17 results on '"Juan D Matute"'
Search Results
2. Standardizing the Evaluation and Management of Necrotizing Enterocolitis in a Level IV NICU
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Megan Aurora, Madeline L. Keyes, Julian Garcia Acosta, Kristen Swartz, Jesiel Lombay, Jason Ciaramitaro, Ariana Rudnick, Cassandra Kelleher, Suzanne Hally, Michael Gee, Vandana Madhavan, Sergei Roumiantsev, Brian M. Cummings, Brett D. Nelson, Paul H. Lerou, and Juan D. Matute
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Piperacillin ,Tazobactam ,Antifungal Agents ,Infant, Newborn ,Infant, Newborn, Diseases ,Article ,Anti-Bacterial Agents ,Fetal Diseases ,Enterocolitis, Necrotizing ,Intensive Care Units, Neonatal ,Pediatrics, Perinatology and Child Health ,Humans ,Female ,Retrospective Studies - Abstract
OBJECTIVES Necrotizing enterocolitis (NEC) is a severe intestinal inflammatory disease and a leading cause of morbidity and mortality in NICUs. Management of NEC is variable because of the lack of evidence-based recommendations. It is widely accepted that standardization of patient care leads to improved outcomes. This quality improvement project aimed to decrease variation in the evaluation and management of NEC in a Level IV NICU. METHODS A multidisciplinary team investigated institutional variation in NEC management and developed a standardized guideline and electronic medical record tools to assist in evaluation and management. Retrospective baseline data were collected for 2 years previously and prospectively for 3.5 years after interventions. Outcomes included the ratio of observed-to-expected days of antibiotics and nil per os (NPO) on the basis of the novel guidelines and the percentage of cases treated with piperacillin/tazobactam. Balancing measures were death, surgery, and antifungal use. RESULTS Over 5.5 years, there were 124 evaluations for NEC. Special cause variation was noted in the observed-to-expected antibiotic and NPO days ratios, decreasing from 1.94 to 1.18 and 1.69 to 1.14, respectively. Piperacillin/tazobactam utilization increased from 30% to 91%. There were no increases in antifungal use, surgery, or death. CONCLUSIONS Variation in evaluation and management of NEC decreased after initiation of a guideline and supporting electronic medical record tools, with fewer antibiotic and NPO days without an increase in morbidity or mortality. A quality improvement approach can benefit patients and decrease variability, even in diseases with limited evidence-based standards.
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- 2022
3. The healing power of language: caring for patients with limited english proficiency and COVID-19
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Juan D. Matute, Alejandra Barrero-Castillero, and Emily M. Herzberg
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Adult ,Male ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Limited English Proficiency ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,MEDLINE ,Multilingualism ,Pediatrics ,Power (social and political) ,Special Article ,Pregnancy ,Humans ,Pediatricians ,Child ,Pandemics ,Language ,Medical education ,SARS-CoV-2 ,Communication Barriers ,Infant, Newborn ,COVID-19 ,Hispanic or Latino ,Limited English proficiency ,Pediatrics, Perinatology and Child Health ,Female ,Patient Care ,Psychology ,Boston - Published
- 2021
4. Single-cell immunophenotyping of the fetal immune response to maternal SARS-CoV-2 infection in late gestation
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Jonathan X. Li, Paul H. Lerou, David Pépin, Andrea G. Edlow, Benjamin Finander, Brian T. Kalish, Neal Smith, Alexandra-Chloé Villani, Xingbin Ai, and Juan D. Matute
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cord blood mononuclear cells ,COVID19 ,T cell ,CD14 ,viruses ,Major histocompatibility complex ,Peripheral blood mononuclear cell ,Article ,Immunophenotyping ,Fetus ,Immune system ,Pregnancy ,medicine ,Humans ,Pregnancy Complications, Infectious ,Child ,skin and connective tissue diseases ,Pandemics ,biology ,SARS-CoV-2 ,business.industry ,T-cell receptor ,fungi ,Immunity ,Infant, Newborn ,COVID-19 ,biochemical phenomena, metabolism, and nutrition ,Basic Science Article ,Infectious Disease Transmission, Vertical ,body regions ,medicine.anatomical_structure ,Cord blood ,Pediatrics, Perinatology and Child Health ,Immunology ,biology.protein ,Female ,business ,CD8 - Abstract
During the COVID-19 pandemic, thousands of pregnant women have been infected with SARS-CoV-2. The implications of maternal SARS-CoV-2 infection on fetal and childhood well-being are unknown. We aimed to characterize the fetal immune response to maternal SARS-CoV-2 infection. We performed single-cell RNA sequencing and T-cell receptor (TCR) sequencing on cord blood mononuclear cells (CBMC) from newborns of mothers infected with SARS-CoV-2 in the third-trimester (cases) or without SARS-CoV-2 infection. We identified widespread gene expression changes in CBMC from cases, including upregulation of interferon-stimulated genes and Major Histocompatibility Complex genes in CD14 + monocytes; transcriptional changes suggestive of activation of plasmacytoid dendritic cells, and activation and exhaustion of NK cells and CD8 + T-cells. Lastly, we observed fetal TCR repertoire expansion in cases. As none of the infants were infected with SARS-CoV-2, our results suggest that SARS-CoV-2 maternal infection might modulate the fetal immune system in the absence of vertical transmission., BRIEF SUMMARY SARS-CoV-2 infection in the third-trimester of pregnancy without vertical transmission promotes widespread gene expression changes and TCR repertoire clonal expansion in cord blood leukocytes.
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- 2021
5. Establishment of a pediatric COVID-19 biorepository: unique considerations and opportunities for studying the impact of the COVID-19 pandemic on children
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Pamela J. Forde, Juan D. Matute, Elizabeth Gootkind, Susan P. Davidson, Anne M. Neilan, Sheila Grimmel, Lael M. Yonker, Evan A. Bordt, Denis De la Flor, Margot Hardcastle, Shen Ning, Kathleen A. Grinke, Katherine Harding, Paolo D'Avino, Jessica E. Shui, Rosiane Lima, Paul H. Lerou, Kathryn E Hall, Grace Park, Katerina Heath, Laura J. Yockey, Andrea G. Edlow, Jaclyn Zois, and Alessio Fasano
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Male ,Epidemiology ,Viral transmission ,Disease ,Fetal Development ,0302 clinical medicine ,Pandemic ,Biorepository ,030212 general & internal medicine ,Child ,Pediatric ,lcsh:R5-920 ,0303 health sciences ,Viral susceptibility ,Multisystem inflammatory syndrome in children (MIS-C) ,Biobank ,Hospitalization ,Vaccination ,Child, Preschool ,Female ,Sample collection ,medicine.symptom ,Coronavirus Infections ,lcsh:Medicine (General) ,Research Article ,medicine.medical_specialty ,Adolescent ,Pneumonia, Viral ,MEDLINE ,Health Informatics ,Article ,Specimen Handling ,Betacoronavirus ,03 medical and health sciences ,medicine ,Humans ,Intensive care medicine ,Pandemics ,030304 developmental biology ,SARS-CoV-2 ,business.industry ,Infant, Newborn ,Infant ,COVID-19 ,Patient recruitment ,Biobank, pediatric ,Sputum ,business - Abstract
Background COVID-19, the disease caused by the highly infectious and transmissible coronavirus SARS-CoV-2, has quickly become a morbid global pandemic. Although the impact of SARS-CoV-2 infection in children is less clinically apparent, collecting high-quality biospecimens from infants, children, and adolescents in a standardized manner during the COVID-19 pandemic is essential to establish a biologic understanding of the disease in the pediatric population. This biorepository enables pediatric centers world-wide to collect samples uniformly to drive forward our understanding of COVID-19 by addressing specific pediatric and neonatal COVID-19-related questions. Methods A COVID-19 biospecimen collection study was implemented with strategic enrollment guidelines to include patients seen in urgent care clinics and hospital settings, neonates born to SARS-CoV-2 infected mothers, and asymptomatic children. The methodology described here, details the importance of establishing collaborations between the clinical and research teams to harmonize protocols for patient recruitment and sample collection, processing and storage. It also details modifications required for biobanking during a surge of the COVID-19 pandemic. Results Considerations and challenges facing enrollment of neonatal and pediatric cohorts are described. A roadmap is laid out for successful collection, processing, storage and database management of multiple pediatric samples such as blood, nasopharyngeal and oropharyngeal swabs, sputum, saliva, tracheal aspirates, stool, and urine. Using this methodology, we enrolled 327 participants, who provided a total of 972 biospecimens. Conclusions Pediatric biospecimens will be key in answering questions relating to viral transmission by children, differences between pediatric and adult viral susceptibility and immune responses, the impact of maternal SARS-CoV-2 infection on fetal development, and factors driving the Multisystem Inflammatory Syndrome in Children. The specimens in this biorepository will allow necessary comparative studies between children and adults, help determine the accuracy of current pediatric viral testing techniques, in addition to, understanding neonatal exposure to SARS-CoV-2 infection and disease abnormalities. The successful establishment of a pediatric biorepository is critical to provide insight into disease pathogenesis, and subsequently, develop future treatment and vaccination strategies.
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- 2020
6. Compromised SARS-CoV-2-specific placental antibody transfer
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Marie-Charlotte Meinsohn, Ngoc Minh Phuong Nguyen, David Pépin, Drucilla J. Roberts, John F. Burke, Lydia L. Shook, Juan D. Matute, Adeline A. Boatin, Ashlin R. Michell, Douglas A. Lauffenburger, Carolin Loos, Caroline Atyeo, Andrea G. Edlow, Anjali J Kaimal, Lael M. Yonker, Stephanie Fischinger, Kaitlyn E. James, Kathryn J. Gray, Galit Alter, Krista M. Pullen, Lisa M. Bebell, Ilona T. Goldfarb, Evan A. Bordt, Maeva Chauvin, Matthew D. Slein, and Laura J. Yockey
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Adult ,THP-1 Cells ,Placenta ,Pregnancy Trimester, Third ,Medizin ,Fc receptor ,Inflammation ,Antibodies, Viral ,Immunoglobulin G ,General Biochemistry, Genetics and Molecular Biology ,Article ,Serology ,03 medical and health sciences ,0302 clinical medicine ,Immunity ,Pregnancy ,medicine ,COVID-19 ,trimester ,placental transfer ,fucose ,antibodies ,infection ,inflammation ,glycosylation ,Fc-receptor ,hypergammablobulinemia ,pregnancy ,SARS-CoV-2 ,Humans ,Pregnancy Complications, Infectious ,skin and connective tissue diseases ,Maternal-Fetal Exchange ,030304 developmental biology ,0303 health sciences ,biology ,Receptors, IgG ,Infant, Newborn ,medicine.disease ,medicine.anatomical_structure ,Immunology ,biology.protein ,Female ,medicine.symptom ,Antibody ,030217 neurology & neurosurgery - Abstract
SARS-CoV-2 infection causes more severe disease in pregnant women compared to age-matched non-pregnant women. Whether maternal infection causes changes in the transfer of immunity to infants remains unclear. Maternal infections have previously been associated with compromised placental antibody transfer, but the mechanism underlying this compromised transfer is not established. Here, we used systems serology to characterize the Fc-profile of influenza-, pertussis-, and SARS-CoV-2-specific antibodies transferred across the placenta. Influenza- and pertussis-specific antibodies were actively transferred. However, SARS-CoV-2-specific antibody transfer was significantly reduced compared to influenza- and pertussis-specific antibodies, and cord titers and functional activity were lower than in maternal plasma. This effect was only observed in third trimester infection. SARS-CoV-2-specific transfer was linked to altered SARS-CoV-2-antibody glycosylation profiles and was partially rescued by infection-induced increases in IgG and increased FCGR3A placental expression. These results point to unexpected compensatory mechanisms to boost immunity in neonates, providing insights for maternal vaccine design., Highlights • SARS-CoV-2-specific antibodies have a decreased placental transfer • SARS-CoV-2-spike antibodies have altered glycosylation profiles in pregnant women • Pregnant women with SARS-CoV-2 during the third trimester have elevated IgG levels • SARS-CoV-2-specific antibody transfer is efficient after second trimester infection, Atyeo et al. reveals a deficiency in SARS-CoV-2-antibody placental transfer among women infected during the third trimester. While bulk antibody transfer remains unaltered, SARS-CoV-2-antibodies show perturbed Fc glycosylation profiles and elevated IgG and FCGR3A placental expression that suggest compensation for poor transfer.
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- 2020
7. Rapid establishment of a COVID-19 perinatal biorepository: early lessons from the first 100 women enrolled
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Samantha Devane, Rosiane Lima, Juan D. Matute, Suzanne Stanton, Xu G. Yu, Laurel Gardner, Robin Azevedo, Evan A. Bordt, Alessio Fasano, Jessica E. Shui, Anjali J Kaimal, Lael M. Yonker, Adeline A. Boatin, Andrea G. Edlow, Laura J. Yockey, Paul H. Lerou, Muriel Schwinn, Dana Cvrk, Jonathan Z. Li, Natalie Croul, and Lydia L. Shook
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Adult ,medicine.medical_specialty ,Epidemiology ,Pneumonia, Viral ,Health Informatics ,Umbilical cord ,Specimen Handling ,Betacoronavirus ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,medicine ,Humans ,030212 general & internal medicine ,Neonatology ,Pregnancy Complications, Infectious ,Patient participation ,Prospective cohort study ,Pandemics ,Biobank ,lcsh:R5-920 ,Pandemic ,SARS-CoV-2 ,business.industry ,Obstetrics ,Patient Selection ,030503 health policy & services ,Infant, Newborn ,Repository ,COVID-19 ,Newborn ,medicine.disease ,Immune ,Perinatal Care ,medicine.anatomical_structure ,Biorepository ,Vertical transmission ,Female ,Sample collection ,Patient Participation ,lcsh:Medicine (General) ,Coronavirus Infections ,0305 other medical science ,business ,Research Article - Abstract
Background Collection of biospecimens is a critical first step to understanding the impact of COVID-19 on pregnant women and newborns - vulnerable populations that are challenging to enroll and at risk of exclusion from research. We describe the establishment of a COVID-19 perinatal biorepository, the unique challenges imposed by the COVID-19 pandemic, and strategies used to overcome them. Methods A transdisciplinary approach was developed to maximize the enrollment of pregnant women and their newborns into a COVID-19 prospective cohort and tissue biorepository, established on March 19, 2020 at Massachusetts General Hospital (MGH). The first SARS-CoV-2 positive pregnant woman was enrolled on April 2, and enrollment was expanded to SARS-CoV-2 negative controls on April 20. A unified enrollment strategy with a single consent process for pregnant women and newborns was implemented on May 4. SARS-CoV-2 status was determined by viral detection on RT-PCR of a nasopharyngeal swab. Wide-ranging and pregnancy-specific samples were collected from maternal participants during pregnancy and postpartum. Newborn samples were collected during the initial hospitalization. Results Between April 2 and June 9, 100 women and 78 newborns were enrolled in the MGH COVID-19 biorepository. The rate of dyad enrollment and number of samples collected per woman significantly increased after changes to enrollment strategy (from 5 to over 8 dyads/week, P P P = 0.0007). The highest sample yield was for placenta (96%), umbilical cord blood (93%), urine (99%), and maternal blood (91%). The lowest-yield sample types were maternal stool (30%) and breastmilk (22%). Of the 61 delivered women who also enrolled their newborns, fewer women agreed to neonatal blood compared to cord blood (39 vs 58, P Conclusions Establishing a COVID-19 perinatal biorepository required patient advocacy, transdisciplinary collaboration and creative solutions to unique challenges. This biorepository is unique in its comprehensive sample collection and the inclusion of a control population. It serves as an important resource for research into the impact of COVID-19 on pregnant women and newborns and provides lessons for future biorepository efforts.
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- 2020
8. Necrotizing Enterocolitis in Neonates With Hyperinsulinemic Hypoglycemia Treated With Diazoxide
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Sergei Roumiantsev, Katherine A. Sparger, Madeline L. Keyes, Lucas E. Orth, Juan D. Matute, Helen Healy, and Mayya Geha
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Male ,Pediatrics ,medicine.medical_specialty ,Infant, Premature, Diseases ,Case Reports ,Hypoglycemia ,medicine.disease_cause ,Enteral administration ,03 medical and health sciences ,0302 clinical medicine ,Fatal Outcome ,Enterocolitis, Necrotizing ,Risk Factors ,030225 pediatrics ,medicine ,Diazoxide ,Humans ,Hyperinsulinemic hypoglycemia ,Adverse effect ,Retrospective Studies ,business.industry ,Incidence ,Infant, Newborn ,medicine.disease ,Low birth weight ,Pediatrics, Perinatology and Child Health ,Necrotizing enterocolitis ,Congenital Hyperinsulinism ,Female ,medicine.symptom ,business ,Hyperinsulinism ,Infant, Premature ,medicine.drug - Abstract
The most common cause of persistent hypoglycemia in the neonatal period is hyperinsulinism. Severe, refractory hypoglycemia resulting from hyperinsulinism can lead to significant brain injury and permanent cognitive disability. Diazoxide is the first-line and only US Food and Drug Administration–approved, pharmacologic treatment for refractory hyperinsulinism. In recent years, the use of diazoxide in neonates with persistent hyperinsulinemic hypoglycemia has increased in the United States. Known adverse effects of diazoxide include fluid retention, hypertrichosis, neutropenia, thrombocytopenia, and more recently, pulmonary hypertension. It is currently unknown if diazoxide exposure is associated with an increased risk of necrotizing enterocolitis (NEC) in neonates. We reviewed the cases of 24 patients in a level IV NICU at Massachusetts General Hospital who received diazoxide over 12 years (April 2006–April 2018). All 24 patients received enteral diazoxide for refractory hyperinsulinemic hypoglycemia. A total of 5 patients developed NEC after initiation of diazoxide based on clinical and radiographic findings, corresponding to 20% of infants exposed to diazoxide. This is above our baseline incidence of NEC (1% for all inborn infants and 6% for all inborn very low birth weight infants). More research and monitoring are necessary to characterize the potential risk of NEC associated with the use of diazoxide in the neonatal period.
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- 2020
9. Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells
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Marco Fritzsche, Melissa Bedard, Gurdyal S. Besra, Dilip Shrestha, Frances M. Platt, Christian Eggeling, Mariolina Salio, Sebastian Zeissig, Shankar S. Iyer, David A. Priestman, Uzi Gileadi, Yuting Wang, Vincenzo Cerundolo, Andrej Shevchenko, Matheswaran Kandasamy, Gennaro Prota, John C. Christianson, Richard S. Blumberg, Falk Schneider, Natacha Veerapen, and Juan D. Matute
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0301 basic medicine ,THP-1 Cells ,Cell ,Lymphocyte Activation ,Autoantigens ,Carcinoma, Lewis Lung ,Mice ,eIF-2 Kinase ,0302 clinical medicine ,Immunology and Inflammation ,Cytoskeleton ,Antigen Presentation ,Multidisciplinary ,biology ,Chemistry ,NKT ,Biological Sciences ,Endoplasmic Reticulum Stress ,Lipids ,3. Good health ,Cell biology ,medicine.anatomical_structure ,PNAS Plus ,030220 oncology & carcinogenesis ,CD1D ,Thapsigargin ,Cell activation ,ER stress ,Antigen-Presenting Cells ,Endosomes ,CD1d ,Glycosphingolipids ,03 medical and health sciences ,Immune system ,Cell Line, Tumor ,medicine ,cancer ,Animals ,Humans ,Protein kinase A ,Antigen-presenting cell ,Endoplasmic reticulum ,Interleukin-2 Receptor alpha Subunit ,Dendritic Cells ,Coculture Techniques ,Mice, Inbred C57BL ,030104 developmental biology ,Unfolded protein response ,biology.protein ,Unfolded Protein Response ,Natural Killer T-Cells ,Antigens, CD1d ,Lysosomes - Abstract
Significance While there is a clear understanding of how invariant NKT (iNKT) cells are activated in foreign infection, it remains unclear how they are activated during sterile inflammation, including cancer, where they have a well-defined role in tumor immunosurveillance. Here we elucidate a mechanism by which iNKT cells are activated through 1) the presentation of self-lipid antigens by endoplasmic reticulum-stressed antigen-presenting cells and 2) enhanced functional avidity driven by actin cytoskeletal remodeling. We further provide evidence that this mechanism of activation is at play in tumor settings. Here we describe a physiological context, relevant to human health and disease, that drives the presentation of immunogenic self-lipids to activate iNKT cells during sterile inflammation., Invariant NKT (iNKT) cells have the unique ability to shape immunity during antitumor immune responses and other forms of sterile and nonsterile inflammation. Recent studies have highlighted a variety of classes of endogenous and pathogen-derived lipid antigens that can trigger iNKT cell activation under sterile and nonsterile conditions. However, the context and mechanisms that drive the presentation of self-lipid antigens in sterile inflammation remain unclear. Here we report that endoplasmic reticulum (ER)-stressed myeloid cells, via signaling events modulated by the protein kinase RNA-like ER kinase (PERK) pathway, increase CD1d-mediated presentation of immunogenic endogenous lipid species, which results in enhanced iNKT cell activation both in vitro and in vivo. In addition, we demonstrate that actin cytoskeletal reorganization during ER stress results in an altered distribution of CD1d on the cell surface, which contributes to enhanced iNKT cell activation. These results define a previously unidentified mechanism that controls iNKT cell activation during sterile inflammation.
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- 2019
10. Epithelial endoplasmic reticulum stress orchestrates a protective IgA response
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Gwenny M. Fuhler, Shengbao Suo, David Q. Shih, Marcel R. de Zoete, Joep Grootjans, Hai Li, Jonathan N. Glickman, Jarom Heijmans, Thomas Gensollen, Juan D. Matute, Richard S. Blumberg, Niklas Krupka, Adrienne M. Luoma, Noah W. Palm, Jinzhi Duan, Richard A. Flavell, Thomas Hanley, C. Janneke van der Woude, Arthur Kaser, Stephanie C. Ganal-Vonarburg, Kathy D. McCoy, Kai W. Wucherpfennig, Philip Rosenstiel, Julien P. Limenitakis, Andrew J. Macpherson, Yosuke Shimodaira, Stephan R. Targan, Shuhei Hosomi, Svetlana Saveljeva, Margaret E. Conner, Guo-Cheng Yuan, dI&I I&I-2, LS Infectiebiologie (Bacteriologie), Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, General Internal Medicine, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Grootjans, Joep [0000-0002-2805-4831], Krupka, Niklas [0000-0001-5948-7536], Hosomi, Shuhei [0000-0002-8808-5672], Hanley, Thomas [0000-0002-4270-8299], Saveljeva, Svetlana [0000-0002-0644-9752], Gensollen, Thomas [0000-0002-9834-5490], Heijmans, Jarom [0000-0001-9615-7851], Limenitakis, Julien P [0000-0002-6785-3492], Ganal-Vonarburg, Stephanie C [0000-0002-2548-7754], Shimodaira, Yosuke [0000-0003-0314-9196], Duan, Jinzhi [0000-0001-9351-4956], Shih, David Q [0000-0003-1335-7044], Conner, Margaret E [0000-0002-7146-8159], Glickman, Jonathan N [0000-0003-0910-2655], Palm, Noah W [0000-0001-7262-9455], van der Woude, C Janneke [0000-0003-3875-6957], Wucherpfennig, Kai W [0000-0002-1829-302X], Flavell, Richard A [0000-0003-4461-0778], McCoy, Kathy D [0000-0002-3900-9227], Macpherson, Andrew J [0000-0002-7192-0184], Kaser, Arthur [0000-0003-1419-3344], Blumberg, Richard S [0000-0002-9704-248X], Apollo - University of Cambridge Repository, and Gastroenterology & Hepatology
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Immunoglobulin A ,X-Box Binding Protein 1 ,Plasma Cells ,Autophagy-Related Proteins ,Inflammation ,digestive system ,Article ,Tissue Culture Techniques ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Intestinal mucosa ,Peritoneum ,medicine ,Autophagy ,Animals ,Humans ,Intestinal Mucosa ,Immunity, Mucosal ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Lamina propria ,Multidisciplinary ,biology ,Chemistry ,Endoplasmic reticulum ,Epithelial Cells ,Endoplasmic Reticulum Stress ,3. Good health ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Unfolded protein response ,biology.protein ,medicine.symptom - Abstract
Stressed gut epithelium gets some relief Immunoglobulin A (IgA) is the most abundantly expressed antibody isotype and can be found at various mucosal surfaces in the body, including the gastrointestinal (GI) tract. IgA is polyreactive and can coat and restrain both commensal bacteria and enteric pathogens. Grootjans et al. found that endoplasmic reticulum (ER) stress in the intestinal epithelial cells of mice induced the T cell– and microbiota-independent expansion of peritoneal B1b cells, which secrete IgA. Similarly, human subjects homozygous for a variant of an autophagy gene ( ATG16L1 ) known to cause ER stress showed increased numbers of GI IgA + cells compared with controls. Thus, epithelial ER stress serves as an advantageous “eustress” response that can functionally antagonize its well-characterized role in promoting inflammation. Science , this issue p. 993
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- 2018
11. Human alkaline phosphatase dephosphorylates microbial products and is elevated in preterm neonates with a history of late-onset sepsis
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Peter Richmond, Tobias Strunk, José Luis Millán, David Burgner, Megan Tresenriter, Julie Hibbert, Matthew A. Pettengill, Juan D. Matute, Ofer Levy, Andrew J. Currie, and Al Ozonoff
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Lipopolysaccharides ,Male ,0301 basic medicine ,medicine.medical_specialty ,Lipopolysaccharide ,lcsh:Medicine ,Gestational Age ,Context (language use) ,Inflammation ,Biology ,Late Onset Disorders ,Phosphates ,Sepsis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Salmonella ,Internal medicine ,Blood plasma ,Rosaniline Dyes ,medicine ,Humans ,lcsh:Science ,Enzyme Assays ,Multidisciplinary ,Neonatal sepsis ,Toll-Like Receptors ,lcsh:R ,Infant, Newborn ,Infant ,Correction ,Alkaline Phosphatase ,medicine.disease ,Recombinant Proteins ,3. Good health ,Isoenzymes ,Klebsiella pneumoniae ,030104 developmental biology ,Endocrinology ,chemistry ,TLR4 ,Alkaline phosphatase ,Female ,030211 gastroenterology & hepatology ,lcsh:Q ,medicine.symptom ,Infant, Premature - Abstract
Background A host defense function for Alkaline phosphatases (ALPs) is suggested by the contribution of intestinal ALP to detoxifying bacterial lipopolysaccharide (endotoxin) in animal models in vivo and the elevation of ALP activity following treatment of human cells with inflammatory stimuli in vitro. However the activity of ALP in human plasma (primarily tissue-nonspecific ALP; TNAP) on lipopolysaccharide and other microbial products has not been assessed, nor has its expression been studied in preterm newborns, a vulnerable population at high risk of sepsis. In this context, the aim of our study was to characterize the activity of TNAP on Toll-like receptor (TLR) agonists and assess the concentrations of plasma ALP during late-onset sepsis in preterm newborns. Methods Recombinant human TNAP was incubated with microbial products and phosphate release was measured by malachite green assay. Plasma ALP activity was measured serially in a cohort of preterm (N = 129) infants at high risk of late-onset sepsis (LOS). Results TNAP dephosphorylates poly-inosine:cytosine (Toll-like receptor (TLR) 3 agonist) and LPS from Klebsiella pneumoniae and Salmonella Minnesota (TLR4 agonists). Plasma ALP significantly increased postnatally over the first 4 weeks of life in preterm and term newborns. Bacteremic LOS in preterm infants (gestational age ≤ 30 weeks) was associated with significantly elevated plasma ALP at 4 weeks postnatal age. Conclusions TNAP, the main circulating isozyme of ALP, de-phosphorylates TLR agonists, demonstrates a post-natal age dependent increase in preterm and term plasma across the first 4 weeks of life, and is elevated in association with preterm LOS.
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- 2017
12. Cutting Edge: NADPH Oxidase Modulates MHC Class II Antigen Presentation by B Cells
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Lawrence A. Quilliam, Andrés Augusto Arias, Heng Zhao, Victoria L. Crotzer, Juan D. Matute, Mary C. Dinauer, and Janice S. Blum
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Intracellular Fluid ,Phagocyte ,T cell ,Immunology ,Antigen presentation ,B-Lymphocyte Subsets ,Lymphocyte Activation ,Article ,Epitope ,MHC class II antigen ,medicine ,Humans ,Immunology and Allergy ,Cell Line, Transformed ,Antigen Presentation ,Oxidase test ,NADPH oxidase ,biology ,NADPH Oxidases ,HLA-DR Antigens ,Phosphoproteins ,Acquired immune system ,Up-Regulation ,Cell biology ,medicine.anatomical_structure ,Biochemistry ,biology.protein ,Reactive Oxygen Species - Abstract
Phagocyte NADPH oxidase plays a key role in pathogen clearance via reactive oxygen species (ROS) production. Defects in oxidase function result in chronic granulomatous disease with hallmark recurrent microbial infections and inflammation. The oxidase’s role in the adaptive immune response is not well understood. Class II presentation of cytoplasmic and exogenous Ag to CD4+ T cells was impaired in human B cells with reduced oxidase p40phox subunit expression. Naturally arising mutations, which compromise p40phox function in a chronic granulomatous disease patient, also perturbed class II Ag presentation and intracellular ROS production. Reconstitution of patient B cells with a wild-type, but not a mutant, p40phox allele restored exogenous Ag presentation and intracellular ROS generation. Remarkably, class II presentation of epitopes from membrane Ag was robust in p40phox-deficient B cells. These studies reveal a role for NADPH oxidase and p40phox in skewing epitope selection and T cell recognition of self Ag.
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- 2012
13. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity
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Samy O. Meroueh, Christopher C. M. Waterhouse, Iwona Wrobel, Christophe C. Marchal, Mary C. Dinauer, Weiming Yu, Xing Jun Li, Juan D. Matute, Andrés Augusto Arias, Natalie D. Stull, MacGregor Steele, Nicola A.M. Wright, James D. Kellner, William M. Nauseef, and David B. Lewis
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Adult ,Male ,Heterozygote ,Neutrophils ,DNA Mutational Analysis ,Immunology ,Mutation, Missense ,Genes, Recessive ,Granulomatous Disease, Chronic ,Compound heterozygosity ,Biochemistry ,Frameshift mutation ,Phagocytes, Granulocytes, and Myelopoiesis ,chemistry.chemical_compound ,Chronic granulomatous disease ,Phagocytosis ,Phosphatidylinositol Phosphates ,Superoxides ,Cell Line, Tumor ,Phorbol Esters ,medicine ,Humans ,Child ,NADPH oxidase ,biology ,Superoxide ,Genetic Diseases, Inborn ,NADPH Oxidases ,Cell Biology ,Hematology ,PX domain ,medicine.disease ,Molecular biology ,N-Formylmethionine Leucyl-Phenylalanine ,Amino Acid Substitution ,chemistry ,NAD(P)H oxidase ,Carcinogens ,Codon, Terminator ,biology.protein ,Female ,P22phox - Abstract
Chronic granulomatous disease (CGD), an immunodeficiency with recurrent pyogenic infections and granulomatous inflammation, results from loss of phagocyte superoxide production by recessive mutations in any 1 of 4 genes encoding subunits of the phagocyte NADPH oxidase. These include gp91phox and p22phox, which form the membrane-integrated flavocytochrome b, and cytosolic subunits p47phox and p67phox. A fifth subunit, p40phox, plays an important role in phagocytosis-induced superoxide production via a phox homology (PX) domain that binds to phosphatidylinositol 3-phosphate (PtdIns(3)P). We report the first case of autosomal recessive mutations in NCF4, the gene encoding p40phox, in a boy who presented with granulomatous colitis. His neutrophils showed a substantial defect in intracellular superoxide production during phagocytosis, whereas extracellular release of superoxide elicited by phorbol ester or formyl-methionyl-leucyl-phenylalanine (fMLF) was unaffected. Genetic analysis of NCF4 showed compound heterozygosity for a frameshift mutation with premature stop codon and a missense mutation predicting a R105Q substitution in the PX domain. Parents and a sibling were healthy heterozygous carriers. p40phoxR105Q lacked binding to PtdIns(3)P and failed to reconstitute phagocytosis-induced oxidase activity in p40phox-deficient granulocytes, with premature loss of p40phoxR105Q from phagosomes. Thus, p40phox binding to PtdIns(3)P is essential for phagocytosis-induced oxidant production in human neutrophils and its absence can be associated with disease.
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- 2009
14. From Bench to Bedside: Preclinical Evaluation of a Self-Inactivating Gammaretroviral Vector for the Gene Therapy of X-linked Chronic Granulomatous Disease
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Mohammed A. Sadat, Uta Müller-Kuller, Raffaele Fronza, Kerstin B. Kaufmann, Manfred Schmidt, Juan D. Matute, Sonja Naundorf, Nancy Pech, Christopher Baum, Ute Modlich, Christian Brendel, Robert G. Presson, Simone Scholz, Stephan Schultze-Strasser, Jeffrey B. Travers, Manuel Grez, Mary C. Dinauer, Christof von Kalle, Klaus Kühlcke, Joachim Schwäble, Hana Kunkel, Eva Rudolf, Linping Chen-Wichmann, Stefan Stein, Margarita Diaz, Axel Schambach, George E. Sandusky, and Adelina Dillmann
- Subjects
Lung Diseases ,Myeloid ,Genetic enhancement ,Transgene ,Genetic Vectors ,Drug Evaluation, Preclinical ,Biology ,Granulomatous Disease, Chronic ,Malignant transformation ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Chronic granulomatous disease ,Superoxides ,medicine ,Animals ,Humans ,ddc:610 ,Promoter Regions, Genetic ,Genetics (clinical) ,Research Articles ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Membrane Glycoproteins ,Aspergillus fumigatus ,NADPH Oxidases ,Genetic Therapy ,DNA Methylation ,medicine.disease ,3. Good health ,Haematopoiesis ,Disease Models, Animal ,medicine.anatomical_structure ,Phenotype ,Proto-Oncogene Proteins c-fes ,030220 oncology & carcinogenesis ,DNA methylation ,Immunology ,NADPH Oxidase 2 ,Primary immunodeficiency ,Gammaretrovirus - Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by impaired antimicrobial activity in phagocytic cells. As a monogenic disease affecting the hematopoietic system, CGD is amenable to gene therapy. Indeed in a phase I/II clinical trial, we demonstrated a transient resolution of bacterial and fungal infections. However, the therapeutic benefit was compromised by the occurrence of clonal dominance and malignant transformation demanding alternative vectors with equal efficacy but safety-improved features. In this work we have developed and tested a self-inactivating (SIN) gammaretroviral vector (SINfes.gp91s) containing a codon-optimized transgene (gp91(phox)) under the transcriptional control of a myeloid promoter for the gene therapy of the X-linked form of CGD (X-CGD). Gene-corrected cells protected X-CGD mice from Aspergillus fumigatus challenge at low vector copy numbers. Moreover, the SINfes.gp91s vector generates substantial amounts of superoxide in human cells transplanted into immunodeficient mice. In vitro genotoxicity assays and longitudinal high-throughput integration site analysis in transplanted mice comprising primary and secondary animals for 11 months revealed a safe integration site profile with no signs of clonal dominance.
- Published
- 2013
15. Characterization of nCD64 expression in neutrophils and levels of s-TREM-1 and HMGB-1 in patients with suspected infection admitted in an emergency department
- Author
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Sergio, Velásquez, Juan D, Matute, Laura Y, Gámez, Luis E, Enríquez, Iván D, Gómez, Fabiola, Toro, Martha L, Valencia, Gisela, De La Rosa, Pablo J, Patiño, and Fabián A, Jaimes
- Subjects
Adult ,Male ,Membrane Glycoproteins ,Neutrophils ,Receptors, IgG ,Middle Aged ,Infections ,Prognosis ,Triggering Receptor Expressed on Myeloid Cells-1 ,Hospitalization ,HMGB Proteins ,Humans ,Female ,Prospective Studies ,HMGB1 Protein ,Receptors, Immunologic ,Emergency Service, Hospital ,Biomarkers ,Aged - Abstract
The nCD64 receptor, the soluble triggering receptor expressed in myeloid cells (s-TREM-1), and the high mobility group-box 1 protein (HMGB-1) have been proposed as significant mediators in sepsis.To evaluate the prognostic value of these markers in patients with suspected infection recently admitted in an emergency department (ED).All patients who presented to the ED with suspected infection were eligible for enrollment in this study. Baseline clinical data, Sequential Organ Failure Assessment score (SOFA) score, APACHE II score, HMGB-1 levels, s-TREM-1 levels, and nCD64 levels were analyzed. The HMGB-1 and sTREM-1 serum concentrations were determined using commercially available ELISA kits, and CD64 on the surface of neutrophils was measured by flow cytometry.. A total of 579 patients with suspected infection as their admission diagnosis were enrolled in this study. The median patient age was 50 years (IQR = 35-68). Morbidity during the 28-day followup period was 11.1% (n=64). The most frequent diagnosis at the time of admission was communityacquired pneumonia (CAP) in 23% (n=133) patients, followed by soft tissue infection in 16.6% (n=96), and urinary tract infection in 15% (n=87). After multivariable analysis, no significant association was identified between any biomarker and 28-day mortality.In the context of a tertiary care hospital emergency department in a Latin-American city, the nCD64 receptor, s-TREM-1, and HMGB-1 biomarkers do not demonstrate prognostic utility in the management of patients with infection. The search continues for more reliable prognostic markers in the early stages of infection.
- Published
- 2012
16. Diagnostic accuracy of HMGB-1, sTREM-1, and CD64 as markers of sepsis in patients recently admitted to the emergency department
- Author
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Laura Y, Gámez-Díaz, Luis E, Enriquez, Juan D, Matute, Sergio, Velásquez, Iván D, Gómez, Fabiola, Toro, Sigifredo, Ospina, Victoria, Bedoya, Clara M, Arango, Martha L, Valencia, Gisela, De La Rosa, Carlos I, Gómez, Alex, García, Pablo J, Patiño, and Fabián A, Jaimes
- Subjects
Adult ,Male ,Membrane Glycoproteins ,Receptors, IgG ,Enzyme-Linked Immunosorbent Assay ,Colombia ,Middle Aged ,Sensitivity and Specificity ,Triggering Receptor Expressed on Myeloid Cells-1 ,Cross-Sectional Studies ,Sepsis ,Humans ,Female ,HMGB1 Protein ,Receptors, Immunologic ,Emergency Service, Hospital ,Biomarkers ,APACHE ,Aged ,Glycoproteins - Abstract
The objectives were to evaluate the diagnostic accuracy for sepsis in an emergency department (ED) population of the cluster of differentiation-64 (CD64) glycoprotein expression on the surface of neutrophils (nCD64), serum levels of soluble triggering receptor expressed on myeloid cells-1 (s-TREM-1), and high-mobility group box-1 protein (HMGB-1).Patients with any of the following as admission diagnosis were enrolled: 1) suspected infection, 2) fever, 3) delirium, or 4) acute hypotension of unexplained origin within 24 hours of ED presentation. Levels of nCD64, HMGB-1, and s-TREM-1 were measured within the first 24 hours of the first ED evaluation. Baseline clinical data, Sepsis-related Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation (APACHE II) score, daily clinical and microbiologic information, and 28-day mortality rate were collected. Because there is not a definitive criterion standard for sepsis, the authors used expert consensus based on clinical, microbiologic, laboratory, and radiologic data collected for each patient during the first 7 days of hospitalization. This expert consensus defined the primary outcome of sepsis, and the primary data analysis was based in the comparison of sepsis versus nonsepsis patients. The cut points to define sensitivity and specificity values, as well as positive and negative likelihood ratios (LRs) for the markers related to sepsis diagnosis, were determined using receiver operative characteristics (ROC) curves. The patients in this study were a prespecified nested subsample population of a larger study.Of 631 patients included in the study, 66% (95% confidence interval [CI] = 62% to 67%, n = 416) had sepsis according with the expert consensus diagnosis. Among these sepsis patients, SOFA score defined 67% (95% CI = 62% to 71%, n = 277) in severe sepsis and 1% (95% CI = 0.3% to 3%, n = 6) in septic shock. The sensitivities for sepsis diagnosis were CD64, 65.8% (95% CI = 61.1% to 70.3%); HMGB-1, 57.5% (95% CI = 52.7% to 62.3%); and s-TREM-1, 60% (95% CI = 55.2% to 64.7%). The specificities were CD64, 64.6% (95% CI = 57.8% to 70.8%), HMGB-1, 57.8% (95% CI = 51.1% to 64.3%), and s-TREM-1, 59.2% (95% CI = 52.5% to 65.6%). The positive LR (LR+) for CD64 was 1.85 (95% CI = 1.52 to 2.26) and the negative LR (LR-) was 0.52 (95% CI = 0.44 to 0.62]; for HMGB-1 the LR+ was 1.36 (95% CI = 1.14 to 1.63) and LR- was 0.73 (95% CI = 0.62 to 0.86); and for s-TREM-1 the LR+ was 1.47 (95% CI = 1.22 to 1.76) and the LR- was 0.67 (95% CI = 0.57 to 0.79).In this cohort of patients suspected of having any infection in the ED, the accuracy of nCD64, s-TREM-1, and HMGB-1 was not significantly sensitive or specific for diagnosis of sepsis.
- Published
- 2011
17. p40phox: the last NADPH oxidase subunit
- Author
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Juan D. Matute, Pablo Javier Patiño, Andrés Augusto Arias, and Mary C. Dinauer
- Subjects
Protein subunit ,Biology ,chemistry.chemical_compound ,Chronic granulomatous disease ,Phagocytosis ,medicine ,Humans ,Molecular Biology ,chemistry.chemical_classification ,Reactive oxygen species ,Oxidase test ,Innate immune system ,NADPH oxidase ,Superoxide ,NADPH Oxidases ,Cell Biology ,Hematology ,medicine.disease ,Phosphoproteins ,Immunity, Innate ,Respiratory burst ,Protein Subunits ,chemistry ,Biochemistry ,biology.protein ,Molecular Medicine - Abstract
The phagocytic NADPH-oxidase is a multiprotein system activated during the inflammatory response to produce superoxide anion (O2−), which is the substrate for formation of additional reactive oxygen species (ROS). The importance of this system for innate immunity is established by chronic granulomatous disease (CGD), a primary immunodeficiency caused by defects in the NADPH oxidase. In this review, we present and discuss recent knowledge about p40phox, the last NADPH oxidase component to be identified. Furthermore, its interaction with cellular pathways outside of the NADPH oxidase is discussed. Described in this review is evidence that p40phox participates in NADPH oxidase dynamics within cells, what is known about its role in the oxidase, the possibility that p40phox participates in non-NADPH oxidase processes in phagocytic and non-phagocytic cells and whether p40phox could mediate a similar function in other NADPH oxidases. An improved understanding of p40phox should provide new insights about NADPH oxidase, the physiology of phagocytic cells and the innate immune system.
- Published
- 2005
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