Curtis D.J.,Royal Melbourne Hospital |
Jane S.M.,Royal Melbourne Hospital |
Brandt S.J.,Vanderbilt Ingram Cancer Center |
Brandt S.J.,VA Tennessee Valley Healthcare System
Molecular and Cellular Biology | Year: 2010
Monocytopoiesis involves the stepwise differentiation in the bone marrow (BM) of common myeloid precursors (CMPs) to monocytes. The basic helix-loop-helix transcription factor TAL1/SCL plays a critical role in other hematopoietic lineages, and while it had been reported to be expressed by BM-derived macrophages, its role in monocytopoiesis had not been elucidated. Using cell explant models of monocyte/macrophage (MM) differentiation, one originating with CMPs and the other from more committed precursors, we characterized the phenotypic and molecular consequences of inactivation of Tal1 expression ex vivo. While Tal1 knockout had minimal effects on cell survival and slightly accelerated terminal differentiation, it profoundly inhibited cell proliferation and decreased entry into and traversal of the G1 and S phases. In conjunction, steady-state levels of p16(Ink4a) mRNA were increased and those of Gata2 mRNA decreased. Chromatin immunoprecipitation analysis demonstrated the association of Tal1 and E47, one of its E protein DNA-binding partners, with an E box-GATA sequence element in intron 4 of the Gata2 gene and with three E boxes upstream of p16(Ink4a). Finally, wild-type Tal1, but not a DNA binding-defective mutant, rescued the proliferative defect in Tal1-null MM precursors. These results document the importance of this transcription factor in cell cycle progression and proliferation during monocytopoiesis and the requirement for direct DNA binding in these processes. Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Smalley-Freed W.G.,Vanderbilt University |
Efimov A.,Vanderbilt University |
Burnett P.E.,Vanderbilt University |
Burnett P.E.,VA Tennessee Valley Healthcare System |
And 7 more authors.
Journal of Clinical Investigation | Year: 2010
Epithelial-cadherin (E-cadherin) is a master organizer of the epithelial phenotype. Its function is regulated in part by p120-catenin (referred to herein as p120), a cytoplasmic binding partner that directly regulates cadherin stability. As it has been suggested that cadherins have a role in inflammatory bowel disease (IBD), we sought to investigate this further by assessing the effect of p120 deficiency in mouse small intestine and colon. p120 conditional KO mice were superficially normal at birth but declined rapidly and died within 21 days. Cell-cell adhesion defects and inflammation led to progressive mucosal erosion and terminal bleeding, similar to what is observed in a dominant-negative cadherin mouse model of IBD. Additionally, selective loss of adherens junctions and accumulation of atypical COX-2-expressing neutrophils in p120-null areas of the colon were observed. To elucidate the mechanism, direct effects of p120 deficiency were assessed in vitro in a polarizing colon cancer cell line. Notably, transepithelial electrical resistance was dramatically reduced, neutrophil binding was increased 30 fold, and levels of COX-2, an enzyme associated with IBD, were markedly increased in neutrophils. Our data suggest that p120 loss disrupts the neonatal intestinal barrier and amplifies neutrophil engagement and that these changes lead to catastrophic inflammation during colonization of the neonatal gut with bacteria and other luminal antigens. Thus, we conclude that p120 has an essential role in barrier function and epithelial homeostasis and survival in the intestine.
Wise E.S.,Vanderbilt University |
Hocking K.M.,Vanderbilt University |
Brophy C.M.,Vanderbilt University |
Brophy C.M.,VA Tennessee Valley Healthcare System
Journal of Vascular Surgery | Year: 2015
Objective Ruptured abdominal aortic aneurysm (rAAA) carries a high mortality rate, even with prompt transfer to a medical center. An artificial neural network (ANN) is a computational model that improves predictive ability through pattern recognition while continually adapting to new input data. The goal of this study was to effectively use ANN modeling to provide vascular surgeons a discriminant adjunct to assess the likelihood of in-hospital mortality on a pending rAAA admission using easily obtainable patient information from the field. Methods Of 332 total patients from a single institution from 1998 to 2013 who had attempted rAAA repair, 125 were reviewed for preoperative factors associated with in-hospital mortality; 108 patients received an open operation, and 17 patients received endovascular repair. Five variables were found significant on multivariate analysis (P <.05), and four of these five (preoperative shock, loss of consciousness, cardiac arrest, and age) were modeled by multiple logistic regression and an ANN. These predictive models were compared against the Glasgow Aneurysm Score. All models were assessed by generation of receiver operating characteristic curves and actual vs predicted outcomes plots, with area under the curve and Pearson r2 value as the primary measures of discriminant ability. Results Of the 125 patients, 53 (42%) did not survive to discharge. Five preoperative factors were significant (P <.05) independent predictors of in-hospital mortality in multivariate analysis: advanced age, renal disease, loss of consciousness, cardiac arrest, and shock, although renal disease was excluded from the models. The sequential accumulation of zero to four of these risk factors progressively increased overall mortality rate, from 11% to 16% to 44% to 76% to 89% (age ≥ 70 years considered a risk factor). Algorithms derived from multiple logistic regression, ANN, and Glasgow Aneurysm Score models generated area under the curve values of 0.85 ± 0.04, 0.88 ± 0.04 (training set), and 0.77 ± 0.06 and Pearson r2 values of.36,.52 and.17, respectively. The ANN model represented the most discriminant of the three. Conclusions An ANN-based predictive model may represent a simple, useful, and highly discriminant adjunct to the vascular surgeon in accurately identifying those patients who may carry a high mortality risk from attempted repair of rAAA, using only easily definable preoperative variables. Although still requiring external validation, our model is available for demonstration at https://redcap.vanderbilt.edu/surveys/?s=NN97NM7DTK. © 2015 Society for Vascular Surgery.
Brissova M.,Vanderbilt University |
Aamodt K.,Vanderbilt University |
Brahmachary P.,Vanderbilt University |
Prasad N.,HudsonAlpha Institute for Biotechnology |
And 10 more authors.
Cell Metabolism | Year: 2014
Pancreatic islet endocrine cell and endothelial cell (EC) interactions mediated by vascular endothelial growth factor-A (VEGF-A) signaling are important for islet differentiation and the formation of highly vascularized islets. To dissect how VEGF-A signaling modulates intra-islet vasculature, islet microenvironment, and β cell mass, we transiently increased VEGF-A production by β cells. VEGF-A induction dramatically increased the number of intra-islet ECs but led to β cell loss. After withdrawal of the VEGF-A stimulus, β cell mass, function, and islet structure normalized as a result of a robust, but transient, burst in proliferation of pre-existing β cells. Bone marrow-derived macrophages (MΦs) recruited to the site of β cell injury were crucial for the β cell proliferation, which was independent of pancreatic location and circulating factors such as glucose. Identification of the signals responsible for the proliferation of adult, terminally differentiated β cells will improve strategies aimed at β cell regeneration and expansion. © 2014 Elsevier Inc.
Tustin A.,Vanderbilt University |
Kim S.J.,Vanderbilt University |
Chomsky A.,Vanderbilt University |
Chomsky A.,VA Tennessee Valley Healthcare System |
And 2 more authors.
Retina | Year: 2014
PURPOSE:: To determine whether the application of subconjunctival 2% lidocaine/0.1% methylparaben for anesthesia may reduce rates of endophthalmitis after intravitreal (IVT) injection. METHODS:: We performed in vitro experiments to determine the antibacterial properties of 2% lidocaine/0.1% methylparaben (lidocaine) against causative organisms of endophthalmitis. Isolates of Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus viridans from patients with endophthalmitis were incubated with or without lidocaine. Aliquots (100 μL) were plated on Mueller-Hinton (S. aureus and S. epidermidis) or blood agar plates (S. viridans) at 0, 10, 30, 120, and 240 minutes, and colonies were counted after 24 hours. A retrospective review of 15,042 IVT injections was performed from January 2004 to February 2011 to determine the rate of endophthalmitis with or without application of subconjunctival lidocaine for anesthesia. RESULTS:: Lidocaine demonstrated rapid bactericidal effects against all 3 organisms. After 10 minutes of exposure, there was approximately a 90% (P < 0.01), 95% (P < 0.001), and 92% (P < 0.001) reduction in colony forming units when compared with time 0 for S. aureus, S. epidermidis, and S. viridans, respectively. Complete elimination of colony forming units occurred at subsequent time points for each organism in contrast to logarithmic increase for control plates. There were a total of 0 cases of endophthalmitis of 6,853 IVT injections performed with subconjunctival lidocaine and 8 cases of endophthalmitis of 8,189 (0.1%) IVT injections performed with other methods of anesthesia (P = 0.03). CONCLUSION:: Application of subconjunctival 2% lidocaine/0.1% methylparaben for anesthesia may reduce the incidence of endophthalmitis after IVT injection. © by Opthamic Communication Society, Inc. Unauthorized reproduction of this article is prohibited.
Horch R.A.,Vanderbilt University |
Gochberg D.F.,Vanderbilt University |
Nyman J.S.,Vanderbilt University |
Nyman J.S.,VA Tennessee Valley Healthcare System |
Does M.D.,Vanderbilt University
PLoS ONE | Year: 2011
Recent advancements in magnetic resonance imaging (MRI) have enabled clinical imaging of human cortical bone, providing a potentially powerful new means for assessing bone health with molecular-scale sensitivities unavailable to conventional X-ray-based diagnostics. To this end, 1H nuclear magnetic resonance (NMR) and high-resolution X-ray signals from human cortical bone samples were correlated with mechanical properties of bone. Results showed that 1H NMR signals were better predictors of yield stress, peak stress, and pre-yield toughness than were the X-ray derived signals. These 1H NMR signals can, in principle, be extracted from clinical MRI, thus offering the potential for improved clinical assessment of fracture risk.
Kim E.H.,VA Tennessee Valley Healthcare System |
Hollon S.D.,Vanderbilt University |
Olatunji B.O.,Vanderbilt University
Psychotherapy | Year: 2016
Although cognitive-behavioral therapy (CBT) has been shown to be highly effective for a wide range of disorders, many patients do not benefit. The failure to fully benefit from CBT may be due to a wide range of factors, one of which includes "clinical errors" that often occur during the therapeutic process. We briefly note 4 such clinical errors including neglecting to conduct a detailed functional analysis of the presenting problem(s), not adequately engaging the patient in developing a case formulation for the purposes of treatment planning, getting wrapped up in simply examining beliefs without behavioral tests, and not holding patients accountable for fear of rupturing the therapeutic alliance. We then discuss the context in which these clinical errors may occur during CBT and highlight alternative approaches. Being mindful of these and other potential clinical errors during CBT may facilitate better treatment outcomes. © 2016 American Psychological Association.
Dai C.,Vanderbilt University |
Brissova M.,Vanderbilt University |
Hang Y.,Vanderbilt University |
Thompson C.,Vanderbilt University |
And 6 more authors.
Diabetologia | Year: 2012
Aims/hypothesis: Our understanding of the transcription factors that control the development and function of rodent islet beta cells is advancing rapidly, yet less is known of the role they play in similar processes in human islets. Methods: To characterise the abundance and regulation of key proteins involved in glucose-regulated insulin secretion in human islets, we examined the expression of MAFA, MAFB, GLUT2 (also known as SLC2A2), βGK (also known as GCK) and PDX1 in isolated, highly purified human islets with an intact insulin secretory pattern. We also assessed these features in islets from two different mouse strains (C57BL/6J and FVB). Results: Compared with mouse islets, human islets secreted more insulin at baseline glucose (5.6 mmol/l), but less upon stimulation with high glucose (16.7 mmol/l) or high glucose plus 3-isobutyl-1-methyl-xanthine. Human islets had relatively more MAFB than PDX1 mRNA, while mouse islets had relatively more Pdx1 than Mafb mRNA. However, v-maf musculoaponeurotic fibrosarcoma oncogene homologue (MAF) B protein was found in human islet alpha and beta cells. This is unusual as this regulator is only produced in islet alpha cells in adult mice. The expression of insulin, MAFA, βGK and PDX1 was not glucose-regulated in human islets with an intact insulin secretory pattern. Conclusions/interpretation: Our results suggest that human islets have a distinctive distribution and function of key regulators of the glucose-stimulated insulin secretion pathway, emphasising the urgent need to understand the processes that regulate human islet beta cell function. © 2011 The Author(s).
Baker J.W.,Anticoagulation and Traveling Veteran Clinics |
Pierce K.L.,Pharmacy Practice Resident PGY1 |
Ryals C.A.,VA Tennessee Valley Healthcare System
Journal of Managed Care Pharmacy | Year: 2011
Background: In January 2009, the Joint Commission implemented a National Patient Safety Goal (NPSG) for ambulatory care, NPSG 3E, intended to reduce harm associated with the use of anticoagulation therapy. The 2011 NPSG 3E encompasses 8 elements of performance, including requirements that each organization (a) provide education regarding anticoagulation therapy to staff, patients, and families and (b) evaluate its safety practices and take appropriate action to improve its practices. The Alvin C. York (ACY) outpatient anticoagulation clinic provides education to new patients and their families at the initial clinic visit, with follow-up reinforcement of education as needed throughout their care. Objectives: To (a) assess the knowledge level of patients receiving warfarin therapy in an anticoagulation clinic using the validated Anticoagulation Knowledge Assessment (AKA) questionnaire and (b) examine the relationship between patient anticoagulation knowledge and anticoagulation control as measured by the international normalized ratio (INR). Methods: All ACY Veterans Affairs (VA) anticoagulation clinic patients seen during their routine visit within an 8-week recruitment period from February 2010 to April 2010 were asked to complete the AKA questionnaire. Upon voluntary consent, the questionnaire was completed by the patient either during the clinic visit or returned later by mail. Demographic and clinical data were manually extracted from the computerized patient record system and included age, gender, indication for and duration of anticoagulation therapy, goal INR range, and the 10 INR values preceding the date of consent. A passing score was defined as at least 21 correct responses on the 29-item AKA questionnaire (72.4% correct). Statistical analyses included comparisons of demographic and clinical characteristics for patients with passing versus failing scores, assessed with Pearson chi-square and Fisher's exact test, and bivariate analyses of INR control with anticoagulation knowledge, assessed with Spearman's rho correlation. INR control was defined by 3 outcome measures: number of INRs within therapeutic range, time in therapeutic range (TTR) calculated using the Rosendaal method, and standard deviation (SD) of INR values. Anticoagulation knowledge was assessed with 2 measures: total AKA score and count of correct answers to a subset of 15 AKA items deemed by the investigators to be relevant to INR control. Results: Of 447 patients enrolled in the anticoagulation clinic, 260 consented to participate in the survey, of whom 185 patients completed the AKA instrument (n = 171 [92.4%] by mail) and were successfully matched to patient record system data. 178 (96.2%) respondents were male with a mean (SD) age of 68 (10.1) years. The majority of patients were undergoing anticoagulation treatment for atrial fibrillation (n = 113, 61.1%) or deep venous/pulmonary thromboembolism (n = 48, 25.9%). The majority of patients had been treated with warfarin for at least 1 year (n = 162, 87.6%). Most patients had goal INR ranges of 2.0 to 3.0 (n = 166, 89.7%). Of the 185 patients who completed the questionnaire, 137 (74.1%) achieved a passing score. The mean (SD) AKA questionnaire score was 78.1% (12.1%). RESEARCH There were 8 questions that were answered correctly by less than 70% of patients and identified as potential deficiencies in patient education. For the 167 patients who had been on warfarin therapy for at least 6 months and had 10 previous INR values, there was no significant Spearman's rho correlation between total number of correct questionnaire responses and INR control, defined as the count of the 10 previous INR values within goal range (rho = -0.022, P = 0.776), TTR (rho = 0.015, P = 0.848), and SD (rho = 0.047, P = 0.550). There was also no significant relationship between number of correct INR-relevant responses and INR control by any of the 3 outcome measures (count in range rho = 0.033, P = 0.676; TTR rho = 0.067, P = 0.388; and SD rho = -0.029, P = 0.708). Conclusions: Although 74.1% of patients on long-term warfarin therapy achieved a passing score of at least 21 correct answers on the 29-question AKA instrument, there was no significant relationship between patient warfarin knowledge and INR control. Areas for improvement in patient education have been identified and procedures for educational modification are currently in development. © 2011, Academy of Managed Care Pharmacy.
Li J.,VA Tennessee Valley Healthcare System
Molecular neurobiology | Year: 2013
Peripheral myelin protein-22 (PMP22) is primarily expressed in the compact myelin of the peripheral nervous system. Levels of PMP22 have to be tightly regulated since alterations of PMP22 levels by mutations of the PMP22 gene are responsible for >50 % of all patients with inherited peripheral neuropathies, including Charcot-Marie-Tooth type-1A (CMT1A) with trisomy of PMP22, hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of PMP22, and CMT1E with point mutations of PMP22. While overexpression and point-mutations of the PMP22 gene may produce gain-of-function phenotypes, deletion of PMP22 results in a loss-of-function phenotype that reveals the normal physiological functions of the PMP22 protein. In this article, we will review the basic genetics, biochemistry and molecular structure of PMP22, followed by discussion of the current understanding of pathogenic mechanisms involving in the inherited neuropathies with mutations in PMP22 gene.