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The University of Texas Southwestern Medical Center is one of the leading medical education and biomedical research institutions in the United States. UT Southwestern is located in Southwestern Medical District, a 231-acre campus in Dallas incorporating UT Southwestern Medical School, UT Southwestern Graduate School of Biomedical science, UT Southwestern School of Health Professions, and four affiliated hospitals: Parkland Memorial Hospital, Children's Medical Center, Zale Lipshy University Hospital, and St. Paul University Hospital. It also has programs with affiliated hospitals at several sites in Dallas, Richardson, Fort Worth, Waco, Austin, and Wichita Falls. Wikipedia.

Kazmierczak B.I.,Yale University | Hendrixson D.R.,University of Texas Southwestern Medical Center
Molecular Microbiology | Year: 2013

Summary: Control of surface organelle number and placement is a crucial aspect of the cell biology of many Gram-positive and Gram-negative bacteria, yet mechanistic insights into how bacteria spatially and numerically organize organelles are lacking. Many surface structures and internal complexes are spatially restricted in the bacterial cell (e.g. type IV pili, holdfasts, chemoreceptors), but perhaps none show so many distinct patterns in terms of number and localization as the flagellum. In this review, we discuss two proteins, FlhF and FlhG (also annotated FleN/YlxH), which control aspects of flagellar assembly, placement and number in polar flagellates, and may influence flagellation in some bacteria that produce peritrichous flagella. Experimental data obtained in a number of bacterial species suggest that these proteins may have acquired distinct attributes influencing flagellar assembly that reflect the diversity of flagellation patterns seen in different polar flagellates. Recent findings also suggest FlhF and FlhG are involved in other processes, such as influencing the rotation of flagella and proper cell division. Continued examination of these proteins in polar flagellates is expected to reveal how different bacteria have adapted FlhF or FlhG with specific activities to tailor flagellar biosynthesis and motility to fit the needs of each species. Copyright © 2013 John Wiley & Sons Ltd.

Carvour M.L.,University of Texas Southwestern Medical Center
Academic Medicine | Year: 2016

Attention to the health and wellness of postgraduate medical trainees has increased considerably in recent years, yet the scholarly literature consistently indicates that, in many instances, the medical and mental health care needs of this population remain unmet or only partially met. As a result, trainee health care often falls short of the current standards of the medical profession. Combined with the prevalence of burnout and other mental health conditions among trainees, inadequate health care for this patient population may result in significant negative consequences for trainees’ health, safety, and performance.Here, the authors review the scholarly literature explicating the health care needs of postgraduate trainees. They explore the patient-centered medical home model as a potentially effective solution to address the unmet and partially met health care needs of trainees. The authors describe several practical interventions to improve access to care. These include care coordination and referral support, confidential care without perceived conflicts of interest in the training environment, co-location of medical and mental health care, and accommodations for schedule constraints. Finally, the authors explore the role of the medical home in developing and supporting broader institutional efforts to promote wellness. © 2016 by the Association of American Medical Colleges

Mitchell J.H.,University of Texas Southwestern Medical Center
Experimental Physiology | Year: 2013

New Findings: • What is the topic of this lecture? Sir William Paton, a distinguished physician scientist, was interested in the origins of concepts in physiology. This lecture explores the early insights on the neural control of the circulation during exercise. • What advances does it highlight? This lecture presents some of the outstanding seminal investigations on the central and peripheral control mechanisms that regulate the autonomic neural activity to the heart and blood vessels during exercise. During exercise, the cardiovascular response is rapidly and appropriately matched to the intensity of the physical activity. The autonomic nervous system plays an important role in achieving this closely matched circulatory response by an increase in the sympathetic nerve activity to the heart, blood vessels and adrenal medulla and a decrease in the parasympathetic nerve activity to the heart. Early insights into the mechanisms that controlled these cardiovascular changes during exercise were reported in the 19th century. At that time, two mechanisms were hypothesized to be responsible for these changes. In one mechanism, a signal arising in a central area of the brain causes a parallel activation of skeletal muscle contraction and of autonomic nervous system changes (now termed 'central command'). In the other mechanism, a signal arising in the contracting skeletal muscle causes a reflex activation of the autonomic nervous system changes (now termed 'exercise pressor reflex'). Some important investigators involved in early studies include Johan Johansson, August Krogh, Johannes Lindhard and Horace Smirk. Also, Florence Buchanan and Louis Fridericia should be recognized for their contributions. In more recent years, the important involvement of a third mechanism, the arterial baroreflex, has been elucidated. Since those early insights, experiments in both animals and humans have added important findings that strongly support these early hypotheses. © 2013 The Physiological Society.

Mayorga C.A.,University of Texas Southwestern Medical Center | Rockey D.C.,Medical University of South Carolina
Clinical Gastroenterology and Hepatology | Year: 2013

Background & Aims: Recent reductions in mortality after acute upper gastrointestinal hemorrhage among patients with cirrhosis have been attributed to early and aggressive use of guideline-recommended pharmacologic agents, antibiotics, and endoscopic therapy. Studies have shown, however, that adherence to recommended guidelines is low. We investigated whether use of a standardized electronic order set would improve adherence to treatment and timeliness of delivery. Methods: We performed a prospective observational study, implementing an electronic order set for 123 patients with known or suspected cirrhosis who presented with symptoms/signs of upper gastrointestinal hemorrhage at Parkland Memorial Hospital (in Dallas, TX) from July 2011 through June 2012. The order set included standard nursing orders, laboratory tests, medications, orders for consultative services, and a brief evidence-based review of the benefits of octreotide and antibiotics in patients with cirrhosis. Primary outcomes included overall adherence to the administration of octreotide and antibiotics and the performance of upper endoscopy, as well as time to these interventions. Results: Administration of antibiotics increased in patients for whom the order set was used (100% vs 89% for whom it was not used; P= .01); the use of the order set significantly reduced the time to administration of antibiotics (3 h 28 min vs 10 h 4 min; P < .001). The time to administration of octreotide also significantly was reduced for patients for whom the order set was used (2 h 16 min vs 6 h 21 min; P < .002). Although all patients underwent endoscopy, there was no significant difference in the time to procedure between patients for whom the order set was used and not used (17 h 54 min vs 18 h 5 min; P= .95). Conclusions: The use of a standardized electronic order set improved not only overall adherence, but also the timeliness of administration of recommended therapies for patients with known or suspected cirrhosis presenting with upper gastrointestinal hemorrhage. © 2013 AGA Institute.

Peng F.,University of Texas Southwestern Medical Center
Annals of the New York Academy of Sciences | Year: 2014

Copper is an essential nutrient for the physiology of live organisms, but excessive copper can be harmful. Copper radioisotopes are used for measurement of copper fluxes in live organisms using a radioactivity assay of body fluids or whole-body positron emission tomography (PET). Hybrid positron emission tomography-computed tomography (PET/CT) is a versatile tool for real-time measurement of copper fluxes combining the high sensitivity and quantification capability of PET and the superior spatial resolution of CT for anatomic localization of radioactive tracer activity. Kinetic analysis of copper metabolism in the liver and extrahepatic tissues of Atp7b-/- knockout mice, a mouse model of Wilson's disease, demonstrated the feasibility of measuring copper fluxes in live organisms with PET/CT using copper-64 chloride (64CuCl2) as a radioactive tracer (64CuCl2-PET/CT). 64CuCl2-PET/CT holds potential as a useful tool for the diagnosis of inherited and acquired human copper metabolism disorders and for monitoring the effects of copper-modulating therapy. © 2014 New York Academy of Sciences.

Amarasingham R.,University of Texas Southwestern Medical Center | Lo B.,University of California at San Francisco
Health Affairs | Year: 2014

Predictive analytics, or the use of electronic algorithms to forecast future events in real time, makes it possible to harness the power of big data to improve the health of patients and lower the cost of health care. However, this opportunity raises policy, ethical, and legal challenges. In this article we analyze the major challenges to implementing predictive analytics in health care settings and make broad recommendations for overcoming challenges raised in the four phases of the life cycle of a predictive analytics model: acquiring data to build the model, building and validating it, testing it in real-world settings, and disseminating and using it more broadly. For instance, we recommend that model developers implement governance structures that include patients and other stakeholders starting in the earliest phases of development. In addition, developers should be allowed to use already collected patient data without explicit consent, provided that they comply with federal regulations regarding research on human subjects and the privacy of health information. © 2014 by Project HOPE - The People-to-People Health Foundation.

Winick N.,University of Texas Southwestern Medical Center
Current Opinion in Pediatrics | Year: 2011

Purpose of Review: There are more than 11 million survivors of pediatric cancers living in the US. The largest proportion had leukemia and the group most severely impacted by their cancer and their therapies are the survivors of central nervous system (CNS) tumors. This review describes the neurocognitive outcome for these groups and outlines work aimed at understanding the pathophysiology of and approach to ameliorating neurocognitive dysfunction. RECENT FINDINGS: The impact of chemotherapy on children treated for leukemia without radiation has been elucidated and the differential impact of different radiation fields and doses among children with CNS malignancies has been described. Newer imaging techniques may predict damage earlier and animal models of chemotherapy-induced neurotoxicity may prove valuable in designing less toxic therapies or finding protective agents. Cognitive training programs, notably computerized programs that can be accessed at home, may be part of successful programs for minimizing neurotoxicity. SUMMARY: This review seeks to describe the neurocognitive consequences of cancer and its therapy among pediatric patients treated for leukemia or a CNS tumor. The consequences of therapy with and without cranial radiation are described and information on potentially valuable animal models and imaging techniques are presented. The impact of host pharmacogenomics is outlined. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Curthoys N.P.,Colorado State University | Moe O.W.,University of Texas Southwestern Medical Center
Clinical Journal of the American Society of Nephrology | Year: 2014

The human kidneys produce approximately 160–170 L of ultrafiltrate per day. The proximal tubule contributes to fluid, electrolyte, and nutrient homeostasis by reabsorbing approximately 60%–70% of the water and NaCl, a greater proportion of the NaHCO3, and nearly all of the nutrients in the ultrafiltrate. The proximal tubule is also the site of active solute secretion, hormone production, and many of the metabolic functions of the kidney. This review discusses the transport of NaCl, NaHCO3, glucose, amino acids, and two clinically important anions, citrate and phosphate. NaCl and the accompanying water are reabsorbed in an isotonic fashion. The energy that drives this process is generated largely by the basolateral Na+/K+-ATPase, which creates an inward negative membrane potential and Na+-gradient. Various Na+-dependent countertransporters and cotransporters use the energy of this gradient to promote the uptake of HCO3 - and various solutes, respectively. A Na+-dependent cotransporter mediates the movement of HCO3 - across the basolateral membrane, whereas various Na+- independent passive transporters accomplish the export of various other solutes. To illustrate its homeostatic feat, the proximal tubule alters its metabolism and transport properties in response to metabolic acidosis. The uptake and catabolism of glutamine and citrate are increased during acidosis, whereas the recovery of phosphate from the ultrafiltrate is decreased. The increased catabolism of glutamine results in increased ammoniagenesis and gluconeogenesis. Excretion of the resulting ammonium ions facilitates the excretion of acid, whereas the combined pathways accomplish the net production of HCO3 - ions that are added to the plasma to partially restore acid-base balance. © 2014 by the American Society of Nephrology.

Sperandio V.,University of Texas Southwestern Medical Center
Gut Microbes | Year: 2010

Chemical communication mediates signaling between cells. Bacteria also engage in chemical signaling, termed quorum sensing (QS), to coordinate population-wide behavior. The bacterial pathogen enterohemorrhagic E. coli (EHEC), responsible for outbreaks of bloody diarrhea worldwide, exploits QS to promote expression of virulence factors in humans. Although EHEC is a human pathogen, it is a member of the gastrointestinal (GI) flora in cattle, the main reservoir for this bacterium. EHEC cattle colonization requires SdiA, a QS transcription factor that uses acylhomoserine lactones (AHLs), for proper folding and function. EHEC harbors SdiA, but does not produce AHLs, consequently having to sense AHLs produced by other bacterial species. We recently showed that SdiA is necessary for efficient EHEC passage through the bovine GI tract, and show that AHLs are prominent within cattle rumen, but absent from the other sections of the GI tract. EHEC utilizes the locus of enterocyte effacement (LEE) to colonize the recto-anal junction of cattle, and the glutamate decarboxylase (gad) system to colonize cows. Transcription of the LEE genes is decreased by rumen AHLs through SdiA, while transcription of the gad acid resistant system is increased. It would be expensive for EHEC to express the LEE genes in the rumen where they are not necessary. However, in preparation for the acidic distal stomachs the EHEC gad is activated in the rumen. Hence AHL signaling through SdiA aids EHEC in gauging these environments, and modulates gene expression towards adaptation to a commensal life-style in cattle.1 Inasmuch as EHEC is largely prevalent in cattle herds, interference with SdiA-mediated QS inhibition of cattle colonization could be an attractive approach to diminish contamination of food products due to cattle shedding of this pathogen. © 2010 Landes Bioscience.

Ahmad Z.,University of Texas Southwestern Medical Center | Wilson D.P.,Cook Medical
Journal of Clinical Lipidology | Year: 2014

Background Severe hypertriglyceridemia predisposes to attacks of acute pancreatitis, a serious condition complicated by multiorgan failure, pancreatic necrosis, and mortality rates up to 20% in adults and 6.5% in children. Overview We describe an infant who suffered from an episode of acute pancreatitis from severe hypertriglyceridemia. Two major challenges complicate the case: identifying the etiology of severe hypertriglyceridemia and finding an efficacious treatment. A thorough history, physical examination, and laboratory workup failed to identify a clear etiology, prompting a genetic workup that identified compound heterozygous mutations in the glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) gene. This patient's hypertriglyceridemia responded to an infant formula rich in medium chain triglycerides (MCTs), and she remained free of pancreatitis 6 months later. Conclusions This case highlights the need to pursue a genetic evaluation in the absence of secondary causes of severe hypertriglyceridemia in infants. Patients with mutations in GPIHBP1 fail to respond to currently available lipid-lowering agents so dietary management - specifically, an extremely low-fat diet and supplementation with MCT - remains the cornerstone of therapy. Treatment in infants should focus on dietary measures rather than pharmacologic agents. © 2014 National Lipid Association. All rights reserved.

Comment A.,Ecole Polytechnique Federale de Lausanne | Merritt M.E.,University of Texas Southwestern Medical Center
Biochemistry | Year: 2014

Hyperpolarized magnetic resonance allows for noninvasive measurements of biochemical reactions in vivo. Although this technique provides a unique tool for assaying enzymatic activities in intact organs, the scope of its application is still elusive for the wider scientific community. The purpose of this review is to provide key principles and parameters to guide the researcher interested in adopting this technology to address a biochemical, biomedical, or medical issue. It is presented in the form of a compendium containing the underlying essential physical concepts as well as suggestions to help assess the potential of the technique within the framework of specific research environments. Explicit examples are used to illustrate the power as well as the limitations of hyperpolarized magnetic resonance. © 2014 American Chemical Society.

Kuro-O M.,University of Texas Southwestern Medical Center
Kidney international. Supplement | Year: 2011

Klotho is a putative aging suppressor gene encoding a single-pass transmembrane co-receptor that makes the fibroblast growth factor (FGF) receptor specific for FGF-23. In addition to multiple endocrine organs, Klotho is expressed in kidney distal convoluted tubules and parathyroid cells, mediating the role of FGF-23 in bone-kidney-parathyroid control of phosphate and calcium. Klotho&x207B;/&x207B; mice display premature aging and chronic kidney disease-associated mineral and bone disorder (CKD-MBD)-like phenotypes mediated by hyperphosphatemia and remediated by phosphate-lowering interventions (diets low in phosphate or vitamin D; knockouts of 1α-hydroxylase, vitamin D receptor, or NaPi cotransporter). CKD can be seen as a state of hyperphosphatemia-induced accelerated aging associated with Klotho deficiency. Humans with CKD experience decreased Klotho expression as early as stage 1 CKD; Klotho continues to decline as CKD progresses, causing FGF-23 resistance and provoking large FGF-23 and parathyroid hormone increases, and hypovitaminosis D. Secreted Klotho protein, formed by extracellular clipping, exerts FGF-23-independent phosphaturic and calcium-conserving effects through its paracrine action on the proximal and distal tubules, respectively. We contend that decreased Klotho expression is the earliest biomarker of CKD and the initiator of CKD-MBD pathophysiology. Maintaining normal phosphate levels with phosphate binders in patients with CKD with declining Klotho expression is expected to reduce mineral and vascular derangements.

Lee Simon J.C.,University of Texas Southwestern Medical Center
Health, Risk and Society | Year: 2010

A core logic of cancer control and prevention, like much in public health, turns on the notion of decision-making under conditions of uncertainty. Population-level data are increasingly used to develop risk profiles, or estimates, that clinicians and the consumer public may use to guide individual decisions about cancer screening. Individual risk perception forms a piece of a larger social economy of decision- making and choice that makes population screening possible. Individual decision- making depends on accessing and interpreting available clinical information, filtered through the lens of personal values and both cognitive and affective behavioural processes. That process is also mediated by changing social roles and interpersonal relationships. This paper begins to elucidate the influence of this 'social context' within the complexity of cancer screening. Reflecting on current work in risk and health, I consider how ethnographic narrative methods can enrich this model. © 2010 Taylor & Francis.

Krawczyk D.C.,University of Texas at Dallas | Krawczyk D.C.,University of Texas Southwestern Medical Center | D'Esposito M.,University of California at Berkeley
Human Brain Mapping | Year: 2013

Cognitive performance is affected by motivation. Few studies, however, have investigated the neural mechanisms of the influence of motivation through potential monetary punishment on working memory. We employed functional MRI during a delayed recognition task that manipulated top-down control demands with added monetary incentives to some trials in the form of potential losses of bonus money. Behavioral performance on the task was influenced by loss-threatening incentives in the form of faster and more accurate performance. As shown previously, we found enhancement of activity for relevant stimuli occurs throughout all task periods (e.g., stimulus encoding, maintenance, and response) in both prefrontal and visual association cortex. Further, these activation patterns were enhanced for trials with possible monetary loss relative to nonincentive trials. During the incentive cue, the amygdala and striatum showed significantly greater activation when money was at a possible loss on the trial. We also evaluated patterns of functional connectivity between regions responsive to monetary consequences and prefrontal areas responsive to the task. This analysis revealed greater delay period connectivity between and the left insula and prefrontal cortex with possible monetary loss relative to nonincentive trials. Overall, these results reveal that incentive motivation can modulate performance on working memory tasks through top-down signals via amplification of activity within prefrontal and visual association regions selective to processing the perceptual inputs of the stimuli to be remembered. Hum Brain Mapp , 2013. © 2011 Wiley Periodicals, Inc. Copyright © 2011 Wiley Periodicals, Inc..

Cronin R.E.,University of Texas Southwestern Medical Center
Pediatric Nephrology | Year: 2010

Contrast-induced nephropathy (CIN) is the third most common cause of acute kidney injury in hospitalized patients. Diagnostic and interventional cardiovascular procedures generate nearly half the cases. Elderly patients and those with chronic kidney disease, diabetes, and cardiovascular disease are at greatest risk. Procedure-related risk factors include large volumes of contrast and agents with a high osmolality. Renal medullary ischemia arising from an imbalance of local vasoconstrictive and vasodilatory influences coupled with increased demand for oxygen-driven sodium transport may be the key to its pathogenesis. Contrast agents may also have a direct cytotoxic effect that operates through the generation of reactive oxygen species. Pre- and post-procedure administration of normal saline, isotonic sodium bicarbonate, N-acetylcysteine, and a variety of other pharmacologic agents have been used to prevent or mitigate CIN. While normal saline is generally accepted as protective against CIN, uncertainty still surrounds the role of sodium bicarbonate and N-acetylcysteine. Dialytic therapies before, during, and after exposure to contrast have been tested with mixed results. Logistical and economic disincentives argue against these modalities. © IPNA 2009.

Miller W.L.,University of California at San Francisco | Auchus R.J.,University of Texas Southwestern Medical Center
Endocrine Reviews | Year: 2011

Steroidogenesis entails processes by which cholesterol is converted to biologically active steroid hormones. Whereas most endocrine texts discuss adrenal, ovarian, testicular, placental, and other steroidogenic processes in a gland-specific fashion, steroidogenesis is better understood as a single process that is repeated in each gland with cell-type-specific variations on a single theme. Thus, understanding steroidogenesis is rooted in an understanding of the biochemistry of the various steroidogenic enzymes and cofactors and the genes that encode them. The first and rate-limiting step in steroidogenesis is the conversion of cholesterol to pregnenolone by a single enzyme, P450scc (CYP11A1), but this enzymatically complex step is subject to multiple regulatory mechanisms, yielding finely tuned quantitative regulation. Qualitative regulation determining the type of steroid to be produced is mediated by many enzymes and cofactors. Steroidogenic enzymes fall into two groups: cytochrome P450 enzymes and hydroxysteroid dehydrogenases. A cytochrome P450 may be either type 1 (in mitochondria) or type 2 (in endoplasmic reticulum), and a hydroxysteroid dehydrogenase may belong to either the aldo-keto reductase or short-chain dehydrogenase/reductase families. The activities of these enzymes are modulated by posttranslational modifications and by cofactors, especially electron-donating redox partners. The elucidation of the precise roles of these various enzymes and cofactors has been greatly facilitated by identifying the genetic bases of rare disorders of steroidogenesis. Some enzymes not principally involved in steroidogenesis may also catalyze extraglandular steroidogenesis, modulating the phenotype expected to result from some mutations. Understanding steroidogenesis is of fundamental importance to understanding disorders of sexual differentiation, reproduction, fertility, hypertension, obesity, and physiological homeostasis. Copyright © 2011 by The Endocrine Society.

Rohrich R.J.,University of Texas Southwestern Medical Center
Plastic and Reconstructive Surgery | Year: 2011

Learning Objectives: After reading this article, the participant should be able to: 1. Discuss desired preoperative aesthetic and functional assessment of the postsurgical nose with rhinoplasty patients. 2. Identify factors that have the potential to affect procedural outcomes. 3. Develop an operative plan to address aesthetic goals while preserving/improving nasal airway function. 4. Recognize and manage complications following rhinoplasty. Rhinoplasty is one of the most commonly performed aesthetic surgical procedures in plastic surgery. Over the past 20 years, the trend has shifted away from ablative techniques involving reduction or division of the osseocartilaginous framework to conserving native anatomy with cartilage-sparing suture techniques and augmentation of deficient areas to correct contour deformities and restore structural support. Accurate preoperative systematic nasal analysis and evaluation of the nasal airway, along with identification of both the patients expectations and the surgeons goals, form the foundation for success. Intraoperatively, adequate anatomical exposure of the nasal deformity; preservation and restoration of the normal anatomy; correction of the deformity using incremental control, maintenance, and restoration of the nasal airway; and recognition of the dynamic interplays among the composite of maneuvers are required. During postoperative recovery, care and reassurance combined with an ability to recognize and manage complications lead to successful outcomes following rhinoplasty. © 2011 by the American Society of Plastic Surgeons.

Rohrich R.J.,University of Texas Southwestern Medical Center
Journal of the American Academy of Dermatology | Year: 2011

The American Academy of Dermatology and the American Society of Plastic Surgeons, with the support of other sister societies, conducted the Facial Soft-Tissue Fillers: Assessing the State of the Science conference in December of 2009. The American Academy of Dermatology and the American Society of Plastic Surgeons established a panel of leading experts in the field of soft-tissue fillers - from researchers to clinicians - and other stakeholders for the conference to examine and discuss issues of patient safety, efficacy, and effectiveness in relation to the approved and off-label use of soft-tissue fillers, and other factors, including the training and level of experience of individuals administering fillers. This report summarizes the deliberations and key points made by the panel and presenters to the panel, and includes a summary of the panel's near-term and longer term recommendations for next steps to help guide future efforts to address the safety, efficacy, and effectiveness of facial soft-tissue fillers. This report represents the panel's assessment of the medical knowledge available on facial soft-tissue fillers at the time of the conference. © 2011 by the American Academy of Dermatology, Inc and Copyright © 2011 by the American Society of Plastic Surgeons.

Rohrich R.J.,University of Texas Southwestern Medical Center
Journal of the American Academy of Dermatology | Year: 2011

The American Academy of Dermatology and the American Society of Plastic Surgeons, with the support of other sister societies, conducted the Facial Soft-Tissue Fillers: Assessing the State of the Science conference in December of 2009. The American Academy of Dermatology and the American Society of Plastic Surgeons established a panel of leading experts in the field of soft-tissue fillers - from researchers to clinicians - and other stakeholders for the conference to examine and discuss issues of patient safety, efficacy, and effectiveness in relation to the approved and off-label use of soft-tissue fillers, and other factors, including the training and level of experience of individuals administering fillers. This report represents the systematic literature review that examines comprehensively the available evidence and gaps in the evidence related to soft-tissue fillers, to inform and support the work of the state-of-the-science conference panel. This evidence-based medicine review will serve as the foundation for future evidence-based medicine reports in this growing field. © 2011 by the American Academy of Dermatology, Inc and Copyright © 2011 by the American Society of Plastic Surgeons.

Lee H.C.,University of Texas Southwestern Medical Center
Molecular cell | Year: 2010

A variety of small RNAs, including the Dicer-dependent miRNAs and the Dicer-independent Piwi-interacting RNAs, associate with Argonaute family proteins to regulate gene expression in diverse cellular processes. These two species of small RNA have not been found in fungi. Here, by analyzing small RNAs associated with the Neurospora Argonaute protein QDE-2, we show that diverse pathways generate miRNA-like small RNAs (milRNAs) and Dicer-independent small interfering RNAs (disiRNAs) in this filamentous fungus. Surprisingly, milRNAs are produced by at least four different mechanisms that use a distinct combination of factors, including Dicers, QDE-2, the exonuclease QIP, and an RNase III domain-containing protein, MRPL3. In contrast, disiRNAs originate from loci producing overlapping sense and antisense transcripts, and do not require the known RNAi components for their production. Taken together, these results uncover several pathways for small RNA production in filamentous fungi, shedding light on the diversity and evolutionary origins of eukaryotic small RNAs. Copyright (c) 2010 Elsevier Inc. All rights reserved.

The interaction of macromolecules with themselves and with other macromolecules is fundamental to the functioning of living systems. Recent advances in the analysis of sedimentation velocity (SV) data obtained by analytical ultracentrifugation allow the experimenter to determine important features of such interactions, including the equilibrium association constant and information about the kinetic off-rate of the interaction. The determination of these parameters is made possible by the ability of modern software to fit numerical solutions of the Lamm Equation with kinetic considerations directly to SV data. Herein, the SV analytical advances implemented in the software package SEDPHAT are summarized. Detailed analyses of SV data using these strategies are presented. Finally, a few highlights of recent literature reports that feature this type of SV data analysis are surveyed. © 2010 Elsevier Inc.

Gagnon K.T.,University of Texas Southwestern Medical Center
Methods in molecular biology (Clifton, N.J.) | Year: 2011

Electrophoretic mobility shift assay, or EMSA, is a well-established technique for separating macromolecules under native conditions based on a combination of shape, size, and charge. The use of EMSA can provide both general and specific information concerning the interaction between two macromolecules such as RNA and protein. Here we present a protocol for the practical use of EMSA to assess protein-RNA interactions and ribonucleoprotein (RNP) assembly. The conceptual framework of the assay is discussed along with a step-by-step procedure for the binding of archaeal ribosomal protein L7Ae to a box C/D sRNA. Potential pitfalls and common mistakes to avoid are emphasized with technical tips and a notes section. This protocol provides a starting point for the design and implementation of EMSA in studying a wide variety of RNP complexes.

Avery L.,University of Texas Southwestern Medical Center
BMC Biology | Year: 2010

Thousands of behavioral mutants of Caenorhabditis elegans have been studied. I suggest a set of criteria by which some genes important in the evolution of behavior might be recognized, and identify neuropeptide signaling pathways as candidates. © 2010 Avery; licensee BioMed Central Ltd.

Corbin I.R.,University of Texas Southwestern Medical Center
Methods in Molecular Biology | Year: 2013

Lipoproteins are natural nanosized delivery vehicles within the circulatory system of all mammals. Scientists have long been interested in utilizing these endogenous macromolecules to transport exogenous imaging or therapeutic agents to specific cells or tissues in the body. The broad distribution of lipoprotein receptors throughout the body however has limited the utility of this approach for targeted delivery of medicinal agents. In recent years lipoprotein rerouting strategies have been developed wherein lipoproteins can be redirected from their natural lipoprotein receptors to an alternate receptor of choice. In this chapter we describe the basic methods of preparing folic acid-conjugated high-density lipoprotein nanoparticles for targeted delivery of imaging or chemotherapeutic agents to ovarian cancer cells. © Springer Science+Business Media, New York 2013.

Toto R.D.,University of Texas Southwestern Medical Center
Current Opinion in Nephrology and Hypertension | Year: 2010

Purpose of this review: The purpose of this review is to explain the rationale and limitations for use of mineralocorticoid receptor blockers (MRBs) for the treatment of chronic kidney disease (CKD) and its complications. Recent findings: Recent studies in animal models of CKD demonstrate that blockade of the mineralocorticoid receptor using spironolactone or eplerenone decreases inflammation, oxidative stress, proteinuria and glomerular and tubular injury. Patients with CKD are at very high risk for progression of kidney disease and major cardiovascular events. Recent studies in patients with CKD demonstrate that administration of low doses of MRBs added onto an angiotensin-converting enzyme inhibitor-based regimen reduces proteinuria-a risk marker for both progressive kidney disease and cardiovascular events. However, incident hyperkalemia, an unwanted side effect, dampened enthusiasm for this approach. There are no large-scale, long-term outcome trials examining whether MRB can slow progression of kidney disease or prevent cardiovascular events. Summary: At this time it is unknown whether mineralocorticoid receptor blockade can improve outcomes in patients with CKD. To move this field forward and determine whether these agents can improve the lives of patients with kidney disease, novel strategies to prevent or ameliorate hyperkalemia are needed. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Manes R.P.,University of Texas Southwestern Medical Center
Medical Clinics of North America | Year: 2010

Epistaxis is a common clinical problem often seen by primary care physicians. This can be caused by multiple factors, each of which should be explored to treat the epistaxis and prevent recurrences. In this article, etiologies and methods of evaluation for the patient with epistaxis are discussed. Treatment strategies are outlined in a stepwise fashion, as are recommendations for situations requiring referral to an otolaryngologist. © 2010 Elsevier Inc.

Liu X.,Stanford University | Liu X.,University of Texas Southwestern Medical Center | Bushnell D.A.,Stanford University | Kornberg R.D.,Stanford University
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2013

A minimal RNA polymerase II (pol II) transcription system comprises the polymerase and five general transcription factors (GTFs) TFIIB, -D, -E, -F, and -H. The addition of Mediator enables a response to regulatory factors. The GTFs are required for promoter recognition and the initiation of transcription. Following initiation, pol II alone is capable of RNA transcript elongation and of proofreading. Structural studies reviewed here reveal roles of GTFs in the initiation process and shed light on the transcription elongation mechanism. This article is part of a Special Issue entitled: RNA Polymerase II Transcript Elongation. © 2012 Elsevier B.V.

Turer A.T.,University of Texas Southwestern Medical Center
Journal of Molecular and Cellular Cardiology | Year: 2013

There is a long history of investigation into the metabolism of the failing heart. Congestive heart failure is marked both by severe disruptions in myocardial energy supply and an inability of the heart to efficiently uptake and oxidize fuels. Despite the many advancements in our understanding, there are still even more outstanding questions in the field. Metabolomics has the power to assist our understanding of the metabolic derangements which accompany myocardial dysfunction. Metabolomic investigations in animal models of heart failure have already highlighted several novel, potentially important pathways of substrate selection and toxicity. Metabolomic biomarker studies in humans, already successfully applied to other forms of cardiovascular disease, have the potential to improve diagnosis and patient care. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism". © 2012 Elsevier Ltd.

Balcer L.J.,University of Pennsylvania | Frohman E.M.,University of Texas Southwestern Medical Center
Neurology | Year: 2010

Background: Disturbances in visual function are common in patients with multiple sclerosis (MS) and are often accompanied by substantial impairments in daily functioning and quality of life. Lesions associated with these impairments frequently involve the afferent visual pathway. Expert Clinical Opinion: Because these impairments are often not readily apparent on commonly used high-contrast acuity tests, low-contrast charts (e.g., low-contrast Sloan letter charts) have gained validity in the assessment of visual dysfunction in patients with MS. Decrements in low-contrast letter acuity are associated with MS and correlate with increasing disability, MRI abnor-malities, and reduced retinal nerve fiber layer (RNFL) thickness as measured by optical coherence tomography (OCT). These findings suggest that low-contrast letter acuity testing is a potentially useful addition to disability scales such as the Multiple Sclerosis Functional Composite, serving as another surrogate marker for MS disability. Assessment of RNFL thickness by OCT, which is also associated with visual impairment, also may be considered for inclusion in clinical trials eval-uating treatments for MS. Future Directions: The effects of disease-modifying therapies on visual dysfunction in patients with MS have been evaluated only recently. Two phase 3 studies of natalizumab showed that low-contrast letter acuity testing, included as an exploratory outcome, demonstrated treatment effects. Other ongoing studies have incorporated low-contrast acuity and OCT measures of RNFL thickness. The availability and wider use of low-contrast letter acuity tests, in combination with ocular imaging techniques, may improve assessment of treatment efficacy in patients with MS. Copyright © 2010 by AAN Enterprises, Inc. All rights reserved.

Fleischmann R.,University of Texas Southwestern Medical Center | Fleischmann R.,Metroplex Clinical Research Center
Current Opinion in Rheumatology | Year: 2012

Purpose of Review: Since the introduction of biologic therapies into the treatment paradigm of rheumatoid arthritis (RA), there has been hope that oral small molecule immune modulators would be developed that would have a risk:benefit profile at least similar to biologic therapies, be more convenient for the patient and, hopefully, be less expensive. This article reviews the progress made in the development of these compounds over the past year. Recent Finding: Additional information has become available in the past year on five oral compounds including kinase inhibitors (tofacitinib, fostamatinib, VX-509), an S1P lyase inhibitor (LX 3305) and a chemokine receptor-1 antagonist (CCX354-C). Efficacy has been shown in phase III with tofacitinib and in phase II with fostamatinib and VX-509; safety was the primary endpoint of the trials of CCX354-C and LX3305. Regarding side effects, liver test elevation and neutropenia occurred with tofacitinib, VX-509 and fostamatinib; lipid elevation with tofacitinib and VX-509; creatinine elevation and anemia with tofacitinib, and hypertension and diarrhea with fostamatinib. Summary: Compounds that inhibit tyrosine kinase pathways involved in cellular signalling have been shown to be effective in the treatment of RA with a reasonable risk:benefit ratio. It is too early to tell about inhibitors of other pathways. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

George M.S.,Orthopaedic Center | Khazzam M.,University of Texas Southwestern Medical Center
Journal of Shoulder and Elbow Surgery | Year: 2012

Failed rotator cuff repair may be caused by surgical complications, diagnostic errors, technical errors, failure to heal, and traumatic failure. Revision rotator cuff repair is made technically more difficult by poor tissue quality, tissue adhesions, and retained suture and suture anchor material. Historically, open revision rotator cuff repair yields inferior results compared with primary rotator cuff repair; however, more recent studies show 52% to 69% satisfactory results in small-sized or medium-sized tears. Arthroscopic revision rotator cuff repair yields greater than 60% good or excellent results. Poor tissue quality, detachment of the deltoid origin, and multiple previous surgeries are risk factors for poor results in revision rotator cuff repair. Level of evidence: Review Article. © 2012.

Brenner A.M.,University of Texas Southwestern Medical Center
Harvard Review of Psychiatry | Year: 2012

Although supportive psychotherapy has had a long history in our field, relatively little attention has been paid to defining a body of material that residents should be taught in order to fulfill our current educational mandate. Teaching the evidence base for the efficacy of supportive psychotherapy is reviewed. The article then discusses three different conceptualizations of supportive psychotherapyas comprising the fundamental elements of all psychotherapies, as one end of a spectrum of dynamic therapies, and as a distinct set of directly helpful therapeutic interventions. The importance of each of these perspectives to an integrated model of supportive therapy is discussed in the context of the teaching and training needs of psychiatric residents. © 2012 President and Fellows of Harvard College.

Babb T.G.,The Texas Institute | Babb T.G.,University of Texas Southwestern Medical Center
Exercise and Sport Sciences Reviews | Year: 2013

Ventilatory limitation to exercise remains an important unresolved clinical issue; as a result, many individuals misinterpret the effects of expiratory flow limitation as an all-or-nothing phenomenon. Expiratory flow limitation is not all or none; approaching maximal expiratory flow can have important effects not only on ventilatory capacity but also on breathing mechanics, ventilatory control, and possibly exertional dyspnea and exercise intolerance. Copyright © 2012 by the American College of Sports Medicine.

Peng Y.,University of Texas Southwestern Medical Center
Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences | Year: 2012

Triple-negative (TN) carcinoma is a molecular subtype of breast cancer characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) and HER-2. It is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical aspects. TN tumors can be further classified into two subtypes: basal-like, defined as expressing epidermal growth factor receptor (EGFR) and/or cytokeratin (CK) 5/6 by immunohistochemistry, and non-basal-like; the majority of TN tumors are basal-like. TN tumors usually have a more aggressive behaviour and poorer outcome compared with non-TN breast cancers, and lack molecular targets commonly used in targeted therapy, making this group of tumors difficult to treat. Developing novel, effective treatment strategies for these tumors is crucial for improving their prognosis. This review describes a recent study series on prognostic and predictive values of tumor biomarker susing in TN breast cancer patients. TN tumors are associated with significantly higher expression of Ki67 and p53 compared to non-TN tumors. Hormone receptor negativity rather than HER-2 negativity is associated with the increased Ki67 and p53 expression in TN tumors. Furthermore, high expression level of Ki67 (>10%) but not p53, is significantly associated with nodal metastasis in TN tumors, indicating that Ki67 has better prognostic value than p53. TN tumors with distant metastases are significantly associated with lower expression of androgen receptor (AR) as compared to those with only loco-regional disease; there is a significant negative correlation between AR and Ki67 expressions among AR expressing TN tumors. Basal-like subtype TN tumors with nodal and distant metastases are associated with significantly higher intratumoral expression of EGFR and CK5/6 as compared to those without metastases. Therefore, increased EGFR and CK5/6 intratumoral expression and decreased AR intratumoral expression, rather than the frequency of their expression, may play a role in the development of metastases and may be predictive of metastatic disease in TN breast cancer patients. Anti-EGFR and anti-AR targeted therapies may provide potential treatment options for TN carcinomas, especially those tumors not responding to chemotherapy.

Roland P.S.,University of Texas Southwestern Medical Center | Tobey E.,University of Texas at Dallas
Cell | Year: 2013

For their work on the development of the modern cochlear implant, which bestows hearing to individuals with profound deafness, Ingeborg Hochmair, Graeme Clark, and Blake Wilson are the 2013 recipients of the Lasker∼DeBakey Clinical Medical Research Award. © 2013 Elsevier Inc.

Burd C.E.,University of North Carolina at Chapel Hill | Sorrentino J.A.,University of North Carolina at Chapel Hill | Clark K.S.,University of North Carolina at Chapel Hill | Darr D.B.,University of North Carolina at Chapel Hill | And 6 more authors.
Cell | Year: 2013

Monitoring cancer and aging in vivo remains experimentally challenging. Here, we describe a luciferase knockin mouse (p16LUC), which faithfully reports expression of p16INK4a, a tumor suppressor and aging biomarker. Lifelong assessment of luminescence in p16+/LUC mice revealed an exponential increase with aging, which was highly variable in a cohort of contemporaneously housed, syngeneic mice. Expression of p16 INK4a with aging did not predict cancer development, suggesting that the accumulation of senescent cells is not a principal determinant of cancer-related death. In 14 of 14 tested tumor models, expression of p16 LUC was focally activated by early neoplastic events, enabling visualization of tumors with sensitivity exceeding other imaging modalities. Activation of p16INK4a was noted in the emerging neoplasm and surrounding stromal cells. This work suggests that p16INK4a activation is a characteristic of all emerging cancers, making the p16 LUC allele a sensitive, unbiased reporter of neoplastic transformation. © 2013 Elsevier Inc.

Flouris A.D.,University of Thessaly | Schlader Z.J.,University of Texas Southwestern Medical Center | Schlader Z.J.,State University of New York at Buffalo
Scandinavian Journal of Medicine and Science in Sports | Year: 2015

The human capacity to perform prolonged exercise is impaired in hot environments. To address this issue, a number of studies have investigated behavioral aspects of thermoregulation that are recognized as important factors in determining performance. In this review, we evaluated and interpreted the available knowledge regarding the voluntary control of exercise work rate in hot environments. Our analysis indicated that: (a) Voluntary reductions in exercise work rate in uncompensable heat aid thermoregulation and are, therefore, thermoregulatory behaviors. (b) Unlike thermal behavior during rest, the role of thermal comfort as the ultimate mediator of thermal behavior during exercise in the heat remains uncertain. By contrast, the rating of perceived exertion appears to be the key perceptual controller under such conditions, with thermal perception playing a more modulatory role. (c) Prior to increases in core temperature (when only skin temperature is elevated), reductions in self-selected exercise work rate in the heat are likely mediated by thermal perception (thermal comfort and sensation) and its influence on the rating of perceived exertion. (d) However, when both core and skin temperatures are elevated, factors associated with cardiovascular strain likely dictate the rate of perceived exertion response, thereby mediating such voluntary reductions in exercise work rate. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Euhus D.,University of Texas Southwestern Medical Center
Annals of Surgical Oncology | Year: 2012

Purpose and Methods. The patient who tests positive for hereditary breast cancer has several important decisions to make regarding management of the breasts. Before making an informed decision, the physician must first review the screening assessment to make sure that the patient does not harbor an undiagnosed breast malignancy. In the absence of a malignancy, the management options for the breast range from nonoperative surveillance to prophylactic mastectomy to prevent cancer. In the event that a breast malignancy is diagnosed after a positive genetic test, implications for management of both the affected and the unaffected breast must be considered. Results and Discussion. The clinical assessment of the patient who tests positive is discussed. If routine pretest mammograms were negative, should additional diagnostic studies be performed to exclude an undetected/occult malignancy, and if so, what are the roles of magnetic resonance imaging, ultrasonography, digital mammogram, and detection of breast cancer circulating tumor cells? Medical management may include increased surveillance and chemopreventative therapy, including tamoxifen and oral contraceptives. Surgical interventions may be undertaken to reduce risk in people with a genetic susceptibility gene for breast or ovarian cancer; risk-reducing surgical options include mastectomy with or without reconstruction and nipple-sparing techniques. Finally, we discuss management decisions for women who test positive and who are diagnosed with aprimary breast cancer, compared to women who have no obvious primary tumor but test positive. © 2012 Society of Surgical Oncology.

Saint-Cyr M.,University of Texas Southwestern Medical Center
Clinics in Plastic Surgery | Year: 2011

A myriad of options exist for autologous tissue perforator-based breast reconstruction. Each perforator selected has its distinct vascular territory, and proper knowledge of perforator perfusion characteristics helps maximize outcome and limit complications. © 2011.

Kuro-O M.,University of Texas Southwestern Medical Center
Pflugers Archiv European Journal of Physiology | Year: 2010

The klotho gene was identified as an "aging-suppressor" gene in mice that accelerates aging when disrupted and extends life span when overexpressed. It encodes a single-pass transmembrane protein and is expressed primarily in renal tubules. The extracellular domain of Klotho protein is secreted into blood and urine by ectodomain shedding. The two forms of Klotho protein, membrane Klotho and secreted Klotho, exert distinct functions. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors and functions as an obligate co-receptor for FGF23, a bone-derived hormone that induces phosphate excretion into urine. Mice lacking Klotho or FGF23 not only exhibit phosphate retention but also display a premature-aging syndrome, revealing an unexpected link between phosphate metabolism and aging. Secreted Klotho functions as a humoral factor that regulates activity of multiple glycoproteins on the cell surface, including ion channels and growth factor receptors such as insulin/insulin-like growth factor-1 receptors. Potential contribution of these multiple activities of Klotho protein to aging processes is discussed. © 2009 Springer-Verlag.

Jilkine A.,University of Texas Southwestern Medical Center | Edelstein-Keshet L.,University of British Columbia
PLoS Computational Biology | Year: 2011

Polarization, a primary step in the response of an individual eukaryotic cell to a spatial stimulus, has attracted numerous theoretical treatments complementing experimental studies in a variety of cell types. While the phenomenon itself is universal, details differ across cell types, and across classes of models that have been proposed. Most models address how symmetry breaking leads to polarization, some in abstract settings, others based on specific biochemistry. Here, we compare polarization in response to a stimulus (e.g., a chemoattractant) in cells typically used in experiments (yeast, amoebae, leukocytes, keratocytes, fibroblasts, and neurons), and, in parallel, responses of several prototypical models to typical stimulation protocols. We find that the diversity of cell behaviors is reflected by a diversity of models, and that some, but not all models, can account for amplification of stimulus, maintenance of polarity, adaptation, sensitivity to new signals, and robustness. © 2011 Jilkine, Edelstein-Keshet.

He L.,University of Sichuan | Lu Q.R.,University of Texas Southwestern Medical Center
Neuroscience Bulletin | Year: 2013

Oligodendrocytes, the myelin-forming cells for axon ensheathment in the central nervous system, are critical for maximizing and maintaining the conduction velocity of nerve impulses and proper brain function. Demyelination caused by injury or disease together with failure of myelin regeneration disrupts the rapid propagation of action potentials along nerve fibers, and is associated with acquired and inherited disorders, including devastating multiple sclerosis and leukodystrophies. The molecular mechanisms of oligodendrocyte myelination and remyelination remain poorly understood. Recently, a series of signaling pathways including Shh, Notch, BMP and Wnt signaling and their intracellular effectors such as Olig1/2, Hes1/5, Smads and TCFs, have been shown to play important roles in regulating oligodendrocyte development and myelination. In this review, we summarize our recent understanding of how these signaling pathways modulate the progression of oligodendrocyte specification and differentiation in a spatiotemporally-specific manner. A better understanding of the complex but coordinated function of extracellular signals and intracellular determinants during oligodendrocyte development will help to devise effective strategies to promote myelin repair for patients with demyelinating diseases. © 2013 Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg.

Smith D.P.,University of Texas Southwestern Medical Center
Physiological Entomology | Year: 2012

Once captured by the antenna, the male-specific pheromone 11-cis vaccenyl acetate (cVA) binds to an extracellular binding protein called LUSH that undergoes a conformational shift upon cVA binding. The stable LUSH-cVA complex is the activating ligand for pheromone receptors present on the dendrites of the aT1 neurones, comprising the only class of neurones that detect volatile cVA pheromone. This mechanism can explain the single molecule sensitivity of pheromone detection. The receptor that recognizes activated LUSH consists of a complex of several proteins, including Or67d, a member of the tuning odourant receptor family, Orco, a co-receptor ion channel, and SNMP, a CD36 homologue that may be an inhibitory subunit. In addition, genetic screens and reconstitution experiments reveal additional factors that are important for pheromone detection. Identification and functional dissection of these factors in Drosophila melanogaster Meigen should permit the identification of homologous factors in pathogenic insects and agricultural pests, which, in turn, may be viable candidates for novel classes of compounds to control populations of target insect species without impacting beneficial species. © 2012 The Author. Physiological Entomology © 2012 The Royal Entomological Society.

Carr C.M.,Texas A&M University | Rizo J.,University of Texas Southwestern Medical Center
Current Opinion in Cell Biology | Year: 2010

Sec1/Munc18 (SM) proteins bind to and function with soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) at each vesicle fusion site in the cell. The purpose for these interactions is becoming clearer, as what had been interpreted as functional divergence between SM proteins acting at different vesicle trafficking steps, or in specialized cells, is giving way to more recent evidence for common functions among all SM proteins. What is emerging is a picture of SM proteins acting not merely as SNARE regulators, but also as central components of the membrane fusion apparatus. The available data suggest sequential models that describe how the soluble SM protein might first regulate SNARE complex assembly and then cooperate with SNAREs to stimulate membrane fusion. © 2010 Elsevier Ltd.

Reuben A.,Medical University of South Carolina | Koch D.G.,Medical University of South Carolina | Lee W.M.,University of Texas Southwestern Medical Center
Hepatology | Year: 2010

Acute liver failure (ALF) due to drug-induced liver injury (DILI), though uncommon, is a concern for both clinicians and patients. The Acute Liver Failure Study Group has prospectively collected cases of all forms of acute liver failure since 1998. We describe here cases of idiosyncratic DILI ALF enrolled during a 10.5-year period. Data were collected prospectively, using detailed case report forms, from 1198 subjects enrolled at 23 sites in the United States, all of which had transplant services. A total of 133 (11.1%) ALF subjects were deemed by expert opinion to have DILI; 81.1% were considered highly likely, 15.0% probable, and 3.8% possible. Subjects were mostly women (70.7%) and there was overrepresentation of minorities for unclear reasons. Over 60 individual agents were implicated, the most common were antimicrobials (46%). Transplant-free (3-week) survival was poor (27.1%), but with highly successful transplantation in 42.1%, overall survival was 66.2%. Transplant-free survival in DILI ALF is determined by the degree of liver dysfunction, specifically baseline levels of bilirubin, prothrombin time/international normalized ratio, and Model for End-Stage Liver Disease scores. Conclusion: DILI is an uncommon cause of ALF that evolves slowly, affects a disproportionate number of women and minorities, and shows infrequent spontaneous recovery, but transplantation affords excellent survival. Copyright © 2010 American Association for the Study of Liver Diseases.

Safdar Z.,Baylor College of Medicine | Bartolome S.,University of Texas Southwestern Medical Center | Sussman N.,Baylor College of Medicine
Liver Transplantation | Year: 2012

Portopulmonary hypertension (POPH) is a serious complication of cirrhosis that is associated with mortality beyond that predicted by the Model for End-Stage Liver Disease (MELD) score. Increased pulmonary vascular resistance (PVR) may be initiated by pulmonary vasoconstriction, altered levels of circulating mediators, or shear stress, and can eventually lead to the classic vascular remodeling (plexiform lesion) that characterizes POPH. Portal hypertension is a prerequisite for the diagnosis of POPH, although the severity of pulmonary hypertension is unrelated to the severity of portal hypertension or the nature or severity of liver disease. POPH precludes liver transplantation (LT) unless the mean pulmonary artery pressure (MPAP) can be reduced to a safe level. The concept of an acceptable pressure has changed: we now consider both MPAP and PVR in the diagnosis, and we include the transpulmonary pressure gradient so that we can factor in fluid overload and left ventricular failure. Pulmonary vasodilator therapy includes oral, inhaled, and parenteral agents, and one or more of these agents may significantly lower pulmonary artery pressures to the point that LT becomes possible. The United Network for Organ Sharing recommends MELD exception points for patients with medically controlled POPH, but this varies by region. Patients who undergo LT need specialized intraoperative and postoperative management, which includes the availability of intraoperative transesophageal echocardiography for assessing right ventricular function, and rapidly acting vasodilators (eg, inhaled nitric oxide and/or epoprostenol). Published case series suggest excellent outcomes after LT for patients who respond to medical therapy. © 2012 American Association for the Study of Liver Diseases.

Baum M.,University of Texas Southwestern Medical Center
American Journal of Physiology - Renal Physiology | Year: 2010

Epidemiologic studies from several different populations have demonstrated that prenatal insults, which adversely affect fetal growth, result in an increased incidence of hypertension when the offspring reaches adulthood. It is now becoming evident that low-birth-weight infants are also at increased risk for chronic kidney disease. To determine how prenatal insults result in hypertension and chronic kidney disease, investigators have used animal models that mimic the adverse events that occur in pregnant women, such as dietary protein or total caloric deprivation, uteroplacental insufficiency, and prenatal administration of glucocorticoids. This review examines the role of the kidney in generating and maintaining an increase in blood pressure in these animal models. This review also discusses how early postnatal adverse events may have repercussions in later life. Causes for the increase in blood pressure by perinatal insults are likely multifactorial and involve a reduction in nephron number, dysregulation of the systemic and intrarenal renin-angiotensin system, increased renal sympathetic nerve activity, and increased tubular sodium transport. Understanding the mechanism for the increase in blood pressure and renal injury resulting from prenatal insults may lead to therapies that prevent hypertension and the development of chronic kidney and cardiovascular disease. Copyright © 2010 the American Physiological Society.

Williamson J.W.,University of Texas Southwestern Medical Center
Experimental Physiology | Year: 2010

This paper briefly reviews the role of central command in the neural control of the circulation during exercise. While defined as a feedfoward component of the cardiovascular control system, central command is also associated with perception of effort or effort sense. The specific factors influencing perception of effort and their effect on autonomic regulation of cardiovascular function during exercise can vary according to condition. Centrally mediated integration of multiple signals occurring during exercise certainly involves feedback mechanisms, but it is unclear whether or how these signals modify central command via their influence on perception of effort. As our understanding of central neural control systems continues to develop, it will be important to examine more closely how multiple sensory signals are prioritized and processed centrally to modulate cardiovascular responses during exercise. The purpose of this article is briefly to review the concepts underlying central command and its assessment via perception of effort, and to identify potential areas for future studies towards determining the role and relevance of central command for neural control of exercise. © 2010 The Author. Journal compilation © 2010 The Physiological Society.

Gerber D.E.,University of Texas Southwestern Medical Center
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

A 60-year-old woman with hypertension, dyslipidemia, and 35-pack-year smoking history is referred for treatment of advanced non-small-cell lung cancer (NSCLC). She initially presented after a transient ischemic attack, when a chest radiograph demonstrated a right lung mass. Computed tomography (CT) of the chest revealed a 5-cm right upper lobe mass, without mediastinal adenopathy, and a 6-cm cystic mass in the spleen. Additional imaging showed no brain metastasis. Endobronchial ulstrasound-guided core biopsies of the lung mass and ipsilateral mediastinal nodes confirmed a poorly differentiated non-small-cell carcinoma. Immunohistochemical stains were positive for napsin A and thyroid transcription factor 1, suggestive of adenocarcinoma (Fig 1). Molecular analysis identified a KRAS G12C mutation. A positron emission tomography (PET) -CT scan demonstrated [(18)F]fluorodeoxyglucose uptake in the right upper lobe mass and splenic lesion (Fig 2A). CT-guided fine-needle aspiration of the splenic lesion was performed and revealed metastatic carcinoma, consistent with the lung primary. Treatment with carboplatin plus pemetrexed was initiated, without bevacizumab because of the recent transient ischemic attack; carboplatin was selected over cisplatin because of similar concerns. The patient received two cycles of chemotherapy without complications, and repeat imaging showed decrease in size of the lung mass and splenic lesion (Figs 2B and 2C). After four cycles of chemotherapy, a chest CT showed ongoing response (Fig 2D). Her Eastern Cooperative Oncology Group performance status remained 0.

Wang H.,National Health Research Institute | Falck J.R.,University of Texas Southwestern Medical Center | Hall T.M.T.,National Health Research Institute | Shears S.B.,National Health Research Institute
Nature Chemical Biology | Year: 2012

Inositol pyrophosphates (such as IP7 and IP8) are multifunctional signaling molecules that regulate diverse cellular activities. Inositol pyrophosphates have 'high-energy' phosphoanhydride bonds, so their enzymatic synthesis requires that a substantial energy barrier to the transition state be overcome. Additionally, inositol pyrophosphate kinases can show stringent ligand specificity, despite the need to accommodate the steric bulk and intense electronegativity of nature's most concentrated three-dimensional array of phosphate groups. Here we examine how these catalytic challenges are met by describing the structure and reaction cycle of an inositol pyrophosphate kinase at the atomic level. We obtained crystal structures of the kinase domain of human PPIP5K2 complexed with nucleotide cofactors and either substrates, product or a MgF 3 - transition-state mimic. We describe the enzyme's conformational dynamics, its unprecedented topological presentation of nucleotide and inositol phosphate, and the charge balance that facilitates partly associative in-line phosphoryl transfer. © 2011 Nature America, Inc. All rights reserved.

Davidson J.A.,University of Texas Southwestern Medical Center
Journal of Managed Care Pharmacy | Year: 2014

BACKGROUND: Oral antihyperglycemic drugs used to treat type 2 diabetes mellitus (T2DM) vary in safety and tolerability. Treatment-related hypoglycemia and weight gain can exacerbate underlying disease. OBJECTIVE: To evaluate the tolerability of saxagliptin using data from phase III clinical trials. METHODS: Six 24-week randomized studies in 4,214 patients with T2DM were assessed. Saxagliptin 2.5 mg or 5 mg was compared with placebo in 2 trials of monotherapy in treatment-naïve patients and in 3 trials of add-on therapy to metformin, glyburide, or a thiazolidinedione; initial combination therapy with saxagliptin 5 mg plus metformin was compared with metformin monotherapy in treatment-naïve patients. Data from the monotherapy and add-on studies were pooled; data from the initial combination study were analyzed separately. No statistical analyses of between-group comparisons across studies were conducted for these safety analyses because of multiplicity of end points and relative lack of statistical power and because small differences not reaching statistical significance have the potential to be clinically relevant. RESULTS: In the pooled analysis, incidence rates for adverse events (AEs) with saxagliptin 2.5 mg, 5 mg, and placebo were 72.0% (635/882), 72.2% (637/882), and 70.6% (564/799), respectively; rates for serious AEs (SAEs) were 3.5% (31/882), 3.4% (30/882), and 3.4% (27/799); rates of discontinuation due to AEs were 2.2% (19/882), 3.3% (29/882), and 1.8% (14/799). AEs reported in ≥ 2% of patients receiving saxagliptin and occurring = 1% more frequently with saxagliptin than with placebo were sinusitis, gastroenteritis, abdominal pain, and vomiting. In the initial combination study, AE incidence rates with saxagliptin 5 mg plus metformin and metformin monotherapy were 55.3% (177/320) and 58.5% (192/328), respectively; incidence rates for SAEs were 2.5% (8/320) and 2.4% (8/328); and rates of discontinuation due to AEs were 2.5% (8/320) and 3.4% (11/328). CONCLUSION: Saxagliptin 2.5 mg or 5 mg was generally well tolerated as monotherapy, add-on combination therapy with other oral antihyperglycemic drugs, and initial combination with metformin.

Bezprozvanny I.,University of Texas Southwestern Medical Center | Bezprozvanny I.,Saint Petersburg State Polytechnic University
Science Signaling | Year: 2013

Mutations in presenilins result in familial Alzheimer's disease (FAD). Presenilins encode a catalytic subunit of the γ-secretase complex, and FAD mutations in presenil-ins alter γ-secretase activity. Many FAD mutations in presenilins also affect intracel-lular calcium signaling. To explain these results, it was proposed that presenilins also function as endoplasmic reticulum (ER) calcium leak channels and that this function is disrupted by FAD mutations. Although this hypothesis has been controversial, new research supports the calcium leak channel hypothesis. One group reported the presence of putative ion-conduction pore in the high-resolution crystal structure of bacterial presenilin homolog PSH1. Another group identifi ed an essential role for presenilins in mediating ER calcium leak in a cell-based screen for calcium homeostasis modulators. These results should enable the fi eld to move forward and to focus on exploring connections between FAD mutations in presenilins, changes in γ-secretase and ER Ca2+ leak functions, and development of the disease. Copyright 2008 American Association for the Advancement of Science. All Rights Reserved.

Abbassi-Ghanavati M.,University of Texas Southwestern Medical Center
Obstetrics and Gynecology | Year: 2010

Objective: To estimate the prevalence of antithyroid peroxidase antibodies in the general obstetric population and to compare pregnancy outcomes in women who are antithyroid peroxidase-antibody positive with those who are antithyroid peroxidase-antibody negative. Methods: Between November 2000 and April 2003, all women who presented for prenatal care underwent thyroid screening. Serum samples from women without clinical hypothyroidism who had been screened in the first 20 weeks of gestation and delivered a singleton newborn weighing 500 g or more were analyzed for concentrations of antithyroid peroxidase antibodies. Serum thyroid peroxidase antibody levels were determined using a chemiluminescent immunoassay. Pregnancy outcomes in women with positive antithyroid peroxidase antibodies (more than 50 international units/mL) were compared with those with negative levels. Results: Serum samples from 17,298 women were tested. Of these, 1,012 (6%) women were identified with positive antithyroid peroxidase antibodies. Women who were antithyroid peroxidase-antibody positive were older, heavier, and more often parous than women with negative antithyroid peroxidase antibodies. Rate of placental abruption was threefold higher in women with antithyroid peroxidase antibodies (1.0% compared with 0.3%, odds ratio 3.4, 95% confidence interval 1.7-6.7) after adjustment for differences in maternal demographics. Seven of the 10 abruptions associated with antithyroid peroxidase antibody occurred in women with normal thyroid-stimulating hormone and free thyroxine levels. Conclusion: Antithyroid peroxidase antibodies are present in 6% of the general obstetric population and are associated with a threefold increase in the rate of placental abruption. However, this increase in placental abruption does not currently warrant routine antithyroid antibody screening during pregnancy. © 2010 by The American College of Obstetricians and Gynecologists.

Agathocleous M.,University of Texas Southwestern Medical Center | Harris W.A.,University of Cambridge
Trends in Cell Biology | Year: 2013

Stem and progenitor cells proliferate and give rise to other types of cells through differentiation. Deregulation of this process can lead to many diseases including cancer. Recent evidence suggests that an extensive metabolic reconfiguration of cancer cells allows them to sustain pathological growth by providing anabolic intermediates for biosynthesis. This raises the question of the physiological role of metabolic pathways during normal cell growth and differentiation. Metabolism changes with differentiation, and metabolic pathways may be controlled by the same signals that control cell proliferation and differentiation. However, metabolism could also reciprocally influence these signals. The role of metabolic regulation may extend beyond the provision of intermediates for the biosynthetic needs of proliferation, to affect cell differentiation. Here we bring together a large number of recent studies that support this suggestion and illustrate some of the mechanisms by which metabolism is linked to cell proliferation and differentiation. © 2013 Elsevier Ltd.

Haley R.W.,University of Texas Southwestern Medical Center | Tuite J.J.,International Security and Risk Management Consultant
Neuroepidemiology | Year: 2013

Background: Military intelligence data published in a companion paper explain how chemical fallout from US and Coalition bombing of Iraqi chemical weapons facilities early in the air campaign transited long distance, triggering nerve agent alarms and exposing US troops. We report the findings of a population-based survey designed to test competing hypotheses on the impact on chronic Gulf War illness of nerve agent from early-war bombing versus post-war demolition. Methods: The US Military Health Survey performed computer-assisted telephone interviews of a stratified random sample of Gulf War-era veterans (n = 8,020). Early-war exposure was measured by having heard nerve agent alarms and post-war exposure, by the computer-generated plume from the Khamisiyah demolition. Gulf War illness was measured by two widely published case definitions. Results: The OR (95% CI) for the association of alarms with the Factor case definition was 4.13 (95% CI 2.51-6.80) compared with 1.21 (95% CI 0.86-1.69) for the Khamisiyah plume. There was a dose-related trend for the number of alarms (ptrend < 0.001) but not for the number of days in the Khamisiyah plume (ptrend = 0.17). Conclusions: Exposure to low-level sarin nerve agent in fallout from bombing early in the air campaign contributed more to chronic illness than post-war demolition. © 2012 S. Karger AG, Basel.

Sperandio V.,University of Texas Southwestern Medical Center
Gut microbes | Year: 2010

Chemical communication mediates signaling between cells. Bacteria also engage in chemical signaling, termed quorum sensing (QS), to coordinate population-wide behavior. The bacterial pathogen enterohemorrhagic E. coli (EHEC), responsible for outbreaks of bloody diarrhea worldwide, exploits QS to promote expression of virulence factors in humans. Although EHEC is a human pathogen, it is a member of the gastrointestinal (GI) flora in cattle, the main reservoir for this bacterium. EHEC cattle colonization requires SdiA, a QS transcription factor that uses acyl-homoserine lactones (AHLs), for proper folding and function. EHEC harbors SdiA, but does not produce AHLs, consequently having to sense AHLs produced by other bacterial species. We recently showed that SdiA is necessary for efficient EHEC passage through the bovine GI tract, and show that AHLs are prominent within cattle rumen, but absent from the other sections of the GI tract. EHEC utilizes the locus of enterocyte effacement (LEE) to colonize the recto-anal junction of cattle, and the glutamate decarboxylase (gad) system to colonize cows. Transcription of the LEE genes is decreased by rumen AHLs through SdiA, while transcription of the gad acid resistant system is increased. It would be expensive for EHEC to express the LEE genes in the rumen where they are not necessary. However, in preparation for the acidic distal stomachs the EHEC gad is activated in the rumen. Hence AHL signaling through SdiA aids EHEC in gauging these environments, and modulates gene expression towards adaptation to a commensal life-style in cattle.1 Inasmuch as EHEC is largely prevalent in cattle herds, interference with SdiA-mediated QS inhibition of cattle colonization could be an attractive approach to diminish contamination of food products due to cattle shedding of this pathogen. © 2010 Landes Bioscience

D'Brot A.,University of Texas Southwestern Medical Center
Oncogene | Year: 2016

p53 is the most frequently mutated gene in human cancer. Compelling evidence argues that full transformation involves loss of growth suppression encoded by wild-type p53 together with poorly understood oncogenic activity encoded by missense mutations. Furthermore, distinguishing disease alleles from natural polymorphisms is an important clinical challenge. To interrogate the genetic activity of human p53 variants, we leveraged the Drosophila model as an in vivo platform. We engineered strains that replace the fly p53 gene with human alleles, producing a collection of stocks that are, in effect, ‘humanized’ for p53 variants. Like the fly counterpart, human p53 transcriptionally activated a biosensor and induced apoptosis after DNA damage. However, all humanized strains representing common alleles found in cancer patients failed to complement in these assays. Surprisingly, stimulus-dependent activation of hp53 occurred without stabilization, demonstrating that these two processes can be uncoupled. Like its fly counterpart, hp53 formed prominent nuclear foci in germline cells but cancer-associated p53 variants did not. Moreover, these same mutant alleles disrupted hp53 foci and inhibited biosensor activity, suggesting that these properties are functionally linked. Together these findings establish a functional platform for interrogating human p53 alleles and suggest that simple phenotypes could be used to stratify disease variants.Oncogene advance online publication, 21 March 2016; doi:10.1038/onc.2016.48. © 2016 Macmillan Publishers Limited

Krawczyk D.C.,University of Texas at Dallas | Krawczyk D.C.,University of Texas Southwestern Medical Center
Brain Research | Year: 2012

There has been a growing interest in understanding the complex cognitive processes that give rise to human reasoning. This review focuses on the cognitive and neural characteristics of relational reasoning and analogy performance. Initially relational reasoning studies that have investigated the neural basis of abstract reasoning with an emphasis on the prefrontal cortex are described. Next studies of analogical reasoning are reviewed with insights from neuropsychological and neuroimaging studies. Additionally, studies of cognitive components in analogical reasoning are described. This review draws together insights from numerous studies and concludes that prefrontal areas exhibit domain independence in relational reasoning, while posterior areas within the temporal, parietal, and occipital lobes show evidence of domain dependence in reasoning. Lastly, future directions in the study of relational reasoning are discussed. © 2010 Elsevier B.V. All rights reserved.

Batra P.S.,University of Texas Southwestern Medical Center
Expert Review of Medical Devices | Year: 2010

The evolution of minimally invasive endoscopic techniques, coupled with advances in surgical instrumentation and computer-aided surgery, has greatly facilitated the management of complex sinonasal and skull-base pathology. This accrued experience has facilitated consideration of the treatment of malignant neoplasms of the paranasal sinuses and skull base via the endoscopic route. This strategy uses the rigid endoscope as the primary surgical modality for resection of neoplasms within the paranasal sinus confines, along with the adjacent orbit and skull base. The endoscopic approach has been demonstrated to be effective, with surgical outcomes approaching the traditional open craniofacial resection, providing unparalleled visualization, avoidance of facial incisions and reduction in morbidity. This article outlines the salient components of the endoscopic paradigm for minimally invasive tumor resection, focusing on requisite technology, surgical techniques and patient outcomes. © 2010 Expert Reviews Ltd.

Friedman D.I.,University of Texas Southwestern Medical Center | Liu G.T.,University of Pennsylvania | Digre K.B.,University of Utah
Neurology | Year: 2013

The pseudotumor cerebri syndrome (PTCS) may be primary (idiopathic intracranial hypertension) or arise from an identifiable secondary cause. Characterization of typical neuroimaging abnormalities, clarification of normal opening pressure in children, and features distinguishing the syndrome of intracranial hypertension without papilledema from intracranial hypertension with papilledema have furthered our understanding of this disorder. We propose updated diagnostic criteria for PTCS to incorporate advances and insights into the disorder realized over the past 10 years. © 2013 American Academy of Neurology.

Kaelin Jr. W.G.,Harvard University | Kaelin Jr. W.G.,Howard Hughes Medical Institute | McKnight S.L.,University of Texas Southwestern Medical Center
Cell | Year: 2013

Chemical modifications of histones and DNA, such as histone methylation, histone acetylation, and DNA methylation, play critical roles in epigenetic gene regulation. Many of the enzymes that add or remove such chemical modifications are known, or might be suspected, to be sensitive to changes in intracellular metabolism. This knowledge provides a conceptual foundation for understanding how mutations in the metabolic enzymes SDH, FH, and IDH can result in cancer and, more broadly, for how alterations in metabolism and nutrition might contribute to disease. Here, we review literature pertinent to hypothetical connections between metabolic and epigenetic states in eukaryotic cells. © 2013 Elsevier Inc.

Journeycake J.M.,University of Texas Southwestern Medical Center
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

Childhood immune thrombocytopenia (ITP) is often considered a benign hematologic disorder. However, 30% of affected children will have a prolonged course and 5%-10% will develop chronic severe refractory disease. Until recently, the only proven therapeutic option for chronic severe ITP was splenectomy, but newer alternatives are now being studied. However, because immunosuppressive agents such as rituximab are not approved for use in ITP and the thrombopoietin receptor agonists are not yet approved in children, the decision to use alternatives to splenectomy needs to be considered carefully. This review describes the factors that should affect decisions to treat ITP at diagnosis and compares the options for the occasional child in whom ITP does not resolve within the first year.

Bird J.A.,University of Texas Southwestern Medical Center
Allergy and Asthma Proceedings | Year: 2016

Background: Diagnosing food allergy is often challenging, and validated testing modalities are mostly limited to immunoglobulin E (IgE)-mediated reactions to foods. Use of food-specific IgE tests and skin prick tests in individuals without a history that supports an IgE-mediated reaction to the specific food being tested diminishes the predictive capabilities of the test. Objective: To review the literature regarding evaluation of patients with a concern for multiple food allergies and to demonstrate an evidence-based approach to diagnosis and management. Methods: A literature search was performed and articles identified as relevant based on the search terms "food allergy," "food allergy diagnosis," "skin prick test," "serum IgE test," "oral food challenge", and "food allergy management." Results: Patients at risk of food allergy are often misdiagnosed and appropriate evaluation of patients with concern for food allergy includes taking a thorough diet history and reaction history, performing specific tests intentionally and when indicated, and conducting an oral food challenge in a safe environment by an experienced provider when test results are inconclusive. Conclusion: An evidence-based approach to diagnosing and managing a patient at risk of having a life-threatening food allergy is reviewed. Copyright © 2016, OceanSide Publications, Inc.

Jialal I.,University of California at Davis | Huet B.A.,University of Texas Southwestern Medical Center | Kaur H.,University of California at Davis | Chien A.,University of California at Davis | Devaraj S.,Baylor College of Medicine
Diabetes Care | Year: 2012

OBJECTIVE - The metabolic syndrome (MetS) is highly prevalent and confers an increased risk for diabetes and cardiovascular disease (CVD). While MetS is a proinflammatory state, there is a paucity of data on cellular inflammation in MetS. Toll-like receptors (TLRs) are classical pattern recognition receptors of the innate immune response. RESEARCH DESIGN AND METHODS - The aim of this study was to examine monocyte TLR2 and TLR4 in MetS patients without diabetes or CVD and control subjects since both of the receptors have been implicated in atherosclerosis and insulin resistance. Fasting blood was obtained for TLR expression and activity. RESULTS - Circulating levels of high-sensitivity C-reactive protein, interleukin (IL)-1β, IL-6, IL-8, and soluble tumor necrosis factor receptor 1 (sTNFR1) were significantly increased in MetS versus control subjects following adjustment for waist circumference. There was a significant increase in both TLR2 and TLR4 surface expression and mRNA on monocytes after adjustment for waist circumference. In addition to increased nuclear factor-κB nuclear binding, there was significantly increased release of IL-1β, IL-6, and IL-8 in MetS versus control subjects following priming of the monocytes with lipopolysaccharides. While both plasma free fatty acids and endotoxin were increased in MetS, they correlated significantly with TLR4 only. CONCLUSIONS - In conclusion, we make the novel observation that both TLR2 and TLR4 expression and activity are increased in the monocytes of patients with MetS and could contribute to increased risk for diabetes and CVD. © 2012 by the American Diabetes Association.

Livingston E.H.,University of Texas Southwestern Medical Center | Burchell I.,University of Texas at Arlington
Archives of Surgery | Year: 2010

Objective: To determine the effect on travel distance for Medicare patients before and after Centers for Medicare & Medicaid Services required that bariatric procedures be performed at Centers of Excellence (COEs). Design: We calculated the distance traveled to our medical center for the 2 years prior (2004-2005) and 2 years after (2006-2007) COE status was required by Medicare. We also compared the proportion of bariatric cases done in large hospitals with those for esophageal and pancreatic resections, procedures whose effects regionalization would have on patient access have been modeled. Setting: University of Texas Southwestern Medical Center, a high-volume tertiary referral center for bariatric surgery. Patients: Patients undergoing bariatric procedures. Main Outcome Measure: Travel distances. Results: Depending on insurance status, before COEs were required, patients traveled a median of 16 to 25 miles to undergo bariatric operations at University of Texas Southwestern. After COEs were required, the median distance Medicare patients were required to travel increased 76% to 44 miles. Conclusions: Center of Excellence requirements have increased the travel distance required for Medicare patients. Prior research has shown that outcomes at COEs are no different than those at non-COEs suggesting that the reduced access to care resulting from requiring COE status is not beneficial. ©2010 American Medical Association. All rights reserved.

Shan Y.,De Shaw Research | Eastwood M.P.,De Shaw Research | Zhang X.,University of Texas Southwestern Medical Center | Kim E.T.,De Shaw Research | And 6 more authors.
Cell | Year: 2012

The mutation and overexpression of the epidermal growth factor receptor (EGFR) are associated with the development of a variety of cancers, making this prototypical dimerization-activated receptor tyrosine kinase a prominent target of cancer drugs. Using long-timescale molecular dynamics simulations, we find that the N lobe dimerization interface of the wild-type EGFR kinase domain is intrinsically disordered and that it becomes ordered only upon dimerization. Our simulations suggest, moreover, that some cancer-linked mutations distal to the dimerization interface, particularly the widespread L834R mutation (also referred to as L858R), facilitate EGFR dimerization by suppressing this local disorder. Corroborating these findings, our biophysical experiments and kinase enzymatic assays indicate that the L834R mutation causes abnormally high activity primarily by promoting EGFR dimerization rather than by allowing activation without dimerization. We also find that phosphorylation of EGFR kinase domain at Tyr845 may suppress the intrinsic disorder, suggesting a molecular mechanism for autonomous EGFR signaling. © 2012 Elsevier Inc.

Koh A.Y.,University of Texas Southwestern Medical Center
Eukaryotic Cell | Year: 2013

Ninety-five percent of infectious agents enter through exposed mucosal surfaces, such as the respiratory and gastrointestinal (GI) tracts. The human GI tract is colonized with trillions of commensal microbes, including numerous Candida spp. Some commensal microbes in the GI tract can cause serious human infections under specific circumstances, typically involving changes in the gut environment and/or host immune conditions. Therefore, utilizing animal models of fungal GI colonization and dissemination can lead to significant insights into the complex pathophysiology of transformation from a commensal organism to a pathogen and host-pathogen interactions. This paper will review the methodologic approaches used for modeling GI colonization versus dissemination, the insights learned from these models, and finally, possible future directions using these animal modeling systems. © 2013, American Society for Microbiology. All Rights Reserved.

Schoggins J.W.,University of Texas Southwestern Medical Center | Randall G.,University of Chicago
Cell Host and Microbe | Year: 2013

It is becoming apparent that infections by a major class of viruses, those with envelopes, can be inhibited during their entry at the step of fusion with cellular membranes. In this review, we discuss multiple innate immune mechanisms that have evolved to modify the lipid composition of cellular and viral membranes to inhibit virion fusion of enveloped viruses. © 2013 Elsevier Inc.

Diamond M.S.,University of Washington | Schoggins J.W.,University of Texas Southwestern Medical Center
Cell Host and Microbe | Year: 2013

In this issue of Cell Host & Microbe, Varble et al. (2013) engineer a library of RNA viruses to express small interfering RNAs and couple this with the power of virus evolution and selection to screen for host genes that when silenced resulted in greater viral infection in vivo. © 2013 Elsevier Inc.

Vernino S.,University of Texas Southwestern Medical Center
Handbook of Clinical Neurology | Year: 2011

One of the most dramatic and devastating examples of a remote effect of cancer is paraneoplastic cerebellar degeneration (PCD). There is convincing evidence that this disorder is caused by autoimmunity directed against cerebellar targets. Typically, the neurological presentation antedates the diagnosis of malignancy, and the cancer, when found, tends to be localized and responsive to treatment. Diagnosis depends on clinical suspicion, serology for paraneoplastic antibodies, and a focused search for cancer. Neuronal autoantibody tests facilitate the diagnosis and help direct the search for malignancy. Unfortunately, even with prompt diagnosis, current treatment strategies meet with limited success. Optimum management includes early diagnosis, treatment of cancer to remission, immunosuppression, symptomatic therapies, and compassionate support. © 2012 Elsevier B.V.

Janis J.E.,University of Texas Southwestern Medical Center
Plastic and reconstructive surgery | Year: 2010

LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Understand the basic stages of wound healing. 2. Apply current techniques to achieve wound closure. 3. Manage patients with simple and complex wounds effectively. SUMMARY: While wound healing can still be divided into stages, numerous intrinsic and extrinsic factors must be considered as well if clinical success is to be reliably achieved. While a routine wound may require nothing more than a simple dressing, the more complex and challenging wounds may benefit from more advanced therapy, such as growth factor applications, specialized dressings, or adjunctive therapy. This article will attempt to provide a concise summary of the advances in the basic and clinical science of wound healing.

Cohen J.C.,University of Texas Southwestern Medical Center
Journal of Clinical Lipidology | Year: 2013

In humans, genetic variation occurs through different types of alleles that vary in frequency and severity of effect. Mendelian mutations, such as those in the low-density lipoprotein (LDL) receptor (LDLR) that result in familial hypercholesterolemia, are rare and have powerful phenotypic effects. Conversely, alleles that are common in the population (such that homozygotes for the minor allele are present even in modest sample sizes) typically have very modest phenotypic effects. In the middle of the spectrum are "Goldilocks" alleles such as mutations in the gene for proprotein convertase subtilisin/kexin type 9 (PCSK9). Loss-of-function mutations in PCSK9 result in significantly decreased LDL-cholesterol levels and a disproportionately large reduction in coronary heart disease risk by reducing the exposure to LDL-cholesterol throughout life. Several agents to inhibit PCSK9 are currently in development, demonstrating the potential utility of translating genetics into clinical therapeutics. To date, most investigations aimed at identifying the genes responsible for hypercholesterolemia have used linkage analysis, which requires samples collected from multiple families with defects in the same gene, or common variant analysis which requires thousands of samples from the population. However, case studies have shown that with advances in whole genome sequencing or exome sequencing (targeted exome capture), the process of discovering causal genetic mutations can be significantly streamlined. Astute clinical observation of individual patients and their families with atypical lipid profiles, followed by sequencing of the affected individual, has the potential to lead to important findings regarding the genetic mutations that cause lipid abnormalities. © 2013 National Lipid Association. All rights reserved.

Egorova P.,Saint Petersburg State Polytechnic University | Popugaeva E.,Saint Petersburg State Polytechnic University | Bezprozvanny I.,University of Texas Southwestern Medical Center
Seminars in Cell and Developmental Biology | Year: 2015

Neurodegenerative disorders, such as spinocerebellar ataxias (SCAs) and Alzheimer's disease (AD) represent a huge scientific and medical question, but the molecular mechanisms of these diseases are still not clear. There is increasing evidence that neuronal calcium signaling is abnormal in many neurodegenerative disorders. Abnormal neuronal calcium release from the endoplasmic reticulum may result in disturbances of cell homeostasis, synaptic dysfunction, and eventual cell death. Neuronal loss is observed in most cases of neurodegenerative diseases. Recent experimental evidence supporting the role of neuronal calcium signaling in the pathogenesis of SCAs and AD is discussed in this review. © 2015 Elsevier Ltd.

Gatica D.,University of Michigan | Chiong M.,University of Chile | Lavandero S.,University of Chile | Lavandero S.,University of Texas Southwestern Medical Center | Klionsky D.J.,University of Michigan
Circulation Research | Year: 2015

Autophagy is a catabolic recycling pathway triggered by various intra-or extracellular stimuli that is conserved from yeast to mammals. During autophagy, diverse cytosolic constituents are enveloped by double-membrane vesicles, autophagosomes, which later fuse with lysosomes or the vacuole to degrade their cargo. Dysregulation in autophagy is associated with a diverse range of pathologies including cardiovascular disease, the leading cause of death in the world. As such, there is great interest in identifying novel mechanisms that govern the cardiovascular response to disease-related stress. First described in failing hearts, autophagy within the cardiovascular system has been characterized widely in cardiomyocytes, cardiac fibroblasts, endothelial cells, and vascular smooth muscle cells. In all cases, a window of optimal autophagic activity seems to be critical to the maintenance of cardiovascular homeostasis and function; excessive or insufficient levels of autophagic flux can each contribute to heart disease pathogenesis. Here, we review the molecular mechanisms that govern autophagosome formation and analyze the link between autophagy and cardiovascular disease. © 2015 American Heart Association, Inc.

Archer E.,University of Texas Southwestern Medical Center | Suel G.M.,University of California at San Diego
Reports on Progress in Physics | Year: 2013

Despite their obvious relationship and overlap, the field of physics is blessed with many insightful laws, while such laws are sadly absent in biology. Here we aim to discuss how the rise of a more recent field known as synthetic biology may allow us to more directly test hypotheses regarding the possible design principles of natural biological networks and systems. In particular, this review focuses on synthetic gene regulatory networks engineered to perform specific functions or exhibit particular dynamic behaviors. Advances in synthetic biology may set the stage to uncover the relationship of potential biological principles to those developed in physics. © 2013 IOP Publishing Ltd.

Jiang X.,University of Texas Southwestern Medical Center
Immunity | Year: 2012

RIG-I and MDA5 detect viral RNA in the cytoplasm and activate signaling cascades leading to the production of type-I interferons. RIG-I is activated through sequential binding of viral RNA and unanchored lysine-63 (K63) polyubiquitin chains, but how polyubiquitin activates RIG-I and whether MDA5 is activated through a similar mechanism remain unresolved. Here, we showed that the CARD domains of MDA5 bound to K63 polyubiquitin and that this binding was essential for MDA5 to activate the transcription factor IRF3. Mutations of conserved residues in MDA5 and RIG-I that disrupt their ubiquitin binding also abrogated their ability to activate IRF3. Polyubiquitin binding induced the formation of a large complex consisting of four RIG-I and four ubiquitin chains. This hetero-tetrameric complex was highly potent in activating the antiviral signaling cascades. These results suggest a unified mechanism of RIG-I and MDA5 activation and reveal a unique mechanism by which ubiquitin regulates cell signaling and immune response. Copyright © 2012 Elsevier Inc. All rights reserved.

Huntington disease is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine (polyQ) expansion (> 35Q) in the first exon (EX1) of huntingtin protein (Htt). mHtt protein is thought to adopt one or more toxic conformation(s) that are involved in pathogenic interactions in cells. However, the structure of mHtt is not known. Here, we present a near atomic resolution structure of mHtt36Q-EX1. To facilitate crystallization, three histidine residues (3H) were introduced within the Htt36Q stretch resulting in the sequence of Q7HQHQHQ27. The Htt36Q3H region adopts α-helix, loop, β-hairpin conformations. Furthermore, we observed interactions between the backbone of the Htt36Q3H β-strand with the aromatic residues mimicking putative-toxic interactions with other proteins. Our findings support previous predictions that the expanded mHtt-polyQ region adopts a β-sheet structure. Detailed structural information about mHtt improves our understanding of the pathogenic mechanisms in HD and other polyQ expansion disorders and may form the basis for rational design of small molecules that target toxic conformations of disease-causing proteins. © 2013 Landes Bioscience.

Neunert C.,University of Texas Southwestern Medical Center | Lim W.,McMaster University | Crowther M.,Worcestershire Royal Hospital | Cohen A.,Childrens Hospital of Philadelphia | Crowther M.A.,McMaster University
Blood | Year: 2011

Immune thrombocytopenia (ITP) is commonly encountered in clinical practice. In 1996 the American Society of Hematology published a landmark guidance paper designed to assist clinicians in the management of this disorder. Since 1996 there have been numerous advances in the management of both adult and pediatric ITP. These changes mandated an update in the guidelines. This guideline uses a rigorous, evidence-based approach to the location, interpretation, and presentation of the available evidence. We have endeavored to identify, abstract, and present all available methodologically rigorous data informing the treatment of ITP. We provide evidence-based treatment recommendations using the GRADE system in those areas in which such evidence exists. We do not provide evidence in those areas in which evidence is lacking, or is of lower quality - interested readers are referred to a number of recent, consensus-based recommendations for expert opinion in these clinical areas. Our review identified the need for additional studies in many key areas of the therapy of ITP such as comparative studies of "front-line" therapy for ITP, the management of serious bleeding in patients with ITP, and studies that will provide guidance about which therapy should be used as salvage therapy for patients after failure of a first-line intervention. © 2011 by The American Society of Hematology.

Gandhi N.S.,University of Hawaii at Hilo | Tekade R.K.,University of Hawaii at Hilo | Tekade R.K.,University of Texas Southwestern Medical Center | Chougule M.B.,University of Hawaii at Hilo | Chougule M.B.,University of Hawaii at Manoa
Journal of Controlled Release | Year: 2014

Chemotherapeutic agents have certain limitations when it comes to treating cancer, the most important being severe side effects along with multidrug resistance developed against them. Tumor cells exhibit drug resistance due to activation of various cellular level processes viz. activation of drug efflux pumps, anti-apoptotic defense mechanisms, etc. Currently, RNA interference (RNAi) based therapeutic approaches are under vibrant scrutinization to seek cancer cure. Especially small interfering RNA (siRNA) and micro RNA (miRNA), are able to knock down the carcinogenic genes by targeting the mRNA expression, which underlies the uniqueness of this therapeutic approach. Recent research focus in the regime of cancer therapy involves the engagement of targeted delivery of siRNA/miRNA in combinations with other therapeutic agents (such as gene, DNA or chemotherapeutic drug) for targeting permeability glycoprotein (P-gp), multidrug resistant protein 1 (MRP-1), B-cell lymphoma (BCL-2) and other targets that are mainly responsible for resistance in cancer therapy. RNAi-chemotherapeutic drug combinations have also been found to be effective against different molecular targets as well and can increase the sensitization of cancer cells to therapy several folds. However, due to stability issues associated with siRNA/miRNA suitable protective carrier is needed and nanotechnology based approaches have been widely explored to overcome these drawbacks. Furthermore, it has been univocally advocated that the co-delivery of siRNA/miRNA with other chemodrugs significantly enhances their capability to overcome cancer resistance compared to naked counterparts. The objective of this article is to review recent nanocarrier based approaches adopted for the delivery of siRNA/miRNA combinations with other anticancer agents (siRNA/miRNA/pDNA/chemodrugs) to treat cancer. © 2014, Elsevier B.V. All rights reserved.

Joset A.,University of Zurich | Dodd D.A.,University of Texas Southwestern Medical Center | Halegoua S.,State University of New York at Stony Brook | Schwab M.E.,University of Zurich
Journal of Cell Biology | Year: 2010

Nogo-A is one of the most potent myelin-associated inhibitors for axonal growth, regeneration, and plasticity in the adult central nervous system. The Nogo-A - specific fragment NogoΔ20 induces growth cone collapse, and inhibits neurite outgrowth and cell spreading by activating RhoA. Here, we show that NogoΔ20 is internalized into neuronal cells by a Pincher- and rac-dependent, but clathrin- and dynamin-independent, mechanism. Pincher-mediated macroendocytosis results in the formation of NogoΔ20-containing signalosomes that direct RhoA activation and growth cone collapse. In compartmentalized chamber cultures, NogoΔ20 is endocytosed into neurites and retrogradely transported to the cell bodies of dorsal root ganglion neurons, triggering RhoA activation en route and decreasing phosphorylated cAMP response element binding levels in cell bodies. Thus, Pincher-dependent macroendocytosis leads to the formation of Nogo-A signaling endosomes, which act both within growth cones and after retrograde transport in the cell body to negatively regulate the neuronal growth program. © 2010 Joset et al.

Zinn A.R.,University of Texas Southwestern Medical Center
American Journal of the Medical Sciences | Year: 2010

Diet and sedentary lifestyle, interacting with "thrifty" genes, are widely accepted as the principal cause of the current global obesity epidemic. However, a number of alternative etiologies for obesity have been proposed, including "drifty" genes, viruses, bacteria, environmental toxins, social network effects, maternal imprinting, sleep deprivation, and others. These Grand Rounds reviews the background of some of these unconventional ideas and evidence for or against their roles in the obesity epidemic. © 2010 Lippincott Williams & Wilkins.

Unger R.H.,University of Texas Southwestern Medical Center | Orci L.,University of Geneva
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

New results have brought to light the importance of the regulation of glucagon by β-cells in the development of diabetes. In this perspective, we examine the normal paracrinology of α- and β-cells in nondiabetic pancreatic islets. We propose a Sherringtonian model of coordinated reciprocal secretory responses of these juxtaposed cells that secrete glucagon and insulin, hormones with opposing actions on the liver. As insulin is a powerful inhibitor of glucagon, we propose that within-islet inhibition of α-cells by β-cells creates an insulin-to-glucagon ratio that maintains glycemic stability even in extremes of glucose influx or efflux. By contrast, in type 1 diabetes mellitus, α-cells lack constant action of high insulin levels from juxtaposed β-cells. Replacement with exogenous insulin does not approach paracrine levels of secreted insulin except with high doses that "overinsulinize" the peripheral insulin targets, thereby promoting glycemic volatility. Based on the stable normoglycemia of mice with type 1 diabetes during suppression of glucagon with leptin, we conclude that, in the absence of paracrine regulation of α-cells, tonic inhibition of α-cells improves the dysregulated glucose homeostasis. These results have considerable medical implications, as they suggest new approaches to normalize the extreme volatility of glycemia in diabetic patients.

Niederkorn J.Y.,University of Texas Southwestern Medical Center
Current Opinion in Allergy and Clinical Immunology | Year: 2010

Purpose of review: Corneal allografts are routinely performed without HLA typing or systemic immunosuppressive drugs. However, certain conditions create high risks for immune rejection. This review discusses recent insights into the mechanisms that rob the corneal allograft of its immune privilegeRecent findings: Studies in mice have revealed that stimuli that induce new blood vessel growth in the cornea also elicit proliferation of lymph vessels. Lymph vessels facilitate migration of antigen-presenting cells to regional lymph nodes in which they induce alloimmune responses. The presence of blood vessels in the corneal graft bed creates a unique chemokine milieu that stimulates recruitment of sensitized lymphocytes into the corneal allograft. Other data indicate that although corneal allograft survival is closely associated with Foxp3 expression in CD4+CD25+Foxp3+ T regulatory cells (Tregs), reduced expression of Foxp3 in Tregs creates a high risk for graft rejection. Recent evidence indicates that allergic diseases have a profound impact on the immune response and produce a dramatic increase in corneal allograft rejection. Summary: Understanding the underlying mechanisms that create 'high-risk' hosts may provide important therapeutic targets for restoring immune privilege of corneal allografts and enhancing their survival. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Souza R.F.,University of Texas Southwestern Medical Center
American Journal of Gastroenterology | Year: 2010

Proton pump inhibitors (PPIs) are extremely effective for mucosal healing of reflux esophagitis, but less so for relieving the symptom of heartburn. PPIs block the secretion of gastric acid, the caustic effects of which have been assumed to be the primary culprit in the pathogenesis of reflux esophagitis. However, mounting data suggest that reflux-stimulated, immune-mediated mechanisms may underlie the development of esophagitis in patients with gastroesophageal reflux disease (GERD). Thus, the future of GERD therapy, particularly for patients who are refractory to PPIs, may be the targeting of proteins such as proteinase-activated receptor-2, which have central roles in the generation of immune-mediated esophageal mucosal damage and in eliciting the symptom of heartburn. © 2010 by the American College of Gastroenterology.

Zhang Y.,University of Texas at Arlington | Zhang Y.,University of Texas Southwestern Medical Center | Yang J.,Pennsylvania State University
Journal of Materials Chemistry B | Year: 2013

The combination of biodegradable polymer and fluorescent imaging has resulted in an important area of polymeric biomaterials: biodegradable fluorescent polymers. Researchers have made significant efforts in developing versatile fluorescent biomaterials due to their promising applications in biological/biomedical labeling, tracking, monitoring, imaging, and diagnostics, especially in drug delivery, tissue engineering, and cancer imaging. Biodegradable fluorescent polymers can function not only as implant biomaterials but also as imaging probes. Currently, there are two major classes of biodegradable polymers, which are used as fluorescent materials. The first class is the combination of non-fluorescent biodegradable polymers and fluorescent agents such as organic dyes and quantum dots. Another class of polymers shows intrinsic photoluminescence as polymers by themselves carrying integral fluorescent chemical structures in or pendent to their polymer backbone, such as Green Fluorescent protein (GFP), and the recently developed biodegradable photoluminescent polymer (BPLP). Thus there is no need to conjugate or encapsulate additional fluorescent materials for the latter. In the present review, we will review the fluorescent biodegradable polymers with emphases on material fluorescence mechanism, design criteria for fluorescence, and their cutting-edge applications in biomedical engineering. We expect that this review will provide an insightful discussion on the fluorescent biomaterial design and lead to innovations for the next generation of fluorescent biomaterials and fluorescence-based biomedical technology. © 2013 The Royal Society of Chemistry.

Shay J.W.,University of Texas Southwestern Medical Center
Cancer Discovery | Year: 2013

The combination of variable telomere length in cancer cells and shorter telomere length in cancerassociated stromal cells strongly correlates with progression to prostate cancer metastasis and cancer death. The implication is that telomere length measurements have potential not only as prognostic indicators of prostate cancer outcomes but also as risk stratification enrichment biomarkers for individualized therapeutic interventions. © 2013 American Association for Cancer Research.

Palmer B.F.,University of Texas Southwestern Medical Center
American Journal of the Medical Sciences | Year: 2010

With increasing altitude, there is a fall in barometric pressure and a progressive fall in the partial pressure of oxygen. Acclimatization describes the physiologic changes that help maintain tissue oxygen delivery and human performance in the setting of hypobaric hypoxemia. These changes include a marked increase in alveolar ventilation, increased hemoglobin concentration and affinity, and increased tissue oxygen extraction. In some individuals, these physiologic changes may be inadequate, such that the sojourn to altitude and the attendant hypoxia are complicated by altitude-associated medical illness. The rate of ascent, the absolute change in altitude, and individual physiology are the primary determinants whether illness will develop or not. The most common clinical manifestations of altitude illness are acute mountain sickness, high altitude pulmonary edema, and high altitude cerebral edema. © 2010 Lippincott Williams & Wilkins.

Sohn J.-W.,University of Texas Southwestern Medical Center
Frontiers in Neuroscience | Year: 2013

Ion channels are critical regulators of neuronal excitability and synaptic function in the brain. Recent evidence suggests that ion channels expressed by neurons within the brain are responsible for regulating energy and glucose homeostasis. In addition, the central effects of neurotransmitters and hormones are at least in part achieved by modificationsof ion channel activity. This review focuses on ion channels and their neuronal functions followed by a discussion of the identified roles for specific ion channels in the central pathways regulating food intake, energy expenditure, and glucose balance. © 2013 Sohn.

Livingston E.H.,University of Texas Southwestern Medical Center | Livingston E.H.,University of Texas at Arlington
American Journal of Surgery | Year: 2010

Background: Estimates of the procedure incidence for bariatric surgery have been derived primarily from surveys of bariatric surgeons or from inpatient data sources. New population-representative databases of outpatient surgery are available that enable accurate estimations of bariatric surgery case volumes. Methods: The 2006 National Hospital Discharge Survey, National Inpatient Sample, and National Survey of Ambulatory Surgery were assessed for bariatric surgery procedures. Data were compared with inpatient data from 1993 to 2007. Procedure costs were estimated. Results: The incidence of bariatric surgery has plateaued at approximately 113,000 cases per year. Open gastric bypass now constitutes only 3% of all cases but costs $4,800 less than laparoscopic procedures. Laparoscopic gastric banding is performed in 37% of all bariatric surgery cases and costs the same as laparoscopic gastric bypass to perform. Complication rates have fallen from 10.5% in 1993 to 7.6% of all cases in 2006. Bariatric surgery costs the health economy at least $1.5 billion annually. Conclusions: Despite predictions of continued growth of bariatric surgery, it appears that the annual incidence for these operations has remained stable since 2003. Most operations are performed laparoscopically, but open gastric bypass is substantially less costly than laparoscopic operations. Despite its simplicity, laparoscopic gastric banding costs the same as gastric bypass. There is no cost savings associated with ambulatory bariatric surgery. © 2010 Elsevier Inc.

Becker P.M.,University of Texas Southwestern Medical Center
Sleep Medicine Clinics | Year: 2015

Hypnosis has been used to manage insomnia and disorders of arousal. The alteration in the state of consciousness produced during hypnotic trance is more similar to relaxed reverie than sleep. Hypnosis typically occurs in a state of repose and the accomplished subject may have no recollection of the experience during a trance, 2 commonalities with sleep. Because hypnosis allows for relaxation, increased suggestibility, posthypnotic suggestion, imagery rehearsal, access to preconscious cognitions and emotions, and cognitive restructuring, disorders of sleep such as the insomnias, parasomnias, and related mood or anxiety disorders can be amenable to this therapeutic intervention. © 2015 Elsevier Inc.

North C.S.,University of Texas Southwestern Medical Center | Oliver J.,University of Texas at Dallas
American Journal of Public Health | Year: 2012

Objectives. Using a comprehensive disaster model, we examined predictors of posttraumatic stress disorder (PTSD) in combined data from 10 different disasters. Methods. The combined sample included data from 811 directly exposed survivors of 10 disasters between 1987 and 1995. We used consistent methods across all 10 disaster samples, including full diagnostic assessment. Results. In multivariate analyses, predictors of PTSD were female gender, younger age, Hispanic ethnicity, less education, ever-married status, predisaster psychopathology, disaster injury, and witnessing injury or death; exposure through death or injury to friends or family members and witnessing the disaster aftermath did not confer additional PTSD risk. Intentionally caused disasters associated with PTSD in bivariate analysis did not independently predict PTSD in multivariate analysis. Avoidance and numbing symptoms represented a PTSD marker. Conclusions. Despite confirming some previous research findings, we found no associations between PTSD and disaster typology. Prospective research is needed to determine whether early avoidance and numbing symptoms identify individuals likely to develop PTSD later. Our findings may help identify at-risk populations for treatment research.

Bartolome S.D.,University of Texas Southwestern Medical Center
Current Opinion in Pulmonary Medicine | Year: 2013

PURPOSE OF REVIEW: The purpose of this review is to summarize the last year of literature developments in the field of pulmonary arterial hypertension (PAH), with a focus on clinical research. RECENT FINDINGS: Pulmonary vascular research has expanded rapidly over the last decade, resulting in a change in the treatment strategy for PAH. Epidemiologic data from recent registries suggest that patients with PAH are increasing in age and comorbidities. In the modern treatment era, risk stratification for early mortality is increasingly used to guide clinicians in the choice of pulmonary vasodilator therapy. Risk-score calculators have been published and validated for PAH, currently in both the United States and Europe. In addition to increased comorbidities, pulmonary hypertension centers are encountering complicated management situations in these patients, such as pregnancy. Current data suggest that mortality for pregnant pulmonary hypertension patients remains high, although not as high as historical reports. Oral prostacyclin and prostacyclin agonist therapies are currently under investigation to aid in the management of these patients. SUMMARY: Despite treatment advances, mortality remains high for PAH patients. Careful evaluation and risk stratification will help guide the appropriate treatment for PAH patients. Additional therapies are on the horizon for the management of this progressive disease. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Jones R.E.,University of Texas Southwestern Medical Center
The bone & joint journal | Year: 2013

Satisfactory primary wound healing following total joint replacement is essential. Wound healing problems can have devastating consequences for patients. Assessment of their healing capacity is useful in predicting complications. Local factors that influence wound healing include multiple previous incisions, extensive scarring, lymphoedema, and poor vascular perfusion. Systemic factors include diabetes mellitus, inflammatory arthropathy, renal or liver disease, immune compromise, corticosteroid therapy, smoking, and poor nutrition. Modifications in the surgical technique are necessary in selected cases to minimise potential wound complications. Prompt and systematic intervention is necessary to address any wound healing problems to reduce the risks of infection and other potential complications.

Ramos-Romn M.A.,University of Texas Southwestern Medical Center
Hormone and Metabolic Research | Year: 2011

Pregnancy and puerperium are periods of intense hormonal changes. Maternal metabolism adapts to spare the mother from harm on behalf of her developing offspring and major alterations maintain normal glucose tolerance. Insulin secretion increases during a normal pregnancy to compensate for pregnancy-induced insulin resistance and maintain euglycemia. Women at risk for gestational diabetes have insulin resistance before conception. Gestational diabetes develops when a woman at risk is unable to meet the insulin secretory demands imposed by the additional insulin resistance characteristic of pregnancy. The lactogens, human placental lactogen and prolactin, are major stimuli for the adaptation of the endocrine pancreas during gestation. This review discusses the role of lactogens on glucose homeostasis during pregnancy and proposes a mechanism by which the hormonal control of lactation, led by prolactin, may regulate adipocyte biology, glucose and lipid metabolism, and guard postpartum women against type 2 diabetes. © Georg Thieme Verlag KG Stuttgart - New York.

Lakoski S.G.,University of Vermont | Kozlitina J.,University of Texas Southwestern Medical Center
Medicine and Science in Sports and Exercise | Year: 2014

PURPOSE: This study aimed to examine ethnic differences in objectively measured physical activity (PA) and the relationship between PA and metabolic risk factors. METHODS: The analysis included 2566 participants of the Dallas Heart Study (53% non-Hispanic black, 32% non-Hispanic white, and 15% Hispanic) who wore an accelerometer for an average of 7 d. PA was assessed as mean activity counts and time spent in moderate and vigorous activity. Outcomes included body mass index (BMI), waist circumference, systolic and diastolic blood pressure, heart rate, fasting glucose, homeostatic model assessment of insulin resistance, and plasma lipid and lipoprotein levels. RESULTS: A higher proportion of Hispanics than either whites or blacks obtained the recommended ≥ 150 min·wk of moderate PA (24%, 14%, and 10%, respectively, P < 0.0001). White males were more likely to engage in vigorous activity than other sex-ethnic groups (P < 0.05). Time in moderate-to-vigorous activity was inversely related to BMI, waist circumference, homeostatic model assessment of insulin resistance, heart rate, and positively associated with high-density lipoprotein cholesterol levels (P < 0.0001) in the combined cohort, and the relationship was similar in all ethnic groups (P interaction > 0.05). A significant inverse association between PA and triglycerides was observed in whites (P = 7.2 × 10). Vigorous activity was associated with greater differences in risk factors than moderate activity (for example, β = -0.30 vs β = -0.02 for BMI). Bouts lasting =10 min were associated with metabolic risk factors independent of <10-min bouts in the overall sample, with similar trends observed within subgroups. CONCLUSIONS: Hispanics had higher levels of moderate activity than whites or blacks, whereas white men had higher levels of vigorous PA than other sex-ethnic groups. The relationship between PA and several metabolic risk factors was similar across ethnicities. Vigorous PA was associated with greater benefits than moderate PA. © 2014 by the American College of Sports Medicine.

Phelan H.A.,University of Texas Southwestern Medical Center
Journal of Neurotrauma | Year: 2012

Despite the frequency and morbidity of venous thromboembolism (VTE) development after traumatic brain injury (TBI), no national standard of care exists to guide TBI caregivers for the use of prophylactic anticoagulation. Fears of iatrogenic propagation of intracranial hemorrhage patterns have led to a dearth of research in this field, and it is only relatively recently that studies dedicated to this question have been performed. These have generally been limited to retrospective and/or observational studies in which patients are classified in a binary fashion as having the presence or absence of intracranial blood. This methodology does not account for the fact that smaller injury patterns stabilize more rapidly, and thus may be able to safely tolerate earlier initiation of prophylactic anticoagulation than larger injury patterns. This review seeks to critically assess the literature on this question by examining the existing evidence on the safety and efficacy of pharmacologic VTE prophylaxis in the setting of elective craniotomy (as this is the closest model available from which to extrapolate) and after TBI. In doing so, we critique studies that approach TBI as a homogenous or a heterogenous study population. Finally, we propose our own theoretical protocol which stratifies patients into low, moderate, and high risk for the likelihood of natural progression of their hemorrhage pattern, and which allows one to tailor a unique VTE prophylaxis regimen to each individual arm. © Copyright 2012, Mary Ann Liebert, Inc.

Huang H.,University of Texas Southwestern Medical Center
Neuroscientist | Year: 2010

Human brain anatomy is extraordinarily complex, and yet, its origin is a simple tubular structure. It is characterized by dramatic structural changes during fetal development. Revealing detailed anatomy at different stages of human fetal brain development not only aids in understanding this highly ordered process but also provides clues to detect abnormalities caused by genetic or environmental factors. However, anatomical studies of human brain development during this period are surprisingly scarce, and histology-based atlases have become available only recently. Diffusion tensor imaging (DTI), a recently developed technology of magnetic resonance imaging (MRI), is capable of noninvasively delineating macroscopic anatomical components with high contrast and revealing structures at the microscopic level. In this article, the fetal brain white matter is explored using contrasts from DTI-derived images and axonal reconstruction from DTI tractography. The highly organized structures in the cerebral layer have been revealed with primary direction of diffusion tensors. Complementary to the histology, the DTI of the fetal brain provides a valuable resource to understand the structural development of the entire brain. The resultant database will provide reference standards for diagnostic radiology of premature newborns. © The Author(s) 2010.

Fernando H.C.,Boston Medical Center | Timmerman R.,University of Texas Southwestern Medical Center
Journal of Thoracic and Cardiovascular Surgery | Year: 2012

During the past decade, tremendous interest has arisen in the use of nonoperative therapies for patients with non-small cell lung cancer. Of these therapies, stereotactic body radiotherapy has become established as an effective modality for treating peripheral cancer in medically inoperable patients. Toxicity is low, and the treatment is effective, with excellent local control rates. Several investigators have suggested that stereotactic body radiotherapy could be effective for high-risk operable patients (usually treated with sublobar resection) and even perhaps for standard-risk operable patients (usually treated with lobectomy); however, this is less accepted. A direct comparison of stereotactic body radiotherapy and sublobar resection is difficult for a number of reasons. These include different definitions of recurrence, different populations of patients in these studies (with those undergoing stereotactic body radiotherapy tending to be the medically inoperable group), and different methods of classifying morbidity in the surgical and radiation oncology studies. Imaging follow-up has also not been standardized among the studies. Thus, a randomized study is necessary and timely. Investigators from the American College of Surgeons Oncology Group and the Radiation Therapy and Oncology Group have collaborated to develop a phase III randomized study comparing stereotactic body radiotherapy and sublobar resection (with or without brachytherapy) for high-risk operable patients with non-small cell lung cancer. This study (American College of Surgeons Oncology Group Z4099/Radiation Therapy Oncology Group 1021) has recently opened for accrual. It is hoped that this will help to better define the role of these therapies for patients with non-small cell lung cancer. Copyright © 2012 by The American Association for Thoracic Surgery.

Davidson J.A.,University of Texas Southwestern Medical Center
Postgraduate medicine | Year: 2013

Type 2 diabetes mellitus is a pandemic, with millions of new diagnoses made each year. In the United States, > 90% of patients with type 2 diabetes mellitus are cared for by primary care physicians who bear the primary responsibility of diagnosing and treating this disease. Building an optimal treatment regimen for a patient from the many choices available depends on many factors, including the ability of a given therapy to safely and effectively lower blood glucose levels, and potential benefits on body weight, cardiovascular risk factors, and hypoglycemia risk. With these considerations at the forefront, this article provides an overview of exenatide once weekly (EQW), a recently available antidiabetes therapy in the glucagon-like peptide-1 receptor agonist class designed to provide continuous glycemic control with once-weekly dosing. We discuss the clinical trials that have demonstrated the ability of EQW to effectively lower blood glucose levels and body weight with a minimal risk of hypoglycemia. In addition, we examine other issues likely to be relevant in a primary care setting, including safety and tolerability profiles, pharmacology and dosing, ease of use, recommended place in treatment, and patient perceptions of EQW.

Lee W.M.,University of Texas Southwestern Medical Center
Clinics in Liver Disease | Year: 2013

Although acute liver failure caused by drug-induced liver injury comprises a small fraction of overall drug-induced liver injury, these patients require high resource use and have relatively poor outcomes. Drug-induced liver injury caused by idiosyncrasy more often leads to death or transplantation than does acetaminophen acute liver failure, but the number of patients in each category receiving a graft is roughly the same. Efforts in the future to improve outcomes should focus on more effective treatments and better methods to identify those that might experience poor outcomes. © 2013 Elsevier Inc.

Komurov K.,University of Texas M. D. Anderson Cancer Center | White M.A.,University of Texas Southwestern Medical Center | Ram P.T.,University of Texas M. D. Anderson Cancer Center
PLoS Computational Biology | Year: 2010

Extracting network-based functional relationships within genomic datasets is an important challenge in the computational analysis of large-scale data. Although many methods, both public and commercial, have been developed, the problem of identifying networks of interactions that are most relevant to the given input data still remains an open issue. Here, we have leveraged the method of random walks on graphs as a powerful platform for scoring network components based on simultaneous assessment of the experimental data as well as local network connectivity. Using this method, NetWalk, we can calculate distribution of Edge Flux values associated with each interaction in the network, which reflects the relevance of interactions based on the experimental data. We show that network-based analyses of genomic data are simpler and more accurate using NetWalk than with some of the currently employed methods. We also present NetWalk analysis of microarray gene expression data from MCF7 cells exposed to different doses of doxorubicin, which reveals a switch-like pattern in the p53 regulated network in cell cycle arrest and apoptosis. Our analyses demonstrate the use of NetWalk as a valuable tool in generating high-confidence hypotheses from high-content genomic data. © 2010 Komurov et al.

Nguyen Y.,University of Texas Southwestern Medical Center
Frontiers in cellular and infection microbiology | Year: 2012

Enterohemorrhagic Escherichia coli (EHEC) serotype O157:H7 is a human pathogen responsible for outbreaks of bloody diarrhea and hemolytic uremic syndrome (HUS) worldwide. Conventional antimicrobials trigger an SOS response in EHEC that promotes the release of the potent Shiga toxin that is responsible for much of the morbidity and mortality associated with EHEC infection. Cattle are a natural reservoir of EHEC, and approximately 75% of EHEC outbreaks are linked to the consumption of contaminated bovine-derived products. This review will discuss how EHEC causes disease in humans but is asymptomatic in adult ruminants. It will also analyze factors utilized by EHEC as it travels through the bovine gastrointestinal (GI) tract that allow for its survival through the acidic environment of the distal stomachs, and for its ultimate colonization in the recto-anal junction (RAJ). Understanding the factors crucial for EHEC survival and colonization in cattle will aid in the development of alternative strategies to prevent EHEC shedding into the environment and consequent human infection.

Sakhaee K.,University of Texas Southwestern Medical Center
Pediatric Nephrology | Year: 2010

An understanding of the pathophysiologic mechanisms of post-renal transplant (PRT) bone disease is of important clinical significance. Although bone disease occurs after all solid organ transplantation, the cumulative skeletal fracture rate remains high in PRT subjects while reaching a plateau with other transplantations. One major difference in the pathophysiology of PRT bone disease is, perhaps, due to persistent renal phosphorus (Pi) wasting. Novel phosphaturic agents have recently been suggested to participate in the development of bone disease in PRT subjects. However, it is unclear as of yet whether these factors alone or in conjunction with excess parathyroid hormone (PTH) secretion play a key role in the development of negative Pi balance and consequent bone disease in this population. In this review, I present a natural history of PRT hypophosphatemia and persistent renal Pi leak, provide pathophysiologic insight into these developments, and discuss the difficulty in diagnosing these phenotypes in both adult and pediatric populations. © IPNA 2009.

Grishin N.V.,University of Texas Southwestern Medical Center
Cell | Year: 2012

A daring experiment is performed. Using sequence alignments to predict contacts between residues in protein spatial structures, Hopf et al. are publishing untested de novo structure models for 11 transmembrane protein families. Will their models stand the test of time and hold up to experimentation? The prospects are excellent. © 2012 Elsevier Inc.

Khan D.A.,University of Texas Southwestern Medical Center | Solensky R.,The Corvallis Clinic
Journal of Allergy and Clinical Immunology | Year: 2010

Drug allergy is one type of adverse reaction to drugs and encompasses a spectrum of hypersensitivity reactions with heterogeneous mechanisms and clinical presentations. A thorough history is essential to the management of drug allergy. Laboratory testing has a very limited role in the management of drug allergy. Graded dose challenges and procedures to induce drug tolerance might be required in patients with drug allergy when there is a definite need for a particular agent. Management of reactions to specific agents, including β-lactam antibiotics, sulfonamides, local anesthetics, radiocontrast media, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, and biologic modifiers, will be discussed in further detail. © 2010 American Academy of Allergy, Asthma & Immunology.

Feagins L.A.,University of Texas Southwestern Medical Center
Inflammatory Bowel Diseases | Year: 2010

Transforming growth factor-β (TGF-β) plays a central role in a wide array of cellular functions including control of cell growth and differentiation, embryonic development, wound healing, angiogenesis, and immune regulation. In the gastrointestinal tract, TGF-β can either promote or suppress inflammation and cancer formation. This report reviews recent data on the role of TGF-β in the pathogenesis of inflammatory bowel disease and how TGF-β might contribute to the cancer risk associated with chronic inflammation of the gut. (Inflamm Bowel Dis 2010) © 2010 Crohns & Colitis Foundation of America, Inc.

Kuro-O M.,University of Texas Southwestern Medical Center
Pediatric Nephrology | Year: 2010

Recent studies have identified a novel bone-kidney endocrine axis that maintains phosphate homeostasis. When phosphate is in excess, fibroblast growth factor-23 (FGF23) is secreted from bone and acts on the kidney to promote phosphate excretion into urine and suppress vitamin D synthesis, thereby inducing negative phosphate balance. One critical feature of FGF23 is that it requires Klotho, a single-pass transmembrane protein expressed in renal tubules, as an obligate coreceptor to bind and activate FGF receptors. Several hereditary disorders that exhibit inappropriately high serum FGF23 levels are associated with phosphate wasting and impaired bone mineralization. In contrast, defects in either FGF23 or Klotho are associated with phosphate retention and a premature-aging syndrome. The aging-like phenotypes in Klotho-deficient or FGF23-deficient mice can be rescued by resolving hyperphosphatemia with dietary or genetic manipulation, suggesting a novel concept that phosphate retention accelerates aging. Phosphate retention is universally observed in patients with chronic kidney disease (CKD) and identified as a potent risk of death in epidemiological studies. Thus, the bone-kidney endocrine axis mediated by FGF23 and Klotho has emerged as a novel target of therapeutic interventions in CKD. © 2009 IPNA.

Pfeiffer J.K.,University of Texas Southwestern Medical Center
Advances in Virus Research | Year: 2010

Poliovirus is an error-prone enteric virus spread by the fecal-oral route and rarely invades the central nervous system (CNS). However, in the rare instances when poliovirus invades the CNS, the resulting damage to motor neurons is striking and often permanent. In the prevaccine era, it is likely that most individuals within an epidemic community were infected; however, only 0.5% of infected individuals developed paralytic poliomyelitis. Paralytic poliomyelitis terrified the public and initiated a huge research effort, which was rewarded with two outstanding vaccines. During research to develop the vaccines, many questions were asked: Why did certain people develop paralysis? How does the virus move from the gut to the CNS? What limits viral trafficking to the CNS in the vast majority of infected individuals? Despite over 100 years of poliovirus research, many of these questions remain unanswered. The goal of this chapter is to review our knowledge of how poliovirus moves within and between hosts, how host barriers limit viral movement, how viral population dynamics impact viral fitness and virulence, and to offer hypotheses to explain the rare incidence of paralytic poliovirus disease. © 2010 Elsevier Inc.

Gazdar A.F.,University of Texas Southwestern Medical Center
Annals of Oncology | Year: 2010

Until recently the major clinical question was 'Is it small-cell or non small-cell cancer'. However, advances in conventional and targeted therapy have completely changed the landscape. Identification of the major non-small-cell lung cancer (NSCLC) types (adenocarcinoma and squamous carcinoma) are important for a number of predictive and prognostic reasons, including pemetrexed treatment, anti-angiogenic therapy and administration of tyrosine kinase inhibitors. Fortunately, advances in pathology of lung cancer have kept abreast, with newer, simplified methods to identify the major NSCLC types in small diagnostic samples, and modifications of the pathological classification of adenocarcinomas reflecting changing clinical and molecular concepts. For the patient to obtain maximum benefit from the recent developments in therapeutics, a multidisciplinary approach is required with co-operation between oncologists, surgeons, radiologists and pathologists. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Choti M.A.,University of Texas Southwestern Medical Center
Current Treatment Options in Oncology | Year: 2014

Opinion statement When possible, surgical resection remains the "gold standard" for the treatment of hepatic colorectal metastases. Liver resection should be considered when complete removal of all macroscopic disease can be achieved safely. For those patients with unresectable metastases, or when a patient may not be a candidate for liver resection, many choices are available to the clinician in an attempt to achieve locoregional control, including tumor ablation, intra-arterial therapies, and radiation therapy. Whereas with surgical resection, durable local control can be considered potentially curable, other liver-directed approaches currently are mostly palliative. Ongoing trials are being undertaken to evaluate the role of such cytoreductive therapies. During the initial evaluation of any patient who might be a candidate for liver-directed therapy, particularly when the intent may be curative, complete assessment with high-quality imaging should be done before any therapy to determine the full extent of disease. Most importantly, the establishment of a multidisciplinary team upon initial diagnosis can optimize the choice and sequencing of the various systemic and locoregional choices available to the colorectal cancer patient. © 2014 Springer Science+Business Media New York.

Taurog J.D.,University of Texas Southwestern Medical Center
Journal of Rheumatology | Year: 2010

This article summarizes the proceedings of a one-day international workshop held in July 2009 on the role of HLA-B27 in the pathogenesis of ankylosing spondylitis (AS) and related disorders. HLA-B27 is found in about 90% of patients with AS, with an odds ratio of about 100, but the mechanism underlying this association is not known. There are currently 3 major mechanistic hypotheses for this association: (1) T cell recognition of one or more B27 presented peptides; (2) B27 heavy-chain misfolding that induces an unfolded protein response; and (3) innate immune recognition of cell-surface expressed B27 heavy-chain dimers. None of these hypotheses accounts for the tissue specificity of the inflammation characteristic of AS. These hypotheses were discussed in the context of known epidemiologic, biochemical, structural, and immunologic differences among HLA-B27 subtypes; data from the HLA-B27 transgenic rat model of spondyloarthritis; the growing list of other genes that have been found to be associated with AS; and other data on the pathogenesis of spondyloarthritis. Proposed directions for future research include expanded efforts to define similarities and differences among the B27 subtypes; further development of animal models; identifying the interactions of B27 with the products of other genes associated with AS; and continued investigation into the pathogenesis of spondyloarthritis. The Journal of Rheumatology Copyright © 2010. All rights reserved.

Dineen S.P.,University of Texas Southwestern Medical Center
Critical Reviews in Oncogenesis | Year: 2012

Rectal cancer will affect approximately 40,000 people per year in the United States. Surgical resection through meticulous total mesorectal excision, combined with preoperative chemoradiation, is considered the standard of care for patients with stage II or III disease. However, as many as a third of patients will develop local or distant progression of disease. Understanding the biology of rectal cancer will allow for a more rational approach to treatment. This report discusses aspects of tumor biology, including angiogenesis and apoptosis, which may allow for better targeted therapy. The ultimate goal will be individualized treatment with the therapy that will maximize tumor response while minimizing toxicity. © 2012 by Begell House, Inc.

Wang J.,University of Texas Southwestern Medical Center | Hou T.,Soochow University of China
Journal of Chemical Information and Modeling | Year: 2010

Drug likeness analysis is widely used in modem drug design, However, most drug likeness filters, represented by Lipinski's "Rule of 5", are based on drugs' simple structural features and some physiochemical properties. In this study, we conducted thorough structural analyses for two drug datasets. The first dataset, ADDS, is composed of 1240 FDA-approved drugs, and the second drug dataset, EDDS, is a nonredundant collection of FDA-approved drugs and experimental drugs in different phases of clinical trials from several drug databases (6932 entries). For each molecule, all possible fragments were enumerated using a brutal force approach. Three kinds of building blocks, namely, the drug scaffold, ring system, and the small fragment, were identified and ranked according to the frequencies of their occurrence in drug molecules. The major finding is that most top fragments are essentially common for both drug datasets; the top 50 fragments cover 52.6% and 48.6% drugs for ADDS and EDDS, respectively. The identified building blocks were further ranked according to their relative hit rates in the drug datasets and in a screening dataset, which is a nonredundant collection of screening compounds from many resources. In comparison with the previous reports in the field, we have identified many more high-quality building blocks. The results obtained in this study could provide useful hints to medicinal chemists in designing drug-like compounds as well as prioritizing screening libraries to filter out those molecules lack of functional building blocks. © 2010 American Chemical Society.

Deberardinis R.J.,University of Texas Southwestern Medical Center | Thompson C.B.,Sloan Kettering Cancer Center
Cell | Year: 2012

An understanding of metabolic pathways based solely on biochemistry textbooks would underestimate the pervasive role of metabolism in essentially every aspect of biology. It is evident from recent work that many human diseases involve abnormal metabolic states - often genetically programmed - that perturb normal physiology and lead to severe tissue dysfunction. Understanding these metabolic outliers is now a crucial frontier in disease-oriented research. This Review discusses the broad impact of metabolism in cellular function and how modern concepts of metabolism can inform our understanding of common diseases like cancer and also considers the prospects of developing new metabolic approaches to disease treatment. © 2012 Elsevier Inc.

Agarwal A.K.,University of Texas Southwestern Medical Center
Current Opinion in Lipidology | Year: 2012

Purpose of Review: Over the past several years, many more isoforms for the same enzymes, specifically for 1-acylglycerol-3-phosphate O-acyltransferases (AGPATs), have been cloned and studied. In this review, we summarize their biochemical features and discuss their functional role. Recent Findings: The most significant role of these AGPATs appeared from our observation of AGPAT2 in the biology of adipose tissue (adipocytes) in humans and mice. Other isoforms are shown to be implicated in lung, reproductive and cardiac muscle function and in the cause of cancer. In-vitro substrate specificities of these AGPATs also suggest the in-vivo role of these AGPATs in remodeling of several of the glycerophospholipids. Summary: Despite significant progress in understanding the role of these AGPATs, much is still to be discovered in terms of how each of these AGPATs function in the presence or absence of other AGPATs and what their functional role might be. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Wang J.,University of Texas Southwestern Medical Center | Hou T.,Soochow University of China
Journal of Chemical Theory and Computation | Year: 2011

Molecular mechanical force field (FF) methods are useful in studying condensed phase properties. They are complementary to experiments and can often go beyond experiments in atomic details. Even if a FF is specific for studying structures, dynamics, and functions of biomolecules, it is still important for the FF to accurately reproduce the experimental liquid properties of small molecules that represent the chemical moieties of biomolecules. Otherwise, the force field may not describe the structures and energies of macromolecules in aqueous solutions properly. In this work, we have carried out a systematic study to evaluate the General AMBER Force Field (GAFF) in studying densities and heats of vaporization for a large set of organic molecules that covers the most common chemical functional groups. The latest techniques, such as the particle mesh Ewald (PME) for calculating electrostatic energies and Langevin dynamics for scaling temperatures, have been applied in the molecular dynamics (MD) simulations. For density, the average percent error (APE) of 71 organic compounds is 4.43% when compared to the experimental values. More encouragingly, the APE drops to 3.43% after the exclusion of two outliers and four other compounds for which the experimental densities have been measured with pressures higher than 1.0 atm. For the heat of vaporization, several protocols have been investigated, and the best one, P4/ntt0, achieves an average unsigned error (AUE) and a root-mean-square error (RMSE) of 0.93 and 1.20 kcal/mol, respectively. How to reduce the prediction errors through proper van der Waals (vdW) parametrization has been discussed. An encouraging finding in vdW parametrization is that both densities and heats of vaporization approach their "ideal" values in a synchronous fashion when vdW parameters are tuned. The following hydration free energy calculation using thermodynamic integration further justifies the vdW refinement. We conclude that simple vdW parametrization can significantly reduce the prediction errors. We believe that GAFF can greatly improve its performance in predicting liquid properties of organic molecules after a systematic vdW parametrization, which will be reported in a separate paper. © 2011 American Chemical Society.

White P.,University of Texas Southwestern Medical Center | Bachega T.S.S.,University of Sao Paulo
Seminars in Reproductive Medicine | Year: 2012

The most frequent form of congenital adrenal hyperplasia (CAH) is steroid 21-hydroxylase deficiency, accounting for more than 90% of cases. Affected patients cannot synthesize cortisol efficiently. Thus the adrenal cortex is stimulated by corticotropin (ACTH) and overproduces cortisol precursors. Some precursors are diverted to sex hormone biosynthesis, causing signs of androgen excess including ambiguous genitalia in newborn females and rapid postnatal growth in both sexes. In the most severe "salt wastingo" form of CAH (~75% of severe or "classico" cases), concomitant aldosterone deficiency may lead to salt wasting with consequent failure to thrive, hypovolemia, and shock. Newborn screening minimizes delays in diagnosis, especially in males, and reduces morbidity and mortality from adrenal crises. CAH is a recessive disorder caused by mutations in the CYP21 (CYP21A2) gene, most of which arise from recombination between CYP21 and a nearby pseudogene, CYP21P (CYP21A1P). Phenotype is generally correlated with genotype. Classic CAH patients require chronic glucocorticoid treatment at the lowest dose that adequately suppresses adrenal androgens and maintains normal growth and weight gain, and most require mineralocorticoid (fludrocortisone). Transition of care of older patients to adult physicians should be planned in advance as a structured, ongoing process. Copyright © 2012 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Sirajuddin M.,Howard Hughes Medical Institute | Rice L.M.,University of Texas Southwestern Medical Center | Vale R.D.,Howard Hughes Medical Institute
Nature Cell Biology | Year: 2014

The 'tubulin-code' hypothesis proposes that different tubulin genes or post-translational modifications (PTMs), which mainly confer variation in the carboxy-terminal tail (CTT), result in unique interactions with microtubule-associated proteins for specific cellular functions. However, the inability to isolate distinct and homogeneous tubulin 1species has hindered biochemical testing of this hypothesis. Here, we have engineered 25 α /β-tubulin heterodimers with distinct CTTs and PTMs and tested their interactions with four different molecular motors using single-molecule assays. Our results show that tubulin isotypes and PTMs can govern motor velocity, processivity and microtubule depolymerization rates, with substantial changes conferred by even single amino acid variation. Revealing the importance and specificity of PTMs, we show that kinesin-1 motility on neuronal β-tubulin (TUBB3) is increased by polyglutamylation and that robust kinesin-2 motility requires detyrosination of α-tubulin. Our results also show that different molecular motors recognize distinctive tubulin 'signatures', which supports the premise of the tubulin-code hypothesis. © 2014 Macmillan Publishers Limited.

Rohatgi A.,University of Texas Southwestern Medical Center
Progress in Cardiovascular Diseases | Year: 2015

A low plasma level of high-density lipoprotein (HDL) cholesterol (HDL-C) is a major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). However, several observations have highlighted the shortcomings of using cholesterol content as the sole reflection of HDL metabolism. In particular, several large randomized controlled trials of extended release niacin and cholesteryl-ester transfer protein (CETP) inhibitors on background statin therapy have failed to show improvement in ASCVD outcomes despite significant increases in HDL-C. Reverse cholesterol transport (RCT) is the principal HDL function that impacts macrophage foam cell formation and other functions such as endothelial activation of endothelial nitric oxide synthase, monocyte adhesion, and platelet aggregation. Cholesterol efflux from macrophages to plasma/serum reflects the first critical step of RCT and is considered a key anti-atherosclerotic function of HDL. Whether this function is operative in humans remains to be seen, but recent studies assessing cholesterol efflux in humans suggest that the cholesterol efflux capacity (CEC) of human plasma or serum is a potent marker of ASCVD risk. This review describes the methodology of measuring CEC ex vivo from human samples and the findings to date linking CEC to human disease. Studies to date confirm that CEC can be reliably measured using stored human blood samples as cholesterol acceptors and suggest that CEC may be a promising new biomarker for atherosclerotic and metabolic diseases. Further studies are needed to standardize measurements and clarify the role CEC may play in predicting risk of developing disease and response to therapies. © 2015 Elsevier Inc.

Mettlen M.,University of Texas Southwestern Medical Center | Danuser G.,Harvard University
Cold Spring Harbor Perspectives in Biology | Year: 2014

Clathrin-mediated endocytosis (CME) plays a central role in cellular homeostasis and is mediated by clathrin-coated pits (CCPs). Live-cell imaging has revealed a remarkable heterogeneity in CCPassembly kinetics, which can be used as an intrinsic source of mechanistic information on CCP regulation but also poses several major problems for unbiased analysis of CME dynamics. The backbone of unveiling the molecular control of CME is an imagingbased inventory of the full diversity of individual CCP behaviors, which requires detection and tracking of structural fiduciaries and regulatory proteins with an accuracy of >99.9%, despite very low signals. This level of confidence can only be achieved by combining appropriate imaging modalities with self-diagnostic computational algorithms for image analysis and data mining. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

Moe O.W.,University of Texas Southwestern Medical Center
Journal of Clinical Investigation | Year: 2012

Uremia is a complex metabolic state marked by derangement of many signaling molecules and metabolic intermediates; of these, the massively increased levels of FGF23 are among the most striking. It has remained unclear whether FGF23 is directly implicated in the pathogenesis of chronic kidney disease (CKD) and its complications, a consequence of other dysregulated pathways, or perhaps an adaptive - and thus desirable - response. In this issue of the JCI, Shalhoub et al. describe the chronic effects of antibody-mediated FGF23 neutralization in a CKD mouse model, shedding new light on this complicated story and moving us one step closer to understanding the role of FGF23 in CKD.

Banerjee R.,University of Texas Southwestern Medical Center
The Journal of foot and ankle surgery : official publication of the American College of Foot and Ankle Surgeons | Year: 2010

Lower extremity blast injuries represent a unique challenge to surgeons and often involve complex, limb-threatening wounds with extensive soft tissue and bone loss. Surgical treatment of these injuries can be difficult because of limited autogenous resources for reconstruction of the defect. In this article, we describe a technique for medial column reconstruction using iliac crest bone graft and soft tissue coverage with an abductor hallucis rotational flap combined with a split-thickness skin graft. This method addresses the extensive bone and soft tissue defects that frequently characterize blast injuries to the foot, and may be applicable in other situations where trauma or infection has caused extensive destruction of the medial column. Copyright 2010 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

Muppidi S.,University of Texas Southwestern Medical Center
Annals of the New York Academy of Sciences | Year: 2012

The myasthenia gravis activities of daily living (MG-ADL) profile is an eight-item patient-reported scale developed to assess MG symptoms and their effects on daily activities. The MG-ADL profile correlated well with the Quantitative MG (QMG) score (r= 0.58, P < 0.001) in 254 consecutive patient visits. Further analysis during clinical trials confirmed the excellent correlation with the QMG test and provided additional evidence that the MG-ADL profile is responsive to clinical improvement. MG-ADL performance was further analyzed during a recent multicenter, prospective scale validation study for two new outcome measures. At the first visit, there was a strong positive correlation between the MG-ADL and the MG Composite (r= 0.85, P < 0.0001) and between the MG-ADL and the MG-Quality of life15 (MG-QOL15) (r= 0.76, P < 0.0001). Test-retest analysis demonstrated a high reliability coefficient. Sensitivity/specificity analysis revealed that a 2-point improvement has the best trade-off attributes to predict clinical improvement. The MG-ADL profile also performed well on Rasch analysis. The MG-ADL scoring system is useful as a secondary outcome measure and in routine clinical management. © 2012 New York Academy of Sciences.

Chakrabarti G.,University of Texas Southwestern Medical Center
Radiation Oncology | Year: 2015

Background: Advanced non-small cell lung cancer (NSCLC) is an aggressive tumor that is treated with a combination of chemotherapy and radiation if the patient is not a candidate for surgery. Predictive biomarkers for response to radiotherapy are lacking in this patient population, making it a non-tailored therapy regimen with unknown outcome. Twenty to 30 % of NSCLC harbor an activating mutation in KRAS that may confer radioresistance. We hypothesized that mutant KRAS can regulate glutamine metabolism genes in NSCLC and maintain tumor redox balance through transamination reactions that generate cytosolic NADPH via malic enzyme 1 (ME1), which may contribute to radioresistance. Findings: A doxycycline-inducible mouse model of KRAS G12D driven NSCLC and patient data was analyzed from multiple publicly accessible databases including TCGA, CCLE, NCBI GEO and Project Achilles. ME1 expression was found to be mutant KRAS associated in both a NSCLC mouse model and human NSCLC cancer cell lines. Perturbing glutamine metabolism sensitized mutant KRAS, but not wild-type KRAS NSCLC cell lines to radiation treatment. NSCLC survival analysis revealed that patients with elevated ME1 and GOT1 expression had significantly worse outcomes after radiotherapy, but this was not seen after chemotherapy alone. Conclusions: KRAS driven glutamine metabolism genes, specifically ME1 and GOT1 reactions, may be a predictive marker and potential therapeutic target for radiotherapy in NSCLC. © 2015 Chakrabarti.

Neyra J.A.,University of Texas Southwestern Medical Center
Critical Care Medicine | Year: 2016

OBJECTIVE:: Incident acute kidney injury and prevalent chronic kidney disease are commonly encountered in septic patients. We examined the differential effect of acute kidney injury and chronic kidney disease on the association between cumulative fluid balance and hospital mortality in critically ill septic patients. DESIGN:: Retrospective cohort study. SETTING:: Urban academic medical center ICU. PATIENTS:: ICU adult patients with severe sepsis or septic shock and serum creatinine measured within 3 months prior to and 72 hours of ICU admission. Patients with estimated glomerular filtration rate less than 15 mL/min/1.73 m or receiving chronic dialysis were excluded. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: A total of 2,632 patients, 1,211 with chronic kidney disease, were followed up until hospital death or discharge. Acute kidney injury occurred in 1,525 patients (57.9%), of whom 679 (44.5%) had chronic kidney disease. Hospital mortality occurred in 603 patients (22.9%). Every 1-L increase in cumulative fluid balance at 72 hours of ICU admission was independently associated with hospital mortality in all patients (adjusted odds ratio, 1.06 [95% CI] 1.04–1.08; p < 0.001), and in each acute kidney injury/chronic kidney disease subgroup (adjusted odds ratio, 1.06 [1.03–1.09] for acute kidney injury+/chronic kidney disease+; 1.09 [1.05–1.13] for acute kidney injury–/chronic kidney disease+; 1.05 [1.03–1.08] for acute kidney injury+/chronic kidney disease–; and 1.07 [1.02–1.11] for acute kidney injury–/chronic kidney disease–). There was a significant interaction between acute kidney injury and chronic kidney disease on cumulative fluid balance (p =0.005) such that different cumulative fluid balance cut-offs with the best prognostic accuracy for hospital mortality were identified: 5.9 L for acute kidney injury+/chronic kidney disease+; 3.8 L for acute kidney injury–/chronic kidney disease+; 4.3 L for acute kidney injury+/chronic kidney disease–; and 1.5 L for acute kidney injury–/chronic kidney disease–. The addition of cumulative fluid balance to the admission Sequential Organ Failure Assessment score had increased prognostic utility for hospital mortality when compared with Sequential Organ Failure Assessment alone, particularly in patients with acute kidney injury. CONCLUSIONS:: Higher cumulative fluid balance at 72 hours of ICU admission was independently associated with hospital mortality regardless of acute kidney injury or chronic kidney disease presence. We characterized cumulative fluid balance cut-offs associated with hospital mortality based on acute kidney injury/chronic kidney disease status, underpinning the heterogeneity of fluid regulation in sepsis and kidney disease. Copyright © by 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Brugarolas J.,University of Texas Southwestern Medical Center
Journal of Clinical Oncology | Year: 2014

Renal cell carcinoma of clear-cell type (ccRCC) is an enigmatic tumor type, characterized by frequent inactivation of the VHL gene (infrequently mutated in other tumor types), responsiveness to angiogenesis inhibitors, and resistance to both chemotherapy and conventional radiation therapy. ccRCC tumors exhibit substantial mutation heterogeneity. Recent studies using massively parallel sequencing technologies have implicated several novel driver genes. In VHL wild-type tumors, mutations were discovered in TCEB1, which encodes Elongin C, a protein that binds to VHL and is required for its function. Several additional tumor suppressor genes have been identified near the VHL gene, within a region that is frequently deleted in ccRCC on chromosome 3p: SETD2, BAP1, and PBRM1. Mutations in BAP1 and PBRM1 are largely mutually exclusive and are associated with different tumor biology and patient outcomes. In addition, the mTORC1 pathway is deregulated by mutations in MTOR, TSC1, PIK3CA, and PTEN in approximately 20% of ccRCCs. Mutations in TSC1, and possibly other genes, may predict for sensitivity to mTORC1 inhibitors. These discoveries provide insight into ccRCC development and set the foundation for the first molecular genetic classification of the disease, paving the way for subtype-specific therapies. © 2014 by American Society of Clinical Oncology.

Wang L.,University of Texas Southwestern Medical Center
Oncogene | Year: 2015

Lung cancer is the leading cause of cancer-related death in the United States, and metastatic behavior is largely responsible for this mortality. Mutations in multiple ‘driver’ oncogenes and tumor suppressors are known to contribute to the lung tumorigenesis and in some cases represent therapeutic targets. Leucine Zipper Transcription Factor-like 1 (LZTFL1) is located in the chromosome region 3p21.3 where allelic loss and genetic alterations occur early and frequently in lung cancers. Previously, we found that LZTFL1 is downregulated in epithelial tumors, including lung cancer, and functions as a tumor suppressor in gastric cancers. However, the functional role of LZTFL1 in lung oncogenesis is undefined. We show here that downregulation of LZTFL1 expression in non-small cell lung cancer is associated with recurrence and poor survival, whereas re-expression of LZTFL1 in lung tumor cells inhibited extravasation/colonization of circulating tumor cells to the lung and inhibited tumor growth in vivo. Mechanistically, we found that LZTFL1 is expressed in ciliated human bronchial epithelial cells (HBECs) and its expression correlates with HBEC differentiation. LZTFL1 inhibits transforming growth factor β-activated mitogen-activated protein kinase and hedgehog signaling. Alteration of intracellular levels of LZTFL1 resulted in changes of expression of genes associated with epithelial-to-mesenchymal transition (EMT). We conclude that LZTFL1 inhibits lung tumorigenesis, possibly by maintaining epithelial cell differentiation and/or inhibition of signalings that lead to EMT and suggest that reactivation of LZTFL1 expression in tumor cells may be a novel lung cancer therapeutic approach.Oncogene advance online publication, 14 September 2015; doi:10.1038/onc.2015.328. © 2015 Macmillan Publishers Limited

Zhang C.,University of Texas Southwestern Medical Center
Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences | Year: 2012

Bone formation is a complex developmental process involving the differentiation of mesenchymal stem cells to osteoblasts. Osteoblast commitment and differentiation are controlled through a multistep molecular pathway regulated by different transcription factors and signaling proteins, including Indian hedgehog, Runx2, Osterix (Osx), and Wnt pathway. Osx is an osteoblast-specific transcription factor required for bone formation. Osx was first discovered as a bone morphogenetic protein-2 inducible gene in mesenchymal stem cells. Osx knock-out mice lack bone completely, and cartilage is normal. This opens a new window to the whole field of how bone forms. The discovery that Osx inhibits Wnt pathway highlights the potential for novel feedback control mechanisms involved in bone formation. Several downstream targets of Osx during bone formation have been identified, including Satb2, vitamin D receptor and vascular endothelial growth factor as well as Dkk1 and Sost. The delineation of the cascade of events leading to bone formation should provide a molecular basis for the development of new and specific anabolic therapeutic agents for bone deficit conditions, such as osteoporosis and osteonecrosis. This review summarizes the recent advances in understanding the molecular mechanisms of Osx effect on bone formation. Studies since the Osx discovery have provided convincing evidences to demonstrate that Osx is the master gene that controls osteoblast lineage commitment and the subsequent osteoblast differentiation and proliferation.

Orme J.,University of Texas Southwestern Medical Center
Discovery medicine | Year: 2012

Systemic lupus erythematosus (SLE) is a heterogeneous group of autoimmune disorders defined by a consensus of clinical and laboratory criteria. Much of the pathophysiology and therapy of SLE has focused on autoimmune B and T cells of the adaptive immune system. Recently, the role of macrophages, part of the innate immune system, in SLE pathogenesis has gained attention. The field of immunology in general has recently changed in the way that it approaches macrophages. Rather than viewing them as a single, concrete whole, it has become clear that different subpopulations of macrophages contribute to various immune and non-immune processes. Such a nomenclature may provide an ideal framework from which to study macrophage pathogenesis in SLE. Studies suggest that M1 subtype macrophages play an important inflammatory role in SLE pathogenesis. Further, apparently reduced populations of M2a and M2c subtype macrophages may contribute to the lack of anti-inflammatory activity apparent in the disease. M2b subtype macrophages may actually have a role in causing disease directly. Regulatory macrophages have yet to be explored thoroughly in SLE, though the presence of a few of their markers may mean that they are active in suppressing SLE-related inflammation.

Wax M.B.,University of Texas Southwestern Medical Center
Experimental Eye Research | Year: 2011

Although the majority of patients with glaucoma have elevated intraocular pressure as the presumed etiology for their resultant neuropathy, it is well known that approximately 25% of patients with glaucoma have intraocular pressure within the normal range for their race. These patients may have conditions that facilitate non-pressure related stress to the retina and optic nerve that might directly contribute to their glaucomatous neuropathy and include chronic or intermittent ischemia (i.e atherosclerosis, heart disease, vasospasm, migraine, sleep apnea), altered scleral/optic nerve head morphology that predisposes to glaucomatous stress (i.e myopia); genetic mutations that predispose to glaucoma damage at normal IOP (OPA-1,optineurin, myocilin) and evidence of aberrant immunity that suggests that their glaucoma might be a form of an autoimmune neuropathy (i.e. presumed autoimmune glaucoma). This review provides a critical assessment of the potential role for autoimmunity as an initiating or exacerbating etiology in some patients with glaucoma. © 2010 Elsevier Ltd.

Olsen N.J.,Pennsylvania State University | Schleich M.A.,Pennsylvania State University | Karp D.R.,University of Texas Southwestern Medical Center
Seminars in Arthritis and Rheumatism | Year: 2013

Objectives: Hydroxychloroquine (HCQ) is a widely used medication for the treatment of rheumatoid arthritis and systemic lupus erythematosus. An increasing body of evidence supports actions of this drug that are not directly related to its immunosuppressive or anti-rheumatic properties. The objective of this systematic review is to characterize the spectrum of conditions that might be responsive to treatment with HCQ. Methods: PubMed was searched using the MeSH for HCQ with relevant subheadings and the limits of human topics and English language. Four-hundred and fifty-six abstracts from this search were examined individually to exclude those that were not focused on the objectives of this review. The resulting 76 articles were grouped according to topic areas and reviewed in detail. Results: HCQ has been reported to have therapeutic effects in a wide array of conditions, including diabetes mellitus, dyslipidemias, coagulopathies, infectious diseases and malignancies. Mechanisms of action responsible for these effects likely include altered signaling through cellular receptors, post-glycosylation modifications of infectious agents, changes in levels of inflammatory mediators and inhibition of autophagy. Many of the pathways are likely dependent on drug-induced changes in intra-endosomal acidity. Conclusions: The use of, and interest in, HCQ has spread into many areas of medicine. Actions of this drug may be directly beneficial to patients with non-rheumatic conditions such as diabetes mellitus or viral infections. Further understanding of underlying mechanisms has potential to reveal modifiable pathogenic pathways that might elucidate approaches to the design of more effective therapeutics for many chronic diseases. © 2013 Elsevier Inc.

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

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

PURPOSE OF REVIEW: As of April 2015, 13 disease modifying therapies (DMTs) have been approved by the Food and Drug Administration. The older agents continue to be utilized across the globe, especially in developing countries where many newer DMTs are still not available. Even though first generation DMTs have modest efficacy they have long term safety profile, and are considered safer than the second generation DMTs. RECENT FINDINGS: A PEGylated interferon beta-1a preparation that is administered subcutaneously every 2 weeks was also recently approved. Less frequent administration potentially reduced administration associated side effects and may improve adherence and compliance. The polyethylene glycol is also thought to make the drug less immunogenic. Glatopa (a glatiramer acetate bioequivalent), now represents the first available generic alternative of a DMT for multiple sclerosis. Its dosing, route of administration, and side effects are the same as for Copaxone. SUMMARY: In this article, we review the potential adverse effects and recommended laboratory studies as part of the monitoring strategy following initiation of various first generation DMTs and their recently approved versions. Copyright © 2016 Wolters Kluwer Health, Inc. All rights resereved.

Becker P.M.,University of Texas Southwestern Medical Center | Sharon D.,Tulane University
Journal of Clinical Psychiatry | Year: 2014

Objective: Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sensorimotor disorder that can result in considerable sleep disruption. This narrative review provides an overview of RLS diagnosis and reports epidemiologic evidence for an association between RLS and mood disorders. Possible links between RLS, sleep disturbances, and mood disorders are considered, and theoretical pathophysiologic pathways are discussed. Finally, pharmacologic therapies for RLS are summarized. Data Sources: A PubMed search was performed using the search term restless legs syndrome in combination with affective/anxiety, antidepressants, anxiety/anxiety disorder, attention deficit hyperactivity disorder, depression/depressive disorder, mood/mood disorder, neuropsychiatric, panic/panic disorder, psychiatric disorder, and psychosis. English-language articles published between January 1993 and May 2013 were retrieved. Additional studies were identified from the reference lists of relevant publications. Study Selection: 173 publications were retrieved. Articles related to the association between idiopathic RLS and depression, anxiety, and mood disorders were reviewed. In total, 32 epidemiologic studies were identified. These studies were reviewed in detail and ranked according to quality. Data Extraction: Data were extracted on the basis of relevance to the topic. Epidemiologic studies were assessed using 3 parameters: methodology, data quality, and generalizability of the results. Each factor was scored from 1 (high quality) to 4 (low quality), giving a total score of between 3 and 12 for each study. Results and Conclusions: RLS and mood disorders are frequently comorbid. Recognition and appropriate treatment of comorbid RLS are particularly important in patients with psychiatric disorders, as RLS is a common medical reason for insomnia, and antidepressant use may exacerbate sensory symptoms. © Copyright 2014 Physicians Postgraduate Press, Inc.

Kim Y.,University of Texas Southwestern Medical Center
Annals of Surgery | Year: 2015

OBJECTIVE:: To evaluate conditional disease-free survival (CDFS) for patients who underwent curative intent surgery for adrenocortical carcinoma (ACC). BACKGROUND:: ACC is a rare but aggressive tumor. Survival estimates are usually reported as survival from the time of surgery. CDFS estimates may be more clinically relevant by accounting for the changing likelihood of disease-free survival (DFS) according to time elapsed after surgery. METHODS:: CDFS was assessed using a multi-institutional cohort of patients. Cox proportional hazards models were used to evaluate factors associated with DFS. Three-year CDFS (CDFS3) estimates at “x” year after surgery were calculated as follows: CDFS3?=?DFS(x+3)/DFS(x). RESULTS:: One hundred ninety-two patients were included in the study cohort; median patient age was 52 years. On presentation, 36% of patients had a functional tumor and median size was 11.5?cm. Most patients underwent R0 resection (75%) and 9% had N1 disease. Overall 1-, 3-, and 5-year DFS was 59%, 34%, and 22%, respectively. Using CDFS estimates, the probability of remaining disease free for an additional 3 years given that the patient had survived without disease at 1, 3, and 5 years, was 43%, 53%, and 70%, respectively. Patients with less favorable prognosis at baseline demonstrated the greatest increase in CDFS3 over time (eg, capsular invasion: 28%–88%, Δ60% vs no capsular invasion: 51%–87%, Δ36%). CONCLUSIONS:: DFS estimates for patients with ACC improved dramatically over time, in particular among patients with initial worse prognoses. CDFS estimates may provide more clinically relevant information about the changing likelihood of DFS over time. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Hutchison M.R.,University of Texas Southwestern Medical Center
PLoS ONE | Year: 2013

Long bone growth results from ordered chondrocyte development within the cartilagenous growth plate. Chondrocytes are recruited from a resting pool to proliferate along the long axis of the bone, until various signals trigger differentiation and hypertrophy. We have shown previously that the neurotrophin receptor TrkB is expressed in growth plate chondrocytes, where the tyrosine kinase receptor regulates the pace of hypertrophic differentiation by modulating the activities of ERK and p38 MAP kinases. To investigate the physiological relevance of TrkB to bone growth in vivo, we generated mice with a targeted disruption of the receptor, and compared them to mice targeted for MAPK14, the gene for p38α. The TrkB mutant and p38α mutant mice showed a similar degree of dwarfism and delayed hypertrophic differentiation. To extend these findings, we showed that both the TrkB and p38α mutant mice have altered expression of Runx2 and Sox9, two key transcription factors required for skeletogenesis. The data provides in vivo evidence for the role of TrkB in bone growth, supports the role of p38 downstream of TrkB, and suggests that Runx2 and Sox9 expression is regulated by this pathway at the growth plate. © 2013 Hutchison.

Phosphorylation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) at the Thr2609 cluster is essential for its complete function in DNA repair and tissue stem cell homeostasis. This phenomenon is demonstrated by congenital bone marrow failure occurring in DNA-PKcs3A/3A mutant mice, which require bone marrow transplantation (BMT) to prevent early mortality. Surprisingly, an increased incidence of spontaneous tumors, especially skin cancer, was observed in adult BMT-rescued DNA-PKcs3A/3A mice. Upon further investigation, we found that spontaneous γH2AX foci occurred in DNA-PKcs3A/3A skin biopsies and primary keratinocytes and that these foci overlapped with telomeres during mitosis, indicating impairment of telomere replication and maturation. Consistently, we observed significantly elevated frequencies of telomere fusion events in DNA-PKcs3A/3A cells as compared with wild-type and DNA-PKcs-knockout cells. In addition, a previously identified DNA-PKcs Thr2609Pro mutation, found in breast cancer, also induces a similar impairment of telomere leading-end maturation. Taken together, our current analyses indicate that the functional DNA-PKcs T2609 cluster is required to facilitate telomere leading strand maturation and prevention of genomic instability and cancer development.Oncogene advance online publication, 30 November 2015; doi:10.1038/onc.2015.459. © 2015 Macmillan Publishers Limited

Willis B.L.,Cooper Institute | Ayers C.R.,University of Texas Southwestern Medical Center
Circulation | Year: 2012

Background-Family history of coronary heart disease (CHD) has been well studied as an independent risk factor for CHD events in the short term (<10 years). However, data are sparse on the association between family history and risk for CHD across long-term follow-up. Methods and Results-We included 49 255 men from the Cooper Center Longitudinal Study. Premature family history of CHD was defined as the presence of angina, myocardial infarction, angioplasty, or bypass surgery in a relative <50 years of age. Cause-specific mortality was obtained from the National Death Index. The association between premature family history and cardiovascular disease (CVD) or CHD death was compared across 3 unique follow-up periods (0-10, >10-20, and >20 years). Lifetime risk was estimated by use of a modified survival analytic technique adjusted for competing risk with non-CVD death as the competing event. After 811 708 person-years of follow-up, there were 919 CHD deaths and 1456 CVD deaths. After adjustment for traditional risk factors, premature family history was associated with CHD mortality >10 to 20 years (1.59; 95% confidence interval, 1.14-2.22) and >20 years (1.43; 95% confidence interval, 1.05-1.95) with wider confidence intervals at 0 to 10 years (1.32; 95% confidence interval, 0.76-2.31). Similar findings were observed for CVD mortality. Compared with men without a family history of coronary artery disease, premature family history was associated with an 50% higher lifetime risk for both CHD and CVD mortality (13.7% versus 8.9% and 21% versus 14.1%, respectively). Conclusion-Premature family history was associated with a persistent increase in both CHD and CVD mortality risk across long-term follow-up, resulting in significantly higher lifetime risk estimates. © 2012 American Heart Association, Inc.

Fulgham P.F.,Texas Health Presbyterian Dallas | Assimos D.G.,Wake forest University | Pearle M.S.,University of Texas Southwestern Medical Center | Preminger G.M.,Duke University
Journal of Urology | Year: 2013

Purpose: This technology assessment addresses the optimal use of imaging in the evaluation and treatment of patients with suspected or documented ureteral stones. Materials and Methods: A comprehensive literature search addressing 4 guiding questions was performed for full text in English articles published between January 1990 and July 2011. The search focused on major subtopics associated with the imaging of ureteral calculi, and included specific imaging modalities used in the diagnosis and management of ureteral calculous disease such as unenhanced (noncontrast) computerized tomography, conventional radiography, ultrasound, excretory urography, magnetic resonance imaging and nuclear medicine studies. Protocols (in the form of decision tree algorithms) were developed based on this literature review and in some instances on panel opinion. The 4 questions addressed were 1) What imaging study should be performed for suspected ureteral calculous disease? 2) What information should be obtained? 3) After diagnosis of a ureteral calculus, what followup imaging should be used? 4) After treatment of a ureteral calculus, what followup imaging studies should be obtained? Results: Based on these protocols, noncontrast computerized tomography is recommended to establish the diagnosis in most cases, with a low energy protocol advocated if body habitus is favorable. Conventional radiography and ultrasound are endorsed for monitoring the passage of most radiopaque stones as well as for most patients undergoing stone removal. Other studies may be indicated based on imaging findings, and patient, stone and clinical factors. Conclusions: The protocols generated assist the clinician in establishing the diagnosis of ureteral calculous disease, monitoring stone passage and following patients after treatment. The protocols take into account not only clinical effectiveness but also cost-effectiveness and risk/harm associated with the various imaging modalities. © 2013 American Urological Association Education and Research, Inc.

Moore J.E.,University of Texas Southwestern Medical Center
Clinics in Perinatology | Year: 2013

Necrotizing enterocolitis affects up to 10% of neonates who are born weighing less than 1500 g. It has a high rate of morbidity and mortality, and predicting infants who will be affected has so far been unsuccessful. In this article, a number of new methods are discussed from the literature to determine if any currently available techniques may allow for the identification of patients who are at increased risk for developing this potentially lethal disease. © 2013 Elsevier Inc.

Yin J.,University of Texas Southwestern Medical Center
Nature Structural and Molecular Biology | Year: 2016

The orexin (also known as hypocretin) G protein–coupled receptors (GPCRs) regulate sleep and other behavioral functions in mammals, and are therapeutic targets for sleep and wake disorders. The human receptors hOX1R and hOX2R, which are 64% identical in sequence, have overlapping but distinct physiological functions and potential therapeutic profiles. We determined structures of hOX1R bound to the OX1R-selective antagonist SB-674042 and the dual antagonist suvorexant at 2.8-Å and 2.75-Å resolution, respectively, and used molecular modeling to illuminate mechanisms of antagonist subtype selectivity between hOX1R and hOX2R. The hOX1R structures also reveal a conserved amphipathic α-helix, in the extracellular N-terminal region, that interacts with orexin-A and is essential for high-potency neuropeptide activation at both receptors. The orexin-receptor crystal structures are valuable tools for the design and development of selective orexin-receptor antagonists and agonists. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Niederkorn J.Y.,University of Texas Southwestern Medical Center
International Reviews of Immunology | Year: 2013

Corneal transplants have been successfully performed in human subjects for over 100 years and enjoy an immune privilege that is unrivaled in the field of transplantation. Immune privilege is defined as the reduced incidence and tempo in the immune rejection of corneal allografts compared to other categories of organ allografts performed under the same conditions. Skin allografts transplanted across various MHC or minor histocompatibility barriers undergo rejection in approximately 100% of the hosts. By contrast, orthotopic corneal allografts experience long-term survival in 50% to >90% of the hosts, depending on the histocompatibility barriers that confront the host. The capacity of corneal allografts to evade immune rejection is attributable to multiple anatomical, physiological and immunoregulatory conditions that conspire to prevent the induction and expression of alloimmunity. © 2013 Informa Healthcare USA, Inc.

Type 2 diabetes mellitus (DM) is a prevalent disorder that affects children, adolescents, and adults worldwide. In addition to risks of microvascular disease, patients with type 2 DM often have multiple risk factors of macrovascular disease; for example, approximately 90% of patients with type 2 DM are overweight/ obese. Type 2 DM is a complex disease that involves a variety of pathophysiologic abnormalities, including insulin resistance, increased hepatic glucose production, and abnormalities in the secretion of hormones, such as insulin, glucagon, amylin, and incretins. Incretins are gut-derived peptides with a variety of glucoregulatory functions. Incretin dysfunction can be treated with glucagon-like peptide 1 (GLP-1) receptor agonists (eg, exenatide and liraglutide) or inhibitors of dipeptidyl peptidase 4 (DPP-4) (eg, sitagliptin and saxagliptin), the enzyme that degrades GLP-1. The GLP-1 receptor agonists and DPP-4 inhibitors both elevate GLP-1 activity and substantially improve glycemic control. The GLP-1 receptor agonists are more effective in lowering blood glucose and result in substantial weight loss, whereas therapy with DPP-4 inhibitors lowers blood glucose levels to a lesser degree, and they are weight neutral. Treatment with GLP-1 receptor agonists has demonstrated durable glycemic control and improvement in multiple cardiovascular disease risk factors. In addition, unlike insulin or sulfonylureas, treatment with a GLP-1 receptor agonist or a DPP-4 inhibitor has not been associated with substantial hypoglycemia. These factors should be considered when selecting monotherapy or elements of combination therapy for patients with type 2 DM who are overweight/obese, for patients who have experienced hypoglycemia with other agents, and when achieving glycemic targets is difficult. © 2010 Mayo Foundation for Medical Education and Research.

Liu B.,University of Texas Southwestern Medical Center
Clinical Lipidology | Year: 2012

Niemann-Pick type C (NPC) disease is an autosomal recessive neurovisceral lipid and storage disorder characterized by abnormal sequestration of unesterified cholesterol within the late endosomal/lysosomal compartment of all cells in the body. This disease primarily affects children and is characterized by hepatic and pulmonary dysfunction, neurodegeneration and death at an early age. Currently, there is no effective treatment for NPC disease. It was recently discovered that 2-hydroxypropyl -cyclodextrin (2HPBCD), when administered systemically to a murine model of either NPC1 or NPC2 disease, significantly reduced lysosomal cholesterol accumulation in almost every organ, delayed the progression of neurodegeneration and significantly prolonged lifespan by allowing trapped cholesterol within the late endosome/lysosome to be released. When 2HPBCD was administered directly into the CNS of Npc1-/- mice, neurodegeneration was completely prevented. This review will explore the pathophysiology of NPC disease and the use of 2HPBCD as a possible therapeutic modality. © 2012 Future Medicine Ltd.

Olson E.N.,University of Texas Southwestern Medical Center
Science Translational Medicine | Year: 2014

MicroRNAs play central roles in cardiovascular disease, and their therapeutic manipulation raises exciting opportunities as well as challenges in the path toward clinical development.

Bennett M.J.,Childrens Hospital of Philadelphia | Rakheja D.,University of Texas Southwestern Medical Center
Developmental Disabilities Research Reviews | Year: 2013

The neuronal ceroid-lipofuscinoses (NCL's, Batten disease) represent a group of severe neurodegenerative diseases, which mostly present in childhood. The phenotypes are similar and include visual loss, seizures, loss of motor and cognitive function, and early death. At autopsy, there is massive neuronal loss with characteristic storage in remaining neurons. Neurons appear to die because of increased rates of apoptosis and altered autophagy. Ten genes have been identified so far that result in an NCL (CLN1-10). The most common forms are CLN1, CLN2, and CLN3, which were previously known as Infantile, Late-Infantile, and Juvenile NCL's, respectively. CLN1 and CLN2 result from mutations in soluble lysosomal enzymes palmitoyl-protein thioesterase (PPT) and tripeptidyl peptidase 1 (TPP1), which can be measured in white blood cells for clinical diagnosis. Molecular diagnostic testing is routinely available for CLN1, CLN2, and CLN3. Sequencing of other NCL genes may be required to establish a diagnosis when the common forms are ruled out. The pathogenesis of NCL neuronal loss resulting from loss of function of any of the NCL gene products remains unknown and no treatment options are presently available. © 2013 Wiley Periodicals, Inc.

Elliott W.J.,Rush University | Ram C.V.S.,University of Texas Southwestern Medical Center
Journal of Clinical Hypertension | Year: 2011

Key Points and Practical Recommendations: Calcium channel blockers, which dilate arteries by reducing calcium flux into cells, effectively lower blood pressure, especially in combination with other drugs, and some formulations of agents of this class are approved for treating angina or cardiac dysrhythmias. Calcium channel blockers reduce blood pressure across all patient groups, regardless of sex, race/ethnicity, age, and dietary sodium intake. Nondihydropyridine calcium channel blockers are more negatively chronotropic and inotropic than the dihydropyridine subclass, which is important for patients with cardiac dysrhythmias or who need β-blockers. Extensive experience in comparative randomized trials indicates that an initial calcium antagonist can prevent all major types of cardiovascular disease, except heart failure (for which a diuretic is superior). Initial dihydropyridine calcium channel blockers have not reduced the rate of progression of renal disease as well as inhibitors of the renin-angiotensin system, although members of the nondihydropyridine subclass can reduce albuminuria. High doses of dihydropyridine calcium channel blockers often cause edema, headache, flushing and tachycardia; high doses of verapamil can cause constipation. Diltiazem and verapamil have important drug interaction with digoxin and cyclosporine, among others. © 2011 Wiley Periodicals, Inc.

Goldsmith E.J.,University of Texas Southwestern Medical Center
Science Signaling | Year: 2011

Mitogen-activated protein kinases (MAPKs) are central players in eukaryotic signaling circuitry and interact with numerous other proteins. The structure of a MAPK with a kinase-binding domain (KBD) from a MAPK phosphatase, MKP5, reveals that the contacts with the MAPK are made with the folded three-dimensional KBD, although the KBD occupies the same binding site on the kinase as canonical linear docking motifs found in substrates and MAPK kinases. This structure offers insights into the action of MKP5 and other MKPs.

Palmer B.F.,University of Texas Southwestern Medical Center
Seminars in Nephrology | Year: 2011

Diuretics are commonly used therapeutic agents that act to inhibit sodium transport systems along the length of the renal tubule. The most effective diuretics are inhibitors of sodium chloride transport in the thick ascending limb of Henle. Loop diuretics mobilize large amounts of sodium chloride and water and produce a copious diuresis with a sharp reduction of extracellular fluid volume. As the site of action of diuretics moves downstream (thiazide and potassium-sparing diuretics), their effectiveness declines because the transport systems they inhibit have low transport capacity. Depending on the site of action diuretics can influence the renal handling of electrolyte-free water, calcium, potassium, protons, sodium bicarbonate, and uric acid. As a result, electrolyte and acid-base disorders commonly accompany diuretic use. Glucose and lipid abnormalities also can occur, particularly with the use of thiazide diuretics. This review focuses on the biochemical complications associated with the use of diuretics. The development of these complications can be minimized with careful monitoring, dosage adjustment, and replacement of electrolyte losses. © 2011 Elsevier Inc.

Ross E.M.,University of Texas Southwestern Medical Center
Science Signaling | Year: 2011

Heterotrimeric G proteins and G protein-coupled receptors represent conserved protein families with origins in the prokaryotes, but the various G protein-regulated effectors are heterogeneous in structure and function. The effectors apparently evolved ways to listen to G proteins late in their evolutionary histories. The structure of a complex between the effector protein phospholipase C-β3 (PLC-β3) and its activator, Gαq, suggests that several effectors independently evolved a structurally similar helix-turn-helix segment for G protein recognition. PLC-βs are also guanosine triphosphatase (GTPase)-activating proteins (GAPs) for the G that activates them. In a second example of convergent evolution, the GAP activity of these proteins depends on a flexible asparagine-containing loop that resembles the GAP site on RGS proteins, another family of G protein GAPs. Together, these two sites are proposed to cooperate to enable fast binding to activated Gαq, followed by fast deactivation. This cycle allows rapid sampling of the activation state of Gq-coupled receptors while providing efficient signal transduction.

Zuniga J.R.,University of Texas Southwestern Medical Center
Journal of Oral and Maxillofacial Surgery | Year: 2015

Purpose The present study describes the results of using a processed nerve allograft, Avance Nerve Graft, as an extracellular matrix scaffold for the reconstruction of lingual nerve (LN) and inferior alveolar nerve (IAN) discontinuities. Patients and Methods A retrospective analysis of the neurosensory outcomes for 26 subjects with 28 LN and IAN discontinuities reconstructed with a processed nerve allograft was conducted to determine the treatment effectiveness and safety. Sensory assessments were conducted preoperatively and 3, 6, and 12 months after surgical reconstruction. The outcomes population, those with at least 6 months of postoperative follow-up, included 21 subjects with 23 nerve defects. The neurosensory assessments included brush stroke directional sensation, static 2-point discrimination, contact detection, pressure pain threshold, and pressure pain tolerance. Using the clinical neurosensory testing scale, sensory impairment scores were assigned preoperatively and at each follow-up appointment. Improvement was defined as a score of normal, mild, or moderate. Results The neurosensory outcomes from LNs and IANs that had been microsurgically repaired with a processed nerve allograft were promising. Of those with nerve discontinuities treated, 87% had improved neurosensory scores with no reported adverse experiences. Similar levels of improvement, 87% for the LNs and 88% for the IANs, were achieved for both nerve types. Also, 100% sensory improvement was achieved in injuries repaired within 90 days of the injury compared with 77% sensory improvement in injuries repaired after 90 days. Conclusions These results suggest that processed nerve allografts are an acceptable treatment option for reconstructing trigeminal nerve discontinuities. Additional studies will focus on reviewing the outcomes of additional cases. © 2015 American Association of Oral and Maxillofacial Surgeons.

Wilson J.D.,University of Texas Southwestern Medical Center
Endocrinology and Metabolism Clinics of North America | Year: 2011

Androgens are involved in every aspect of prostate development, growth, and function from early in male embryogenesis to prostatic hyperplasia in aging men and dogs. Likewise, androgen deprivation at any phase of life causes a decrease in prostate cell number and DNA content. The process by which the circulating androgen testosterone is converted to dihydrotestosterone in the tissue and dihydrotestosterone in turn gains access to the nucleus where it regulates gene expression, largely via interaction with a receptor protein, is understood, but the downstream control mechanisms by which hormonal signals are translated into differentiation, growth, and function are being unraveled. © 2011 Elsevier Inc.

Reilly R.F.,University of Texas Southwestern Medical Center
Clinical Journal of the American Society of Nephrology | Year: 2014

Intradialytic hypotension is the most common adverse event that occurs during the hemodialysis procedure. Despite advances in machine technology, it remains a difficult management issue. The pathophysiology of intradialytic hypotension and measures to reduce its frequency are discussed. An accurate assessment of dry weight is crucial in all patients on dialysis and especially those patients prone to intradialytic hypotension. The presence of edema and hypertension has recently been shown to be a poor predictor of volume overload. Noninvasive methods to assess volume status, such as whole body and segmental bioimpedance, hold promise to more accurately assess fluid status. Reducing salt intake is key to limiting interdialytic weight gain. A common problem is that patients are often told to restrict fluid but not salt intake. Lowering the dialysate temperature, prohibiting food ingestion during hemodialysis, and midodrine administration are beneficial. Sodium modeling in the absence of ultrafiltration modeling should be abandoned. There is not enough data on the efficacy of L-carnitine to warrant its routine use. © 2014 by the American Society of Nephrology.

Unger R.H.,University of Texas Southwestern Medical Center | Cherrington A.D.,Vanderbilt University
Journal of Clinical Investigation | Year: 2012

The hormone glucagon has long been dismissed as a minor contributor to metabolic disease. Here we propose that glucagon excess, rather than insulin deficiency, is the sine qua non of diabetes. We base this on the following evidence: (a) glucagon increases hepatic glucose and ketone production, catabolic features present in insulin deficiency; (b) hyperglucagonemia is present in every form of poorly controlled diabetes; (c) the glucagon suppressors leptin and somatostatin suppress all catabolic manifestations of diabetes during total insulin deficiency; (d) total β cell destruction in glucagon receptor-null mice does not cause diabetes; and (e) perfusion of normal pancreas with anti-insulin serum causes marked hyperglucagonemia. From this and other evidence, we conclude that glucose- responsive β cells normally regulate juxtaposed α cells and that without intraislet insulin, unregulated α cells hypersecrete glucagon, which directly causes the symptoms of diabetes. This indicates that glucagon suppression or inactivation may provide therapeutic advantages over insulin monotherapy.

Palmer B.F.,University of Texas Southwestern Medical Center
Clinical Journal of the American Society of Nephrology | Year: 2014

Potassium is the most abundant cation in the intracellular fluid, and maintaining the proper distribution of potassium across the cell membrane is critical for normal cell function. Long-term maintenance of potassium homeostasis is achieved by alterations in renal excretion of potassium in response to variations in intake. Understanding the mechanism and regulatory influences governing the internal distribution and renal clearance of potassium under normal circumstances can provide a framework for approaching disorders of potassium commonly encountered in clinical practice. This paper reviews key aspects of the normal regulation of potassium metabolism and is designed to serve as a readily accessible review for the well informed clinician as well as a resource for teaching trainees and medical students. © 2015 by the American Society of Nephrology.

Cunnusamy K.,University of Texas Southwestern Medical Center
Discovery medicine | Year: 2010

Corneal transplantation is the oldest, most common, and arguably the most successful form of organ transplantation. In uncomplicated first-time cases, corneal allografts enjoy a success rate of up to 90% even though the transplants are performed without HLA matching or the use of systemic immunosuppressive drugs. In rodents, corneal allografts transplanted across entire MHC and multiple minor histocompatibility barriers enjoy long-term survival in >50% of the hosts, while skin grafts invariably undergo immune rejection. These observations are the basis for "immune privilege" of corneal transplants. In spite of this immune privilege, immune rejection can occur and remains the leading cause of corneal graft failure. Rodent models of penetrating keratoplasty have facilitated studies that have challenged, and in some cases, refuted prevailing dogmas. The long-held belief that CD4+ T helper 1 (Th1) cells were the sole mediators of corneal allograft rejection has fallen to the wayside based on studies in interferon-gamma (IFN-γ)(/) mice. The dogma that biasing the alloimmune response down a Th2 pathway would enhance graft survival has also been disproven, and in fact, compelling evidence indicates that Th2-based immune rejection of corneal allografts is swifter and more intense than Th1-based rejection. Animal studies have also pre-empted emerging dogmas including the hypothesis that Th17 cells play a crucial role in allograft rejection. Instead, IL-17A appears to be necessary for corneal allograft survival. Finally, IFN-γ, and IL-17A, which were normally viewed as proinflammatory, exert the opposite effect in the context of corneal transplantation and are necessary for corneal allograft survival.

Kutz Jr. J.W.,University of Texas Southwestern Medical Center
Neurosurgery | Year: 2012

The incidence of small vestibular schwannomas in patients with serviceable hearing is increasing because of the widespread use of MRI. The middle fossa approach provides the patient with an opportunity for tumor removal with hearing preservation. To determine the rate of hearing preservation and facial nerve outcomes after removal of a vestibular schwannoma with the use of the middle fossa approach. A retrospective case review at a tertiary, academic medical center was performed identifying patients from 1998 through 2008 that underwent removal of a vestibular schwannoma by the middle fossa approach. Preoperative and postoperative audiograms were compared to determine hearing preservation rates. In addition, facial nerve outcomes at last follow-up were recorded. Forty-six patients underwent a middle fossa craniotomy for the removal of a vestibular schwannoma. Of the 38 patients that had class A or class B hearing preoperatively, 24 (63.2%) retained class A or B hearing and 29 (76.3%) retained class A, B, or C hearing. When tumors were 10 mm or less in patients with class A or B preoperative hearing, 22 of 30 patients (73.3%) retained class A or B hearing. When the tumor size was greater than 10 mm in patients with class A or B preoperative hearing, 2 of 8 patients (25%) retained class A or B hearing. At most recent follow-up, 76.1% of patients had House-Brackmann grade I facial function, 13.0% had House-Brackmann grade II facial function, and 10.9% had House-Brackmann grade III facial function. Hearing preservation rates are excellent using the middle fossa approach, especially for smaller tumors. No patient experienced long-term facial nerve function worse than House-Brackmann grade III.

Modur P.N.,University of Texas Southwestern Medical Center
Annals of Indian Academy of Neurology | Year: 2014

In pre-surgical evaluation of epilepsy, there has been an increased interest in the study of electroencephalogram (EEG) activity outside the 1-70 Hz band of conventional frequency activity (CFA). Research over the last couple of decades has shown that EEG activity in the 70-600 Hz range, termed high frequency oscillations (HFOs), can be recorded intracranially from all brain regions both interictally and at seizure onset. In patients with epilepsy, HFOs are now considered as pathologic regardless of their frequency band although it may be difficult to distinguish them from the physiologic HFOs, which occur in a similar frequency range. Interictal HFOs are likely to be confined mostly to the seizure onset zone, thus providing a new measure for localizing it. More importantly, several studies have linked HFOs to underlying epileptogenicity, suggesting that HFOs can serve as potential biomarkers for the illness. Along with HFOs, analysis of ictal baseline shifts (IBS; or direct current shifts) and infraslow activity (ISA) (ISA: <0.1 Hz) has also attracted attention. Studies have shown that: IBSs can be recorded using the routine AC amplifiers with long time constants; IBSs occur at the time of conventional EEG onset, but in a restricted spatial distribution compared with conventional frequencies; and inclusion of IBS contacts in the resection can be associated with favorable seizure outcome. Only a handful of studies have evaluated all the EEG frequencies together in the same patient group. The latter studies suggest that the seizure onset is best localized by the ictal HFOs, the IBSs tend to provide a broader localization and the conventional frequencies could be non-localizing. However, small number of patients included in these studies precludes definitive conclusions regarding post-operative seizure outcome based on selective or combined resection of HFO, IBS and CFA contacts. Large, preferably prospective, studies are needed to further evaluate the implications of different EEG frequencies in epilepsy.

Scherer P.E.,University of Texas Southwestern Medical Center
Diabetes | Year: 2016

A number of different cell types contribute to the cellular architecture of adipose tissue. Although the adipocyte is functionally making important contributions to systemic metabolic homeostatis, several additional cell types contribute a supportive role to bestow maximal flexibility on the tissue with respect to many biosynthetic and catabolic processes, depending on the metabolic state. These cells include vascular endothelial cells, a host of immune cells, and adipocyte precursor cells and fibroblasts. Combined, these cell types give rise to a tissue with remarkable flexibility with respect to expansion and contraction, while optimizing the ability of the tissue to act as an endocrine organ through the release of many protein factors, critically influencing systemic lipid homeostasis and biochemically contributing many metabolites. Using an example from each of these categories - adiponectin as a key adipokine, sphingolipids as critical mediators of insulin sensitivity, and uridine as an important metabolite contributed by the adipocyte to the systemic pool - I will discuss the emerging genesis of the adipocyte over the past 20 years from metabolic bystander to key driver of metabolic flexibility. © 2016 by the American Diabetes Association.

Lotan Y.,University of Texas Southwestern Medical Center
Urologic Oncology: Seminars and Original Investigations | Year: 2010

Molecular markers are not established in management of bladder cancer. There is, however, a limit to the ability of clinical and pathological parameters to predict patients at high risk for urothelial carcinoma of the bladder (UCB) recurrence or mortality. The assessment of molecular biomarkers in surgical UCB specimens offers additional information on the biology of the disease, and might improve the prediction of oncologic end points. There is also a potential for molecular biomarkers to predict the response to adjuvant or neoadjuvant therapies. Furthermore, markers may guide targeted therapy. Prospective trials are needed to validate the clinical benefit of assessing expression patterns of molecular biomarkers. © 2010 Elsevier Inc. All rights reserved.

Villasenor A.,University of California at San Francisco | Cleaver O.,University of Texas Southwestern Medical Center
Seminars in Cell and Developmental Biology | Year: 2012

Growth and development of embryonic organs goes hand in hand with development of the vascular system. Blood vessels have been known for centuries to supply nutrients and oxygen to all cell types in an organism, however, they have more recently been shown to provide specific cues required for the formation and functionality of a number of tissues. Here, we review the role of blood vessels during pancreas formation, from early specification of the initial pancreatic bud, to its growth and maturation. The overarching theme that emerges from the many studies carried out in the past decade is that the vasculature likely plays diverse and changing roles during pancreas organogenesis. Blood vessels are required for endocrine specification at the onset of pancreatic budding, while only a few days later, blood vessels suppress pancreatic branching and exocrine differentiation. In this review, we summarize our understanding to date about the crosstalk between the pancreas and its vasculature, and we provide a perspective on the promises and challenges of the field. © 2012 .

Coppari R.,University of Texas Southwestern Medical Center | Coppari R.,University of Geneva | Coppari R.,University of California at Irvine | Bjorbaek C.,Beth Israel Deaconess Medical Center
Nature Reviews Drug Discovery | Year: 2012

Since the discovery of leptin in 1994, we now have a better understanding of the cellular and molecular mechanisms underlying its biological effects. In addition to its established anti-obesity effects, leptin exerts antidiabetic actions that are independent of its regulation of body weight and food intake. In particular, leptin can correct diabetes in animal models of type 1 and type 2 diabetes. In addition, long-term leptin replacement therapy improves glycaemic control, insulin sensitivity and plasma triglycerides in patients with severe insulin resistance due to lipodystrophy. These results have spurred enthusiasm for the use of leptin therapy to treat diabetes. Here, we review the current understanding of the glucoregulatory functions of leptin, emphasizing its central mechanisms of action and lessons learned from clinical studies, and discuss possible therapeutic applications of leptin in the treatment of type 1 and type 2 diabetes. © 2012 Macmillan Publishers Limited. All rights reserved.

Monteggia L.M.,University of Texas Southwestern Medical Center | Zarate C.,U.S. National Institutes of Health
Current Opinion in Neurobiology | Year: 2015

In the past decade the emergence of glutamate N-methyl- d-aspartate (NMDA) receptor blockers such as ketamine as fast-acting antidepressants fostered a major conceptual advance by demonstrating the possibility of a rapid antidepressant response. This discovery brings unique mechanistic insight into antidepressant action, as there is a substantial amount of basic knowledge on glutamatergic neurotransmission and how blockade of NMDA receptors may elicit plasticity. The combination of this basic knowledge base and the growing clinical findings will facilitate the development of novel fast acting antidepressants. © 2014 Elsevier Ltd.

Nijhawan A.E.,University of Texas Southwestern Medical Center
Journal of acquired immune deficiency syndromes (1999) | Year: 2012

Readmission after hospitalization is costly, time-consuming, and remains common among HIV-infected individuals. We sought to use data from the Electronic Medical Record (EMR) to create a clinical, robust, multivariable model for predicting readmission risk in hospitalized HIV-infected patients. We extracted clinical and nonclinical data from the EMR of HIV-infected patients admitted to a large urban hospital between March 2006 and November 2008. These data were used to build automated predictive models for 30-day risk of readmission and death. We identified 2476 index admissions among HIV-infected inpatients who were 73% males, 57% African American, with a mean age of 43 years. One-quarter were readmitted, and 3% died within 30 days of discharge. Those with a primary diagnosis during the index admission of HIV/AIDS accounted for the largest proportion of readmissions (41%), followed by those initially admitted for other infections (10%) or for oncologic (6%), pulmonary (5%), gastrointestinal (4%), and renal (3%) causes. Factors associated with readmission risk include: AIDS defining illness, CD4 ≤ 92, laboratory abnormalities, insurance status, homelessness, distance from the hospital, and prior emergency department visits and hospitalizations (c = 0.72; 95% confidence interval: 0.70 to 0.75). The multivariable predictors of death were CD4 < 132, abnormal liver function tests, creatinine >1.66, and hematocrit <30.8 (c = 0.79; 95% confidence interval: 0.74 to 0.84) for death. Readmission rates among HIV-infected patients were high. An automated model composed of factors accessible from the EMR in the first 48 hours of admission performed well in predicting the 30-day risk of readmission among HIV patients. Such a model could be used in real-time to identify HIV patients at highest risk so readmission prevention resources could be targeted most efficiently.

Janis J.E.,University of Texas Southwestern Medical Center
Plastic and Reconstructive Surgery | Year: 2012

Components separation is a widely used technique for defect size reduction in abdominal wall reconstruction, and ultimately helps achieve gold standard primary fascial reapproximation in many cases. Even with perforator-sparing techniques, oftentimes there are undermined skin flaps to varying degrees that can lead to complications such as seromas. In this article, the author describes the previously published technique of "progressive tension sutures" reported in the cosmetic literature and extrapolates it to reconstructive abdominal surgery with statistically significant decreases in drain output. This technique also enables recruitment of skin to the midline to afford tension-free reapproximation and excision of redundancy, thereby discarding the most random portion of the skin flaps. Copyright © 2012 by the American Society of Plastic Surgeons.

Wooding S.,University of Texas Southwestern Medical Center
Journal of Molecular Evolution | Year: 2011

Bitter taste receptors (TAS2Rs) enable animals to detect and avoid toxins in the environment, including noxious defense compounds produced by plants. This suggests that TAS2Rs are under complex pressures from natural selection. To investigate these pressures, we examined signatures of selection in the primate TAS2R38 gene. Whole-gene (1,002 bp) sequences from 40 species representing all major primate taxa uncovered extensive variation. Nucleotide substitutions occurred at 448 positions, resulting in 201 amino acid changes. Two single-nucleotide deletions, one three-nucleotide in-frame deletion, and one premature stop codon were also observed. The rate of non-synonymous substitution (x = dN/dS), was high in TAS2R38 (x = 0.60) compared to other genes, but significantly lower than expected under neutrality (P = 4.0 9 10-9), indicating that purifying selection has maintained the basic structure of the receptor. However, differences were present among receptor subregions. Non-synonymous rates were significantly lower than expected in transmembrane domains (x = 0.55, P = 1.18 9 10-12) and internal loops (x = 0.51, P = 7.04 9 10 -5), but not external loops (x = 1.16, P = 0.53), and evidence of positive selection was found in external loop 2, which exhibited a high rate (x = 2.53) consistent with rapid shifts in ligand targeting. These patterns point to a history of rapid yet constrained change in bitter taste responses in the course of primate evolution. © Springer Science+Business Media, LLC 2012.

Chen M.,University of Texas Southwestern Medical Center | Cho J.,Yale University | Zhao H.,Yale University
PLoS Genetics | Year: 2011

Genome-wide association studies (GWAS) examine a large number of markers across the genome to identify associations between genetic variants and disease. Most published studies examine only single markers, which may be less informative than considering multiple markers and multiple genes jointly because genes may interact with each other to affect disease risk. Much knowledge has been accumulated in the literature on biological pathways and interactions. It is conceivable that appropriate incorporation of such prior knowledge may improve the likelihood of making genuine discoveries. Although a number of methods have been developed recently to prioritize genes using prior biological knowledge, such as pathways, most methods treat genes in a specific pathway as an exchangeable set without considering the topological structure of a pathway. However, how genes are related with each other in a pathway may be very informative to identify association signals. To make use of the connectivity information among genes in a pathway in GWAS analysis, we propose a Markov Random Field (MRF) model to incorporate pathway topology for association analysis. We show that the conditional distribution of our MRF model takes on a simple logistic regression form, and we propose an iterated conditional modes algorithm as well as a decision theoretic approach for statistical inference of each gene's association with disease. Simulation studies show that our proposed framework is more effective to identify genes associated with disease than a single gene-based method. We also illustrate the usefulness of our approach through its applications to a real data example. © 2011 Chen et al.

Butovich I.A.,University of Texas Southwestern Medical Center
Investigative ophthalmology & visual science | Year: 2012

Secretions that are produced by meibomian glands (also known as meibum) are a major source of lipids for the ocular surface of humans and animals alike. Many animal species have been evaluated for their meibomian lipidomes. However, there have been a very small number of studies in which the animals were compared with humans side by side. Therefore, the purpose of this study was to compare meibum collected from humans and three typical laboratory animals, canines, mice, and rabbits, for their meibomian lipid composition in order to determine which animal species most resembles humans. High pressure liquid chromatography (HPLC) and gas-liquid chromatography (GLC) in combination with mass spectrometry were used to evaluate lipidomes of all tested species. Among three tested animal species, mice were found to be the closest match to humans in terms of their meibomian lipidomes, while canines were the second closest species. The lipids of these three species were close to each other structurally and, for most lipid classes, quantitatively. The rabbit meibomian lipidome, on the other hand, was vastly different from lipidomes of all other tested species. Interestingly, a previously described class of lipids, acylated omega-hydroxy fatty acids (OAHFA), was found to be present in every tested species as the major amphiphilic component of meibum. Our side by side comparison of the rabbit and the human meibum demonstrated their vast differences. Thus, the rabbit seems to be a poor animal model of the human tear film, at least when studying its biochemistry and biophysics.

Shang J.,University of Texas Southwestern Medical Center
Methods in Enzymology | Year: 2011

When the homeostasis of endoplasmic reticulum (ER) is disturbed by the accumulation of unfolded or misfolded proteins, a series of signaling responses collectively called the unfolded protein response (UPR) is triggered. UPR transducers IRE1, PERK, ATF6, and UPR-responsive genes such as GRP78/BiP, ERAD genes such as EDEM, and synthesis of the protein N-linked glycosylation donor lipid-linked oligosaccharides (LLOs) are mobilized. This chapter provides methods used in our laboratory to quantitatively measure the accumulation of mRNAs encoding BiP and EDEM, splicing of XBP1, cleavage of ATF6, inhibition of protein synthesis by PERK, and extension of LLOs under control and stress conditions. © 2011 Elsevier Inc.

Stafford I.A.,University of Texas Southwestern Medical Center
Obstetrics and gynecology | Year: 2012

To estimate the rate of early-onset group B streptococcal (GBS) neonatal sepsis with combined maternal and neonatal chemoprophylaxis. Since 1995, GBS chemoprophylaxis at our institution has consisted of intrapartum antibiotic prophylaxis to all women with identified risk factors. In addition, a single dose of penicillin G was administered within 1 hour of birth to all newborns without clinical signs or symptoms of infection. All neonates born between January 1, 2000, and December 31, 2008, and who developed early-onset (occurring at 72 hours of age or younger) invasive bacterial disease were identified. Incidence rates for sepsis resulting from GBS and other organisms were estimated. Compliance with risk factor identification and appropriate treatment was also ascertained. Rates of β-lactam resistance among cases of neonatal disease caused by Gram-negative organisms were calculated. Ninety-four cases of early-onset GBS sepsis were identified among 143,467 live births with a rate of 0.66 per 1,000 births (0.53-0.80 per 1,000). Of available GBS sensitivities, 8.8% demonstrated clindamycin resistance, and 26.6% were resistant to erythromycin. Thirty-four cases of non-GBS early-onset sepsis were identified for a rate of 0.24 per 1,000 live births. Of available sensitivity reports, 42.1% of Gram-negative isolates were sensitive to β-lactams. No significant difference in rates of early-onset GBS disease was found between the years 1995 and 2008. The sustained rates in early-onset GBS sepsis from 1995 to 2008, along with the low rates of neonatal disease caused by other pathogens, confirms the continued feasibility and efficacy of a combined maternal and neonatal GBS chemoprophylaxis.

Phelan H.,University of Texas Southwestern Medical Center
Seminars in Thrombosis and Hemostasis | Year: 2013

No standard exists for venous thromboembolism (VTE) prophylaxis after traumatic brain injury (TBI). Caregivers agree that there is an early time point after injury in which the chances of spontaneous injury progression are high and the risks of prophylactic anticoagulation are excessive, and that these injuries eventually stabilize to the point that anticoagulation may be safely started. Translating this consensus into an application that can inform bedside decision making has not occurred. National groups have promulgated guidelines in the United States suggesting that anticoagulants be used when the risk of renewed intracranial hemorrhage has ceased with no guidance beyond this vague recommendation. This is largely due to the relative paucity of literature about pharmacologic prophylaxis, which has in turn been due to fears of propagation of intracranial hemorrhage. Although interest in this field has increased of late, many studies are limited by the simple dichotomization of TBI patients as having the presence or absence of intracranial blood. Although methodologically easier, this approach does not account for the heterogeneity of TBI and, consequently, the spectrum of time to stabilization. To address this, our group has created an algorithm which stratifies patients by risk for spontaneous progression and tailors a unique VTE prophylaxis regimen to each arm. © 2013 by Thieme Medical Publishers, Inc.

Kuro-O M.,University of Texas Southwestern Medical Center
Kidney International Supplements | Year: 2013

Extracellular phosphate is toxic to the cell at high concentrations. When the phosphate level is increased in the blood by impaired urinary phosphate excretion, premature aging ensues. When the phosphate level is increased in the urine by dietary phosphate overload, this may lead to kidney damage (tubular injury and interstitial fibrosis). Extracellular phosphate exerts its cytotoxicity when it forms insoluble nanoparticles with calcium and fetuin-A, referred to as calciprotein particles (CPPs). CPPs are highly bioactive ligands that can induce various cellular responses, including osteogenic transformation of vascular smooth muscle cells and cell death in vascular endothelium and renal tubular epithelium. CPPs are detected in the blood of animal models and patients with chronic kidney disease (CKD) and associated with adaptation of the endocrine axes mediated by fibroblast growth factor-23 (FGF23) and Klotho that regulate mineral metabolism and aging. These observations have raised the possibility that CPPs may contribute to the pathophysiology of CKD. This notion, if validated, is expected to provide new diagnostic and therapeutic targets for CKD. © 2013 International Society of Nephrology.

Lee W.M.,University of Texas Southwestern Medical Center
Best Practice and Research: Clinical Gastroenterology | Year: 2012

Acute liver failure is a remarkably rare syndrome, the result of rapid hepatocyte injury occurring over days or a few weeks, and encompassing multiple etiologies, but all with a remarkably similar clinical picture. The clinical features of coagulopathy and encephalopathy characterize this severe and often fatal condition. To date, transplantation has been the only reliable form of rescue for many patients. Recent developments have included a clearer understanding of the different contributing etiologies, how to build a diagnosis and prognosis based on initial laboratory findings, a more aggressive approach to intensive care management and more detailed understanding of the role of transplantation in this setting. This review will provide an overview of standard practices and new research initiatives and findings for this interesting but vexing orphan disease. Particular attention will be paid to practical matters for clinicians to consider in approaching the ALF patient. Few controlled clinical trials have been possible because of the condition's rarity. Critical care of these rare patients is key to their survival and decisions must be made decisively, sometimes with inadequate information. Experience is helpful but experienced clinician managers are even rarer than the disease: few hepatologists or intensivists have in-depth experience with ALF patients. © 2012 Elsevier Ltd. All rights reserved.

Sarode R.,University of Texas Southwestern Medical Center
Transfusion | Year: 2012

Antiplatelet agents (APAs) are commonly used in clinical practice to either treat or prevent arterial thrombotic disorders in patients at high risk. The newer APAs are more potent with higher bleeding risk profiles. Patients who present with serious bleeds or need urgent surgical interventions while on APAs may require reversal of these agents' effect on PLTs. Currently, there are no guidelines for management of such patients. This article describes my approach to PLT transfusion or use of pharmacologic agents in such clinical scenarios based solely on personal experience and very limited published data. © 2011 American Association of Blood Banks.

Davidson J.,University of Texas Southwestern Medical Center
Endocrine Practice | Year: 2013

Objective: To review the most recent clinical data on the safety and efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors and to evaluate their position in current treatment guidelines and algorithms.Methods: PubMed searches were performed to identify published data regarding both the safety and efficacy of DPP-4 inhibitors approved for use in the United States and clinical guidelines describing recommendations for their use.Results: In the past 2 years, more than 100 publications have added clinical trial data on DPP-4 inhibitors to the medical literature. Since becoming available in 2006, these agents have demonstrated an excellent safety/tolerability profile, and as add-on to metformin, DPP-4 inhibitors may have comparable glycemic efficacy as other oral agents. As a result, DPP-4 inhibitors have assumed roles in clinical practice guidelines and treatment algorithms that are comparable to the sulfonylurea class. Advantages of DPP-4 inhibitors include an oral route of administration, a mechanism of action based on glucose-stimulated insulin secretion, and a low risk of hypoglycemia. The main disadvantage associated with this class is a relatively high cost. There is also less clinical experience with DPP-4 agents than classes of agents that have been in use for decades; however, long-term data on the safety and efficacy of DPP-4 agents will be available in the near future to refine their place in therapy. From 2 large clinical trials recently reported, EXAMINE and SAVOR, this class of agents does not increase overall adverse cardiovascular outcomes nor the risk of pancreatitis or pancreatic cancer.Conclusion: Based on comparisons of nonglycemic effects such as risk of hypoglycemia, weight gain, and durability, DPP-4 inhibitors may be considered as an alternative to sulfonylureas. However, direct cost may be a determining factor in the choice of therapy. © 2013 AACE.

Kuro-O M.,University of Texas Southwestern Medical Center
Nature Reviews Nephrology | Year: 2013

High concentrations of extracellular phosphate are toxic to cells. Impaired urinary phosphate excretion increases serum phosphate level and induces a premature-ageing phenotype. Urinary phosphate levels are increased by dietary phosphate overload and might induce tubular injury and interstitial fibrosis. Extracellular phosphate exerts its cytotoxic effects by forming insoluble nanoparticles with calcium and fetuin-A; these nanoparticles are referred to in this Review as calciprotein particles. Calciprotein particles are highly bioactive ligands that can induce various cellular responses, including the osteogenic transformation of vascular smooth muscle cells and cell death of vascular endothelial cells and renal tubular epithelial cells. Calciprotein particles are detected in the serum of animal models of kidney disease and in patients with chronic kidney disease (CKD) and might be associated with a (mal)adaptation of the endocrine axes mediated by fibroblast growth factors and Klothos that regulate phosphate homeostasis and ageing. These observations raise the possibility that calciprotein particles contribute to the pathogenesis of CKD. This theory, if verified, is expected to provide novel diagnostic markers and therapeutic targets in CKD. © 2013 Macmillan Publishers Limited. All rights reserved.

Mishra P.,University of Texas Southwestern Medical Center
Cell Calcium | Year: 2016

In the cellular context, mitochondria display a number of dynamic behaviors including fusion, division (or fission), directed transport, and targeted destruction (mitophagy). The relevance of these processes to human diseases has been intensively studied over the last several years, and emphasize the importance of mitochondrial dynamics to the central nervous system. Intriguingly, a common theme is that these behaviors do not function in isolation, but influence one another either directly or indirectly. Here, we review the dynamic properties of mitochondria and summarize their relationships to human diseases. © 2016 Elsevier Ltd.

Berry J.D.,University of Texas Southwestern Medical Center | Dyer A.,Northwestern University | Cai X.,Northwestern University | Garside D.B.,Northwestern University | And 6 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: The lifetime risks of cardiovascular disease have not been reported across the age spectrum in black adults and white adults. METHODS: We conducted a meta-analysis at the individual level using data from 18 cohort studies involving a total of 257,384 black men and women and white men and women whose risk factors for cardiovascular disease were measured at the ages of 45, 55, 65, and 75 years. Blood pressure, cholesterol level, smoking status, and diabetes status were used to stratify participants according to risk factors into five mutually exclusive categories. The remaining lifetime risks of cardiovascular events were estimated for participants in each category at each age, with death free of cardiovascular disease treated as a competing event. RESULTS: We observed marked differences in the lifetime risks of cardiovascular disease across risk-factor strata. Among participants who were 55 years of age, those with an optimal risk-factor profile (total cholesterol level, <180 mg per deciliter [4.7 mmol per liter]; blood pressure, <120 mm Hg systolic and 80 mm Hg diastolic; nonsmoking status; and nondiabetic status) had substantially lower risks of death from cardiovascular disease through the age of 80 years than participants with two or more major risk factors (4.7% vs. 29.6% among men, 6.4% vs. 20.5% among women). Those with an optimal risk-factor profile also had lower lifetime risks of fatal coronary heart disease or nonfatal myocardial infarction (3.6% vs. 37.5% among men, <1% vs. 18.3% among women) and fatal or nonfatal stroke (2.3% vs. 8.3% among men, 5.3% vs. 10.7% among women). Similar trends within risk-factor strata were observed among blacks and whites and across diverse birth cohorts. CONCLUSIONS: Differences in risk-factor burden translate into marked differences in the lifetime risk of cardiovascular disease, and these differences are consistent across race and birth cohorts. (Funded by the National Heart, Lung, and Blood Institute.) Copyright © 2012 Massachusetts Medical Society.

Gilboa S.M.,Centers for Disease Control and Prevention | Salemi J.L.,University of South Florida | Nembhard W.N.,University of South Florida | Fixler D.E.,University of Texas Southwestern Medical Center | Correa A.,Centers for Disease Control and Prevention
Circulation | Year: 2010

Background-: Previous reports suggest that mortality resulting from congenital heart disease (CHD) among infants and young children has been decreasing. There is little population-based information on CHD mortality trends and patterns among older children and adults. Methods and results-: We used data from death certificates filed in the United States from 1999 to 2006 to calculate annual CHD mortality by age at death, race-ethnicity, and sex. To calculate mortality rates for individuals â‰1 1 year of age, population counts from the US Census were used in the denominator; for infant mortality, live birth counts were used. From 1999 to 2006, there were 41 494 CHD-related deaths and 27 960 deaths resulting from CHD (age-standardized mortality rates, 1.78 and 1.20 per 100 000, respectively). During this period, mortality resulting from CHD declined 24.1% overall. Mortality resulting from CHD significantly declined among all race-ethnicities studied. However, disparities persisted; overall and among infants, mortality resulting from CHD was consistently higher among non-Hispanic blacks compared with non-Hispanic whites. Infant mortality accounted for 48.1% of all mortality resulting from CHD; among those who survived the first year of life, 76.1% of deaths occurred during adulthood (≥18 years of age). Conclusions-: CHD mortality continued to decline among both children and adults; however, differences between race-ethnicities persisted. A large proportion of CHD-related mortality occurred during infancy, although significant CHD mortality occurred during adulthood, indicating the need for adult CHD specialty management. © 2010 American Heart Association, Inc.

LeComte M.D.,University of Vermont | Shimada I.S.,University of Vermont | Shimada I.S.,University of Texas Southwestern Medical Center | Sherwin C.,University of Vermont | Spees J.L.,University of Vermont
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Defining the signaling network that controls reactive astrogliosis may provide novel treatment targets for patients with diverse CNS injuries and pathologies. We report that the radial glial cell antigen RC2 identifies the majority of proliferating glial fibrillary acidic protein-positive (GFAP+) reactive astrocytes after stroke. These cells highly expressed endothelin receptor type B (ETBR) and Jagged1, a Notch1 receptor ligand. To study signaling in adult reactive astrocytes, we developed a model based on reactive astrocyte-derived neural stem cells isolated from GFAP-CreER-Notch1 conditional knockout (cKO) mice. By loss- and gain-of-function studies and promoter activity assays, we found that Jagged1/Notch1 signaling increased ETBR expression indirectly by raising the level of phosphorylated signal transducer and activator of transcription 3 (STAT3), a previously unidentified EDNRB transcriptional activator. Similar to inducible transgenic GFAP-CreER-Notch1-cKO mice, GFAP-CreER-ETBR-cKO mice exhibited a defect in reactive astrocyte proliferation after cerebral ischemia. Our results indicate that the Notch1-STAT3-ETBR axis connects a signaling network that promotes reactive astrocyte proliferation after brain injury. © 2015, National Academy of Sciences. All rights reserved.

Ye J.,University of Texas Southwestern Medical Center
Cold Spring Harbor perspectives in biology | Year: 2011

In mammals, intracellular levels of cholesterol and fatty acids are controlled through a feedback regulatory system mediated by a family of transcription factors called sterol regulatory element-binding proteins (SREBPs). SREBPs are synthesized as inactive precursors bound to membranes of the endoplasmic reticulum. When cells are deprived of cholesterol and fatty acids, NH(2)-terminal fragments of SREBPs become proteolytically released from membranes and migrate to the nucleus to activate transcription of genes required for lipid synthesis and uptake. Conversely, lipid repletion inhibits proteolytic processing of SREBPs and thereby suppresses lipid accumulation. We review here studies in cultured cells that reveal the mechanism for regulation of SREBP proteolytic activation, and those in animal models in which SREBP proteolysis has been either activated or inhibited to show the essential role of SREBPs in regulating hepatic lipid homeostasis.

Butovich I.A.,University of Texas Southwestern Medical Center
Experimental Eye Research | Year: 2013

Human meibomian gland secretions (MGS, or meibum) are formed from a complex mixture of lipids of different classes such as wax esters, cholesteryl esters, (O-acyl)-ω-hydroxy fatty acids (OAHFA) and their esters, acylglycerols, diacylated diols, free fatty acids, cholesterol, and a smaller amount of other polar and nonpolar lipids, whose chemical nature and the very presence in MGS have been a matter of intense debates. The purpose of this review is to discuss recent results that were obtained using different experimental techniques, estimate limitations of their usability, and discuss their biochemical, biophysical, and physiological implications. To create a lipid map of MGS and tears, the results obtained in the author's laboratory were integrated with available information on chemical composition of MGS andtears. The most informative approaches that are available today to researchers, such as HPLC-MS, GC-MS, and proton NMR, are discussed in details. A map of the meibomian lipidome (as it is seen in reverse phase liquid chromatography/mass spectrometry experiments) is presented. Directions of future efforts in the area are outlined. © 2013 Elsevier Ltd.

Tarnawa E.D.,University of Texas Southwestern Medical Center
Biology of reproduction | Year: 2013

The Foxos are key effectors of the PI3K/Akt signaling pathway and regulate diverse physiologic processes. Two of these factors, Foxo1 and Foxo3, serve specific roles in reproduction in the mouse. Foxo3 is required for suppression of primordial follicle activation in females, while Foxo1 regulates spermatogonial stem cell maintenance in males. In the mouse ovary, Foxo1 is highly expressed in somatic cells (but not in oocytes), suggesting an important functional role for Foxo1 in these cells. Given that invertebrate model species such as Caenorhabditis elegans and Drosophila melanogaster harbor a single ancestral Foxo homolog, these observations suggest that gene duplication conferred a selective advantage by permitting the Foxos to adopt distinct roles in oogenesis and spermatogenesis. Our objective was to determine if the remarkably specific expression patterns of Foxo1 and Foxo3 in mouse gonads (and, by inference, Foxo function) are conserved in diverse mammalian species. Western blotting was used to validate isoform-specific antibodies in rodents, companion animals, farm animals, nonhuman primates, and humans. Following validation of each antibody, immunohistochemistry was performed to ascertain Foxo1 and Foxo3 gonadal expression patterns. While Foxo1 expression in spermatogonia and granulosa cells was conserved in each species evaluated, Foxo3 expression in oocytes was not. Our findings suggest that Foxo3 is not uniquely required for primordial follicle maintenance in nonrodent species and that other Foxos, particularly Foxo1, may contribute to oocyte maintenance in a functionally redundant manner.

Palmer B.F.,University of Texas Southwestern Medical Center
American Journal of Kidney Diseases | Year: 2010

Hypokalemia is a common electrolyte disorder. Transient causes of hypokalemia are due to cell shift, whereas sustained hypokalemia is caused by either inadequate intake or excessive potassium loss. Evaluation of the intake, distribution, and excretion of potassium should include the following: (1) a careful history, including use of drugs, medications, and the presence of vomiting or diarrhea; (2) physical examination, including orthostatic changes in blood pressure and heart rate; and (3) measurement of urine and plasma electrolytes. Urinary potassium wasting is caused by pathophysiologic conditions that couple increased distal sodium delivery with increased plasma aldosterone levels or aldosterone-like effects. If urinary potassium loss is identified, the next step is to determine whether the loss is caused by a primary increase in distal delivery of sodium or a primary increase in mineralocorticoid level. A primary increase in distal delivery should be associated with volume depletion, whereas a primary increase in mineralocorticoid level generally is associated with volume expansion and hypertension. In patients with a primary increase in mineralocorticoid activity, it is useful to measure plasma renin activity and plasma aldosterone levels. Complications of hypokalemia include muscle weakness, rhabdomyolysis, cardiac arrhythmias, impaired urinary concentrating ability, and glucose intolerance. © 2010 National Kidney Foundation, Inc.

Babb T.G.,University of Texas Southwestern Medical Center
Respiratory Physiology and Neurobiology | Year: 2013

Among the many physiological changes induced by obesity, it also presents a unique challenge to ventilatory control during exercise due to increased metabolic demand of moving larger limbs, increased work of breathing due to extra weight on the chest wall, and changes in breathing mechanics. These challenges to ventilatory control in obesity can be inconspicuous or overt among obese adults but for the most part adaptation of ventilatory control during exercise in obesity appears remarkably unnoticed in the majority of obese people. In this brief review, the changes to ventilatory control required for maintaining normal ventilation during exercise will be examined, especially the interaction between respiratory neural drive and ventilation. Also, gaps in our current knowledge will be discussed. © 2013 Elsevier B.V.

Singal A.G.,University of Texas Southwestern Medical Center | El-Serag H.B.,Baylor College of Medicine
Clinical Gastroenterology and Hepatology | Year: 2015

The epidemiology of hepatocellular carcinoma (HCC) is characterized by dynamic temporal trends, several major established (i.e., HCV, HBV, alcohol) and emerging (i.e., diabetes, obesity, NAFLD) risk factors. Epidemiologic studies and clinical trials have identified additional demographic, clinical, pharmacological, genetic and life style factors that further affect or modify the likelihood of HCC and can be used in clinical practice to identify at-risk patients (i.e., risk stratification or prognostic algorithms) that can be targeted for prevention and early detection programs. These studies have also paved the way toward several well established preventive measures including HBV vaccination, HBV treatment, HCV treatment and HCC surveillance, and potential chemoprevention using statins, metformin or coffee. However, the effectiveness of HCC prevention in clinical practice and at the population level has lagged behind due to patient, provider, system, and societal factors. The Quality in the Continuum of Cancer Care model provides a framework for evaluating the HCC prevention processes, including potential failures that create a gap between efficacy and effectiveness. © 2015 AGA Institute.

Aiyagari V.,University of Texas Southwestern Medical Center
Expert Review of Neurotherapeutics | Year: 2015

Intracerebral hemorrhage (ICH) is a stroke subtype with high mortality and significant disability among survivors. The management of ICH has been influenced by the results of several major trials completed in the last decade. It is now recognized that hematoma expansion is a major cause of morbidity and mortality. However, efforts to improve clinical outcome through mitigation of hematoma expansion have so far been unsuccessful. Acute blood pressure management has recently been shown to be safe in the setting of acute ICH but there was no reduction in mortality with early blood pressure (BP) lowering. Two large trials of surgical evacuation of supratentorial ICH have not shown improvement in outcome with surgery, thus minimally invasive surgical strategies are currently being studied. Lastly, a better understanding of the pathophysiology of ICH has led to the identification of several new mechanisms of injury that could be potential therapeutic targets. © 2015 Taylor & Francis.

Wan Y.,University of Texas Southwestern Medical Center
Trends in Endocrinology and Metabolism | Year: 2010

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ is a crucial cellular and metabolic switch that regulates many physiologic and disease processes. Emerging evidence reveals that PPARγ is also a key modulator of skeletal remodeling. Long-term use of rosiglitazone, a synthetic PPARγ agonist and a drug to treat insulin resistance, increases fracture rates among patients with diabetes. Recent studies have revealed that PPARγ activation not only suppresses osteoblastogenesis, but also activates osteoclastogenesis, thereby decreasing bone formation while sustaining or increasing bone resorption. The pro-osteoclastogenic effect of rosiglitazone is mediated by a transcriptional network comprised of PPARγ, PPAR-gamma coactivator 1β and estrogen-related receptor α, which promotes both osteoclast differentiation and mitochondrial activation. Therefore, PPARγ plays dual roles in bone homeostasis by regulating both mesenchymal and hematopoietic lineages. © 2010 Elsevier Ltd.

Brownell N.,University of Texas Southwestern Medical Center
Current Opinion in Lipidology | Year: 2016

PURPOSE OF REVIEW: Low HDL-cholesterol (HDL-C) levels are predictive of incident atherosclerotic cardiovascular disease events. However, the use of medication to raise HDL-C levels has not consistently shown clinical benefit. As a result, studies have shifted toward HDL function, specifically cholesterol efflux, which has been inversely associated with prevalent subclinical atherosclerosis as well as subsequent atherosclerotic cardiovascular disease events. The purpose of this review is to summarize the effects of current medications and interventions on cholesterol efflux capacity. RECENT FINDINGS: Medications for cardiovascular health, including statins, fibrates, niacin, and novel therapeutics, are reviewed for their effect on cholesterol efflux. Differences in population studied and assay used are addressed appropriately. Lifestyle interventions, including diet and exercise, are also included in the review. SUMMARY: The modification of cholesterol efflux capacity (CEC) by current medications and interventions has been investigated in both large randomized control trials and smaller observational cohorts. This review serves to compile the results of these studies and evaluate CEC modulation by commonly used medications. Altering CEC could be a novel therapeutic approach to improving cardiovascular risk profiles. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Lowrey P.L.,Rider University | Takahashi J.S.,University of Texas Southwestern Medical Center
Advances in Genetics | Year: 2011

The mammalian circadian system is a complex hierarchical temporal network which is organized around an ensemble of uniquely coupled cells comprising the principal circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus. This central pacemaker is entrained each day by the environmental light/dark cycle and transmits synchronizing cues to cell-autonomous oscillators in tissues throughout the body. Within cells of the central pacemaker and the peripheral tissues, the underlying molecular mechanism by which oscillations in gene expression occur involves interconnected feedback loops of transcription and translation. Over the past 10 years, we have learned much regarding the genetics of this system, including how it is particularly resilient when challenged by single-gene mutations, how accessory transcriptional loops enhance the robustness of oscillations, how epigenetic mechanisms contribute to the control of circadian gene expression, and how, from coupled neuronal networks, emergent clock properties arise. Here, we will explore the genetics of the mammalian circadian system from cell-autonomous molecular oscillations, to interactions among central and peripheral oscillators and ultimately, to the daily rhythms of behavior observed in the animal. © 2011 Elsevier Inc.

Lotan Y.,University of Texas Southwestern Medical Center
Urologic Oncology: Seminars and Original Investigations | Year: 2015

Introduction: Fluorescence based photodynamic diagnostic (PDD) techniques have been developed to improve detection and treatment of non-muscle invasive bladder cancer. The goal of this article is to evaluate the promises and challenges of blue light cystoscopy. Methods: The literature was reviewed regarding articles pertaining to fluorescent cystoscopy and blue light cystoscopy (BLC). Results: Blue light cystoscopy improves detection of bladder cancer tumors especially CIS. Randomized trials have demonstrated a reduction of recurrences. BLC has been demonstrated to be safe and effective in treatment of NMIBC of varying risk. The main obstacle to BLC will be adoption by urologists. Purchase cost of capital equipment may impact usage especially if adopted for outpatient clinics. Conclusions: BLC has been demonstrated to be safe and effective in treatment of NMIBC of varying risk. The reduction of recurrences and yet unproven but potential reduction in progression should be viewed favorably by urologists and patients. The main obstacle to BLC will be adoption by urologists who can put pressure on hospitals to acquire the capital equipment and who will seek the training to become proficient in using the technology. Patient demand for the technology may also help increase availability. Finally, the companies involved with BLC need to support trials that will demonstrate reduction in progression and that will answer the practical issues regarding usage in proximity to BCG and repeated usage. © 2015 Elsevier Inc..

Yanagisawa H.,University of Texas Southwestern Medical Center | Davis E.C.,McGill University
International Journal of Biochemistry and Cell Biology | Year: 2010

Evolution of elastic fibers is associated with establishment of the closed circulation system. Primary roles of elastic fibers are to provide elasticity and recoiling to tissues and organs and to maintain the structural integrity against mechanical strain over a lifetime. Elastic fibers are comprised of an insoluble elastin core and surrounding mantle of microfibrils. Elastic fibers are formed in a regulated, stepwise manner, which includes the formation of a microfibrillar scaffold, deposition and integration of tropoelastin monomers into the scaffold, and cross-linking of the monomers to form an insoluble, functional polymer. In recent years, an increasing number of glycoproteins have been identified and shown to be located on or surrounding elastic fibers. Among them, the short fibulins-3, -4 and -5 particularly drew attention because of their potent elastogenic activity. Fibulins-3, -4 and -5 are characterized by tandem repeats of calcium binding EGF-like motifs and a C-terminal fibulin module, which is conserved throughout fibulin family members. Initial biochemical characterization and gene expression studies predicted that fibulins might be involved in structural support and/or matrix-cell interactions. Recent analyses of short fibulin knockout mice have revealed their critical roles in elastic fiber development in vivo. We review recent findings on the elastogenic functions of short fibulins and discuss the molecular mechanism underlying their activity in vitro and in vivo. © 2010 Elsevier Ltd.

Mau T.,University of Texas Southwestern Medical Center
Journal of Voice | Year: 2012

Objectives: To create a high-resolution three-dimensional (3D) reconstruction of a case of cricoarytenoid subluxation and perform quantitative analysis to understand its anatomy and functional consequence. Study Design: Computational, with image processing and analysis. Methods: High-resolution axial computed tomography images of the larynx of a patient with an anteriorly subluxed arytenoid were processed with custom MATLAB routines to create a versatile 3D reconstruction. The geometries of the subluxed and nonsubluxed arytenoids were quantitatively compared. Results: The anteriorly subluxed arytenoid has an inferoposteriorly displaced vocal process (VP), resulting in an elongated and inferiorly positioned vocal fold. The paradoxical posterior displacement of the VP with elongation of the vocal fold has not been described previously. Quantitative analysis reveals significant rotational components and a unidirectional translational component in anterior arytenoid subluxation. Conclusions: Quantitative 3D analysis yielded insight into the biomechanics of anterior arytenoid subluxation. Subluxation in this case appeared to involve more pure rotational than translational motion. Overrocking of the subluxed arytenoid can produce paradoxical elongation of the involved vocal fold. © 2012 The Voice Foundation.

Deng Y.,University of Texas Southwestern Medical Center
Annals of the New York Academy of Sciences | Year: 2010

Over the past two decades our view of adipose tissue has undergone a dramatic change from an inert energy storage tissue to an active endocrine organ. Adipose tissue communicates with other central and peripheral organs by synthesis and secretion of a host of molecules that we generally refer to as adipokines. The levels of some adipokines correlate with specific metabolic states and have the potential to impact directly upon the metabolic homeostasis of the system. A dysregulation of adipokines has been implicated in obesity, type 2 diabetes, hypertension, cardiovascular disease, and an ever-growing larger list of pathological changes in a number of organs. Here, we review the recent progress regarding the synthesis, secretion, and physiological function of adipokines with perspectives on future directions and potential therapeutic goals. © 2010 New York Academy of Sciences.

Brown L.M.,University of North Carolina at Greensboro | Clegg D.J.,University of Texas Southwestern Medical Center
Journal of Steroid Biochemistry and Molecular Biology | Year: 2010

In recent years, obesity and its associated health disorders and costs have increased. Accumulation of adipose tissue, or fat, in the intra-abdominal adipose depot is associated with an increased risk of developing cardiovascular problems, type-2 diabetes mellitus, certain cancers, and other disorders like the metabolic syndrome. Males and females differ in terms of how and where their body fat is stored, in their hormonal secretions, and in their neural responses to signals regulating weight and body fat distribution. Men and post-menopausal women accumulate more fat in their intra-abdominal depots than pre-menopausal women, resulting in a greater risk of developing complications associated with obesity. The goal of this review is to discuss the current literature on sexual dimorphisms in body weight regulation, adipose tissue accrual and deposition. © 2009 Elsevier Ltd.

Manzanillo P.S.,University of California at San Francisco | Shiloh M.U.,University of Texas Southwestern Medical Center | Portnoy D.A.,University of California at Berkeley | Cox J.S.,University of California at San Francisco
Cell Host and Microbe | Year: 2012

Cytosolic bacterial pathogens activate the cytosolic surveillance pathway (CSP) and induce innate immune responses, but how the host detects vacuolar pathogens like Mycobacterium tuberculosis is poorly understood. We show that M. tuberculosis also initiates the CSP upon macrophage infection via limited perforation of the phagosome membrane mediated by the ESX-1 secretion system. Although the bacterium remains within the phagosome, this permeabilization results in phagosomal and cytoplasmic mixing and allows extracellular mycobacterial DNA to access host cytosolic receptors, thus blurring the distinction between "vacuolar" and "cytosolic" pathogens. Activation of cytosolic receptors induces signaling through the Sting/Tbk1/Irf3 axis, resulting in IFN-β production. Surprisingly, Irf3-/- mice, which cannot respond to cytosolic DNA, are resistant to long-term M. tuberculosis infection, suggesting that the CSP promotes M. tuberculosis infection. Thus, cytosolic sensing of mycobacterial DNA plays a key role in M. tuberculosis pathogenesis and likely contributes to the high type I IFN signature in tuberculosis. © 2012 Elsevier Inc.

Carroll T.J.,University of Texas Southwestern Medical Center
Organogenesis | Year: 2011

Planar cell polarity (PCP) describes the coordinated polarization of tissue cells in a direction that is orthogonal to their apical/basal axis. In the last several years, studies in flies and vertebrates have defined evolutionarily conserved pathways that establish and maintain PCP in various cellular contexts. Defective responses to the polarizing signal(s) have deleterious effects on the development and repair of a wide variety of organs/tissues. In this review, we cover the known and hypothesized roles for PCP in the metanephric kidney. We highlight the similarities and differences in PCP establishment in this organ compared with flies, especially the role of Wnt signaling in this process. Finally, we present a model whereby the signal(s) that organizes PCP in the kidney epithelium, at least in part, comes from the adjacent stromal fibroblasts.

Huang S.,University of Texas Southwestern Medical Center
Autophagy | Year: 2013

Efficient apoptotic corpse clearance is essential for metazoan development and adult tissue homeostasis. Several autophagy proteins have been previously shown to function in apoptotic cell clearance; however, it remains unknown whether autophagy genes are essential for efficient apoptotic corpse clearance in the developing embryo. Here we show that, in Caenorhabditis elegans embryos, loss-of-function mutations in several autophagy genes that act at distinct steps in the autophagy pathway resulted in increased numbers of cell corpses and delayed cell corpse clearance. Further analysis of embryos with a null mutation in bec- 1, the C. elegans ortholog of yeast VPS30/ATG6/mammalian beclin 1 (BECN1), revealed normal phosphatidylserine exposure on dying cells. Moreover, the corpse clearance defects of bec- 1(ok691) embryos were rescued by BEC-1 expression in engulfing cells, and bec- 1(ok691) enhanced corpse clearance defects in nematodes with simultaneous mutations in the engulfment genes, ced- 1, ced- 6 or ced- 12. Together, these data demonstrate that autophagy proteins play an important role in cell corpse clearance during nematode embryonic development, and likely function in parallel to known pathways involved in corpse removal.

Granberg C.F.,University of Texas Southwestern Medical Center
Pediatric clinics of North America | Year: 2012

Over the past 3 decades, minimally invasive stone surgery has completely overtaken open surgical approaches to upper tract pediatric urolithiasis. Progressing from least to most minimally invasive, extracorporeal shock wave lithotripsy, ureteroscopy, and percutaneous nephrolithotomy are the surgical methods of today for kidney and ureteral stones. The choice of treatment modality is individualized in children, considering patient age, stone size, number, location, and anatomic and clinical contributing factors. The purpose of this article is to review these techniques for pediatric upper urinary tract stones and summarize outcomes and complications. Copyright © 2012 Elsevier Inc. All rights reserved.

Gumbo T.,University of Texas Southwestern Medical Center
Nature Genetics | Year: 2013

A new study demonstrates that bacterial mutation rates associated with the Mycobacterium tuberculosis lineage most commonly linked to multidrug-resistant tuberculosis are multifold higher than shown in previous studies. This discovery, when considered together with recent findings on pharmacokinetic variability in patients, leads to new models of how multidrug-resistant tuberculosis arises, with direct therapeutic implications. © 2013 Nature America, Inc. All rights reserved.

Popugaeva E.,Saint Petersburg State University | Bezprozvanny I.,University of Texas Southwestern Medical Center
Frontiers in Molecular Neuroscience | Year: 2013

Alzheimer disease (AD) is a major threat of twenty-first century that is responsible for the majority of dementia in the elderly. Development of effective AD-preventing therapies are the top priority tasks for neuroscience research. Amyloid hypothesis of AD is a dominant idea in the field, but so far all amyloid-targeting therapies have failed in clinical trials. In addition to amyloid accumulation, there are consistent reports of abnormal calcium signaling in AD neurons. AD neurons exhibit enhanced intracellular calcium (Ca2+) liberation from the endoplasmic reticulum (ER) and reduced store-operated Ca2+ entry (SOC). These changes occur primarily as a result of ER Ca2+ overload. We argue that normalization of intracellular Ca2+ homeostasis could be a strategy for development of effective disease-modifying therapies. The current review summarizes recent data about changes in ER Ca2+ signaling in AD. Ca2+ channels that are discussed in the current review include: inositol trisphosphate receptors, ryanodine receptors, presenilins as ER Ca2+ leak channels, and neuronal SOC channels. We discuss how function of these channels is altered in AD and how important are resulting Ca2+ signaling changes for AD pathogenesis. © 2013 Popugaeva and Bezprozvanny.

Hutchison M.R.,University of Texas Southwestern Medical Center
Molecular Endocrinology | Year: 2012

The ERK and p38 MAPK pathways are well-known transducers of signals that regulate proliferation and differentiation, but precisely how these pathways control growth plate chondrocyte development is unclear. For example, the ERK pathway has been reported to be required by some investigators but inhibitory to chondrocyte development by others. Moreover, how these two pathways interact to regulate chondrocyte development is even less clear. Using primary bovine growth plate chondrocytes and murine ATDC5 cells, we demonstrate that the ERK and p38 pathways have opposing effects on proliferation but are both absolutely required for differentiation. Two factors that promote chondrocyte differentiation, brain-derived neurotrophic factor (BDNF) and C-type natriuretic peptide, increase p38 activity while decreasing, but not completely inhibiting, ERK activity. The attenuation of ERK activity by BDNF occurs via p38-dependent raf-1 inhibition. The inhibition of raf-1 by p38 is direct, because purified p38 protein inhibits the kinase activity of purified active raf-1 as well as raf-1 immunoprecipitated from chondrocyte lysates. Moreover, IGF-I, which stimulates proliferation, suppresses p38 activation. This work describes a model wherein unopposed IGF-I promotes high ERK/p38 activity ratios favoring proliferation, whereas BDNF signals a transition to differentiation by decreasing the ERK/p38 activity ratio without completely inhibiting ERK, which involves the direct inhibition of raf-1 by p38. © 2012 by The Endocrine Society.

Hsieh J.,University of Texas Southwestern Medical Center
Genes and Development | Year: 2012

Stem cells have captured our imagination and generated hope, representing a source of replacement cells to treat a host of medical conditions. Tucked away in specialized niches, stem cells maintain tissue function and rejuvenate organs. Balancing the equation between cellular supply and demand is especially important in the adult brain, as neural stem cells (NSCs) in two discrete regions, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) next to the lateral ventricles, continuously self-renew and differentiate into neurons in a process called adult neurogenesis. Through the interplay of intrinsic and extrinsic factors, adult neurogenic niches ensure neuronal turnover throughout life, contributing to plasticity and homeostatic processes in the brain. This review summarizes recent progress on the molecular control of adult neurogenesis in the SGZ and SVZ, focusing on the role of specific transcription factors that mediate the progression from NSCs to lineagecommitted progenitors and, ultimately, the generation of mature neurons and glia. © 2012 by Cold Spring Harbor Laboratory Press.

Kalwat M.A.,University of Texas Southwestern Medical Center | Thurmond D.C.,Indiana University
Experimental and Molecular Medicine | Year: 2013

The maintenance of whole-body glucose homeostasis is critical for survival, and is controlled by the coordination of multiple organs and endocrine systems. Pancreatic islet β cells secrete insulin in response to nutrient stimuli, and insulin then travels through the circulation promoting glucose uptake into insulin-responsive tissues such as liver, skeletal muscle and adipose. Many of the genes identified in human genome-wide association studies of diabetic individuals are directly associated with β cell survival and function, giving credence to the idea that β-cell dysfunction is central to the development of type 2 diabetes. As such, investigations into the mechanisms by which β cells sense glucose and secrete insulin in a regulated manner are a major focus of current diabetes research. In particular, recent discoveries of the detailed role and requirements for reorganization/remodeling of filamentous actin (F-actin) in the regulation of insulin release from the β cell have appeared at the forefront of islet function research, having lapsed in prior years due to technical limitations. Recent advances in live-cell imaging and specialized reagents have revealed localized F-actin remodeling to be a requisite for the normal biphasic pattern of nutrient-stimulated insulin secretion. This review will provide an historical look at the emergent focus on the role of the actin cytoskeleton and its regulation of insulin secretion, leading up to the cutting-edge research in progress in the field today. © 2013 KSBMB.

Ko C.H.,University of Texas Southwestern Medical Center
PLoS biology | Year: 2010

Bmal1 is an essential transcriptional activator within the mammalian circadian clock. We report here that the suprachiasmatic nucleus (SCN) of Bmal1-null mutant mice, unexpectedly, generates stochastic oscillations with periods that overlap the circadian range. Dissociated SCN neurons expressed fluctuating levels of PER2 detected by bioluminescence imaging but could not generate circadian oscillations intrinsically. Inhibition of intercellular communication or cyclic-AMP signaling in SCN slices, which provide a positive feed-forward signal to drive the intracellular negative feedback loop, abolished the stochastic oscillations. Propagation of this feed-forward signal between SCN neurons then promotes quasi-circadian oscillations that arise as an emergent property of the SCN network. Experimental analysis and mathematical modeling argue that both intercellular coupling and molecular noise are required for the stochastic rhythms, providing a novel biological example of noise-induced oscillations. The emergence of stochastic circadian oscillations from the SCN network in the absence of cell-autonomous circadian oscillatory function highlights a previously unrecognized level of circadian organization.

Byrd H.S.,University of Texas Southwestern Medical Center
Plastic and Reconstructive Surgery | Year: 2010

Background: A review of a single physician's experience in managing over 831 infant ear deformities (488 patients) is presented. Methods: The authors' methods of molding have advanced from the use of various tapes, glues, and stents, to a comprehensive yet simple system that shapes the antihelix, the triangular fossa, the helical rim, and the overly prominent conchal-mastoid angle (EarWell Infant Ear Correction System). Results: The types of deformities managed, and their relative occurrence, are as follows: (1) prominent/cup ear, 373 ears (45 percent); (2) lidding/lop ear, 224 ears (27 percent); (3) mixed ear deformities, 83 ears (10 percent) (all had associated conchal crus); (4) Stahl's ear, 66 ears (8 percent); (5) helical rim abnormalities, 58 ears (7 percent); (6) conchal crus, 25 ears (3 percent); and (7) cryptotia, two ears (0.2 percent). Bilateral deformities were present in 340 patients (70 percent), with unilateral deformities in 148 patients (30 percent). Fifty-eight infant ears (34 patients) were treated using the final version of the EarWell Infant Ear Correction System with a success rate exceeding 90 percent (good to excellent results). The system was found to be most successful when begun in the first week of the infant's life. When molding was initiated after 3 weeks from birth, only approximately half of the infants had a good response. Conclusions: Congenital ear deformities are common and only approximately 30 percent self-correct. These deformities can be corrected by initiating appropriate molding in the first week of life. Neonatal molding reduces the need for surgical correction with results that often exceed what can be achieved with the surgical alternative. Copyright © 2010 by the American Society of Plastic Surgeons.

Goldstein J.L.,NorthShore University Health System | Cryer B.,University of Texas Southwestern Medical Center
Drug, Healthcare and Patient Safety | Year: 2015

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective anti-inflammatory and analgesic agents and are among the most commonly used classes of medications worldwide. However, their use has been associated with potentially serious dose-dependent gastrointestinal (GI) complications such as upper GI bleeding. GI complications resulting from NSAID use are among the most common drug side effects in the United States, due to the widespread use of NSAIDs. The risk of upper GI complications can occur even with short-term NSAID use, and the rate of events is linear over time with continued use. Although gastroprotective therapies are available, they are underused, and patient and physician awareness and recognition of some of the factors influencing the development of NSAID-related upper GI complications are limited. Herein, we present a case report of a patient experiencing a gastric ulcer following NSAID use and examine some of the risk factors and potential strategies for prevention of upper GI mucosal injuries and associated bleeding following NSAID use. These risk factors include advanced age, previous history of GI injury, and concurrent use of medications such as anticoagulants, aspirin, corticosteroids, and selective serotonin reuptake inhibitors. Strategies for prevention of GI injuries include anti-secretory agents, gastroprotective agents, alternative NSAID formulations, and nonpharmacologic therapies. Greater awareness of the risk factors and potential therapies for GI complications resulting from NSAID use could help improve outcomes for patients requiring NSAID treatment. © 2015 Goldstein and Cryer.

Chen Y.,University of Texas Southwestern Medical Center
Respiratory research | Year: 2012

Distal alveolar morphogenesis is marked by differentiation of alveolar type (AT)-II to AT-I cells that give rise to the primary site of gas exchange, the alveolar/vascular interface. Endothelial-Monocyte Activating Polypeptide (EMAP) II, an endogenous protein with anti-angiogenic properties, profoundly disrupts distal lung neovascularization and alveolar formation during lung morphogenesis, and is robustly expressed in the dysplastic alveolar regions of infants with Bronchopulmonary dysplasia. Determination as to whether EMAP II has a direct or indirect affect on ATII → ATI trans-differentiation has not been explored. In a controlled nonvascular environment, an in vitro model of ATII → ATI cell trans-differentiation was utilized to demonstrate the contribution that one vascular mediator has on distal epithelial cell differentiation. Here, we show that EMAP II significantly blocked ATII → ATI cell transdifferentiation by increasing cellular apoptosis and inhibiting expression of ATI markers. Moreover, EMAP II-treated ATII cells displayed myofibroblast characteristics, including elevated cellular proliferation, increased actin cytoskeleton stress fibers and Rho-GTPase activity, and increased nuclear:cytoplasmic volume. However, EMAP II-treated cells did not express the myofibroblast markers desmin or αSMA. Our findings demonstrate that EMAP II interferes with ATII → ATI transdifferentiation resulting in a proliferating non-myofibroblast cell. These data identify the transdifferentiating alveolar cell as a possible target for EMAP II's induction of alveolar dysplasia.

Buchanan G.R.,University of Texas Southwestern Medical Center
Blood | Year: 2014

In this issue of Blood, Steinberg et al describe the clinical importance of the distribution or "packaging" of fetal hemoglobin (HbF) within erythrocytes of persons with sickle cell anemia. © 2014 by The American Society of Hematology.

Hutcheson J.,University of Texas Southwestern Medical Center
Cytokine | Year: 2015

Over the past few decades, our understanding of the role of adipose tissue has changed dramatically. Far from simply being a site of energy storage or a modulator of the endocrine system, adipose tissue has emerged as an important regulator of multiple important processes including inflammation. Adipokines are a diverse family of soluble mediators with a range of specific actions on the immune response. Autoimmune diseases are perpetuated by chronic inflammatory responses but the exact etiology of these diseases remains elusive. While researchers continue to investigate these causes, millions of people continue to suffer from chronic diseases. To this end, an increased interest has developed in the connection between adipose tissue-secreted proteins that influence inflammation and the onset and perpetuation of autoimmunity. This review will focus on recent advances in adipokine research with specific attention on a subset of adipokines that have been associated with autoimmune diseases. © 2015 Elsevier Ltd.

Zuzak K.J.,University of Texas Southwestern Medical Center
Analytical chemistry | Year: 2011

We report use of a novel hyperspectral imaging system utilizing digital light processing (DLP) technology to noninvasively visualize in vivo tissue oxygenation during surgical procedures. The system's novelty resides in its method of illuminating tissue with precisely predetermined continuous complex spectra. The Texas Instruments digital micromirror device, DMD, chip consisting of 768 by 1024 mirrors, each 16 μm square, can be switched between two positions at 12.5 kHz. Switching the appropriate mirrors controls the intensity of light illuminating the tissue as a function of wavelength, active spectral illumination. Meaning, the tissue can be illuminated with a different spectrum of light within 80 μs. Precisely, predetermined spectral illumination penetrates into patient tissue, its chemical composition augments the spectral properties of the light, and its reflected spectra are detected and digitized at each pixel detector of a silicon charge-coupled device, CCD. Using complex spectral illumination, digital signal processing and chemometric methods produce chemically relevant images at near video rates. Specific to this work, tissue is illuminated spectrally with light spanning the visible electromagnetic spectrum (380 to 780 nm). Spectrophotometric images are detected and processed visualizing the percentage of oxyhemoglobin at each pixel detector and presented continuously, in real time, at 3 images per second. As a proof of principle application, kidneys of four live anesthetized pigs were imaged before, during, and after renal vascular occlusion. DLP Hyperspectral Imaging with active spectral illumination detected a 64.73 ± 1.5% drop in the oxygenation of hemoglobin within 30 s of renal arterial occlusion. Producing chemically encoded images at near video rate, time-resolved hyperspectral imaging facilitates monitoring renal blood flow during animal surgery and holds considerable promise for doing the same during human surgical interventions.

Janis J.E.,University of Texas Southwestern Medical Center
Plastic and Reconstructive Surgery | Year: 2010

Background: Clinical experience with surgical decompression of specific peripheral nerves in the head and neck for the relief of migraine headache symptoms has proven to be effective in most patients. Some patients, however, continue to have residual symptoms after these procedures. In an effort to better understand potential etiologies for failure of treatment, an investigation was performed to determine whether or not vascular-mediated peripheral trigger points exist that have heretofore been undescribed that may be contributing to persistent symptomatology. One such potential trigger point is the superficial temporal artery's interaction with the auriculotemporal nerve. A cadaveric investigation was performed to advance this anatomical understanding of this relationship. Methods: Both sides of 25 fresh cadaveric heads were dissected in the preauricular and temporal regions. The superficial temporal artery and auriculotemporal nerve were identified and dissected both proximally and distally. Their relationship was examined, and a topographical map of their intersections was generated. Results: The auriculotemporal nerve and superficial temporal artery run together in the superficial soft tissue in the preauricular and temple regions. A contiguous relationship between the two was found in 17 hemiheads (34.0 percent). Conclusions: There are variations in the relationship between the auriculotemporal nerve and the superficial temporal artery. These variations may serve as an anatomical explanation for this point as a source of migraine headaches in some patients. A topographical map of the relationship between these two structures may serve as a guide for surgeons interested in decompressing the nerve from the artery when indicated. Copyright © 2010 by the American Society of Plastic Surgeons.

Liu P.,University of Texas Southwestern Medical Center
Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine | Year: 2011

A major difference between arterial-spin-labeling MRI and gold-standard radiotracer blood flow methods is that the compartment localization of the labeled spins in the arterial-spin-labeling image is often ambiguous, which may affect the quantification of cerebral blood flow. In this study, we aim to probe whether the spins are located in the vascular system or tissue by using T2 of the arterial-spin-labeling signal as a marker. We combined two recently developed techniques, pseudo-continuous arterial spin labeling and T2-Relaxation-Under-Spin-Tagging, to determine the T2 of the labeled spins at multiple postlabeling delay times. Our data suggest that the labeled spins first showed the T2 of arterial blood followed by gradually approaching and stabilizing at the tissue T2. The T2 values did not decrease further toward the venous T2. By fitting the experimental data to a two-compartment model, we estimated gray matter cerebral blood flow, arterial transit time, and tissue transit time to be 74.0 ± 10.7 mL/100g/min (mean ± SD, N = 10), 938 ± 156 msec, and 1901 ± 181 msec, respectively. The arterial blood volume was calculated to be 1.18 ± 0.21 mL/100 g. A postlabeling delay time of 2 s is sufficient to allow the spins to completely enter the tissue space for gray matter but not for white matter. © 2010 Wiley-Liss, Inc.

Camp M.E.,University of Texas Southwestern Medical Center
Current Opinion in Psychiatry | Year: 2011

PURPOSE OF REVIEW: The role of religion and spirituality in psychiatric practice has long been a topic of discussion among mental health providers, patients, and faith communities. This review examines the recent findings in the literature that shape current dialogues on this topic and provide implications for patient care. RECENT FINDINGS: An increasing body of evidence correlates certain aspects of religion/spirituality with mental and physical health outcomes, and researchers continue to explore how and when psychiatrists should intervene in matters of faith. As this topic is inherently multidisciplinary, many encourage approaches that incorporate neurobiology, faith, and psychology for enhanced understanding of patient experience. Many also stress the importance of effective interpersonal communication between providers and patients, using a person-centered framework. In all of these dialogues, implications for patient care are highlighted. SUMMARY: The proper role of religion and spirituality in psychiatry continues as a matter of debate. However, current publications attempt to clarify issues that may lead to more evidence-based and empathic care in this area. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Yek C.,University of Texas Southwestern Medical Center
AIDS | Year: 2016

OBJECTIVES:: Curative strategies using agents to perturb the HIV reservoir have demonstrated only modest activity, whereas increases in viremia after standard vaccination have been described. We investigated whether vaccination against non-HIV pathogens can induce HIV transcription and thereby play a role in future eradication strategies. DESIGN:: A randomized controlled trial (NCT00329251) was performed to compare the effects of clinical vaccines to placebo on HIV transcription and immune activation. METHODS:: Twenty-six HIV-infected individuals on suppressive ART were randomized to receive a vaccination schedule (n?=?13) or placebo (n?=?13). Cell-associated RNA (ca-RNA) and DNA were extracted from peripheral blood mononuclear cells and HIV was quantified by droplet digital PCR using primers for gag and 2-LTR (for HIV DNA), unspliced gag RNA (gag usRNA), multispliced tat-rev RNA (tat-rev msRNA) and polyA mRNA. RESULTS:: Significant increases in gag usRNA after influenza/hepatitis B vaccination (p?=?0.02) and in gag usRNA (p?=?0.04) and polyA mRNA (p?=?0.04) after pneumococcus/hepatitis B vaccination were seen in vaccinees but not controls. HIV DNA and plasma HIV RNA did not change in either group. Increases in CD4 and CD8 T-cell activation markers (p?=?0.08 and p?

Ram C.V.S.,University of Texas Southwestern Medical Center
Vascular Health and Risk Management | Year: 2011

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have shown cardioprotective and renoprotective properties. These agents are recommended as first-line therapy for the treatment of hypertension and the reduction of cardiovascular risk. Early studies pointed to the cardioprotective and renoprotective effects of ARBs in high-risk patients. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) established the clinical equivalence of the cardioprotective and renoprotective effects of telmisartan and ramipril, but did not find an added benefit of the combination over ramipril alone. Similar findings were observed in the Telmisartan Randomized AssessmeNt Study in aCE INtolerant subjects with cardiovascular Disease (TRANSCEND) trial conducted in ACEI-intolerant patients. In ONTARGET, telmisartan had a better tolerability profile with similar renoprotective properties compared with ramipril, suggesting a potential clinical benefit over ramipril. The recently completed Olmesartan Reducing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial (ORIENT) and Olmesartan and Calcium Antagonists Randomized (OSCAR) studies will further define the role of ARBs in cardioprotection and renoprotection for high-risk patients. © 2011 Ram, publisher and licensee Dove Medical Press Ltd.

Baek H.-M.,University of Texas Southwestern Medical Center
The Scientific World Journal | Year: 2012

The purpose of this study was to investigate the usefulness of quantitative proton magnetic resonance spectroscopy (1H-MRS) for characterizing breast lesions at 1.5T, and to evaluate the diagnostic performance of in vivo breast 1H-MRS using receiver operating characteristics (ROC) analysis. 112 patients (99 malignant and 13 benign tumors) who were scanned with the MRI/MRS protocol were included in this study. Choline-containing compounds (tCho) levels were measured and compared with histological findings. The measured tCho levels in this work had range of 0.08-9.99mmol/kg from 65 (66) of 99 patients with malignant tumors. Of the 13 benign lesions, 1H-MRS detected one as false positive, with tCho level of 0.66mmol/kg. The optimal tCho level cutoff point that yielded the highest accuracy was found to be 0.0mmol/kg. The resulting sensitivity was 66 and specificity 92 for distinguishing benign from malignant lesions. The tCho levels were found to be higher in invasive cancer compared to ductal carcinoma in situ or benign lesions, possibly associated with more aggressive behavior or faster cell replication in invasive cancer. Quantitative in vivo1H-MRS may provide useful information for characterizing histopatholoigical types in breast cancer. Copyright © 2012 Hyeon-Man Baek.

Ram C.V.S.,University of Texas Southwestern Medical Center
Expert Review of Cardiovascular Therapy | Year: 2011

Hypertension is an increasingly prevalent cardiovascular risk factor associated with high rates of morbidity and mortality. Lowering blood pressure (BP) to recommended levels reduces the risk of hypertension-associated cardiovascular events. Despite current treatment options and recommendations, the BP of many patients remains suboptimally controlled. There is a need for more effective management in patients not achieving BP goals on current monotherapy or combination therapy. Regimens combining three or more antihypertensive agents have been shown to increase the proportion of patients achieving BP goals. Recent data suggest that the combination of olmesartan medoxomil, amlodipine and hydrochlorothiazide is a rational treatment option offering safe and effective BP reductions and goal attainment in a greater proportion of patients compared with dual-combination regimens. As the understanding of the importance of BP control grows, treatment options that enable patients to achieve BP goals quickly and safely will become increasingly important in hypertension management. © 2011 Expert Reviews Ltd.

Asterholm I.W.,University of Texas at Dallas | Scherer P.E.,University of Texas at Dallas | Scherer P.E.,University of Texas Southwestern Medical Center
American Journal of Pathology | Year: 2010

Metabolically healthy individuals effectively adapt to changes in nutritional state. Here, we focus on the effects of the adipocyte-derived secretory molecule adiponectin on adipose tissue in mouse models with genetically altered adiponectin levels. We found that higher adiponectin levels increased sensitivity to the lipolytic effects of adrenergic receptor agonists. In parallel, adiponectin-overexpressing mice also display enhanced clearance of circulating fatty acids and increased expansion of subcutaneous adipose tissue with chronic high fat diet (HFD) feeding. These adaptive changes to the HFD were associated with increased mitochondrial density in adipocytes, smaller adipocyte size, and a general transcriptional up-regulation of factors involved in lipid storage through efficient esterification of free fatty acids. The physiological response to adiponectin overexpression resembles in many ways the effects of chronic exposure to β3-adrenergic agonist treatment, which also results in improvements in insulin sensitivity. In addition, using a novel computed tomography-based method for measurements of hepatic lipids , we resolved the temporal events taking place in the liver in response to acute HFD exposure in both wild-type and adiponectin-overexpressing mice. Increased levels of adiponectin potently protect against HFD-induced hepatic lipid accumulation and preserve insulin sensitivity. Given these profound effects of adiponectin, we propose that adiponectin is a factor that increases the metabolic flexibility of adipose tissue, enhancing its ability to maintain proper function under metabolically challenging conditions. Copyright © American Society for Investigative Pathology.

Bulut G.B.,University of Texas Southwestern Medical Center
Blood | Year: 2013

Erythropoietin (Epo) binding to the Epo receptor (EpoR) elicits downstream signaling that is essential for red blood cell production. One important negative regulatory mechanism to terminate Epo signaling is Epo-induced EpoR endocytosis and degradation. Defects in this mechanism play a key role in the overproduction of erythrocytes in primary familial and congenital polycythemia (PFCP). Here we have identified a novel mechanism mediating Epo-dependent EpoR internalization. Epo induces Cbl-dependent ubiquitination of the p85 regulatory subunit of PI3K, which binds to phosphotyrosines on EpoR. Ubiquitination allows p85 to interact with the endocytic protein epsin-1, thereby driving EpoR endocytosis. Knockdown of Cbl, expression of its dominant negative forms, or expression of an epsin-1 mutant devoid of ubiquitin-interacting motifs all compromise Epo-induced EpoR internalization. Mutated EpoRs mimicking those from PFCP patients cannot bind p85, co-localize with epsin-1, or internalize on Epo stimulation and exhibit Epo hypersensitivity. Similarly, knockdown of Cbl also causes Epo hypersensitivity in primary erythroid progenitors. Restoring p85 binding to PFCP receptors rescues Epo-induced epsin-1 co-localization and EpoR internalization and normalizes Epo hypersensitivity. Our results uncover a novel Cbl/p85/epsin-1 pathway in EpoR endocytosis and show that defects in this pathway contribute to excessive Epo signaling and erythroid hyperproliferation in PFCP.

Maalouf N.M.,University of Texas Southwestern Medical Center
Journal of Renal Nutrition | Year: 2011

Uric acid stones are significantly more common among nephrolithiasis patients with type 2 diabetes, obesity, and/or the metabolic syndrome. The principal metabolic feature responsible for this association is an overly acidic urine, which leads to the precipitation of sparingly soluble uric acid crystals in urine and subsequent development of stones. The unduly acidic urine in uric acid stone formers is caused by a combination of excessive dietary intake of animal proteins and a defect in renal ammoniagenesis and/or excretion that leads to impaired buffering and amplifies the acidic urine caused by an increased acid excretion. © 2011 National Kidney Foundation, Inc.

Auchus R.J.,University of Texas Southwestern Medical Center
Endocrine Development | Year: 2011

Adrenarche refers to the rise in adrenal 19-carbon steroid production, primarily dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Adrenarche, which occurs only in humans and a few higher primates, is independent of puberty and manifests clinically as the appearance of axillary and pubic hair, usually about age 8. The physiologic correlate of adrenarche is the development of the adrenal zona reticularis, which has many of the biochemical properties of the fetal adrenal. Recentstudies have shown that adrenarche is not an abrupt and 'signaled' process occurring in mid childhood but rather a continuous process since birth. In addition, some differences in gene expression between the zona reticularis and the fetal adrenal gland have begun to emerge. The purpose of adrenarche in human physiology remains enigmatic, although disease states associated with abnormalities in DHEA(S) production provide some clues. Copyright © 2011 S. Karger AG, Basel.

Olson E.N.,University of Texas Southwestern Medical Center | Nordheim A.,University of Tubingen
Nature Reviews Molecular Cell Biology | Year: 2010

Numerous physiological and pathological stimuli promote the rearrangement of the actin cytoskeleton, thereby modulating cellular motile functions. Although it seems intuitively obvious that cell motility requires coordinated protein biosynthesis, until recently the linkage between cytoskeletal actin dynamics and correlated gene activities remained unknown. This knowledge gap was filled in part by the discovery that globular actin polymerization liberates myocardin-related transcription factor (MRTF) cofactors, thereby inducing the nuclear transcription factor serum response factor (SRF) to modulate the expression of genes encoding structural and regulatory effectors of actin dynamics. This insight stimulated research to better understand the actinĝ€"MRTFĝ€"SRF circuit and to identify alternative mechanisms that link cytoskeletal dynamics and genome activity. © 2010 Macmillan Publishers Limited. All rights reserved.

Punaro M.,University of Texas Southwestern Medical Center
Journal of the American Academy of Orthopaedic Surgeons | Year: 2011

Juvenile idiopathic arthritis, formerly known as juvenile rheumatoid arthritis, is a heterogeneous group of diseases characterized by onset of chronic arthritis in childhood. Diagnosis requires onset of disease by age 16 years, persistent arthritis in any joint for ≥6 weeks, and exclusion of other conditions that cause arthritis (eg, infection, malignancy, acute rheumatic fever, inflammatory bowel disease). Most patients with juvenile idiopathic arthritis present with subacute arthritis with minimal pain and few constitutional symptoms. Laboratory evaluation and imaging are useful to exclude other diagnoses and establish the presence of systemic inflammation. However, these modalities are of limited value in screening for rheumatic diseases, and they may be misleading because of the high rate of false-positive results. Most rheumatologic conditions are diagnosed based on pattern recognition, which is established with a thorough history and physical examination. Copyright 2011 by the American Academy of Orthopaedic Surgeons.

Attanasio M.,University of Texas Southwestern Medical Center
Pediatric Nephrology | Year: 2011

Nephrolithiasis is a cause of significant morbidity and medical care expenses worldwide. Its prevalence has increased steadily during the last three decades among both adults and children. This trend suggests that changing environmental factors play a significant role in the risk of developing kidney stones although, conversely, there are many indications that genes play an important role in this condition as well. A limited number of monogenic forms have been identified, but the majority of nephrolithiasis cases are the result of complex, multi-factorial interactions between genetic inheritance and environmental exposure. Scientific evidence indicates that inheritance accounts for about half of the risk of common forms, making these forms suitable for investigation by genetic analysis. Here, we review the numerous studies that have been conducted to establish the role of genes in determining the risk of nephrolithiasis, the differential contribution of genes to this risk, and the confounding influence that environmental variables have on genetic studies. © 2010 IPNA.

Lambracht-Washington D.,University of Texas Southwestern Medical Center
Cellular and molecular neurobiology | Year: 2011

The pathogenesis of Alzheimer's disease (AD) has been strongly associated with the accumulation of amyloid beta (Aβ) peptides in brain, and immunotherapy targeting Aβ provides potential for AD prevention. A clinical trial in which AD patients were immunized with Aβ42 peptide was stopped when 6% of participants showed meningoencephalitis, apparently due to an inflammatory Th1 immune response. Previously, we and other have shown that Aβ42 DNA vaccination via gene gun generates a Th2 cellular immune response, which was shown by analyses of the respective antibody isotype profiles. We also determined that in vitro T cell proliferation in response to Aβ42 peptide re-stimulation was absent in DNA Aβ42 trimer-immunized mice when compared to Aβ42 peptide-immunized mice. To further characterize this observation prospectively and longitudinally, we analyzed the immune response in wild-type mice after vaccination with Aβ42 trimer DNA and Aβ42 peptide with Quil A adjuvant. Wild-type mice were immunized with short-term (1-3× vaccinations) or long-term (6× vacinations) immunization strategies. Antibody titers and isotype profiles of the Aβ42 specific antibodies, as well as cytokine profiles and cell proliferation studies from this longitudinal study were determined. Sufficient antibody titers to effectively reduce Aβ42, but an absent T cell proliferative response and no IFNγ or IL-17 secretion after Aβ42 DNA trimer immunization minimizes the risk of inflammatory activities of the immune system towards the self antigen Aβ42 in brain. Therefore, Aβ42 DNA trimer immunization has a high probability to be effective and safe to treat patients with early AD.

Inrig J.K.,University of Texas Southwestern Medical Center
American Journal of Kidney Diseases | Year: 2010

Intradialytic hypertension, defined as an increase in blood pressure during or immediately after hemodialysis that results in postdialysis hypertension, has long been recognized to complicate the hemodialysis procedure, yet often is largely ignored. In light of recent investigations suggesting that intradialytic hypertension is associated with adverse outcomes, this review broadly covers the epidemiologic characteristics, prognostic significance, potential pathogenic mechanisms, prevention, and possible treatment of intradialytic hypertension. Intradialytic hypertension affects up to 15% of hemodialysis patients and occurs more frequently in patients who are older, have lower dry weights, are prescribed more antihypertensive medications, and have lower serum creatinine levels. Recent studies associated intradialytic hypertension independently with higher hospitalization rates and decreased survival. Although the pathophysiologic mechanisms of intradialytic hypertension are uncertain, it likely is multifactorial and includes subclinical volume overload, sympathetic overactivity, activation of the renin-angiotensin system, endothelial cell dysfunction, and specific dialytic techniques. Prevention and treatment of intradialytic hypertension may include careful attention to dry weight, avoidance of dialyzable antihypertensive medications, limiting the use of high-calcium dialysate, achieving adequate sodium solute removal during hemodialysis, and using medications that inhibit the renin-angiotensin-aldosterone system or decrease endothelin 1 levels. In summary, although intradialytic hypertension often is underappreciated, recent studies suggest that it should not be ignored. However, further work is necessary to elucidate the pathophysiologic mechanisms of intradialytic hypertension and its appropriate management and determine whether treatment of intradialytic hypertension can improve clinical outcomes. © 2010 National Kidney Foundation, Inc.

Wells C.E.,University of Texas Southwestern Medical Center
Seminars in Perinatology | Year: 2010

This survey was conducted to assess physician opinion regarding vaginal birth after cesarean delivery (VBAC) and to examine how physician and hospital characteristics influence the private obstetrical provider's decision to offer or not to offer trial of labor after cesarean delivery. A confidential postal survey of private practicing obstetricians in the Dallas-Ft. Worth Region (n = 774) of North Texas. Of 774 obstetrician-gynecologists, 458 completed and returned the survey for a response rate of 59%. The survey revealed that 52% of respondents offer VBAC to their patients and indicated that the most common reasons for declining use or discontinuation of VBAC were maternal-fetal safety concerns associated with uterine rupture followed by medico-legal liability concerns. Factors associated with physicians not providing VBAC for their patients were physicians in obstetrical practice <10 years, a physician's previous involvement in the care of women with uterine rupture complicated by maternal or neonatal complications, and a physician's previous involvement in cesarean delivery-related medical malpractice litigation. © 2010 Elsevier Inc.

Rockey D.C.,University of Texas Southwestern Medical Center
Gastroenterology Clinics of North America | Year: 2010

Computed tomographic (CT) colonography is a noninvasive method to evaluate the colon and has received considerable attention in the last decade as a colon-imaging tool. The technique has also been proposed as a potential primary colon cancer-screening method in the United States. The accuracy of the technique for the detection of large lesions seems to be high, perhaps in the range of colonoscopy. Overall, the field is rapidly evolving. Available data suggest that CT colonography, although a viable colon cancer screening modality in the United States, is not ready for widespread implementation, largely because of the lack of standards for training and reading and the limited number of skilled readers. © 2010 Elsevier Inc.

Claassen J.A.H.R.,Radboud University Nijmegen | Zhang R.,University of Texas Southwestern Medical Center
Journal of Cerebral Blood Flow and Metabolism | Year: 2011

Cerebral autoregulation aims to stabilize blood flow to the brain during variations in perfusion pressure, thus protecting the brain against the risks of low or high systemic blood pressure. This vital mechanism is severely impaired in the transgenic mouse model of Alzheimer's disease (AD) that abundantly produces amyloid-Β peptide Β 1-42. These observations have been extrapolated to human AD, wherein impairment of autoregulation could have important implications for the clinical management and prevention of AD. Research on cerebral autoregulation in human AD, however, has only recently become available. Contrary to the animal models, preliminary studies suggest that cerebral autoregulation is preserved in patients with AD. Further research is urgently needed to elucidate this discrepancy in the current literature, given the accumulating evidence that implicates cerebrovascular pathology in AD. © 2011 ISCBFM All rights reserved.

Choudhury D.,University of Texas Southwestern Medical Center | Levi M.,University of Colorado at Denver
Nature Reviews Nephrology | Year: 2011

The aging process affects all organs, including the kidneys. As part of this process, progressive scarring and a measurable decline in renal function occur in most people over time. The improved understanding of the processes that can lead to and/or hasten scarring and loss of renal function over time parallels advances in our understanding of the aging process. Clinical factors, including hypertension, diabetes mellitus, obesity, abnormal lipid levels and vitamin D deficiency, have been associated with increasing renal sclerosis with age. In addition, tissue factors such as angiotensin II, advanced glycation end products, oxidative stress and Klotho are associated with renal aging. These associations and possible interventions, including the control of blood pressure, blood sugar, weight, diet and calorie restriction might make renal aging more preventable than inevitable. © 2011 Macmillan Publishers Limited. All rights reserved.

Spechler S.J.,University of Texas Southwestern Medical Center | Spechler S.J.,Dallas Medical Center
Digestive Diseases | Year: 2013

The American Gastroenterological Association (AGA) defines Barrett's esophagus as the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the squamous epithelium that normally lines the distal esophagus. Although cardiac mucosa may be metaplastic, its malignant predisposition is not clear, and the AGA still requires the demonstration of intestinal metaplasia (with goblet cells) for a diagnosis of Barrett's esophagus. The AGA generally recommends endoscopic eradication therapy for patients with high-grade dysplasia, who otherwise develop esophageal adenocarcinoma at the rate of 6% per year. Endoscopic therapy is often curative for mucosal neoplasms in Barrett's esophagus because the risk of lymph node metastases is only 1-2%. American gastroenterologists generally do not recommend endoscopic therapy for patients whose neoplasms involve any portion of the submucosa because of the high rate of lymph node metastases that has been described in these cases. The management of low-grade dysplasia is disputed because of poor agreement among pathologists on the diagnosis and because of contradictory data on the natural history, but the AGA recommends that radiofrequency ablation (RFA) should be a therapeutic option for patients with confirmed low-grade dysplasia in Barrett's esophagus. Arguments for using RFA to treat nondysplastic Barrett's metaplasia are based on the premise that RFA decreases cancer risk, but no study has established that premise. In the absence of definitive data, concerns about the frequency and importance of buried metaplastic glands and recurrent metaplasia should temper enthusiasm for treating nondysplastic Barrett's esophagus with RFA. © 2013 S. Karger AG, Basel.

Kim T.-K.,University of Texas Southwestern Medical Center | Hemberg M.,Boston Childrens Hospital | Gray J.M.,Harvard University
Cold Spring Harbor Perspectives in Biology | Year: 2015

Recent studies have revealed that active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs). eRNAs are distinct from long noncoding RNAs (lncRNAs), but these two species of noncoding RNAs may share a similar role in the activation of mRNA transcription. Emerging studies, showing that eRNAs function in controlling mRNA transcription, challenge the idea that enhancers are merely sites of transcription factor assembly. Instead, communicationbetween promoters andenhancers canbebidirectional with promoters required to activate enhancer transcription. Reciprocally, eRNAs may then facilitate enhancer–promoter interaction or activate promoter-driven transcription. © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

Friedberg E.C.,University of Texas Southwestern Medical Center
DNA Repair | Year: 2015

Photoreactivation, an enzyme-catalyzed reaction during which two covalently linked pyrimidine dimers in DNA are monomerized and restored to their native conformation was the first DNA repair mechanism to be discovered, an event that transpired in the late 1940's through the efforts of the American biologist Albert Kelner while at the Cold Spring Harbor Laboratories in upstate New York. The phenomenon was Independently observed by Renato Dulbecco shortly thereafter, then a post-doctoral fellow in Salvador Luria's Laboratory in Bloomington Indiana. However, Luria and Dulbecco yielded priority to Kelner's discovery. © 2015 Published by Elsevier B.V.

Kim T.-K.,University of Texas Southwestern Medical Center | Shiekhattar R.,University of Miami
Cell | Year: 2015

With the explosion of genome-wide studies of regulated transcription, it has become clear that traditional definitions of enhancers and promoters need to be revisited. These control elements can now be characterized in terms of their local and regional architecture, their regulatory components, including histone modifications and associated binding factors, and their functional contribution to transcription. This Review discusses unifying themes between promoters and enhancers in transcriptional regulatory mechanisms. © 2015 Elsevier Inc.

Lotan Y.,University of Texas Southwestern Medical Center
Current Opinion in Urology | Year: 2012

Purpose of Review: Utilization of robotic surgery has increased dramatically in recent years, but there are significant cost implications to acquisition and utilization of robots. This review will evaluate the cost-effectiveness of using robotics in urologic surgery. Recent Findings: This study will evaluate studies comparing outcomes for open, laparoscopic and robotic procedures as well as costs associated with these procedures. Summary: Current studies have not found the robotic approaches to be cost-effective. In order for the robot to be cost-effective, there needs to be an improvement in efficacy over alternative approaches and a decrease in costs of the robot or instrumentation. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Brickner M.E.,University of Texas Southwestern Medical Center
Circulation | Year: 2014

The population of adults with CHD continues to expand, and thus the number of women with CHD who contemplate pregnancy or become pregnant is also growing. Mothers with low-risk defects can be managed by general cardiologist, whereas those with more complex defects should be managed by or with the assistance of ACHD cardiologists. It is important to acknowledge that all patients with CHD may have unique anatomy or physiology, despite their classification as having a simple, moderate, or complex defect. As such, clinicians evaluating these patients should have adequate knowledge and expertise when assessing patient's risk for pregnancy, when performing imaging or hemodynamic studies, and when managing these patients during pregnancy. The American Board of Medical Specialties has recently recognized ACHD as a subspecialty of cardiovascular disease to treat the specialized needs of these patients in adulthood. ACHD experts can provide expertise in the management of specific defects or lesions, imaging techniques, prepregnancy risk assessment, and can manage these patients or comanage them with other medical providers during their pregnancy. Because many of these ACHD patients are lost to follow-up in adulthood, pregnancy represents a time when these patients seek medical care (and for some, represents a time of vulnerability and increased risk). This represents an opportunity to establish or reestablish care with ACHD specialists and to reestablish continuing long-term care for their CHD. Pregnancy also provides an opportunity to create partnerships between primary care physicians, adult cardiologists, and ACHD specialists to provide optimal care for these women throughout their lives.

Palmer B.F.,University of Texas Southwestern Medical Center
American Journal of Kidney Diseases | Year: 2010

Hyperkalemia generally is attributable to cell shifts or abnormal renal potassium excretion. Cell shifts account for transient increases in serum potassium levels, whereas sustained hyperkalemia generally is caused by decreased renal potassium excretion. Impaired renal potassium excretion can be caused by a primary decrease in distal sodium delivery, a primary decrease in mineralocorticoid level or activity, or abnormal cortical collecting duct function. Excessive potassium intake is an infrequent cause of hyperkalemia by itself, but can worsen the severity of hyperkalemia when renal excretion is impaired. Before concluding that a cell shift or renal defect in potassium excretion is present, pseudohyperkalemia should be excluded. © 2010 National Kidney Foundation, Inc.

Frost R.J.A.,University of Texas Southwestern Medical Center
Journal of Cardiovascular Translational Research | Year: 2010

Ischemic heart disease is a form of congestive heart failure that is caused by insufficient blood supply to the heart, resulting in a loss of viable tissue. In response to the injury, the non-ischemic myocardium displays signs of secondary remodeling, like interstitial fibrosis and hypertrophy of cardiac myocytes. This remodeling process further deteriorates pump function and increases susceptibility to arrhythmias. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression in a sequence-dependent manner. Recently, several groups identified miRNAs as crucial gene regulators in response to myocardial infarction (MI) and during post-MI remodeling. In this review, we discuss how modulation of these miRNAs represents a promising new therapeutic strategy to improve the clinical outcome in ischemic heart disease. © Springer Science+Business Media, LLC 2010.