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509 AMG487, A CXCR3 Antagonist, changes the Inflammatory Milieu in Familial Hemophagocytic Lymphohistiocytosis (FHL) Hepatitis
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- Tamir Diamond, Michelle M. Lau, Niansheng Chu, Edward M. Behrens
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- Journal:
- Journal of Clinical and Translational Science / Volume 7 / Issue s1 / April 2023
- Published online by Cambridge University Press:
- 24 April 2023, pp. 144-145
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OBJECTIVES/GOALS: Familial Hemophagocytic Lymphohistiocytosis (FHL) is a systemic inflammatory disease, causing acute liver failure (ALF). Elevated Interferon gamma (IFN-γ) results in increased hepatic transcription of the chemokines CXCL9 and CXCL10. Inhibition of their receptor CXCR3 may reduce leukocyte recruitment and ameliorate hepatitis. METHODS/STUDY POPULATION: To determine the functional role of the IFN-γ-induced ligands, CXCL9 and CXCL10, in hepatic leukocyte recruitment via CXCR3 we used a prf-/- mouse infected with Lymphocytic Choriomeningitis Virus (LCMV) in our well-established model mimicking human FHL. We used AMG487, a small molecule CXCR3 antagonist, while maintaining intact IFN-γ signaling. Mice were sacrificed 10 days after infection when mice developed features of FHL: cytopenias, organomegaly, elevated serum ferritin and sCD25, and hepatic inflammation. Hepatic inflammation was characterized using flow cytometry, liver histology and noninvasive markers of hepatitis (ALT, liver size). RESULTS/ANTICIPATED RESULTS: AMG487 did not ameliorate the overall disease phenotype with mice developing similar FHL characteristics compared to control, including weight loss, elevation of ALT and sIL-2r as well as degree of thrombocytopenia and anemia. There was significant reduction of recruitment of CXCR3+CD4+ T cells and B cells in mice treated with AMG487. This indicates the importance of CXCR3 receptor in humoral response in FHL hepatitis. In addition, treatment with AMG487 resulted in reduction of CXCR3 expression in hepatic inflammatory monocyte (iMonos) measured by mean fluorescence intensity (MFI). DISCUSSION/SIGNIFICANCE: This is the first pre-clinical experience using AMG487, a small molecule CXCR3 antagonist, to treat FHL hepatitis. AMG487 changed the hepatic inflammatory milieu, reducing CD4 T-cell and B-cell recruitment, as well as CXCR3 expression on iMonos. However, it did not ameliorate FHL hepatitis and other therapeutic approaches should be pursued.
Six Years of Admission Screening for Carbapenemase-Producing Organisms at the NIH Clinical Center
- Robin T. Odom, Michele E. Woolbert, Anna F. Lau, John P. Dekker, Angela V. Michelin, MaryAnn Bordner, David Henderson, Karen M. Frank, Tara Palmore
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- Journal:
- Infection Control & Hospital Epidemiology / Volume 41 / Issue S1 / October 2020
- Published online by Cambridge University Press:
- 02 November 2020, pp. s79-s80
- Print publication:
- October 2020
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Background: Transmission of carbapenemase-producing organisms (CPO) threatens patient safety in healthcare facilities. As a result of a 2011 outbreak of blaKPC+ Klebsiella pneumoniae, the NIH Clinical Center (NIHCC) has prioritized early detection and isolation of CPO carriers, using point-prevalence surveys and targeted high-risk ward surveillance since 2011 and admission surveillance since 2013. We describe our experience over 6 years of admission surveillance. Methods: The NIHCC is a 200-bed research hospital that provides care for a highly immunocompromised patient population. From September 2013 to September 2019, perirectal swabs were ordered automatically for all patients on admission to nonbehavioral health wards. Swabs were ordered twice weekly for ICU patients, weekly in other high-risk wards, and monthly for hospital-wide point prevalence (excluding behavioral health). Patients hospitalized in the United States in the previous week or abroad in the previous 6 months were considered high risk for carriage and isolated pending results from 2 swabs. Most swabs (n = 37,526) were cultured onto HardyCHROM CRE. If gram-negative bacilli (GNB) were present, a molecular screen for carbapenemases was performed on a sweep of cultured material (day 1) pending organism isolation. GNB were identified by MALDI-TOF MS. Prior to June 2019, isolates were screened by blaKPC/blaNDM PCR. Starting in June 2019, Enterobacteriaceae and Pseudomonas aeruginosa were screened using the phenotypic modified carbapenem inactivation method (mCIM), reflexing to the GeneXpert CARBA-R molecular assay if positive; other GNB were tested directly with CARBA-R. Selected GNB underwent susceptibility testing (Sensititre). Whole-genome sequencing was used to assess relatedness among CPO isolates. Swabs from high-risk patients were tested directly by blaKPC PCR (n = 699) until August 2019 (most in parallel with culture) and thereafter by CARBA-R (n = 13). Results: Among 54,188 orders for perirectal swabs, 38,238 were collected from 14,497 patients (compliance 71%). Among 33 CPO-colonized patients identified from September 2013 through September 2019, 15 were identified on admission, 6 were identified in point-prevalence surveys, 8 were identified from high-risk ward surveillance, and 4 were identified from clinical cultures. Sequencing demonstrated no relatedness among CPO isolates. Although only 1.4% of patients sampled on admission were colonized with CPO, those meeting high-risk criteria were 21 times as likely to be colonized. Conclusion: Admission surveillance for CPO identified a low rate of colonization, but it detected nearly half of known CPO-colonized NIHCC patients over the past 6 years. Modest compliance with swab collection leaves room for improvement and likely results in missed instances of colonization. Although we cannot determine its effectiveness, we view our strategy as one of several key safety measures for our highly vulnerable patient population.
Funding: None
Disclosures: None
Magnetic resonance imaging in dogs with neuroangiostrongyliasis (rat lungworm disease)
- Matthew K. Wun, Richard Malik, Jane Yu, Kathleen E. Chow, Michelle Lau, Juan M. Podadera, Natalie Webster, Rogan Lee, Jan Šlapeta, Sarah Davies
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- Journal:
- Parasitology / Volume 148 / Issue 2 / February 2021
- Published online by Cambridge University Press:
- 21 September 2020, pp. 198-205
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The magnetic resonance imaging (MRI) appearance of the brain and spinal cord in humans with neuroangiostrongyliasis (NA) due to Angiostrongylus cantonensis infection has been well reported. Equivalent studies in animals are lacking. This case series describes clinical and MRI findings in 11 dogs with presumptively or definitively diagnosed NA. MRI of the brain and/or spinal cord was performed using high-field (1.5 T) or low-field (0.25 T) scanners using various combinations of transverse, sagittal, dorsal and three-dimensional (3D) T1-weighted (T1W), transverse, sagittal and dorsal T2-weighted (T2W), T2W fluid-attenuated inversion recovery (FLAIR) and T2*-weighted (T2*W) gradient echo (GRE), dorsal T2W short tau inversion recovery (STIR) and post-gadolinium transverse, sagittal, dorsal and 3D T1W and transverse T2W FLAIR sequences. In 4/6 cases where the brain was imaged, changes consistent with diffuse meningoencephalitis were observed. Evidence of meningeal involvement was evident even when not clinically apparent. The spinal cord was imaged in 9 dogs, with evidence of meningitis and myelitis detected in regions consistent with the observed neuroanatomical localization. Pathognomonic changes of neural larva migrans, as described in some human patients with NA, were not detected. NA should be considered in the differential diagnosis of dogs with MRI evidence of focal or diffuse meningitis, myelitis and/or encephalitis, especially in areas where A. cantonensis is endemic. If not precluded by imaging findings suggestive of brain herniation, cerebrospinal fluid (CSF) collection for cytology, fluid analysis, real-time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) testing should be considered mandatory in such cases after the MRI studies.
Contributors
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- By Jane E. Adcock, Yahya Aghakhani, A. Anand, Eva Andermann, Frederick Andermann, Alexis Arzimanoglou, Sandrine Aubert, Nadia Bahi-Buisson, Carman Barba, Agatino Battaglia, Geneviève Bernard, Nadir E. Bharucha, Laurence A. Bindoff, William Bingaman, Francesca Bisulli, Thomas P. Bleck, Stewart G. Boyd, Andreas Brunklaus, Harry Bulstrode, Jorge G. Burneo, Laura Canafoglia, Laura Cantonetti, Roberto H. Caraballo, Fernando Cendes, Kevin E. Chapman, Patrick Chauvel, Richard F. M. Chin, H. T. Chong, Fahmida A. Chowdhury, Catherine J. Chu-Shore, Rolando Cimaz, Andrew J. Cole, Bernard Dan, Geoffrey Dean, Alessio De Ciantis, Fernando De Paolis, Rolando F. Del Maestro, Irissa M. Devine, Carlo Di Bonaventura, Concezio Di Rocco, Henry B. Dinsdale, Maria Alice Donati, François Dubeau, Michael Duchowny, Olivier Dulac, Monika Eisermann, Brent Elliott, Bernt A. Engelsen, Kevin Farrell, Natalio Fejerman, Rosalie E. Ferner, Silvana Franceschetti, Robert Friedlander, Antonio Gambardella, Hector H. Garcia, Serena Gasperini, Lorenzo Genitori, Gioia Gioi, Flavio Giordano, Leif Gjerstad, Daniel G. Glaze, Howard P. Goodkin, Sidney M. Gospe, Andrea Grassi, William P. Gray, Renzo Guerrini, Marie-Christine Guiot, William Harkness, Andrew G. Herzog, Linda Huh, Margaret J. Jackson, Thomas S. Jacques, Anna C. Jansen, Sigmund Jenssen, Michael R. Johnson, Dorothy Jones-Davis, Reetta Kälviäinen, Peter W. Kaplan, John F. Kerrigan, Autumn Marie Klein, Matthias Koepp, Edwin H. Kolodny, Kandan Kulandaivel, Ruben I. Kuzniecky, Ahmed Lary, Yolanda Lau, Anna-Elina Lehesjoki, Maria K. Lehtinen, Holger Lerche, Michael P. T. Lunn, Snezana Maljevic, Mark R. Manford, Carla Marini, Bindu Menon, Giulia Milioli, Eli M. Mizrahi, Manish Modi, Márcia Elisabete Morita, Manuel Murie-Fernandez, Vivek Nambiar, Lina Nashef, Vincent Navarro, Aidan Neligan, Ruth E. Nemire, Charles R. J. C. Newton, John O'Donavan, Hirokazu Oguni, Teiichi Onuma, Andre Palmini, Eleni Panagiotakaki, Pasquale Parisi, Elena Parrini, Liborio Parrino, Ignacio Pascual-Castroviejo, M. Scott Perry, Perrine Plouin, Charles E. Polkey, Suresh S. Pujar, Karthik Rajasekaran, R. Eugene Ramsey, Rahul Rathakrishnan, Roberta H. Raven, Guy M. Rémillard, David Rosenblatt, M. Elizabeth Ross, Abdulrahman Sabbagh, P. Satishchandra, Swati Sathe, Ingrid E. Scheffer, Philip A. Schwartzkroin, Rod C. Scott, Frédéric Sedel, Michelle J. Shapiro, Elliott H. Sherr, Michael Shevell, Simon D. Shorvon, Adrian M. Siegel, Gagandeep Singh, S. Sinha, Barbara Spacca, Waney Squier, Carl E. Stafstrom, Bernhard J. Steinhoff, Andrea Taddio, Gianpiero Tamburrini, C. T. Tan, Raymond Y. L. Tan, Erik Taubøll, Robert W. Teasell, Mario Giovanni Terzano, Federica Teutonico, Suzanne A. Tharin, Elizabeth A. Thiele, Pierre Thomas, Paolo Tinuper, Dorothée Kasteleijn-Nolst Trenité, Sumeet Vadera, Pierangelo Veggiotti, Jean-Pierre Vignal, J. M. Walshe, Elizabeth J. Waterhouse, David Watkins, Ruth E. Williams, Yue-Hua Zhang, Benjamin Zifkin, Sameer M. Zuberi
- Edited by Simon D. Shorvon, Frederick Andermann, Renzo Guerrini
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- Book:
- The Causes of Epilepsy
- Published online:
- 05 March 2012
- Print publication:
- 14 April 2011, pp ix-xvi
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Assessing gene–environment interactions on anxiety symptom subtypes across childhood and adolescence
- Jennifer Y. F. Lau, Alice M. Gregory, Michelle A. Goldwin, Daniel S. Pine, Thalia C. Eley
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- Journal:
- Development and Psychopathology / Volume 19 / Issue 4 / Fall 2007
- Published online by Cambridge University Press:
- 11 October 2007, pp. 1129-1146
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Consistent evidence shows both genetic and stress-related risks on child and adolescent anxiety, yet few studies have considered the degree to which genetic effects are moderated by stress (gene–environment interaction). We used longitudinal data from both a child and adolescent sample of twins to examine three novel issues on the presence of gene–environment interaction on anxiety symptoms. First, we assessed moderation of genetic risks on anxiety symptoms by negative life events in each age group. Second, by distinguishing between “stable” and “age-specific” genetic factors, we explored the continuity of gene–environment interaction across time and/or its emergence at specific ages. Third, we compared the presence of gene–environment interaction across different symptom types (general, panic, social, and separation). Genetic effects on separation anxiety symptoms in childhood (mean age = 8 years, 6 months) and panic anxiety symptoms in adolescence (mean age = 15 years) increased across independent negative life events. Shared environmental effects on separation anxiety symptoms and nonshared environmental effects on general anxiety symptoms in adolescence were also moderated by negative life events. We interpret these preliminary findings tentatively in the context of gene–environment interaction on anxiety in general, and on early separation and later panic anxiety in particular.
Spherical indentation load-relaxation of soft biological tissues
- Jason M. Mattice, Anthony G. Lau, Michelle L. Oyen, Richard W. Kent
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- Journal:
- Journal of Materials Research / Volume 21 / Issue 8 / August 2006
- Published online by Cambridge University Press:
- 01 August 2006, pp. 2003-2010
- Print publication:
- August 2006
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Elastic-viscoelastic correspondence was used to generate displacement–time solutions for spherical indentation testing of soft biological materials with time-dependent mechanical behavior. Boltzmann hereditary integral operators were used to determine solutions for indentation load-relaxation following a constant displacement rate ramp. A “ramp correction factor” approach was used for routine analysis of experimental load-relaxation data. Experimental load-relaxation tests were performed on rubber, as well as kidney tissue and costal cartilage, two hydrated soft biological tissues with vastly different mechanical responses. The experimental data were fit to the spherical indentation ramp-relaxation solutions to obtain values of short- and long-time shear modulus and of material time constants. The method is used to demonstrate linearly viscoelastic responses in rubber, level-independent indentation results for costal cartilage, and age-independent indentation results for kidney parenchymal tissue.