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S Webber, A Zeevi, K Mason, L Addonizio, E Blume, A Dipchand, R Shaddy, B Feingold, C Canter, D Hsu, W Mahle, B Armstrong, Y Morrison, D Ikle, H Diop, J Odim
Sensitization is common in pediatric heart transplant candidates and waitlist mortality is high. Transplantation across a positive crossmatch may reduce wait time, but is considered high risk. We prospectively recruited consecutive candidates at eight North American centers. At transplantation, subjects were categorized as nonsensitized or sensitized (presence of ≥1 HLA antibody with MFI ≥1000 using single antigen beads). Sensitized subjects were further classified as complement-dependent cytotoxicity crossmatch (CDC-crossmatch) positive or negative and as donor-specific antibodies (DSA) positive or negative...
April 19, 2018: American Journal of Transplantation
Warren A Zuckerman, Adriana Zeevi, Kristen L Mason, Brian Feingold, Carol Bentlejewski, Linda J Addonizio, Elizabeth D Blume, Charles E Canter, Anne I Dipchand, Daphne T Hsu, Robert E Shaddy, William T Mahle, Anthony J Demetris, David M Briscoe, Thalachallour Mohanakumar, Joseph M Ahearn, David N Iklé, Brian D Armstrong, Yvonne Morrison, Helena Diop, Jonah Odim, Steven A Webber
Anti-HLA donor-specific antibodies are associated with worse outcomes after organ transplantation. Among sensitized pediatric heart candidates, requirement for negative donor-specific cytotoxicity crossmatch increases wait times and mortality. However, transplantation with positive crossmatch may increase posttransplantation morbidity and mortality. We address this clinical challenge in a prospective, multicenter, observational cohort study of children listed for heart transplantation (Clinical Trials in Organ Transplantation in Children-04 [CTOTC-04])...
February 15, 2018: American Journal of Transplantation
A I Dipchand, S Webber, K Mason, B Feingold, C Bentlejewski, W T Mahle, R Shaddy, C Canter, E D Blume, J Lamour, W Zuckerman, H Diop, Y Morrison, B Armstrong, D Ikle, J Odim, A Zeevi
Data on the clinical importance of newly detected donor-specific anti-HLA antibodies (ndDSAs) after pediatric heart transplantation are lacking despite mounting evidence of the detrimental effect of de novo DSAs in solid organ transplantation. We prospectively tested 237 pediatric heart transplant recipients for ndDSAs in the first year posttransplantation to determine their incidence, pattern, and clinical impact. One-third of patients developed ndDSAs; when present, these were mostly detected within the first 6 weeks after transplantation, suggesting that memory responses may predominate over true de novo DSA production in this population...
February 14, 2018: American Journal of Transplantation
Andrew Parrish, Matthew Fenchel, Gregory A Storch, Richard Buller, Sheila Mason, Nikki Williams, David Ikle, Carol Conrad, Albert Faro, Samuel Goldfarb, Don Hayes, Ernestina Melicoff-Portillo, Marc Schecter, Gary Visner, Stuart Sweet, Lara Danziger-Isakov
Prediction of PTLD after pediatric lung transplant remains difficult. Use of EBV VL in WB has been poorly predictive, while measurement of VL in BAL fluid has been suggested to have enhanced utility. The NIH-sponsored Clinical Trials in Organ Transplantation in Children (CTOTC-03) prospectively obtained serial quantitative measurements of EBV PCR in both WB and BAL fluid after pediatric lung transplantation. Descriptive statistics, contingency analyses, and Kaplan-Meier analyses evaluated possible association between EBV and PTLD...
September 2017: Pediatric Transplantation
K A Newell, A K Mehta, C P Larsen, P G Stock, A B Farris, S G Mehta, D Ikle, B Armstrong, Y Morrison, N Bridges, M Robien, R B Mannon
The intent of this National Institutes of Health-sponsored study was to compare a belatacept-based immunosuppressive regimen with a maintenance regimen of tacrolimus and mycophenolate. Nineteen primary, Epstein-Barr virus-immune renal transplant recipients with a negative cross-match were randomized to one of three groups. All patient groups received perioperative steroids and maintenance mycophenolate mofetil. Patients in groups 1 and 2 were induced with alemtuzumab and maintained on tacrolimus or belatacept, respectively...
October 2017: American Journal of Transplantation
Jay A Fishman, David N Iklé, Robert A Wilkinson
Vaccine immunoprotection for Streptococcus pneumoniae is mediated by opsonizing antibodies targeting serotype-specific capsular polysaccharides. Quantitative antibody levels enzyme-linked immunosorbent assay (ELISA) and antibody-mediated opsonophagocytic assays (OPA) measure vaccine-induced protection; correlation of these assays in transplantation requires investigation. This study examines the laboratory assessment of antibody titers in vaccinated renal recipients. Streptococcus pneumoniae 19A is common in immunocompromised hosts and is represented in protein-conjugate vaccines (PCV) and polysaccharide vaccines (PSV)...
July 2017: Transplant International: Official Journal of the European Society for Organ Transplantation
Jennifer M Iklé, Andre L P Tavares, Marisol King, Hailei Ding, Sophie Colombo, Beth A Firulli, Anthony B Firulli, Kimara L Targoff, Deborah Yelon, David E Clouthier
In gnathostomes, dorsoventral (D-V) patterning of neural crest cells (NCC) within the pharyngeal arches is crucial for the development of hinged jaws. One of the key signals that mediate this process is Endothelin-1 (EDN1). Loss of EDN1 binding to the Endothelin-A receptor (EDNRA) results in loss of EDNRA signaling and subsequent facial birth defects in humans, mice and zebrafish. A rate-limiting step in this crucial signaling pathway is the conversion of immature EDN1 into a mature active form by Endothelin converting enzyme-1 (ECE1)...
March 2017: Genesis: the Journal of Genetics and Development
Xiao-Jie Cao, Donata Oertel
Low-voltage-activated K+ (gKL ) and hyperpolarization-activated mixed cation conductances (gh ) mediate currents, IKL and Ih , through channels of the Kv1 (KCNA) and HCN families respectively and give auditory neurons the temporal precision required for signaling information about the onset, fine structure, and time of arrival of sounds. Being partially activated at rest, gKL and gh contribute to the resting potential and shape responses to even small subthreshold synaptic currents. Resting gKL and gh also affect the coupling of somatic depolarization with the generation of action potentials...
March 2017: Hearing Research
Ali Javaheri, Maria Molina, Payman Zamani, Amrith Rodrigues, Eric Novak, Susan Chambers, Patricia Stutman, Wilhelmina Maslanek, Mary Williams, Scott M Lilly, Peter Heeger, Mohamed H Sayegh, Anil Chandraker, David M Briscoe, Kevin P Daly, Randall Starling, David Ikle, Jason Christie, J Eduardo Rame, Lee R Goldberg, Jeffrey Billheimer, Daniel J Rader
BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major cause of mortality after cardiac transplantation. High-density lipoprotein (HDL) cholesterol efflux capacity (CEC) is inversely associated with coronary artery disease. In 2 independent studies, we tested the hypothesis that reduced CEC is associated with mortality and disease progression in CAV. METHODS: We tested the relationship between CEC and survival in a cohort of patients with CAV (n = 35). To determine whether reduced CEC is associated with CAV progression, we utilized samples from the Clinical Trials in Organ Transplantation 05 (CTOT05) study to determine the association between CEC and CAV progression and status at 1 year (n = 81), as assessed by average change in maximal intimal thickness (MIT) on intravascular ultrasound...
November 2016: Journal of Heart and Lung Transplantation
Tess Wright, Lisa N Gillespie, Stephen J O'Leary, Karina Needham
Primary auditory neurons rely on neurotrophic factors for development and survival. We previously determined that exposure to brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) alters the activity of hyperpolarization-activated currents (Ih) in this neuronal population. Since potassium channels are sensitive to neurotrophins, and changes in Ih are often accompanied by a shift in voltage-gated potassium currents (IK), this study examined IK with exposure to both BDNF and NT3 and the impact on firing entrainment during high frequency pulse trains...
June 23, 2016: Scientific Reports
Sandy Feng, Anthony J Demetris, Katharine M Spain, Sai Kanaparthi, Bryna E Burrell, Udeme D Ekong, Estella M Alonso, Philip Rosenthal, Laurence A Turka, David Ikle, Nadia K Tchao
Pediatric liver transplant recipients arguably have the most to gain and the most to lose from discontinuing immunosuppression (IS). Whereas IS undoubtedly exerts a cumulative toll, there is concern that insufficient or no IS may contribute to allograft deterioration. Twelve pediatric recipients of parental living donor liver grafts, identified as operationally tolerant through complete IS withdrawal (WISP-R; NCT00320606), were followed for a total of 5 years (1 year of IS withdrawal and 4 years off IS) with serial liver tests and autoantibody and alloantibody assessments...
February 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Kim D Jones, Terri Gelbart, Thomas C Whisenant, Jill Waalen, Tony S Mondala, David N Iklé, Daniel R Salomon, Robert M Bennett, Sunil M Kurian
OBJECTIVES: Fibromyalgia (FM) is a common pain disorder characterized by nociceptive dysregulation. The basic biology of FM is poorly understood. Herein we have used agnostic gene expression as a potential probe for informing its underlying biology and the development of a proof-of-concept diagnostic gene expression signature. METHODS: We analyzed RNA expression in 70 FM patients and 70 healthy controls. The isolated RNA was amplified and hybridized to Affymetrix® Human Gene 1...
March 2016: Clinical and Experimental Rheumatology
Ariel E Hight, Radha Kalluri
The vestibular nerve is characterized by two broad groups of neurons that differ in the timing of their interspike intervals; some fire at highly regular intervals, whereas others fire at highly irregular intervals. Heterogeneity in ion channel properties has been proposed as shaping these firing patterns (Highstein SM, Politoff AL. Brain Res 150: 182-187, 1978; Smith CE, Goldberg JM. Biol Cybern 54: 41-51, 1986). Kalluri et al. (J Neurophysiol 104: 2034-2051, 2010) proposed that regularity is controlled by the density of low-voltage-activated potassium currents (IKL)...
August 1, 2016: Journal of Neurophysiology
Sebastian Unizony, Miguel Villarreal, Eli M Miloslavsky, Na Lu, Peter A Merkel, Robert Spiera, Philip Seo, Carol A Langford, Gary S Hoffman, Cg M Kallenberg, E William St Clair, David Ikle, Nadia K Tchao, Linna Ding, Paul Brunetta, Hyon K Choi, Paul A Monach, Fernando Fervenza, John H Stone, Ulrich Specks
OBJECTIVE: To evaluate whether the classification of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) according to ANCA type (anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) antibodies) predicts treatment response. METHODS: Treatment responses were assessed among patients enrolled in the Rituximab in ANCA-associated Vasculitis trial according to both AAV diagnosis (granulomatosis with polyangiitis (GPA)/microscopic polyangiitis (MPA)) and ANCA type (PR3-AAV/MPO-AAV)...
June 2016: Annals of the Rheumatic Diseases
Guoshi Li, Christiane Linster, Thomas A Cleland
Olfactory bulb granule cells are modulated by both acetylcholine (ACh) and norepinephrine (NE), but the effects of these neuromodulators have not been clearly distinguished. We used detailed biophysical simulations of granule cells, both alone and embedded in a microcircuit with mitral cells, to measure and distinguish the effects of ACh and NE on cellular and microcircuit function. Cholinergic and noradrenergic modulatory effects on granule cells were based on data obtained from slice experiments; specifically, ACh reduced the conductance densities of the potassium M current and the calcium-dependent potassium current, whereas NE nonmonotonically regulated the conductance density of an ohmic potassium current...
December 2015: Journal of Neurophysiology
R C Starling, J Stehlik, D A Baran, B Armstrong, J R Stone, D Ikle, Y Morrison, N D Bridges, P Putheti, T B Strom, M Bhasin, I Guleria, A Chandraker, M Sayegh, K P Daly, D M Briscoe, P S Heeger
Identification of biomarkers that assess posttransplant risk is needed to improve long-term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)-05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS)...
January 2016: American Journal of Transplantation
D E Hricik, J Augustine, P Nickerson, R N Formica, E D Poggio, D Rush, K A Newell, J Goebel, I W Gibson, R L Fairchild, K Spain, D Iklé, N D Bridges, P S Heeger
Previous studies suggest that quantifying donor-reactive memory T cells prior to kidney transplantation by interferon gamma enzyme-linked immunosorbent spot assay (IFNγELISPOT) can assist in assessing risk of posttransplant allograft injury. Herein, we report an analysis of IFNγELISPOT results from the multicenter, Clinical Trials in Organ Transplantation-01 observational study of primary kidney transplant recipients treated with heterogeneous immunosuppression. Within the subset of 176 subjects with available IFNγELISPOT results, pretransplant IFNγELISPOT positivity surprisingly did not correlate with either the incidence of acute rejection (AR) or estimated glomerular filtration rate (eGFR) at 6- or 12-month...
December 2015: American Journal of Transplantation
Karsten Suhre, Joseph E Schwartz, Vijay K Sharma, Qiuying Chen, John R Lee, Thangamani Muthukumar, Darshana M Dadhania, Ruchuang Ding, David N Ikle, Nancy D Bridges, Nikki M Williams, Gabi Kastenmüller, Edward D Karoly, Robert P Mohney, Michael Abecassis, John Friedewald, Stuart J Knechtle, Yolanda T Becker, Benjamin Samstein, Abraham Shaked, Steven S Gross, Manikkam Suthanthiran
Noninvasive diagnosis and prognostication of acute cellular rejection in the kidney allograft may help realize the full benefits of kidney transplantation. To investigate whether urine metabolites predict kidney allograft status, we determined levels of 749 metabolites in 1516 urine samples from 241 kidney graft recipients enrolled in the prospective multicenter Clinical Trials in Organ Transplantation-04 study. A metabolite signature of the ratio of 3-sialyllactose to xanthosine in biopsy specimen-matched urine supernatants best discriminated acute cellular rejection biopsy specimens from specimens without rejection...
February 2016: Journal of the American Society of Nephrology: JASN
Donald E Hricik, Richard N Formica, Peter Nickerson, David Rush, Robert L Fairchild, Emilio D Poggio, Ian W Gibson, Chris Wiebe, Kathryn Tinckam, Suphamai Bunnapradist, Milagros Samaniego-Picota, Daniel C Brennan, Bernd Schröppel, Osama Gaber, Brian Armstrong, David Ikle, Helena Diop, Nancy D Bridges, Peter S Heeger
Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants...
December 2015: Journal of the American Society of Nephrology: JASN
E M Miloslavsky, U Specks, P A Merkel, P Seo, R Spiera, C A Langford, G S Hoffman, C G M Kallenberg, E W St Clair, N K Tchao, L Ding, D Iklé, M Villareal, N Lim, P Brunetta, F C Fervenza, P A Monach, J H Stone
OBJECTIVE: Nonsevere relapses are more common than severe relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We undertook this study to analyze the outcomes of patients with nonsevere relapses in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who were treated with prednisone according to a prespecified protocol. METHODS: RAVE was a randomized, double-blind, placebo-controlled trial comparing rituximab (RTX) to cyclophosphamide (CYC) followed by azathioprine (AZA) for induction of remission...
June 2015: Arthritis & Rheumatology
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