variables such as age and degree of hearing loss showed no strong or consistent relationship to either subjective or objective measures of listening effort or mental fatigue. Conclusions: Results from subjective and select objective measures suggest sustained speech-processing demands can lead to mental fatigue in persons with hearing loss. It is important to note that the use of clinically fit hearing aids may reduce listening effort and susceptibility to mental fatigue associated with sustained speech-processing demands. The present study design did not reveal additional benefits, in terms of reduced listening effort or fatigue, from use of directional processing and digital noise-reduction algorithms. However, experimental design limitations suggest further work in this area is needed. Finally, subjective and objective measures of listening effort and mental fatigue due to sustained speech-processing demands, were not strongly associated, suggesting that these measures may assess different aspects of listening effort and mental fatigue. © 2013 by Lippincott Williams and Wilkins.

Von Figura G.,University of California at San Francisco | Morris IV J.P.,University of California at San Francisco | Wright C.V.E.,Vanderbilt University | Hebrok M.,University of California at San Francisco
Gut | Year: 2014

Objectives: Emerging evidence from mouse models suggests that mutant Kras can drive the development of pancreatic ductal adenocarcinoma (PDA) precursors from acinar cells by enforcing ductal de-differentiation at the expense of acinar identity. Recently, human genomewide association studies have identified NR5A2, a key regulator of acinar function, as a susceptibility locus for human PDA. We investigated the role of Nr5a2 in exocrine maintenance, regeneration and Kras driven neoplasia. Design: To investigate the function of Nr5a2 in the pancreas, we generated mice with conditional pancreatic Nr5a2 deletion (PdxCrelate; Nr5a2c/c). Using this model, we evaluated acinar differentiation, regeneration after caerulein pancreatitis and Kras driven pancreatic neoplasia in the setting of Nr5a2 deletion. Results: We show that Nr5a2 is not required for the development of the pancreatic acinar lineage but is important for maintenance of acinar identity. Nr5a2 deletion leads to destabilisation of the mature acinar differentiation state, acinar to ductal metaplasia and loss of regenerative capacity following acute caerulein pancreatitis. Loss of Nr5a2 also dramatically accelerates the development of oncogenic Kras driven acinar to ductal metaplasia and PDA precursor lesions. Conclusions: Nr5a2 is a key regulator of acinar plasticity. It is required for maintenance of acinar identity and re-establishing acinar fate during regeneration. Nr5a2 also constrains pancreatic neoplasia driven by oncogenic Kras, providing functional evidence supporting a potential role as a susceptibility gene for human PDA.

DeLaughter D.M.,Vanderbilt University
Journal of molecular and cellular cardiology | Year: 2013

Valvular Interstitial Cells (VICs) are a common substrate for congenital and adult heart disease yet the signaling mechanisms governing their formation during early valvulogenesis are incompletely understood. We developed an unbiased strategy to identify genes important in endocardial epithelial-to-mesenchymal transformation (EMT) using a spatial transcriptional profile. Endocardial cells overlaying the cushions of the atrioventricular canal (AVC) and outflow tract (OFT) undergo an EMT to yield VICs. RNA sequencing (RNA-seq) analysis of gene expression between AVC, OFT, and ventricles (VEN) isolated from chick and mouse embryos at comparable stages of development (chick HH18; mouse E11.0) was performed. EMT occurs in the AVC and OFT cushions, but not VEN at this time. 198 genes in the chick (n=1) and 105 genes in the mouse (n=2) were enriched 2-fold in the cushions. Gene regulatory networks (GRN) generated from cushion-enriched gene lists confirmed TGFβ as a nodal point and identified NF-κB as a potential node. To reveal previously unrecognized regulators of EMT four candidate genes, Hapln1, Id1, Foxp2, and Meis2, and a candidate pathway, NF-κB, were selected. In vivo spatial expression of each gene was confirmed by in situ hybridization and a functional role for each in endocardial EMT was determined by siRNA knockdown in a collagen gel assay. Our spatial-transcriptional profiling strategy yielded gene lists which reflected the known biology of the system. Further analysis accurately identified and validated previously unrecognized novel candidate genes and the NF-κB pathway as regulators of endocardial cell EMT in vitro. Copyright © 2013 Elsevier Ltd. All rights reserved.

Harris R.C.,Vanderbilt University
Transactions of the American Clinical and Climatological Association | Year: 2013

In the mammalian kidney, prostaglandins are important mediators of physiologic processes, including modulation of vascular tone and salt and water. Prostaglandins arise from enzymatic metabolism of free arachidonic acid (AA), which is cleaved from membrane phospholipids by phospholipase A2 activity. The cyclooxygenase (COX) enzyme system is a major pathway for metabolism of arachidonic acid in the kidney. Cyclooxygenases are the enzymes responsible for the initial conversion of AA to PGG2 and subsequently to PGH2, which serves as the precursor for subsequent metabolism by specific prostaglandin and thromboxane synthases. In addition to high levels of expression of the "constitutive" rate-limiting enzyme responsible for prostanoid production, COX-1, the "inducible" isoform of cyclooxygenase, COX-2, is also constitutively expressed in the kidney and is highly regulated in response to alterations in intravascular volume. Prostaglandins and thromboxane A2 exert their biological functions predominantly through activation of specific 7-transmembrane G-protein-coupled receptors. We and others have shown that COX-2-derived prostaglandins exert important physiologic functions in maintenance of renal blood flow, mediation of renin release, and regulation of sodium excretion. In addition to physiologic regulation of prostanoid production in the kidney, increases in prostanoid production are also observed in a variety of inflammatory renal injuries, and we have found a role for COX metabolites to serve as mediators of inflammatory injury in renal disease.

Dikalov S.I.,Vanderbilt University | Ungvari Z.,The University of Oklahoma Health Sciences Center
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2013

Based on mosaic theory, hypertension is a multifactorial disorder that develops because of genetic, environmental, anatomical, adaptive neural, endocrine, humoral, and hemodynamic factors. It has been recently proposed that oxidative stress may contribute to all of these factors and production of reactive oxygen species (ROS) play an important role in the development of hypertension. Previous studies focusing on the role of vascular NADPH oxidases provided strong support of this concept. Although mitochondria represent one of the most significant sources of cellular ROS generation, the regulation of mitochondrial ROS generation in the cardiovascular system and its pathophysiological role in hypertension are much less understood. In this review, the role of mitochondrial oxidative stress in the pathophysiology of hypertension and cross talk between angiotensin II signaling, pathways involved in mechanotransduction, NADPH oxidases, and mitochondria-derived ROS are considered. The possible benefits of therapeutic strategies that have the potential to attenuate mitochondrial oxidative stress for the prevention/treatment of hypertension are also discussed. © 2013 the American Physiological Society.

Liu Q.,Vanderbilt University
BMC genomics | Year: 2012

Accurate calling of SNPs and genotypes from next-generation sequencing data is an essential prerequisite for most human genetics studies. A number of computational steps are required or recommended when translating the raw sequencing data into the final calls. However, whether each step does contribute to the performance of variant calling and how it affects the accuracy still remain unclear, making it difficult to select and arrange appropriate steps to derive high quality variants from different sequencing data. In this study, we made a systematic assessment of the relative contribution of each step to the accuracy of variant calling from Illumina DNA sequencing data. We found that the read preprocessing step did not improve the accuracy of variant calling, contrary to the general expectation. Although trimming off low-quality tails helped align more reads, it introduced lots of false positives. The ability of markup duplication, local realignment and recalibration, to help eliminate false positive variants depended on the sequencing depth. Rearranging these steps did not affect the results. The relative performance of three popular multi-sample SNP callers, SAMtools, GATK, and GlfMultiples, also varied with the sequencing depth. Our findings clarify the necessity and effectiveness of computational steps for improving the accuracy of SNP and genotype calls from Illumina sequencing data and can serve as a general guideline for choosing SNP calling strategies for data with different coverage.

Lowe M.L.,Texas A&M University | Haws K.L.,Vanderbilt University
Journal of Consumer Research | Year: 2014

Although most consumer self-control decisions are made individually, they are rarely made in isolation. Temptations are often simultaneously encountered by multiple members of a group or dyad and thereby susceptible to social influence. However, little is known about these "parallel" self-control decisions or the resulting social consequences. In a series of studies spanning the domains of money, time management, and food consumption, consumers demonstrated a tendency to bond over matched self-control decisions through "coindulgence" or "coabstinence." The perceived severity of choosing vice over virtue influenced when each of these matched outcomes produced greater affiliation. When indulgence threatened to seriously hinder goal progress, consumers bonded through moral support evidenced by joint abstention. When the consequences were perceived as relatively less severe, consumers found friendship through partnering in crime by both indulging. Throughout, guilt underlies the relationship between self-control behaviors and social outcomes, as peer compliance reduces guilt and thus improves affiliation. © 2014 by JOURNAL OF CONSUMER RESEARCH, Inc.

Even with hormone-targeted and human epidermal growth factor receptor 2 (HER2)-targeted anticancer agents, intrinsic resistance or acquired resistance are common occurrences in estrogen receptor-positive and HER2-positive breast cancers, respectively. Potential mechanisms for resistance to targeted agents include steric inhibition imposed by other cellular elements, molecular changes in the target receptor, alterations in the regulation of downstream signaling components, compensatory cross-talk with other signaling pathways, and pharmacogenetic alterations in the host. Evidence suggests that both hormone receptor-positive tumors and HER2-overexpressing tumors use the phosphoinositide 3-kinase/Akt/ mammalian target of rapamycin (mTOR) pathway to escape control of antihormone and anti-HER2 therapies. The combination of mTOR inhibitors with hormone-targeted or HER2-targeted therapies appears to be a promising strategy for overcoming resistant disease and preventing the development of resistance.

Bone remodeling is a delicate balancing act between the bone matrix synthesizing osteoblasts and bone resorbing osteoclasts. Active bone metastases typically subvert this process to generate lesions that are comprised of extensive areas of pathological osteogenesis and osteolysis. The resultant increase in bone matrix remodeling enhances cytokine/growth factor bioavailability thus creating a vicious cycle that stimulates tumor progression. Given the extent of matrix remodeling occurring in the tumor-bone microenvironment, the expression of matrix metalloproteinases (MMPs) would be expected, since collectively they have the ability to degrade all components of the extracellular matrix (ECM). However, in addition to being "matrix bulldozers", MMPs control the bioavailability and bioactivity of factors such as RANKL and TGFβ that have been described as crucial for tumor-bone interaction, thus implicating MMPs as key regulators of the vicious cycle of bone metastases. © 2010 Elsevier Inc.

Telomeres are specialized chromatin structures essential for the maintenance of chromosomal integrity and stability. Telomere shortening has been linked to multiple aging-related diseases, including cancer. Evidence associating telomere length with breast cancer risk - most of which has been from retrospective case-control studies - is conflicting. We conducted a nested case-control study based on the Shanghai Women's Health Study (1997-2009) in which we evaluated the association of telomere length and breast cancer risk using peripheral blood samples collected before cancer diagnosis (601 cases and 695 controls). We used monochrome multiplex quantitative polymerase chain reaction to measure relative telomere length. Multiple logistic regressions were used to derive adjusted odds ratios with 95% confidence intervals as the measure of association. Telomere length was inversely correlated with age (r = -0.22). Women with moderately long telomeres (those in the fourth quintile) had the lowest breast cancer risk. Risk increased in a dose-response manner with decreasing quintile of telomere length; odds ratios were 1.39 (95% confidence interval (CI): 0.95, 2.04), 1.79 (95% CI: 1.17, 2.75), and 2.39 (95% CI: 1.45, 3.92), respectively, for the third, second, and first quintiles compared with the fourth quintile. A slightly elevated risk of breast cancer (odds ratio = 1.35, 95% CI: 0.90, 2.04), although one that was not statistically significant, was found in the top quintile (longest telomeres). Our results support the hypothesis that telomere shortening is associated with increased risk of breast cancer and suggest a possible elevated risk associated with long telomeres. © 2013 The Author.

Miller T.W.,Vanderbilt University
Breast Cancer Research | Year: 2012

PIK3CA mutations confer constitutive activation of PI3K, which initiates intracellular kinase signaling cascades that promote cell proliferation and survival. Recent studies by Meyer and colleagues, and Liu and colleagues demonstrate that expression of the H1047R exon 20 mutant of PIK3CA in luminal mammary epithelial cells induces tumorigenesis, implying that PIK3CA mutation is an early event in breast cancer. PIK3CA-H1047R-initiated tumors exhibit variable dependence on the oncogene and variable sensitivity to PI3K inhibition. Amplification of the oncogenes MYC and MET was observed in tumors that recurred following silencing of PIK3CA-H1047R, suggesting that these pathways represent mechanisms of escape from PI3K inhibition. © 2012 BioMed Central Ltd.

Alex Brown H.,Vanderbilt University
Current Opinion in Chemical Biology | Year: 2012

Lipidomics is a branch of the field of metabolomics. Although only about a decade since its inception, lipidomics has already had a major influence on the way in which questions about lipid metabolism and signaling are posed. The field is intertwined in the culture and rich history of mass spectrometry. Early work emphasized analytical issues such as limits of detection and numbers of molecular species quantitated in single injections. Increased sophistication in applications of lipidomic analysis and emerging technologies, such as imaging mass spectrometry, are facilitating the study of lipid metabolism and signaling species in cellular functions and human diseases. In the coming years we anticipate a richer understanding of how specific lipid species mediate complex biological processes and interconnections between cellular pathways that were thought to be disparate. © 2012 Elsevier Ltd.

Webster III R.J.,Vanderbilt University | Jones B.A.,Mississippi State University
International Journal of Robotics Research | Year: 2010

Continuum robotics has rapidly become a rich and diverse area of research, with many designs and applications demonstrated. Despite this diversity in form and purpose, there exists remarkable similarity in the fundamental simplified kinematic models that have been applied to continuum robots. However, this can easily be obscured, especially to a newcomer to the field, by the different applications, coordinate frame choices, and analytical formalisms employed. In this paper we review several modeling approaches in a common frame and notational convention, illustrating that for piecewise constant curvature, they produce identical results. This discussion elucidates what has been articulated in different ways by a number of researchers in the past several years, namely that constant-curvature kinematics can be considered as consisting of two separate submappings: one that is general and applies to all continuum robots, and another that is robot-specific. These mappings are then developed both for the single-section and for the multi-section case. Similarly, we discuss the decomposition of differential kinematics (the robot's Jacobian) into robot-specific and robot-independent portions. The paper concludes with a perspective on several of the themes of current research that are shaping the future of continuum robotics. © The Author(s) 2010.

Phospholipid bilayers that constitute endo-lysosomal vesicles can pose a barrier to delivery of biologic drugs to intracellular targets. To overcome this barrier, a number of synthetic drug carriers have been engineered to actively disrupt the endosomal membrane and deliver cargo into the cytoplasm. Here, we describe the hemolysis assay, which can be used as rapid, high-throughput screen for the cytocompatibility and endosomolytic activity of intracellular drug delivery systems. In the hemolysis assay, human red blood cells and test materials are co-incubated in buffers at defined pHs that mimic extracellular, early endosomal, and late endo-lysosomal environments. Following a centrifugation step to pellet intact red blood cells, the amount of hemoglobin released into the medium is spectrophotometrically measured (405 nm for best dynamic range). The percent red blood cell disruption is then quantified relative to positive control samples lysed with a detergent. In this model system the erythrocyte membrane serves as a surrogate for the lipid bilayer membrane that enclose endo-lysosomal vesicles. The desired result is negligible hemolysis at physiologic pH (7.4) and robust hemolysis in the endo-lysosomal pH range from approximately pH 5-6.8.

Brown N.J.,Vanderbilt University
Journal of the American Society of Hypertension | Year: 2012

Hyperglycemia is associated with increased risk of cardiovascular disease. Nevertheless, results of large clinical trials suggest that tight glucose control does not reduce the risk of macrovascular cardiovascular events in type 2 diabetes mellitus and may cause harm. This may reflect the adverse consequences of increased hypoglycemia or the adverse effects of many antidiabetic agents on weight gain. The consequences of intensive therapy may also depend on the mechanism of the antidiabetic agent(s) used to achieve tight control. Metformin, an antidiabetic agent that reduces weight and activates AMP-activated protein kinase, reduces risk of cardiovascular events in overweight diabetics. In contrast, the thiazolidinedione rosiglitazone increases cardiovascular risk. Sulfonylureas may increase the risk of cardiovascular events through effects on the SUR1 of the cardiac KATP channel. Stable analogues of glucagon-like peptide-1 reduce body weight and blood pressure, and have favorable effects on ischemia following reperfusion in animal models. The dipeptidyl peptidase IV inhibitors prevent the breakdown of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, but also decrease the degradation of several vasoactive peptides. Dipeptidyl peptidase IV inhibitors have favorable effects in animal models of ischemia/reperfusion. They have been reported both to decrease and to increase blood pressure. Clinical trials will address the effect of the incretin-based agents on macrovascular cardiovascular events. © 2012 American Society of Hypertension. All rights reserved.

Velkovska J.,Vanderbilt University
Journal of Physics G: Nuclear and Particle Physics | Year: 2011

We report on the CMS measurements of charged hadron anisotropic azimuthal distributions from PbPb collisions at √SNN = 2.76 TeV and their decomposition into a Fourier series up to the sixth coefficient. The results are presented as a function of transverse momentum (PT), centrality and pseudorapidity (η) and cover a broad kinematic range. The scaling with the respective participant eccentricity is studied. The sensitivity of different harmonic coefficients to the dynamical models that describe the medium produced in the collisions is discussed. © CERN 2011. Published under licence by IOP Publishing Ltd.

Luther J.M.,Vanderbilt University
Current Opinion in Nephrology and Hypertension | Year: 2014

PURPOSE OF REVIEW: Aldosterone and the mineralocorticoid receptor contribute to resistant hypertension and cardiovascular mortality, and mineralocorticoid receptor antagonists effectively reduce these complications. Their use is limited in certain populations with a higher risk of hyperkalemia or renal dysfunction. This review will highlight recent developments in extra-renal mineralocorticoid receptor research and the development of novel mineralocorticoid receptor antagonists. RECENT FINDINGS: Tissue-specific knockout-out models provide definitive evidence that the vascular mineralocorticoid receptor directly contributes to hypertension and vascular remodeling, independent of renal effects. Several nonsteroidal mineralocorticoid receptor antagonists are in preclinical development or early-stage clinical trials. Several nonsteroidal mineralocorticoid receptor antagonists have demonstrated preserved cardiovascular benefit with a reduced incidence of hyperkalemia in preclinical studies. SUMMARY: Novel, potent nonsteroidal mineralocorticoid receptor antagonists are in development, although their effect on cardiovascular and adverse drug events requires further investigation. Copyright © Lippincott Williams & Wilkins.

Wolery M.,Vanderbilt University
Topics in Early Childhood Special Education | Year: 2011

In this commentary, the issue of fidelity assessment is addressed as it relates to Strain and Bovey's article (2011). Four reasons are provided for measuring fidelity in intervention studies. Measuring fidelity (a) potentially allows investigators to document the findings were not due to the lack of fidelity in a study; (b) presents information about how transportable interventions are to the real world; (c) provides information for replication studies; and (d) sheds light on the nature of children's experiences in the study. © Hammill Institute on Disabilities 2011.

Zimmerman L.J.,Vanderbilt University
Molecular & cellular proteomics : MCP | Year: 2012

Peptide-based mass spectrometry approaches, such as multiple reaction monitoring, provide a powerful means to measure candidate protein biomarkers in plasma. A potential confounding problem is the effect of preanalytical variables, which may affect the integrity of proteins and peptides. Although some blood proteins undergo rapid physiological proteolysis ex vivo, the stability of most plasma proteins to preanalytical variables remains largely unexplored. We applied liquid chromatography-tandem mass spectrometry shotgun proteomics and multiple reaction monitoring analyses to characterize the stability of proteins at the peptide level in plasma. We systematically evaluated the effects of delay in plasma preparation at different temperatures, multiple freeze-thaw cycles and erythocyte hemolysis on peptide and protein inventories in prospectively collected human plasma. Time course studies indicated few significant changes in peptide and protein identifications, semitryptic peptides and methionine-oxidized peptides in plasma from blood collected in EDTA plasma tubes and stored for up to a week at 4 °C or room temperature prior to plasma isolation. Similarly, few significant changes were observed in similar analyses of plasma subjected to up to 25 freeze-thaw cycles. Hemolyzed samples produced no significant differences beyond the presence of hemoglobin proteins. Finally, paired comparisons of plasma and serum samples prepared from the same patients also yielded few significant differences, except for the depletion of fibrinogen in serum. Blood proteins thus are broadly stable to preanalytical variables when analyzed at the peptide level. Collection protocols to generate plasma for multiple reaction monitoring-based analyses may have different requirements than for other analyses directed at intact proteins.

West J.,Vanderbilt University
Advances in Experimental Medicine and Biology | Year: 2010

The gene for the type 2 receptor for the bone morphogenic pathway, BMPR2, is mutated in a large majority of familial pulmonary arterial hypertension (PAH),. However, the mechanisms linking BMPR2 mutation to disease remain obscure. BMPR2 potentially signals through multiple immediate downstream pathways, including Smad, MAPK, LIM domain kinase 1 (LIMK) and dynein, light chain, Tctex-type 1 (TCTEX), v-src sarcoma viral oncogene homolog (SRC), and nuclear factor kappa-B (NFkB). Functional consequences of BMPR2 mutation, largely ascertained from animal models, include a shift from contractile to synthetic phenotype in smooth muscle, probably downstream of Smad signal; alterations in expression of actin organization related genes, possibly related to focal adhesions; alterations in cytokines and inflammatory cell recruitment; increased proliferation and apoptosis; and increased collagen and matrix. A synthesis of the available data suggests that the normal role of BMPR2 in adult animals is to assist in injury repair. BMPR2 is suppressed in injured tissue, which facilitates inflammatory response, shift to a synthetic cellular phenotype, and alterations in migration or permeability of cells in the vascular wall. We thus hypothesize that BMPR2 mutation thus leads to an impaired ability to terminate the injury repair process, leading to strong predisposition to PAH. © Humana Press, a part of Springer Science+ Business Media, LLC 2010.

Unni P.,Vanderbilt University
The journal of trauma and acute care surgery | Year: 2012

Trauma registries capture data about injuries that can be used to objectively guide injury prevention initiatives. This article analyzes trauma registry data to describe the nature and distribution of all-terrain vehicle (ATV) injuries in Middle Tennessee. A community injury prevention effort, based on this analysis, is also presented. A retrospective analysis of data (2007-2009) from the trauma registry of a Level I pediatric trauma center in Middle Tennessee was conducted. Patients younger than 16 years with ATV-related injuries were included in the analysis (n = 163). The key variables examined were demographics, injury severity, helmet use, injury mechanism, length of stay, and patient's county of residence. In addition, Geographic Information Systems software was used to examine the distribution of injuries and graphically represent counties with highest injury rates in the youth population. ATV injuries were more prevalent among boys than girls (66% vs. 34%; p < 0.001). Approximately 64% of the ATV injuries were in the age group 10 years to 15 years. Most injuries were either moderately severe (44%) or severe (30%). Injury mechanism varied by age; younger children experienced more rollovers while older children tended to be injured from ejections (p < 0.05). Helmet use was low (33%). Data from this study suggest that helmet use resulted in fewer injuries to the head, neck, and face. Counties with high rates of ATV injuries were targeted for ATV training programs. 4-H agents trained by the ATV Safety Institute provided ATV training classes. Rural youth are clearly at greater risk for ATV injuries than urban populations. Young ATV riders are often self-taught and lack the knowledge to ride ATVs safely. Organizations such as the 4-H, provide effective injury prevention outreach. Epidemiologic study, level III.

Buller H.R.,University of Amsterdam | Bethune C.,Isis Pharmaceuticals | Bhanot S.,Isis Pharmaceuticals | Gailani D.,Vanderbilt University | And 5 more authors.
New England Journal of Medicine | Year: 2015

Background Experimental data indicate that reducing factor XI levels attenuates thrombosis without causing bleeding, but the role of factor XI in the prevention of postoperative venous thrombosis in humans is unknown. FXI-ASO (ISIS 416858) is a secondgeneration antisense oligonucleotide that specifically reduces factor XI levels. We compared the efficacy and safety of FXI-ASO with those of enoxaparin in patients undergoing total knee arthroplasty. Methods In this open-label, parallel-group study, we randomly assigned 300 patients who were undergoing elective primary unilateral total knee arthroplasty to receive one of two doses of FXI-ASO (200 mg or 300 mg) or 40 mg of enoxaparin once daily. The primary efficacy outcome was the incidence of venous thromboembolism (assessed by mandatory bilateral venography or report of symptomatic events). The principal safety outcome was major or clinically relevant nonmajor bleeding. Results Around the time of surgery, the mean (+ACY-plusmn;SE) factor XI levels were 0.38+ACY-plusmn;0.01 units per milliliter in the 200-mg FXI-ASO group, 0.20+ACY-plusmn;0.01 units per milliliter in the 300-mg FXI-ASO group, and 0.93+ACY-plusmn;0.02 units per milliliter in the enoxaparin group. The primary efficacy outcome occurred in 36 of 134 patients (27+ACU-) who received the 200-mg dose of FXI-ASO and in 3 of 71 patients (4+ACU-) who received the 300-mg dose of FXI-ASO, as compared with 21 of 69 patients (30+ACU-) who received enoxaparin. The 200-mg regimen was noninferior, and the 300-mg regimen was superior, to enoxaparin (P+ACY-lt;0.001). Bleeding occurred in 3+ACU-, 3+ACU-, and 8+ACU- of the patients in the three study groups, respectively. Conclusions This study showed that factor XI contributes to postoperative venous thromboembolism; reducing factor XI levels in patients undergoing elective primary unilateral total knee arthroplasty was an effective method for its prevention and appeared to be safe with respect to the risk of bleeding. Copyright + 2014 Massachusetts Medical Society.

Veenstra-VanderWeele J.,Columbia University | Warren Z.,Vanderbilt University
Neuropsychopharmacology | Year: 2015

Neuropsychiatric disorders vary substantially in age of onset but are best understood within the context of neurodevelopment. Here, we review opportunities for intervention at critical points in developmental trajectories. We begin by discussing potential opportunities to prevent neuropsychiatric disorders. Once symptoms begin to emerge, a number of interventions have been studied either before a diagnosis can be made or shortly after diagnosis. Although some of these interventions are helpful, few are based upon an understanding of pathophysiology, and most ameliorate rather than resolve symptoms. As such, in the next portion of the review, we turn our discussion to genetic syndromes that are rare phenocopies of common diagnoses such as autism spectrum disorder or schizophrenia. Cellular or animal models of these syndromes point to specific regulatory or signaling pathways. As examples, findings from the mouse models of Fragile X and Rett syndromes point to potential treatments now being tested in randomized clinical trials. Paralleling oncology, we can hope that our treatments will move from nonspecific, like chemotherapies thrown at a wide range of tumor types, to specific, like the protein kinase inhibitors that target molecularly defined tumors. Some of these targeted treatments later show benefit for a broader, yet specific, array of cancers. We can hope that medications developed within rare neurodevelopmental syndromes will similarly help subgroups of patients with disruptions in overlapping signaling pathways. The insights gleaned from treatment development in rare phenocopy syndromes may also teach us how to test treatments based upon emerging common genetic or environmental risk factors. © 2015 American College of Neuropsychopharmacology. All rights reserved.

The mammalian target of rapamycin (mTOR), an essential serine/threonine kinase, functions in biochemically distinct multiprotein complexes, but little is known about roles of the complexes in B cells. The acutely rapamycin-sensitive mTOR complex 1 (mTORC1) is defined by a core subunit Raptor, whereas mTORC2 lacks Raptor and, instead, has Rictor and SIN1 as distinct essential components. We now show that homeostasis and function of B cells require Rictor. Conditional deletion of Rictor before lymphoid specification impaired generation of mature follicular, marginal zone, and B1a B lymphocytes. Induced inactivation in adult mice caused cell-autonomous defects in B lymphoid homeostasis and antibody responses in vivo, along with affecting plasma cells in bone marrow. Survival of B lymphocytes depended on Rictor, which was vital for normal induction of prosurvival genes, suppression of proapoptotic genes, nuclear factor κB induction after B-cell receptor stimulation, and B-cell activating factor-induced nuclear factor κB2/p52 generation. Collectively, the findings provide evidence that mTOR signaling affects survival and proliferation of mature B lymphocytes, and establish Rictor as an important signal relay in B-cell homeostasis, fate, and functions.

Logan G.D.,Vanderbilt University
Quarterly Journal of Experimental Psychology | Year: 2015

Bartlett (1958. Thinking. New York: Basic Books) described the point of no return as a point of irrevocable commitment to action, which was preceded by a period of gradually increasing commitment. As such, the point of no return reflects a fundamental limit on the ability to control thought and action. I review the literature on the point of no return, taking three perspectives. First, I consider the point of no return from the perspective of the controlled act, as a locus in the architecture and anatomy of the underlying processes. I review experiments from the stop-signal paradigm that suggest that the point of no return is located late in the response system. Then I consider the point of no return from the perspective of the act of control that tries to change the controlled act before it becomes irrevocable. From this perspective, the point of no return is a point in time that provides enough “lead time” for the act of control to take effect. I review experiments that measure the response time to the stop signal as the lead time required for response inhibition in the stop-signal paradigm. Finally, I consider the point of no return in hierarchically controlled tasks, in which there may be many points of no return at different levels of the hierarchy. I review experiments on skilled typing that suggest different points of no return for the commands that determine what is typed and the countermands that inhibit typing, with increasing commitment to action the lower the level in the hierarchy. I end by considering the point of no return in perception and thought as well as action. © 2015, The Experimental Psychology Society.

Peter Guengerich F.,Vanderbilt University
Drug Metabolism and Pharmacokinetics | Year: 2011

Toxicity has been estimated to be responsible for the attrition of approximately one-third of drug candidates and is a major contributor to the high cost of drug development, particularly when not recognized until late in clinical trials or post-marketing. The causes of drug toxicity can be classified in several ways and include mechanism-based (on-target) toxicity, immune hypersensitivity, off-target toxicity, and bioactivation/covalent modification. In addition, idiosyncratic responses are rare but can be one of the most problematic issues; several hypotheses for these have been advanced. Although covalent binding of drugs to proteins was described almost 40 years ago, the significance to toxicity has been difficult to establish; recent literature in this field is considered. The development of more useful biomarkers and short-term assays for rapid screening of drug toxicity early in the drug discovery/development process is a major goal, and some progress has been made using "omics" approaches.

Hammock E.A.D.,Vanderbilt University
Neuropsychopharmacology | Year: 2015

The related neuropeptides oxytocin and vasopressin are involved in species-typical behavior, including social recognition behavior, maternal behavior, social bonding, communication, and aggression. A wealth of evidence from animal models demonstrates significant modulation of adult social behavior by both of these neuropeptides and their receptors. Over the last decade, there has been a flood of studies in humans also implicating a role for these neuropeptides in human social behavior. Despite popular assumptions that oxytocin is a molecule of social bonding in the infant brain, less mechanistic research emphasis has been placed on the potential role of these neuropeptides in the developmental emergence of the neural substrates of behavior. This review summarizes what is known and assumed about the developmental influence of these neuropeptides and outlines the important unanswered questions and testable hypotheses. There is tremendous translational need to understand the functions of these neuropeptides in mammalian experience-dependent development of the social brain. The activity of oxytocin and vasopressin during development should inform our understanding of individual, sex, and species differences in social behavior later in life. © 2015 American College of Neuropsychopharmacology. All rights reserved.

Geng Y.,Vanderbilt University
Blood | Year: 2013

Factor XI (fXI) is a homodimeric zymogen that is converted to a protease with 1 (1/2-fXIa) or 2 (fXIa) active subunits by factor XIIa (fXIIa) or thrombin. It has been proposed that the dimeric structure is required for normal fXI activation. Consistent with this premise, fXI monomers do not reconstitute fXI-deficient mice in a fXIIa-dependent thrombosis model. FXI activation by fXIIa or thrombin is a slow reaction that can be accelerated by polyanions. Phosphate polymers released from platelets (poly-P) can enhance fXI activation by thrombin and promote fXI autoactivation. Poly-P increased initial rates of fXI activation 30- and 3000-fold for fXIIa and thrombin, respectively. FXI monomers were activated more slowly than dimers by fXIIa in the presence of poly-P. However, this defect was not observed when thrombin was the activating protease, nor during fXI autoactivation. The data suggest that fXIIa and thrombin activate fXI by different mechanisms. FXIIa may activate fXI through a trans-activation mechanism in which the protease binds to 1 subunit of the dimer, while activating the other subunit. For activation by thrombin, or during autoactivation, the data support a cis-activation mechanism in which the activating protease binds to and activates the same fXI subunit.

Eichbaum Q.,Vanderbilt University
Academic Medicine | Year: 2015

The demand for global health educational opportunities among students and trainees in high-income countries (HICs) has led to a proliferation of available global health programs. In keeping with the drive towards competency-based medical education, many of these programs have been defining their own global health competencies. Developing such competencies presents several unique challenges, including (1) a failure to take sufficient account of local contexts coupled with a lack of inclusiveness in developing these competencies, (2) the disjunction between the learning approaches of "individualism" in HICs and the relative "collectivism" of most host countries, and (3) shortcomings associated with assessing competencies in resource-limited settings. To meet these challenges, the author recommends reenvisioning the approach to competencies in global health using fresh metaphors, innovative modes of assessment, and the creation of more appropriate competency domains.

Newcomer M.E.,Louisiana State University | Brash A.R.,Vanderbilt University
Protein Science | Year: 2015

Many intriguing facets of lipoxygenase (LOX) catalysis are open to a detailed structural analysis. Polyunsaturated fatty acids with two to six double bonds are oxygenated precisely on a particular carbon, typically forming a single chiral fatty acid hydroperoxide product. Molecular oxygen is not bound or liganded during catalysis, yet it is directed precisely to one position and one stereo configuration on the reacting fatty acid. The transformations proceed upon exposure of substrate to enzyme in the presence of O2 (RH + O2 → ROOH), so it has proved challenging to capture the precise mode of substrate binding in the LOX active site. Beginning with crystal structures with bound inhibitors or surrogate substrates, and most recently arachidonic acid bound under anaerobic conditions, a picture is consolidating of catalysis in a U-shaped fatty acid binding channel in which individual LOX enzymes use distinct amino acids to control the head-to-tail orientation of the fatty acid and register of the selected pentadiene opposite the non-heme iron, suitably positioned for the initial stereoselective hydrogen abstraction and subsequent reaction with O2. Drawing on the crystal structures available currently, this review features the roles of the N-terminal β-barrel (C2-like, or PLAT domain) in substrate acquisition and sensitivity to cellular calcium, and the α-helical catalytic domain in fatty acid binding and reactions with O2 that produce hydroperoxide products with regio and stereospecificity. LOX structures combine to explain how similar enzymes with conserved catalytic machinery differ in product, but not substrate, specificities. Interactive Figure 2; Interactive Figure 3; Interactive Figure 8. © 2014 The Protein Society.

Fine J.-D.,Vanderbilt University
Orphanet Journal of Rare Diseases | Year: 2010

Inherited epidermolysis bullosa (EB) encompasses a number of disorders characterized by recurrent blister formation as the result of structural fragility within the skin and selected other tissues. All types and subtypes of EB are rare; the overall incidence and prevalence of the disease within the United States is approximately 19 per one million live births and 8 per one million population, respectively. Clinical manifestations range widely, from localized blistering of the hands and feet to generalized blistering of the skin and oral cavity, and injury to many internal organs. Each EB subtype is known to arise from mutations within the genes encoding for several different proteins, each of which is intimately involved in the maintenance of keratinocyte structural stability or adhesion of the keratinocyte to the underlying dermis. EB is best diagnosed and subclassified by the collective findings obtained via detailed personal and family history, in concert with the results of immunofluorescence antigenic mapping, transmission electron microscopy, and in some cases, by DNA analysis. Optimal patient management requires a multidisciplinary approach, and revolves around the protection of susceptible tissues against trauma, use of sophisticated wound care dressings, aggressive nutritional support, and early medical or surgical interventions to correct whenever possible the extracutaneous complications. Prognosis varies considerably and is based on both EB subtype and the overall health of the patient. © 2010 Fine; licensee BioMed Central Ltd.

Macara I.G.,Vanderbilt University | McCaffrey L.,McGill University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2013

Most human cancers arise either from epithelial cells or their progenitors. Epithelial cells possess a distinctive apical-basal polarity and loss of polarity is frequently assumed to be a common feature of cancer progression. In particular, cancer cell dissemination to ectopic sites, and metastatic growth at those sites, is often considered to require a mesenchymal transition in which the transformed epithelial cells lose their apical-basal polarity. However, many cancers retain epithelial characteristics, and until recently there has been little conclusive evidence for an involvement of the cell polarity machinery in tumour growth and metastasis. In this article, we discuss evidence that polarity proteins can be potent invasion suppressors but that loss of epithelial character is not essential either for tumour growth and invasion, or metastatic colonization. © 2013 The Author(s) Published by the Royal Society. All rights reserved.

Ransom C.E.,Vanderbilt University
Journal of acquired immune deficiency syndromes (1999) | Year: 2013

To determine whether maternal use of tenofovir disoproxil fumarate for treatment of HIV in pregnancy predicts fetal and infant growth. The study population included HIV-uninfected live-born singleton infants of mothers enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group protocol P1025 (born 2002-2011) in the United States and exposed in utero to a combined (triple or more) antiretroviral regimen. Infant weight at birth and 6 months was compared between infants exposed and unexposed to tenofovir in utero using 2-sample t test, χ test, and multivariable linear and logistic regression models, including demographic and maternal characteristics. Among 2025 infants with measured birth weight, there was no difference between those exposed (N = 630, 31%) versus unexposed to tenofovir in mean birth weight (2.75 vs. 2.77 kg, P = 0.64) or mean gestational age- and sex-adjusted birth weight z-score (WASZ) (0.14 vs. 0.14, P = 0.90). Among 1496 infants followed for 6 months, there was no difference in mean weight at 6 months between tenofovir-exposed (N = 457, 31%) and tenofovir-unexposed infants (7.64 vs. 7.59 kg, P = 0.52) or in mean WASZ (0.29 vs. 0.26, P = 0.61). Tenofovir exposure during the second/third trimester, relative to no exposure, significantly predicted underweight (WASZ < 5%) at age 6 months [odds ratio (95% confidence interval): 2.06 (1.01 to 3.95), P = 0.04]. Duration of tenofovir exposure did not predict neonatal or infant growth. By most measures, in utero exposure to tenofovir did not significantly predict infant birth weight or growth through 6 months of age.

Blackburn J.,Vanderbilt University
Journal of Operations Management | Year: 2012

Over the past two decades the growth in international trade and the offshore migration of US manufacturing have created global supply chains with longer lead-times and slower response. This suggests that traditional supply chains have encountered limits to time-based competition in which the cost of faster replenishment exceeds the benefits. This paper explores and quantifies those limits to time-based competition in make-to-stock supply chains for functional products (products with stable demand over relatively long life cycles). The marginal value of time is used to define the limits of time-based competition in a supply chain, and we define it as the change in total inventory costs per unit change in supply chain lead-time. To calculate the value of time, we develop a set of simple analytical expressions that apply to most standard reorder-point inventory policies under deterministic and variable lead-times. By not requiring optimal inventory policies and expressing the value of time in terms of the unit cost of the product, we obtain very general results that are essentially product-free. We validate the analytical expressions using data from actual supply chains to simulate the inventory cost effects of changes in the lead-time. The results show that the marginal value of time in a supply chain is surprisingly low; it generally falls within a range of 0.4-0.8% of product unit cost per week. Our analytical models explain why there has been expansive growth in global supply chains for functional products. The key tradeoff in outsourcing is between reduced variable production cost and the increased inventory cost of longer supply chain lead-times. The models show analytically that the incremental inventory cost is extremely small relative to the cost benefit. The growth in global supply chains with long lead-times is cost, rather than time, driven. © 2012 Elsevier B.V. All rights reserved.

Nwazue V.C.,Vanderbilt University
Journal of the American Heart Association | Year: 2014

Inappropriate sinus tachycardia (IST) and postural tachycardia syndrome (POTS) are 2 disorders characterized by sinus tachycardia. It is debated whether the pathophysiology of IST and POTS results from abnormal autonomic regulation or abnormal sinus node function. We hypothesized that intrinsic heart rate (IHR) after autonomic blockade would be increased in patients with IST but not POTS. We enrolled 48 POTS patients, 8 IST patients, and 17 healthy control (HC) subjects. Intravenous propranolol and atropine were given to block the sympathetic and parasympathetic limbs of the autonomic nervous system in order to determine the IHR. Patients with IST have a higher sympathetic contribution to heart rate when compared with POTS patients (31±13 bpm versus 12±7 bpm, P<0.001) and HC (8±4 bpm; P<0.001) and a trend to less parasympathetic contribution than POTS and HC (IST: 31±11 bpm versus POTS: 46±11 bpm versus HC: 48±11 bpm, ANOVA P=0.108). IHR was not significantly different between IST and either POTS or HC (IST: 111±11 bpm versus POTS: 108±11 bpm versus HC: 106±12 bpm, ANOVA P=0.237). IST patients have more sympathetic tone when compared with either POTS or HC, but IST patients do not have abnormal sinus node automaticity. These data suggest that the treatment of IST and POTS should focus on sympatholysis, reserving sinus node modification for patients with continued debilitating symptoms after beta-blockade and possibly ivabradine. http://clinicaltrials.gov/. Unique identifier: NCT00262470.

Libster R.,Vanderbilt University
Expert review of vaccines | Year: 2012

Whooping cough, due to Bordetella pertussis and Bordetella parapertussis, is an important cause of childhood morbidity and mortality. Despite widespread pertussis immunization in childhood, there are an estimated 50 million cases and 300,000 deaths due to pertussis globally each year. Infants who are too young to be vaccinated, children who are partially vaccinated and fully-vaccinated persons with waning immunity are especially vulnerable to disease. Since pertussis is one of the vaccine-preventable diseases on the rise, additional vaccine approaches are needed. These approaches include vaccination of newborns, additional booster doses for older adolescents and adults, and immunization of pregnant women with existing vaccines. Innovative new vaccines are also being studied. Each of these options will be discussed and their potential impact on pertussis control assessed.

Rho Y.H.,Vanderbilt University
Arthritis care & research | Year: 2011

Activation of macrophages may contribute to increased atherosclerosis and coronary artery disease in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Neopterin, a pteridine derivative, is a novel marker of monocyte and macrophage activation that is associated with atherosclerosis and cardiovascular risk in the general population. We examined the hypothesis that macrophage activation is associated with accelerated atherosclerosis in SLE and RA. We compared serum neopterin concentrations, adjusted for age, race, sex, and serum creatinine concentration, in patients with SLE (n=148) or RA (n=166) and control subjects (n=177). In patients with SLE or RA, serum neopterin concentrations were then tested for association (adjusted for age, race, sex, serum creatinine, and medication use) with measures of disease activity or damage, inflammatory markers and mediators, and coronary artery calcium measured by electron beam computed tomography. Neopterin concentrations were significantly higher in patients with SLE (median 8.0, interquartile range [IQR] 6.5-9.8 nmoles/liter) and RA (median 6.7, IQR 5.3-8.9 nmoles/liter) than controls (median 5.7, IQR 4.8-7.1 nmoles/liter), and were higher in SLE patients than in RA patients (all P<0.001). In SLE, neopterin was significantly correlated with higher erythrocyte sedimentation rate (ESR; P=0.001), tumor necrosis factor α (P<0.001), monocyte chemoattractant protein 1 (P=0.005), and homocysteine concentrations (P=0.01), but in RA, it was only associated with ESR (P=0.01). Neopterin was not associated with coronary calcium in either SLE (P=0.65) or RA (P=0.21). Macrophage activation, reflected by increased serum neopterin concentrations, was increased in both SLE and RA. Neopterin was more robustly associated with atherogenic mediators of inflammation and homocysteine in SLE than in RA, but was not associated with coronary atherosclerosis in either disease. Copyright © 2011 by the American College of Rheumatology.

Emotional distress and depression are common psychological disturbances associated with low-back and leg pain. The effects of lumbar discectomy on pain, disability, and physical quality of life are well described. The effects of discectomy on emotional distress and mental well-being are less well understood. To assess the effect of microdiscectomy on depression, somatization, and mental well-being in patients with herniated lumbar discs. Patients undergoing surgical discectomy for single-level, herniated lumbar disc were prospectively evaluated preoperatively, and at 6 weeks and 3, 6, and 12 months postoperatively. Back and leg pain, depression, somatic perception, and mental well-being were assessed. One hundred patients were enrolled. All were available for 1-year follow-up. Preoperatively, the visual analog scale for low-back pain (BP-VAS), visual analog scale for leg pain (LP-VAS), Zung Self-Rating Depression Scale (ZUNG), Modified Somatic Perception Questionnaire (MSPQ), and Medical Outcomes Short Form-36 mental component summary scale (SF-36-MCS) were 6.3 ± 2.5, 6.3 ± 2.5, 19 ± 11, 9 ± 7, and 4 ± 14. BP-VAS and LP-VAS significantly improved by 6 weeks. Significant improvement in SF-36-MCS was observed by 6 weeks postoperatively, improvement in MSPQ score was observed 3 months postoperatively, and improvement in the ZUNG depression score was observed 12 months postoperatively. No statistical difference occurred during the remainder of follow-up for any outcome measured once improvement reached statistical significance. Eighteen patients were somatized preoperatively, 67% of which were nonsomatized 1 year postoperatively. Ten patients were clinically depressed preoperatively, 70% of which were nondepressed 1 year postoperatively. Improvement in SF-36-MCS, ZUNG, and MSPQ correlated (P < .001) with improvement in BP-VAS and LP-VAS. The majority of patients somatized or depressed preoperatively returned to good mental well-being postoperatively. Improvement in pain and overall mental well-being was seen immediately after discectomy. Improvement in somatic anxiety and depression occurred months later. Microdiscectomy significantly improves pain-associated depression, somatic anxiety, and mental well-being in patients with herniated lumbar disc.

Olatunji B.O.,Vanderbilt University
Journal of consulting and clinical psychology | Year: 2013

To examine symptom change over time, the effect of attrition on treatment outcome, and the putative mediators of cognitive therapy (CT) versus behavior therapy (BT) for obsessive-compulsive disorder (OCD) using archival data. Sixty-two adults with OCD were randomized to 20 sessions of CT (N = 30) or BT (N = 32) that consisted of 4 weeks of intensive treatment (16 hr total) and 12 weeks of maintenance sessions (4 hr). Independent evaluators assessed OCD severity using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline and at Weeks 4, 16 (posttreatment), 26, and 52 (follow-up). Behavioral avoidance, depressive symptoms, and dysfunctional beliefs regarding responsibility were also measured at each assessment. Study hypotheses were tested using multilevel modeling. The slope of change in Y-BOCS scores was significantly greater in BT than in CT (d = 0.69), and those receiving BT had lower Y-BOCS scores at the final assessment than those receiving CT (d = 1.17). The greater slope of change in BT versus CT did not differ for dropouts versus completers. Reduction in depressed mood mediated changes in Y-BOCS across the 2 treatments, but a reduction in sense of responsibility and a decrease in avoidance did not. Instead, Y-BOCS improvements appeared to precede a decrease in avoidance. BT may have some therapeutic advantage over CT in the treatment of OCD, and this advantage does not appear to be due to a differential pattern of responding for treatment dropouts versus completers. Further, inconsistent with hypotheses, improvements in OCD symptoms were mediated by reductions in depressed mood instead of decreases in avoidance and responsibility. Theoretical, methodological, and clinical implications are discussed.

Noble J.H.,Vanderbilt University
Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention | Year: 2012

Cochlear implant (CI) surgery is considered standard of care treatment for severe hearing loss. CIs are currently programmed using a one-size-fits-all type approach. Individualized, position-based CI programming schemes have the potential to significantly improve hearing outcomes. This has not been possible because the position of stimulation targets is unknown due to their small size and lack of contrast in CT. In this work, we present a segmentation approach that relies on a weighted active shape model created using microCT scans of the cochlea acquired ex-vivo in which stimulation targets are visible. The model is fitted to the partial information available in the conventional CTs and used to estimate the position of structures not visible in these images. Quantitative evaluation of our method results in Dice scores averaging 0.77 and average surface errors of 0.15 mm. These results suggest that our approach can be used for position-dependent image-guided CI programming methods.

Asman A.J.,Vanderbilt University
Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention | Year: 2012

Multi-atlas segmentation provides a general purpose, fully automated class of techniques for transferring spatial information from an existing dataset ("atlases") to a previously unseen context ("target") through image registration. The method used to combine information after registration ("label fusion") has a substantial impact on the overall accuracy and robustness. In practice, weighted voting techniques have dramatically outperformed algorithms based on statistical fusion (i.e., algorithms that incorporate rater performance into the estimation process--STAPLE). We posit that a critical limitation of statistical techniques (as generally proposed) is that they fail to incorporate intensity seamlessly into the estimation process and models of observation error. Herein, we propose a novel statistical fusion algorithm, non-local STAPLE, which merges the STAPLE framework with a non-local means perspective. Non-local STAPLE (1) seamlessly integrates intensity into the estimation process, (2) provides a theoretically consistent model of multi-atlas observation error, and (3) largely bypasses the need for group-wise unbiased registrations. We demonstrate significant improvements in two empirical multi-atlas experiments.

Wallston K.A.,Vanderbilt University
Journal of general internal medicine | Year: 2014

The three-item Brief Health Literacy Screen (BHLS) has been validated in research settings, but not in routine practice, administered by clinical personnel. As part of the Health Literacy Screening (HEALS) study, we evaluated psychometric properties of the BHLS to validate its administration by clinical nurses in both clinic and hospital settings. Beginning in October 2010, nurses in clinics and the hospital at an academic medical center have administered the BHLS during patient intake and recorded responses in the electronic health record. Trained research assistants (RAs) administered the short Test of Functional Health Literacy in Adults (S-TOFHLA) and re-administered the BHLS to convenience samples of hospital and clinic patients. Analyses included tests of internal consistency reliability, inter-administrator reliability, and concurrent validity by comparing the nurse-administered versus RA-administered BHLS scores (BHLS-RN and BHLS-RA, respectively) to the S-TOFHLA. Cronbach's alpha for the BHLS-RN was 0.80 among hospital patients (N = 498) and 0.76 among clinic patients (N = 295), indicating high internal consistency reliability. Intraclass correlation between the BHLS-RN and BHLS-RA among clinic patients was 0.77 (95 % CI 0.71-0.82) and 0.49 (95 % CI 0.40-0.58) among hospital patients. BHLS-RN scores correlated significantly with BHLS-RA scores (r = 0.33 among hospital patients; r = 0.62 among clinic patients), and with S-TOFHLA scores (r = 0.35 among both hospital and clinic patients), providing evidence of inter-administrator reliability and concurrent validity. In regression models, BHLS-RN scores were significant predictors of S-TOFHLA scores after adjustment for age, education, gender, and race. Area under the receiver operating characteristic curve for BHLS-RN to predict adequate health literacy on the S-TOFHLA was 0.71 in the hospital and 0.76 in the clinic. The BHLS, administered by nurses during routine clinical care, demonstrates adequate reliability and validity to be used as a health literacy measure.

Breast cancer patients, who are already at increased risk of developing bone metastases and osteolytic bone damage, are often treated with doxorubicin. Unfortunately, doxorubicin has been reported to induce damage to bone. Moreover, we have previously reported that doxorubicin treatment increases circulating levels of TGFβ in murine pre-clinical models. TGFβ has been implicated in promoting osteolytic bone damage, a consequence of increased osteoclast-mediated resorption and suppression of osteoblast differentiation. Therefore, we hypothesized that in a preclinical breast cancer bone metastasis model, administration of doxorubicin would accelerate bone loss in a TGFβ-mediated manner. Administration of doxorubicin to 4T1 tumor-bearing mice produced an eightfold increase in osteolytic lesion areas compared untreated tumor-bearing mice (P = 0.002) and an almost 50% decrease in trabecular bone volume expressed in BV/TV (P = 0.0005), both of which were rescued by anti-TGFβ antibody (1D11). Doxorubicin, which is a known inducer of oxidative stress, decreased osteoblast survival and differentiation, which was rescued by N-acetyl cysteine (NAC). Furthermore, doxorubicin treatment decreased Cu-ZnSOD (SOD1) expression and enzyme activity in vitro, and treatment with anti-TGFβ antibody was able to rescue both. In conclusion, a combination therapy using doxorubicin and anti-TGFβ antibody might be beneficial for preventing therapy-related bone loss in cancer patients.

Koury M.J.,Vanderbilt University
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

We present herein an approach to diagnosing the cause of chronic anemia based on a patient's history and complete blood cell count (CBC). Four patterns that are encountered frequently in CBCs associated with chronic anemias are considered: (1) anemia with abnormal platelet and/or leukocyte counts, (2) anemia with increased reticulocyte counts, (3) life-long history of chronic anemia, and (4) anemia with inappropriately low reticulocytes. The pathophysiologic bases for some chronic anemias with low reticulocyte production are reviewed in terms of the bone marrow (BM) events that reduce normal rates of erythropoiesis. These events include: apoptosis of erythroid progenitor and precursor cells by intrinsic and extrinsic factors, development of macrocytosis when erythroblast DNA replication is impaired, and development of microcytosis due to heme-regulated eIF2α kinase inhibition of protein synthesis in iron-deficient or thalassemic erythroblasts.

Kelly J.W.,Iowa State University | McNamara T.P.,Vanderbilt University
Cognition | Year: 2010

Four experiments investigated the role of reference frames during the acquisition and development of spatial knowledge, when learning occurs incrementally across views. In two experiments, participants learned overlapping spatial layouts. Layout 1 was first studied in isolation, and Layout 2 was later studied in the presence of Layout 1. The Layout 1 learning view was manipulated, whereas the Layout 2 view was held constant. Manipulation of the Layout 1 view influenced the reference frame used to organize Layout 2, indicating that reference frames established during early environmental exposure provided a framework for organizing locations learned later. Further experiments demonstrated that reference frames established after learning served to reorganize an existing spatial memory. These results indicate that existing reference frames can structure the acquisition of new spatial memories and that new reference frames can reorganize existing spatial memories. © 2010 Elsevier B.V.

Fine J.-D.,Vanderbilt University
Current Opinion in Pediatrics | Year: 2010

Purpose of review: This review highlights key findings, both clinical and basic, that have been published in the field of inherited epidermolysis bullosa within the past few years. Recent findings: New epidermolysis bullosa phenotypes, genotypes and modes of transmission have been identified, resulting in a revised classification system. Detailed evidence-based data are now available on the risk of extracutaneous complications in each of the major epidermolysis bullosa subtypes. Studies are now underway to try to better explain the biological aggressiveness of squamous cell carcinomas arising in epidermolysis bullosa skin. Cell and animal models have been refined and used to ascertain the feasibility of gene replacement therapy, stem cell transplantation, and treatment with injected allogeneic fibroblasts or recombinant type VII collagen. As a result, clinical trials are now being pursued to test each of these in humans. Summary: Epidermolysis bullosa is caused by mutations in at least 14 genes, leading to a broad spectrum of entities, each of which has its own relative risk for the development of specific extracutaneous complications and/or premature death. Intensive research, both basic and clinical, is bringing us closer to more effective treatments and possibly even a cure. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

OBJECTIVE: The glands of the stomach body and antral mucosa contain a complex compendium of cell lineages. In lower mammals, the distribution of oxyntic glands and antral glands define the anatomical regions within the stomach. We examined in detail the distribution of the full range of cell lineages within the human stomach.DESIGN: We determined the distribution of gastric gland cell lineages with specific immunocytochemical markers in entire stomach specimens from three non-obese organ donors.RESULTS: The anatomical body and antrum of the human stomach were defined by the presence of ghrelin and gastrin cells, respectively. Concentrations of somatostatin cells were observed in the proximal stomach. Parietal cells were seen in all glands of the body of the stomach as well as in over 50% of antral glands. MIST1 expressing chief cells were predominantly observed in the body although individual glands of the antrum also showed MIST1 expressing chief cells. While classically described antral glands were observed with gastrin cells and deep antral mucous cells without any parietal cells, we also observed a substantial population of mixed type glands containing both parietal cells and G cells throughout the antrum.CONCLUSIONS: Enteroendocrine cells show distinct patterns of localisation in the human stomach. The existence of antral glands with mixed cell lineages indicates that human antral glands may be functionally chimeric with glands assembled from multiple distinct stem cell populations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

David Merryman W.,Vanderbilt University
Journal of Biomechanics | Year: 2010

Aortic valve leaflets experience varying applied loads during the cardiac cycle. These varying loads act on both cell types of the leaflets, endothelial and interstitial cells, and cause molecular signaling events that are required for repairing the leaflet tissue, which is continually damaged from the applied loads. However, with increasing age, this reparative mechanism appears to go awry as valve interstitial cells continue to remain in their 'remodeling' phenotype and subsequently cause the tissue to become stiff, which results in heart valve disease. The etiology of this disease remains elusive; however, multiple clues are beginning to coalesce and mechanical cues are turning out to be large predicators of cellular function in the aortic valve leaflets, when compared to the cells from the pulmonary valve leaflets, which are under a significantly less demanding mechanical loading regime. Finally, this paper discusses the mechanical environment of the constitutive cell populations, mechanobiological processes that are currently unclear, and a mechano-potential etiology of aortic disease will be presented. © 2009 Elsevier Ltd. All rights reserved.

DeBaun M.R.,Vanderbilt University | Telfair J.,University of North Carolina at Greensboro
Pediatrics | Year: 2012

Sickle cell disease (SCD), the most common genetic disease screened for in the newborn period, occurs in ∼1 in 2400 newborns in the general population and 1 in 400 individuals of African descent in the United States. Despite the relative high prevalence and low pediatric mortality rate of SCD when compared with other genetic diseases or chronic diseases in pediatrics, few evidence-based guidelines have been developed to facilitate the transition from pediatrics to an internal medicine or family practice environment. As with any pediatric transition program, common educational, social, and health systems themes exist to prepare for the next phase of health care; however, unique features characterizing the experience of adolescents with SCD must also be addressed. These challenges include, but are not limited to, a higher proportion of SCD adolescents receiving public health insurance when compared with any other pediatric genetic or chronic diseases; the high proportion of overt strokes or silent cerebral infarcts (∼30%) affecting cognition; risk of low high school graduation; and a high rate of comorbid disease, including asthma. Young adults with SCD are living longer; consequently, the importance of transitioning from a pediatric primary care provider to adult primary care physician has become a critical step in the health care management plan. We identify how the primary care physicians in tandem with the pediatric specialist can enhance transition interventions for children and adolescents with SCD. Copyright © 2012 by the American Academy of Pediatrics.

Di Salvo T.G.,Vanderbilt University
Current Opinion in Cardiology | Year: 2012

Purpose of Review: Pulmonary hypertension and right ventricular failure (RVF) in left ventricular systolic dysfunction (LVSD) is associated with high morbidity and mortality. This review presents an overview of the classification, pathophysiology, natural history, clinical features, prevention and treatment of this common clinical problem with a focus on the most recent studies. Many of the current evidence-based therapeutic agents for pulmonary hypertension in the absence of systolic or diastolic heart failure (e.g. prostaglandins, endothelin antagonists) are not efficacious in pulmonary hypertension with LVSD. Recent Findings: Recent clinical evidence strongly supports an evolving role for phosphodiesterase type 5 (PDE5) inhibition in patients with pulmonary hypertension and LVSD. Chronic PDE5 inhibition in the short-to-intermediate duration studies to date significantly reduces pulmonary pressures and pulmonary vascular resistance (PVR), effects reverse right ventricle and left ventricle remodeling, improves ventilator efficiency, improves peak exercise capacity and improves quality of life in selected patients with stable, moderately symptomatic LVSD and pulmonary hypertension. Summary: Although long-term outcome studies are currently lacking, chronic PDE5 inhibition should be considered in carefully selected LVSD patients who manifest persistent significant elevation of pulmonary hypertension or PVR or uncontrolled RVF after aggressive management with all standard current evidence-based LVSD therapies (neurohormonal antagonists, diuretics and cardiac resynchronization in appropriate candidates). © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Moore E.R.,Vanderbilt University
Cochrane database of systematic reviews (Online) | Year: 2012

Mother-infant separation postbirth is common in Western culture. Early skin-to-skin contact (SSC) begins ideally at birth and involves placing the naked baby, head covered with a dry cap and a warm blanket across the back, prone on the mother's bare chest. According to mammalian neuroscience, the intimate contact inherent in this place (habitat) evokes neurobehaviors ensuring fulfillment of basic biological needs. This time may represent a psychophysiologically 'sensitive period' for programming future physiology and behavior. To assess the effects of early SSC on breastfeeding, physiological adaptation, and behavior in healthy mother-newborn dyads. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2011), made personal contact with trialists, and consulted the bibliography on kangaroo mother care (KMC) maintained by Dr. Susan Ludington. Randomized controlled trials comparing early SSC with usual hospital care. We independently assessed trial quality and extracted data. Study authors were contacted for additional information. Thirty-four randomized controlled trials were included involving 2177 participants (mother-infant dyads). Data from more than two trials were available for only eight outcome measures. For primary outcomes, we found a statistically significant positive effect of early SSC on breastfeeding at one to four months postbirth (13 trials; 702 participants) (risk ratio (RR) 1.27, 95% confidence interval (CI) 1.06 to 1.53, and SSC increased breastfeeding duration (seven trials; 324 participants) (mean difference (MD) 42.55 days, 95% CI -1.69 to 86.79) but the results did not quite reach statistical significance (P = 0.06). Late preterm infants had better cardio-respiratory stability with early SSC (one trial; 31 participants) (MD 2.88, 95% CI 0.53 to 5.23). Blood glucose 75 to 90 minutes following the birth was significantly higher in SSC infants (two trials, 94 infants) (MD 10.56 mg/dL, 95% CI 8.40 to 12.72).The overall methodological quality of trials was mixed, and there was high heterogeneity for some outcomes. Limitations included methodological quality, variations in intervention implementation, and outcomes. The intervention appears to benefit breastfeeding outcomes, and cardio-respiratory stability and decrease infant crying, and has no apparent short- or long-term negative effects. Further investigation is recommended. To facilitate meta-analysis, future research should be done using outcome measures consistent with those in the studies included here. Published reports should clearly indicate if the intervention was SSC with time of initiation and duration and include means, standard deviations and exact probability values.

Egli M.,Vanderbilt University
Accounts of Chemical Research | Year: 2012

In DNA, bases pair in a molecular interaction that is both highly predictable and exquisitely specific. Therefore researchers have generally believed that the insertion of the matching nucleotide opposite a template base by DNA polymerases (pols) required Watson-Crick (W-C) hydrogen bond formation. However pioneering work by Kool and co-workers using hydrophobic base analogs such as the thymine (T) isostere 2,4-difluorotoluene (F) showed that shape rather than H-bonding served as the primary source of specificity in DNA replication by certain pols. This steric hypothesis for DNA replication has gained popularity, perhaps discouraging further experimental studies to address potential limitations of this new idea.The idea that shape trumps H-bonding in terms of pol selectivity largely hinges on the belief that fluorine is a poor H-bond acceptor. However, the shape complementarity model was embraced in the absence of any detailed structural data for match (F:A) and mismatch pairs (F:G, F:C, F:T) in DNA duplexes or at active sites of pols. Although the F and T nucleosides are roughly isosteric, it is unclear whether F:A and T:A pairs exhibit similar geometries. If the F:A pair is devoid of H-bonding, it will be notably wider than a T:A pair. Because shape and size and H-bonding are intimately related, it may not be possible to separate these two properties. Thus the geometries of an isolated F:A pair in water may differ considerably from an F:A pair embedded in a stretch of duplex DNA, at the tight active site of an A-family replicative pol, or within the spacious active site of a Y-family translesion pol. The shape complementarity model may have more significance for pol accuracy than efficiency: this model appears to be most relevant for replicative pols that use specific residues to probe the identity of the nascent base pair from the minor groove side. However, researchers have not fully considered the importance of such interactions that include H-bonds compared with W-C H-bonds in terms of pol fidelity and the shape complementarity model.This Account revisits the steric hypothesis for DNA replication in light of recent structural data and discusses the role of fluorine as an H-bond acceptor. Over the last 5 years, crystal structures have emerged for nucleic acid duplexes with F paired opposite to natural bases or located at the active sites of DNA pols. These data permit a more nuanced understanding of the role of shape in DNA replication and the capacity of fluorine to form H-bonds. These studies and additional research involving RNA or other fluorine-containing nucleoside analogs within duplexes indicate that fluorine engages in H-bonding in many cases. Although T and F are isosteric at the nucleoside level, replacement of a natural base by F in pairs often changes their shapes and sizes, and dF in DNA behaves differently from rF in RNA. Similarly, the pairing geometries observed for F and T opposite dATP, dGTP, dTTP, or dCTP and their H-bonding patterns at the active site of a replicative pol differ considerably. © 2012 American Chemical Society.

Boyd A.S.,Vanderbilt University
Journal of the American Academy of Dermatology | Year: 2012

Trips abroad to underdeveloped countries for the purpose of providing dermatologic care (medical missions), while both exciting and gratifying, require planning and forethought. What do I bring? What conditions will I encounter? What medications will be available? This paper outlines my experiences on such trips over the past 15 years, providing an approach and formulary which facilitates the performance of daily medical dermatology clinics. © 2010 by the American Academy of Dermatology, Inc.

Cook-Mills J.M.,Northwestern University | Abdala-Valencia H.,Northwestern University | Hartert T.,Vanderbilt University
American Journal of Respiratory and Critical Care Medicine | Year: 2013

Asthma and allergic lung disease occur as complex environmental and genetic interactions. Clinical studies of asthma indicate a number of protective dietary factors, such as vitamin E, on asthma risk. However, these studies have had seemingly conflicting outcomes. In this perspective, we discuss opposing regulatory effects of tocopherol isoforms of vitamin E, mechanisms for tocopherol isoform regulation of allergic lung inflammation, association of vitamin E isoforms with outcomes in clinical studies, and how the variation in global prevalence of asthma may be explained, at least in part, by vitamin E isoforms. © 2013 by the American Thoracic Society.

Haase V.H.,Vanderbilt University
Journal of the American Society of Nephrology | Year: 2013

pO2 in the kidney is maintained at relatively stable levels by a unique and complex functional interplay between renal blood flow, GFR, O 2 consumption, and arteriovenous O2 shunting. The fragility of this interplay makes the kidney susceptible to hypoxic injury. Cells in the kidney utilize variousmolecular pathways that allow them to respond and adapt to changes in renal oxygenation. This review provides an integrative perspective on the role ofmolecular hypoxia responses in normal kidney physiology and pathophysiology, and discusses their therapeutic potential for the treatment of renal diseases. Copyright © 2013 by the American Society of Nephrology.

Calkins D.J.,Vanderbilt University
Investigative Ophthalmology and Visual Science | Year: 2013

The aging visual system is marked by a decline in some, but not all, key functions. Some of this decline is attributed to changes in the optics of the eye, but other aspects must have a neural basis. Across mammals, with aging there is remarkable persistence of central structures to which retinal ganglion cell (RGC) axons project with little or no loss of neurons. Similarly, RGC bodies in the retina are subject to variable age-related loss, with most mammals showing none over time. In contrast, the RGC axon itself is highly vulnerable. Across species, the rate of axon loss in the optic nerve is related inversely to the total number of axons at maturity and lifespan. The result of this scaling is approximately a 40% total decline in axon number. Evidence suggests that the consistent vulnerability of RGC axons to aging arises from their high metabolic demand combined with diminishing resources. Thus, therapeutic interventions that conserve bioenergetics may have potential to abate age-related decline in visual function. © The Association for Research in Vision and Ophthalmology, Inc.

Up to 50 % of patients do not take medications as prescribed. Interventions to improve adherence are needed, with an understanding of which patients benefit most. To test the effect of two low-literacy interventions on medication adherence. Randomized controlled trial, 2 × 2 factorial design. Adults with coronary heart disease in an inner-city primary care clinic. For 1 year, patients received usual care, refill reminder postcards, illustrated daily medication schedules, or both interventions. The primary outcome was cardiovascular medication refill adherence, assessed by the cumulative medication gap (CMG). Patients with CMG<0.20 were considered adherent. We assessed the effect of the interventions overall and, post-hoc, in subgroups of interest. Most of the 435 participants were elderly (mean age=63.7 years), African-American (91 %), and read below the 9th-grade level (78 %). Among the 420 subjects (97 %) for whom CMG could be calculated, 138 (32.9 %) had CMG<0.20 during follow-up and were considered adherent. Overall, adherence did not differ significantly across treatments: 31.2 % in usual care, 28.3 % with mailed refill reminders, 34.2 % with illustrated medication schedules, and 36.9 % with both interventions. In post-hoc analyses, illustrated medication schedules led to significantly greater odds of adherence among patients who at baseline had more than eight medications (OR=2.2; 95 % CI, 1.21 to 4.04) or low self-efficacy for managing medications (OR=2.15; 95 % CI, 1.11 to 4.16); a trend was present among patients who reported non-adherence at baseline (OR=1.89; 95 % CI, 0.99 to 3.60). The interventions did not improve adherence overall. Illustrated medication schedules may improve adherence among patients with low self-efficacy, polypharmacy, or baseline non-adherence, though this requires confirmation.

G protein-coupled receptor kinases (GRKs) and arrestins mediate desensitization of G protein-coupled receptors (GPCR). Arrestins also mediate G protein-independent signaling via GPCRs. Since GRK and arrestins demonstrate no strict receptor specificity, their functions in the brain may depend on their cellular complement, expression level, and subcellular targeting. However, cellular expression and subcellular distribution of GRKs and arrestins in the brain is largely unknown. We show that GRK isoforms GRK2 and GRK5 are similarly expressed in direct and indirect pathway neurons in the rat striatum. Arrestin-2 and arrestin-3 are also expressed in neurons of both pathways. Cholinergic interneurons are enriched in GRK2, arrestin-3, and GRK5. Parvalbumin-positive interneurons express more of GRK2 and less of arrestin-2 than medium spiny neurons. The GRK5 subcellular distribution in the human striatal neurons is altered by its phosphorylation: unphosphorylated enzyme preferentially localizes to synaptic membranes, whereas phosphorylated GRK5 is found in plasma membrane and cytosolic fractions. Both GRK isoforms are abundant in the nucleus of human striatal neurons, whereas the proportion of both arrestins in the nucleus was equally low. However, overall higher expression of arrestin-2 yields high enough concentration in the nucleus to mediate nuclear functions. These data suggest cell type- and subcellular compartment-dependent differences in GRK/arrestin-mediated desensitization and signaling.

Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Following treatment of the primary cancer, emotional and psychosocial factors within this population precipitate time to recurrence and death, however the underlying mechanism(s) remain unclear. Using a mouse model of bone metastasis, we provide experimental evidence that activation of the sympathetic nervous system, which is one of many pathophysiological consequences of severe stress and depression, promotes MDA-231 breast cancer cell colonization of bone via a neurohormonal effect on the host bone marrow stroma. We demonstrate that induction of RANKL expression in bone marrow osteoblasts, following β2AR stimulation, increases the migration of metastatic MDA-231 cells in vitro, independently of SDF1-CXCR4 signaling. We also show that the stimulatory effect of endogenous (chronic stress) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked with the β-blocker propranolol, and by knockdown of RANK expression in MDA-231 cells. These findings indicate that RANKL promotes breast cancer cell metastasis to bone via its pro-migratory effect on breast cancer cells, independently of its effect on bone turnover. The emerging clinical implication, supported by recent epidemiological studies, is that βAR-blockers and drugs interfering with RANKL signaling, such as Denosumab, could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the "vicious cycle" of bone destruction induced by these cells.

Sirbu B.M.,Vanderbilt University
Cold Spring Harbor perspectives in biology | Year: 2013

Genome integrity is challenged by DNA damage from both endogenous and environmental sources. This damage must be repaired to allow both RNA and DNA polymerases to accurately read and duplicate the information in the genome. Multiple repair enzymes scan the DNA for problems, remove the offending damage, and restore the DNA duplex. These repair mechanisms are regulated by DNA damage response kinases including DNA-PKcs, ATM, and ATR that are activated at DNA lesions. These kinases improve the efficiency of DNA repair by phosphorylating repair proteins to modify their activities, by initiating a complex series of changes in the local chromatin structure near the damage site, and by altering the overall cellular environment to make it more conducive to repair. In this review, we focus on these three levels of regulation to illustrate how the DNA damage kinases promote efficient repair to maintain genome integrity and prevent disease.

Kelley N.P.,Smithsonian Institution | Kelley N.P.,Vanderbilt University | Pyenson N.D.,Smithsonian Institution
Science | Year: 2015

Many top consumers in today's oceans are marine tetrapods, a collection of lineages independently derived from terrestrial ancestors. The fossil record illuminates their transitions from land to sea, yet these initial invasions account for a small proportion of their evolutionary history. We review the history of marine invasions that drove major changes in anatomy, physiology, and ecology overmore than 250 million years. Many innovations evolved convergently in multiple clades, whereas others are unique to individual lineages. The evolutionary arcs of these ecologically important clades are framed against the backdrop of mass extinctions and regime shifts in ocean ecosystems. Past and present human disruptions to marine tetrapods, with cascading impacts on marine ecosystems, underscore the need to link macroecology with evolutionary change. © 2015, American Association for the Advancement of Science. All rights reserved.

This study tests how divergent natural selection promotes genomic differentiation during ecological speciation. Specifically, we use adaptive ecological divergence (here, population divergence in host plant use and preference) as a proxy for selection strength and evaluate the correlation between levels of adaptive and genetic differentiation across pairwise population comparisons. Positive correlations would reveal the pattern predicted by our hypothesis, that of 'isolation by adaptation' (IBA). Notably, IBA is predicted not only for selected loci but also for neutral loci. This may reflect the effects of divergent selection on neutral loci that are 'loosely linked' to divergently selected loci or on geneflow restriction that facilitates genetic drift at all loci, including neutral loci that are completely unlinked to those evolving under divergent selection. Here, we evaluate IBA in maple- and willow-associated populations of Neochlamisus bebbianae leaf beetles. To do so, we collected host preference data to construct adaptive divergence indices and used AFLPs (amplified fragment length polymorphisms) and mitochondrial sequences to quantify genetic differentiation. Partial Mantel tests showed significant IBA in 'pooled' analyses of putatively neutral and of putatively selected ('outlier') AFLP loci. This pattern was also recovered in 12% of 'locus-specific' analyses that separately evaluated genetic differentiation at individual neutral loci. These results provided evidence for widespread effects of selection on neutral genomic divergence. Our collective findings indicate that host-related selection may play important roles in the population genomic differentiation of both neutral and selected gene regions in herbivorous insects. © 2011 Blackwell Publishing Ltd.

Fleetwood D.M.,Vanderbilt University
IEEE Transactions on Nuclear Science | Year: 2013

An overview is presented of total ionizing dose (TID) effects in MOS and bipolar devices from a historical perspective, focusing primarily on work presented at the annual IEEE Nuclear and Space Radiation Effects Conference (NSREC). From the founding of the IEEE NSREC in 1964 until ∼ 1976, foundational work led to the discovery of TID effects in MOS devices, the characterization of basic charge transport and trapping processes in SiO 2, and the development of the first generations of metal-gate radiation-hardened MOS technologies. From ∼ 1977 until ∼ 1985, significant progress was made in the understanding of critical defects and impurities that limit the radiation response of MOS devices. These include O vacancies in SiO2 , dangling Si bonds at the Si/SiO2 interface, and hydrogen. In addition, radiation-hardened Si-gate CMOS technologies were developed. From ∼ 1986 until ∼ 1997, a significant focus was placed on understanding postirradiation effects in MOS devices and implementing hardness assurance test methods to qualify devices for use in space systems. Enhanced low-dose-rate sensitivity (ELDRS) was discovered and investigated in linear bipolar devices and integrated circuits. From ∼ 1998 until the present, an increasing focus has been placed on theoretical studies enabled by rapidly advancing computational capabilities, modeling and simulation, effects in ultra-thin oxides and alternative dielectrics to SiO 2 , and in developing a comprehensive model of ELDRS. © 1963-2012 IEEE.

Abreu M.T.,University of Miami | Peek Jr. R.M.,Vanderbilt University
Gastroenterology | Year: 2014

Microbial species participate in the genesis of a substantial number of malignancies - in conservative estimates, at least 15% of all cancer cases are attributable to infectious agents. Little is known about the contribution of the gastrointestinal microbiome to the development of malignancies. Resident microbes can promote carcinogenesis by inducing inflammation, increasing cell proliferation, altering stem cell dynamics, and producing metabolites such as butyrate, which affect DNA integrity and immune regulation. Studies in human beings and rodent models of cancer have identified effector species and relationships among members of the microbial community in the stomach and colon that increase the risk for malignancy. Strategies to manipulate the microbiome, or the immune response to such bacteria, could be developed to prevent or treat certain gastrointestinal cancers. © 2014 by the AGA Institute.

Fisher J.A.,Vanderbilt University | Kalbaugh C.A.,University of North Carolina at Chapel Hill
PLoS Medicine | Year: 2012

Background: There have been dramatic increases over the past 20 years in the number of nonacademic, private-sector physicians who serve as principal investigators on US clinical trials sponsored by the pharmaceutical industry. However, there has been little research on the implications of these investigators' role in clinical investigation. Our objective was to study private-sector clinics involved in US pharmaceutical clinical trials to understand the contract research arrangements supporting drug development, and specifically how private-sector physicians engaged in contract research describe their professional identities. Methods and Findings: We conducted a qualitative study in 2003-2004 combining observation at 25 private-sector research organizations in the southwestern United States and 63 semi-structured interviews with physicians, research staff, and research participants at those clinics. We used grounded theory to analyze and interpret our data. The 11 private-sector physicians who participated in our study reported becoming principal investigators on industry clinical trials primarily because contract research provides an additional revenue stream. The physicians reported that they saw themselves as trial practitioners and as businesspeople rather than as scientists or researchers. Conclusions: Our findings suggest that in addition to having financial motivation to participate in contract research, these US private-sector physicians have a professional identity aligned with an industry-based approach to research ethics. The generalizability of these findings and whether they have changed in the intervening years should be addressed in future studies. Please see later in the article for the Editors' Summary. © 2012 Fisher, Kalbaugh.

Currie K.P.,Vanderbilt University
Channels (Austin, Tex.) | Year: 2010

Voltage-gated Ca(2+) channels translate the electrical inputs of excitable cells into biochemical outputs by controlling influx of the ubiquitous second messenger Ca(2+) . As such the channels play pivotal roles in many cellular functions including the triggering of neurotransmitter and hormone release by CaV2.1 (P/Q-type) and CaV2.2 (N-type) channels. It is well established that G protein coupled receptors (GPCRs) orchestrate precise regulation neurotransmitter and hormone release through inhibition of CaV2 channels. Although the GPCRs recruit a number of different pathways, perhaps the most prominent, and certainly most studied among these is the so-called voltage-dependent inhibition mediated by direct binding of Gβγ to the α1 subunit of CaV2 channels. This article will review the basics of Ca(2+) -channels and G protein signaling, and the functional impact of this now classical inhibitory mechanism on channel function. It will also provide an update on more recent developments in the field, both related to functional effects and crosstalk with other signaling pathways, and advances made toward understanding the molecular interactions that underlie binding of Gβγ to the channel and the voltage-dependence that is a signature characteristic of this mechanism.

Blake R.,Vanderbilt University
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2014

This essay critically examines the extent to which binocular rivalry can provide important clues about the neural correlates of conscious visual perception. Our ideas are presented within the framework of four questions about the use of rivalry for this purpose: (i) what constitutes an adequate comparison condition for gauging rivalry's impact on awareness, (ii) how can one distinguish abolished awareness from inattention, (iii) when one obtains unequivocal evidence for a causal link between a fluctuating measure of neural activity and fluctuating perceptual states during rivalry, will it generalize to other stimulus conditions and perceptual phenomena and (iv) does such evidence necessarily indicate that this neural activity constitutes a neural correlate of consciousness? While arriving at sceptical answers to these four questions, the essay nonetheless offers some ideas about how a more nuanced utilization of binocular rivalry may still provide fundamental insights about neural dynamics, and glimpses of at least some of the ingredients comprising neural correlates of consciousness, including those involved in perceptual decision-making.

Dykens E.M.,Vanderbilt University
Journal of Autism and Developmental Disorders | Year: 2014

Although hyperphagia and compulsivity in Prader-Willi syndrome (PWS) are well described, recreation and adaptive skills are relatively unexplored. Parents of 123 participants with PWS (4-48 years) completed measures of their child's adaptive, recreation, and problem behaviors. Offspring received cognitive testing. Watching TV was the most frequent recreational activity, and was associated with compulsivity and skin picking. BMIs were negatively correlated with physical play, and highest in those who watched TV and played computer games. Computer games and physical activities were associated with higher IQ and adaptive scores. People with PWS and other disabilities need to watch less TV and be more engaged in physical activities, games, and leisure pursuits that are fun, and may bring cognitive or adaptive advantages. © Springer Science+Business Media, LLC 2012.

Morris B.J.,Lexington Clinic Orthopedics Sports Medicine Center | Mir H.R.,Vanderbilt University
Journal of the American Academy of Orthopaedic Surgeons | Year: 2015

The past few decades have seen an alarming rise in opioid use in the United States, and the negative consequences from diversion of opioids for nontherapeutic use are dramatically increasing. A significant number of orthopaedic patients are at risk for repercussions from both therapeutic and nontherapeutic opioid use. Orthopaedic surgeons are the third highest prescribers of opioid prescriptions among physicians in the United States. Thus, it is important for orthopaedic surgeons to understand the detrimental effects of opioid abuse on individuals and society and to recognize objective measures to identify patients at risk for nontherapeutic opioid use. These measures include elements of the patient history, recognition of aberrant behaviors, prescription drug monitoring programs, and opioid risk-assessment tools. © the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.

Heckers S.,Vanderbilt University
Psychophysiology | Year: 2016

Neuroscientists have been exploring the mechanism of auditory verbal hallucinations. In this commentary, I review studies by Judy Ford, who employed a vocalization paradigm to test the hypothesis of impaired corollary discharge in psychotic patients who experience auditory verbal hallucinations. I highlight the strengths of this research program and reflect on the challenge of reducing a complex clinical feature to an abnormality of basic cognitive processes, such as language and memory. © 2016 Society for Psychophysiological Research.

Naik R.D.,Vanderbilt University
Oncogene | Year: 2016

Myeloid translocation genes (MTGs), originally identified as chromosomal translocations in acute myelogenous leukemia, are transcriptional corepressors that regulate hematopoietic stem cell programs. Analysis of The Cancer Genome Atlas (TCGA) database revealed that MTGs were mutated in epithelial malignancy and suggested that loss of function might promote tumorigenesis. Genetic deletion of MTGR1 and MTG16 in the mouse has revealed unexpected and unique roles within the intestinal epithelium. Mtgr1-/- mice have progressive depletion of all intestinal secretory cells, and Mtg16-/- mice have a decrease in goblet cells. Furthermore, both Mtgr1-/- and Mtg16-/- mice have increased intestinal epithelial cell proliferation. We thus hypothesized that loss of MTGR1 or MTG16 would modify Apc1638/+-dependent intestinal tumorigenesis. Mtgr1-/- mice, but not Mtg16-/- mice, had a 10-fold increase in tumor multiplicity. This was associated with more advanced dysplasia, including progression to invasive adenocarcinoma, and augmented intratumoral proliferation. Analysis of chromatin immunoprecipitation sequencing data sets for MTGR1 and MTG16 targets indicated that MTGR1 can regulate Wnt and Notch signaling. In support of this, immunohistochemistry and gene expression analysis revealed that both Wnt and Notch signaling pathways were hyperactive in Mtgr1-/- tumors. Furthermore, in human colorectal cancer (CRC) samples MTGR1 was downregulated at both the transcript and protein level. Overall our data indicates that MTGR1 has a context-dependent effect on intestinal tumorigenesis.Oncogene advance online publication, 6 June 2016; doi:10.1038/onc.2016.167. © 2016 Macmillan Publishers Limited

Wilson M.S.,Vanderbilt University
Fetal Diagnosis and Therapy | Year: 2012

Introduction: Due to the controversy surrounding diagnostic ultrasound evaluations and elective preterm delivery of fetuses with gastroschisis, we sought to calculate the predictive value of bowel dilation in fetuses with gastroschisis and evaluate the effect of preterm delivery on neonatal outcomes. Materials and Methods: Ultrasounds and medical records of 103 mother-infant pairs with fetal gastroschisis were reviewed. Eighty-nine pairs met the criteria. Intestinal complications, gestational age at delivery, birth weight, and number of abdominal surgeries were documented. Results: Forty-eight fetuses (54%) had bowel dilation and 41 (46%) did not. The positive predictive value of bowel dilation for complicated gastroschisis was 21%. There were 50 (56%) preterm and 39 (44%) term deliveries. The mean birth weight was 2,114 g (SD = 507) and 2,659 g (SD = 687), p = 0.001. For infants delivered preterm, the mean number of postnatal abdominal surgeries was 2.1 (SD = 1.1) as compared to 1.3 (SD = 0.5) surgical procedures for those infants delivered at term gestation. This was not statistically significant. With respect to hospital stay for each group, the mean length of neonatal intensive care unit admission was 48 days (SD = 33) in the preterm group and 35 days (SD = 50) in the term group, which was not statistically significant. Discussion: Ultrasound-detected bowel dilation was not predictive of important intestinal complications. Our data did not substantiate any benefit for elective preterm delivery of neonates with gastroschisis. Copyright © 2012 S. Karger AG, Basel.