114 results on '"Atkinson TP"'
Search Results
2. Author Correction: GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway.
- Author
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Park AY, Leney-Greene M, Lynberg M, Gabrielski JQ, Xu X, Schwarz B, Zheng L, Balasubramaniyam A, Ham H, Chao B, Zhang Y, Matthews HF, Cui J, Yao Y, Kubo S, Chanchu JM, Morawski AR, Cook SA, Jiang P, Ravell JC, Cheng YH, George A, Faruqi A, Pagalilauan AM, Bergerson JRE, Ganesan S, Chauvin SD, Aluri J, Edwards-Hicks J, Bohrnsen E, Tippett C, Omar H, Xu L, Butcher GW, Pascall J, Karakoc-Aydiner E, Kiykim A, Maecker H, Tezcan İ, Esenboga S, Heredia RJ, Akata D, Tekin S, Kara A, Kuloglu Z, Unal E, Kendirli T, Dogu F, Karabiber E, Atkinson TP, Cochet C, Filhol O, Bosio CM, Davis MM, Lifton RP, Pearce EL, Daumke O, Aytekin C, Şahin GE, Aksu AÜ, Uzel G, Koneti Rao V, Sari S, Dalgıç B, Boztug K, Cagdas D, Haskologlu S, Ikinciogullari A, Schwefel D, Vilarinho S, Baris S, Ozen A, Su HC, and Lenardo MJ
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- 2024
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3. GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway.
- Author
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Park AY, Leney-Greene M, Lynberg M, Gabrielski JQ, Xu X, Schwarz B, Zheng L, Balasubramaniyam A, Ham H, Chao B, Zhang Y, Matthews HF, Cui J, Yao Y, Kubo S, Chanchu JM, Morawski AR, Cook SA, Jiang P, Ravell JC, Cheng YH, George A, Faruqi A, Pagalilauan AM, Bergerson JRE, Ganesan S, Chauvin SD, Aluri J, Edwards-Hicks J, Bohrnsen E, Tippett C, Omar H, Xu L, Butcher GW, Pascall J, Karakoc-Aydiner E, Kiykim A, Maecker H, Tezcan İ, Esenboga S, Heredia RJ, Akata D, Tekin S, Kara A, Kuloglu Z, Unal E, Kendirli T, Dogu F, Karabiber E, Atkinson TP, Cochet C, Filhol O, Bosio CM, Davis MM, Lifton RP, Pearce EL, Daumke O, Aytekin C, Şahin GE, Aksu AÜ, Uzel G, Koneti Rao V, Sari S, Dalgıç B, Boztug K, Cagdas D, Haskologlu S, Ikinciogullari A, Schwefel D, Vilarinho S, Baris S, Ozen A, Su HC, and Lenardo MJ
- Subjects
- Animals, Humans, Longevity genetics, Endothelial Cells metabolism, Mammals metabolism, GTP-Binding Proteins, Ceramides
- Abstract
Preserving cells in a functional, non-senescent state is a major goal for extending human healthspans. Model organisms reveal that longevity and senescence are genetically controlled, but how genes control longevity in different mammalian tissues is unknown. Here, we report a new human genetic disease that causes cell senescence, liver and immune dysfunction, and early mortality that results from deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed in lymphocytes and endothelial cells. We show that GIMAP5 restricts the pathological accumulation of long-chain ceramides (CERs), thereby regulating longevity. GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2), attenuating its ability to activate CER synthases. Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration. Thus, GIMAP5 controls longevity assurance pathways crucial for immune function and healthspan in mammals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2024
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4. Latest Advances in Laboratory Detection of Mycoplasma genitalium.
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Waites KB, Crabb DM, Ratliff AE, Geisler WM, Atkinson TP, and Xiao L
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- Male, Humans, Female, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Laboratories, Drug Resistance, Bacterial, Macrolides, Mycoplasma genitalium genetics, Mycoplasma Infections microbiology, Urethritis microbiology
- Abstract
Mycoplasma genitalium is an important sexually transmitted pathogen affecting both men and women. Its extremely slow growth in vitro and very demanding culture requirements necessitate the use of molecular-based diagnostic tests for its detection in clinical specimens. The recent availability of U.S. Food and Drug Administration (FDA)-cleared commercial molecular-based assays has enabled diagnostic testing to become more widely available in the United States and no longer limited to specialized reference laboratories. Advances in the knowledge of the epidemiology and clinical significance of M. genitalium as a human pathogen made possible by the availability of molecular-based testing have led to updated guidelines for diagnostic testing and treatment that have been published in various countries. This review summarizes the importance of M. genitalium as an agent of human disease, explains the necessity of obtaining a microbiological diagnosis, describes currently available diagnostic methods, and discusses how the emergence of antimicrobial resistance has complicated treatment alternatives and influenced the development of diagnostic tests for resistance detection, with an emphasis on developments over the past few years.
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- 2023
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5. Omadacycline Is Highly Active In Vitro against Mycoplasma genitalium.
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Waites KB, Crabb DM, Atkinson TP, Geisler WM, and Xiao L
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- Humans, Tetracycline pharmacology, Drug Resistance, Bacterial, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Macrolides pharmacology, Minocycline pharmacology, Minocycline therapeutic use, Mitomycin pharmacology, Mitomycin therapeutic use, Protein Synthesis Inhibitors pharmacology, Mycoplasma genitalium, Mycoplasma Infections drug therapy, Quinolones pharmacology, Quinolones therapeutic use
- Abstract
Here, we performed in vitro susceptibility testing on 10 Mycoplasma genitalium isolates against omadacycline, minocycline, tetracycline, doxycycline, moxifloxacin, levofloxacin, and azithromycin. Omadacycline was the most potent agent, with all MICs of ≤0.5 μg/mL. MICs were not affected by resistance to other agents, including resistance to other tetracycline class drugs. Omadacycline may be a potential treatment option for M. genitalium infection. IMPORTANCE There are very few clinical isolates of Mycoplasma genitalium available for in vitro susceptibility testing. We studied 10 isolates and determined that the new semisynthetic aminomethylcycline omadacycline is active against isolates that are resistant to tetracyclines, macrolides, and quinolones. These data suggest that clinical studies should be performed in order to see if omadacycline may be useful to treat urogenital infections caused by M. genitalium.
- Published
- 2022
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6. Corrigendum: Clinical efficacy, safety and tolerability of a new subcutaneous immunoglobulin 16.5% (Octanorm [Cutaquig ® ]) in the treatment of patients with primary immunodeficiencies.
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Kobayashi RH, Gupta S, Melamed I, Mandujano JF, Kobayashi AL, Ritchie B, Geng B, Atkinson TP, Rehman S, Turpel-Kantor E, and Litzman J
- Abstract
[This corrects the article DOI: 10.3389/fimmu.2019.00040.]., (Copyright © 2022 Kobayashi, Gupta, Melamed, Mandujano, Kobayashi, Ritchie, Geng, Atkinson, Rehman, Turpel-Kantor and Litzman.)
- Published
- 2022
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7. Long-term efficacy, safety, and tolerability of a subcutaneous immunoglobulin 16.5% (cutaquig®) in the treatment of patients with primary immunodeficiencies.
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Kobayashi RH, Litzman J, Melamed I, Mandujano JF, Kobayashi AL, Ritchie B, Geng B, Atkinson TP, Rehman S, Höller S, Turpel-Kantor E, Kreuwel H, Speer JC, and Gupta S
- Subjects
- Humans, Prospective Studies, Infusions, Subcutaneous, Immunoglobulin G therapeutic use, Treatment Outcome, Immunoglobulins, Intravenous therapeutic use, Immunologic Deficiency Syndromes drug therapy, Bacterial Infections
- Abstract
A prospective study and its long-term extension examined whether weekly treatment of patients with primary immunodeficiencies (PIDs) with a 16.5% subcutaneous immunoglobulin (SCIg; cutaquig®) confers acceptable efficacy, safety, and tolerability over a follow-up of up to 238 weeks (>4 years). Seventy-five patients received 4462 infusions during up to 70 weeks of follow-up in the main study and 27 patients received 2777 infusions during up to 168 weeks of follow-up in the extension. In the main study, there were no serious bacterial infections (SBIs), and the annual rate of other infections was 3.3 (95% CI 2.4, 4.5). One SBI was recorded in the extension, for an SBI rate of 0.02 (upper 99% CI 0.19). The annual rate of all infections over the duration of the extension study was 2.2 (95% CI 1.2, 3.9). Only 15.0% (1085) of 7239 infusions were associated with infusion site reactions (ISRs), leaving 85.0% (6153) of infusions without reactions. The majority of ISRs were mild and transient. ISR incidence decreased over time, from 36.9% to 16% during the main study and from 9% to 2.3% during the extension. The incidence of related systemic adverse events was 14.7% in the main study and 7.4% in the extension. In conclusion, this prospective, long-term study with cutaquig showed maintained efficacy and low rates of local and systemic adverse reactions in PID patients over up to 238 weeks of follow-up., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology.)
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- 2022
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8. Defective Immune Response to SARS-CoV-2 Immunization in Down Syndrome Correlates With Increased Susceptibility to Severe Illness With Infection.
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Atkinson TP
- Subjects
- Antibody Formation, Humans, SARS-CoV-2, Vaccination, COVID-19, Down Syndrome
- Published
- 2022
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9. Antimicrobial susceptibilities and mechanisms of resistance of commensal and invasive Mycoplasma salivarium isolates.
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Xiao L, Totten AH, Crabb DM, Atkinson TP, and Waites KB
- Abstract
Mycoplasma salivarium , an oral commensal organism, can cause severe invasive infections in immunocompromised individuals. Currently there is no treatment guidance for such infections. We performed antimicrobial susceptibility tests on 39 commensal and invasive M. salivarium isolates and investigated the mechanisms of antimicrobial resistance. Clindamycin was the most active agent [minimum inhibition concentration (MIC) range: 0.004-128 mg/L, MIC
50 = 0.031 mg/L, MIC90 = 0.125 mg/ml], followed by tetracycline and levofloxacin. All isolates were resistant to erythromycin (MIC ≥4 mg/L) due to the presence of 2057A ( Escherichia coli numbering) in 23S rRNA. Three isolates with elevated clindamycin MICs (≥8 mg/L) harbored A2058T/G mutations in 23S rRNA gene; four sequential isolates from one patient developed C2611T and A2059G mutations accompanying the increase of clindamycin MICs. Five isolates with elevated tetracycline MICs (≥4 mg/L) had mutations in 16S rRNA gene (A965G/T, G966T, or A967C/T) and one of them harbored TetM . Nine isolates with elevated levofloxacin MICs (≥4 mg/L) had one or more mutations in gyrA , gyrB , parC , or parE . Susceptibility breakpoints for clindamycin, tetracycline and levofloxacin were suggested to be ≤0.125, ≤2, and ≤2 mg/L, respectively. Antimicrobial resistance to any of the three agents (clindamycin, tetracycline, or levofloxacin) was documented in 12 (34.3%) non-duplicate isolates, of which 10 were invasive. Levofloxacin resistance was most frequent (25.7%). Multi-drug resistance was also observed (14.3%). This study demonstrates the frequent occurrence of antimicrobial resistance in M. salivarium , emphasizing the need for culture and susceptibility testing to guide antimicrobial therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xiao, Totten, Crabb, Atkinson and Waites.)- Published
- 2022
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10. Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia.
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Bertaina A, Grimm PC, Weinberg K, Parkman R, Kristovich KM, Barbarito G, Lippner E, Dhamdhere G, Ramachandran V, Spatz JM, Fathallah-Shaykh S, Atkinson TP, Al-Uzri A, Aubert G, van der Elst K, Green SG, Agarwal R, Slepicka PF, Shah AJ, Roncarolo MG, Gallo A, Concepcion W, and Lewis DB
- Subjects
- Arteriosclerosis genetics, Arteriosclerosis therapy, Graft Rejection prevention & control, Humans, Kidney physiology, Pulmonary Embolism genetics, Pulmonary Embolism therapy, Transplantation Conditioning methods, Hematopoietic Stem Cell Transplantation, Immunologic Deficiency Syndromes therapy, Kidney Transplantation adverse effects, Nephrotic Syndrome genetics, Nephrotic Syndrome therapy, Osteochondrodysplasias genetics, Osteochondrodysplasias therapy, Primary Immunodeficiency Diseases genetics, Primary Immunodeficiency Diseases therapy
- Abstract
Lifelong immunosuppression is required for allograft survival after kidney transplantation but may not ultimately prevent allograft loss resulting from chronic rejection. We developed an approach that attempts to abrogate immune rejection and the need for post-transplantation immunosuppression in three patients with Schimke immuno-osseous dysplasia who had both T-cell immunodeficiency and renal failure. Each patient received sequential transplants of αβ T-cell-depleted and CD19 B-cell-depleted haploidentical hematopoietic stem cells and a kidney from the same donor. Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation. (Funded by the Kruzn for a Kure Foundation.)., (Copyright © 2022 Massachusetts Medical Society.)
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- 2022
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11. Fusobacterium necrophorum oral infections - A need for guidance.
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Centor RM, Atkinson TP, and Xiao L
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- Anti-Bacterial Agents therapeutic use, Fusobacterium necrophorum, Humans, Communicable Diseases drug therapy, Fusobacterium Infections diagnosis, Fusobacterium Infections drug therapy, Fusobacterium Infections microbiology, Lemierre Syndrome diagnosis, Lemierre Syndrome drug therapy, Lemierre Syndrome microbiology, Peritonsillar Abscess diagnosis, Peritonsillar Abscess drug therapy, Peritonsillar Abscess microbiology, Tonsillitis microbiology
- Abstract
F. necrophorum, a gram-negative obligate anaerobe, causes pharyngotonsillitis, peritonsillar abscess and the Lemierre Syndrome as well as other significant infections. Clinical information on this bacterium has increased dramatically over the past 20 years, yet no standard guidance exists for treating these infections. While data support F. necrophorum as a cause of pharyngotonsillitis, no consensus exists on the clinical importance of these findings especially in the 15-30 age group. Similarly, recent data find this bacterium the most frequent and most likely to recur in peritonsillar abscess for that age group. Should this impact how we treat these patients? Finally, we have no studies of either antibiotics or anticoagulation for the Lemierre Syndrome. Thus, each physician making the diagnosis of the Lemierre Syndrome chooses antibiotics (and their duration) and whether or not to anticoagulate without guidance. Infectious disease specialists and hospitalists would benefit from consensus expert opinions based on reviewing data on these infections., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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12. B-assembler: a circular bacterial genome assembler.
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Huang F, Xiao L, Gao M, Vallely EJ, Dybvig K, Atkinson TP, Waites KB, and Chong Z
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- Bacteria genetics, DNA, Humans, Sequence Analysis, DNA methods, Genome, Bacterial, High-Throughput Nucleotide Sequencing methods
- Abstract
Background: Accurate bacteria genome de novo assembly is fundamental to understand the evolution and pathogenesis of new bacteria species. The advent and popularity of Third-Generation Sequencing (TGS) enables assembly of bacteria genomes at an unprecedented speed. However, most current TGS assemblers were specifically designed for human or other species that do not have a circular genome. Besides, the repetitive DNA fragments in many bacterial genomes plus the high error rate of long sequencing data make it still very challenging to accurately assemble their genomes even with a relatively small genome size. Therefore, there is an urgent need for the development of an optimized method to address these issues., Results: We developed B-assembler, which is capable of assembling bacterial genomes when there are only long reads or a combination of short and long reads. B-assembler takes advantage of the structural resolving power of long reads and the accuracy of short reads if applicable. It first selects and corrects the ultra-long reads to get an initial contig. Then, it collects the reads overlapping with the ends of the initial contig. This two-round assembling procedure along with optimized error correction enables a high-confidence and circularized genome assembly. Benchmarked on both synthetic and real sequencing data of several species of bacterium, the results show that both long-read-only and hybrid-read modes can accurately assemble circular bacterial genomes free of structural errors and have fewer small errors compared to other assemblers., Conclusions: B-assembler provides a better solution to bacterial genome assembly, which will facilitate downstream bacterial genome analysis., (© 2022. The Author(s).)
- Published
- 2022
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13. Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity.
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Perelygina L, Faisthalab R, Abernathy E, Chen MH, Hao L, Bercovitch L, Bayer DK, Noroski LM, Lam MT, Cicalese MP, Al-Herz W, Nanda A, Hajjar J, Vanden Driessche K, Schroven S, Leysen J, Rosenbach M, Peters P, Raedler J, Albert MH, Abraham RS, Rangarjan HG, Buchbinder D, Kobrynski L, Pham-Huy A, Dhossche J, Cunningham Rundles C, Meyer AK, Theos A, Atkinson TP, Musiek A, Adeli M, Derichs U, Walz C, Krüger R, von Bernuth H, Klein C, Icenogle J, Hauck F, and Sullivan KE
- Subjects
- Aged, Antigens, Viral metabolism, Cohort Studies, Cytokines metabolism, Disease Susceptibility, Female, Genetic Diseases, Inborn, Hematopoietic Stem Cell Transplantation, Humans, Immunohistochemistry, Immunologic Deficiency Syndromes, Male, Middle Aged, Receptors, Interleukin-1 antagonists & inhibitors, Rubella complications, Th2 Cells immunology, Tumor Necrosis Factor-alpha antagonists & inhibitors, Granuloma immunology, Inflammation immunology, Macrophages immunology, Neutrophils immunology, Rubella immunology, Rubella virus physiology
- Abstract
Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, and a defect of innate immunity were identified as being susceptible to RuV-associated granulomas. Hematopoietic cell transplantation was the most successful treatment in this case series resulting in granuloma resolution; steroids, and TNF-α and IL-1R inhibitors were moderately effective. In addition to M2 macrophages, neutrophils were identified by immunohistochemical analysis as a novel cell type infected with RuV. Four patterns of RuV-associated granulomatous inflammation were classified based on the structural organization of granulomas and identity and location of cell types harboring RuV antigen. Identification of conditions that increase susceptibility to RuV-associated granulomas combined with structural characterization of the granulomas may lead to a better understanding of the pathogenesis of RuV-associated granulomas and discover new targets for therapeutic interventions., Competing Interests: MA is employed by Sidra Medicine and Hamad Medical Corporation, Qatar. HB is employed by Labor Berlin GmbH, Germany. JH received grants from Immune Deficiency Foundation, the US immunodeficiency network, Chao-physician Scientist award, the Texas Medical Center Digestive Diseases Center and the Jeffrey Modell Foundation. JH received honorarium, consultation fees from Horizon, Pharming, Baxalta, CSL Behring, the National guard, and Al-Faisal University Hospital. TPA received consultation fees from Horizon, Pharming, CSL Behring. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Perelygina, Faisthalab, Abernathy, Chen, Hao, Bercovitch, Bayer, Noroski, Lam, Cicalese, Al-Herz, Nanda, Hajjar, Vanden Driessche, Schroven, Leysen, Rosenbach, Peters, Raedler, Albert, Abraham, Rangarjan, Buchbinder, Kobrynski, Pham-Huy, Dhossche, Cunningham Rundles, Meyer, Theos, Atkinson, Musiek, Adeli, Derichs, Walz, Krüger, von Bernuth, Klein, Icenogle, Hauck and Sullivan.)
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- 2021
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14. Genetic Analysis of a Cohort of 275 Patients with Hyper-IgE Syndromes and/or Chronic Mucocutaneous Candidiasis.
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Frede N, Rojas-Restrepo J, Caballero Garcia de Oteyza A, Buchta M, Hübscher K, Gámez-Díaz L, Proietti M, Saghafi S, Chavoshzadeh Z, Soler-Palacin P, Galal N, Adeli M, Aldave-Becerra JC, Al-Ddafari MS, Ardenyz Ö, Atkinson TP, Kut FB, Çelmeli F, Rees H, Kilic SS, Kirovski I, Klein C, Kobbe R, Korganow AS, Lilic D, Lunt P, Makwana N, Metin A, Özgür TT, Karakas AA, Seneviratne S, Sherkat R, Sousa AB, Unal E, Patiroglu T, Wahn V, von Bernuth H, Whiteford M, Doffinger R, Jouhadi Z, and Grimbacher B
- Subjects
- Adolescent, Adult, Candidiasis, Chronic Mucocutaneous blood, Child, Child, Preschool, Cohort Studies, Eczema genetics, Eosinophilia genetics, Female, Humans, Immunoglobulin E blood, Infant, Job Syndrome blood, Male, Middle Aged, Mutation, Young Adult, Candidiasis, Chronic Mucocutaneous genetics, Job Syndrome genetics
- Abstract
Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers., (© 2021. The Author(s).)
- Published
- 2021
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15. Candidatus Mycoplasma haemohominis: Emerging Infection in New Caledonia.
- Author
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Atkinson TP
- Subjects
- Humans, New Caledonia, Mycoplasma genetics, Mycoplasma Infections diagnosis, Mycoplasma Infections epidemiology
- Published
- 2021
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16. Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
- Author
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Le Coz C, Nguyen DN, Su C, Nolan BE, Albrecht AV, Xhani S, Sun D, Demaree B, Pillarisetti P, Khanna C, Wright F, Chen PA, Yoon S, Stiegler AL, Maurer K, Garifallou JP, Rymaszewski A, Kroft SH, Olson TS, Seif AE, Wertheim G, Grant SFA, Vo LT, Puck JM, Sullivan KE, Routes JM, Zakharova V, Shcherbina A, Mukhina A, Rudy NL, Hurst ACE, Atkinson TP, Boggon TJ, Hakonarson H, Abate AR, Hajjar J, Nicholas SK, Lupski JR, Verbsky J, Chinn IK, Gonzalez MV, Wells AD, Marson A, Poon GMK, and Romberg N
- Subjects
- Adolescent, Adult, B-Lymphocytes physiology, Cell Differentiation genetics, Cell Line, Child, Child, Preschool, Dendritic Cells physiology, Female, Gene Expression Regulation, Developmental genetics, HEK293 Cells, Hematopoiesis genetics, Hematopoietic Stem Cells physiology, Humans, Infant, Lymphopoiesis genetics, Male, Mutation genetics, Precursor Cells, B-Lymphoid physiology, Stem Cells physiology, Young Adult, Agammaglobulinemia genetics, Chromatin genetics, Proto-Oncogene Proteins genetics, Trans-Activators genetics
- Abstract
The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper., Competing Interests: Disclosures: D. Nguyen reported a patent to PCT/US2019/066079 with royalties paid. T. Olson reported personal fees from Bluebird Bio outside of the submitted work. J. Puck reported other from Invitae (spouse's employer) and other from UpToDate (royalties) outside the submitted work. J. Hajjar reported grants from Immune Deficiency Foundation, the US immunodeficiency network, Chao-physician Scientist award, the Texas Medical Center Digestive Diseases Center, and the Jeffrey Modell Foundation, other from Horizon, Pharming, Baxalta, CSL Behring, and the National Guard and Al-Faisal University Hospital outside the submitted work. J. Lupski reported grants from NIH/NINDS (R35 NS105078), and NIH/NIGMS (R01 GM106373), personal fees from Regeneron Genetics Center and Novartis, and other from 23andMe outside the submitted work. A. Marson reported personal fees from Arsenal Biosciences, Spotlight Therapeutics, PACT Pharma, Merck, Vertex, AlphaSights, ALDA, Amgen, Trizell, Juno Therapeutics, Health Advances, Lonza, Bernstein, Abbvie, Genentech, Illumina, Arcus, Jackson Laboratories, NanoString Technologies, GLG, and Rupert Case Management, grants from Anthem, Gilead, GlaxoSmithKline, Juno Therapeutics, Epinomics, Sanofi, and Parker Institute for Cancer Immunotherapy (PICI), non-financial support from Illumina, other from Parker Institute for Cancer Immunotherapy (PICI), ThermoFisher, and Third Rock Ventures outside the submitted work. In addition, A. Marson had a patent to WO 2016/123578 licensed (The identity of the licensee has not been made public) and a patent to PCT/US19/66079 licensed (The identity of the licensee has not been made public); and is an investor in and informal advisor to Offline Ventures. No other disclosures were reported., (© 2021 Le Coz et al.)
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- 2021
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17. Treatment of children with primary immunodeficiencies with a subcutaneous immunoglobulin 16.5% (cutaquig ® [octanorm]).
- Author
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Kobayashi RH, Mandujano JF, Rehman SM, Kobayashi AL, Geng B, Atkinson TP, Melamed I, Turpel-Kantor E, Clodi E, and Gupta S
- Subjects
- Adolescent, Child, Child, Preschool, Female, Humans, Immunoglobulins administration & dosage, Infusions, Subcutaneous, Male, Prospective Studies, Immunoglobulins therapeutic use, Primary Immunodeficiency Diseases drug therapy
- Abstract
Background: Subcutaneous human immunoglobulin (16.5%; octanorm/cutaquig
® ) was efficacious and well tolerated in patients with primary immunodeficiencies in a Phase III study. A subanalysis of pediatric data is presented here. Materials & methods: Children (2-16 years) previously treated with intravenous human immunoglobulin received weekly subcutaneous human immunoglobulin infusions over 64 weeks. The main objective was to assess the efficacy of cutaquig in preventing serious bacterial infections. Results: 38 children received 2213 infusions of cutaquig. No serious bacterial infections developed during the study. The rate of other infections was 3.1 per person-year and the rate of adverse drug reactions was 0.083 per infusion. Higher immunoglobulin G trough levels were achieved with cutaquig compared with previous intravenous therapy. Conclusion: Once-weekly infusions of cutaquig were efficacious and well tolerated in children with primary immunodeficiencies.- Published
- 2021
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18. Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas.
- Author
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Friedman GK, Johnston JM, Bag AK, Bernstock JD, Li R, Aban I, Kachurak K, Nan L, Kang KD, Totsch S, Schlappi C, Martin AM, Pastakia D, McNall-Knapp R, Farouk Sait S, Khakoo Y, Karajannis MA, Woodling K, Palmer JD, Osorio DS, Leonard J, Abdelbaki MS, Madan-Swain A, Atkinson TP, Whitley RJ, Fiveash JB, Markert JM, and Gillespie GY
- Subjects
- Adolescent, Brain Neoplasms diagnostic imaging, Brain Neoplasms pathology, Brain Neoplasms radiotherapy, Child, Child, Preschool, Combined Modality Therapy, Female, Glioma diagnostic imaging, Glioma pathology, Glioma radiotherapy, Humans, Kaplan-Meier Estimate, Killer Cells, Natural, Leukocyte Count, Male, T-Lymphocytes, Brain Neoplasms therapy, Glioma therapy, Oncolytic Virotherapy adverse effects
- Abstract
Background: Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or "cold," with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue., Methods: We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (10
7 or 108 plaque-forming units) by controlled-rate infusion over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after G207 administration. Viral shedding from saliva, conjunctiva, and blood was assessed by culture and polymerase-chain-reaction assay. Matched pre- and post-treatment tissue samples were examined for tumor-infiltrating lymphocytes by immunohistologic analysis., Results: Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes., Conclusions: Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically "cold" tumors to "hot." (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.)., (Copyright © 2021 Massachusetts Medical Society.)- Published
- 2021
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19. Septic polyarthritis with Mycoplasma salivarium in a patient with common variable immunodeficiency: case report and review of the literature.
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Totten AH, Xiao L, Crabb DM, Ratliff AE, Waites KB, Hwangpo T, and Atkinson TP
- Abstract
Mycoplasma salivarium is a common mycoplasma usually isolated from human oropharynx, particularly from individuals with periodontal disease. It is also among the more common mycoplasmal contaminants of eukaryotic cell cultures. Although M. salivarium has been isolated occasionally from abscesses and other sterile sites, to our knowledge, only three cases of septic arthritis have been documented in the past due to this organism, all in patients with humoral immunodeficiency. We now report a fourth case of septic polyarthritis in a patient with profound hypoimmunoglobulinemia who had experienced dental abscesses within the preceding 2 years. Our case highlights the importance of considering invasive mycoplasmal infection in hypogammaglobulinemic patients. It is likely of significance that the patient had suffered recurrent dental abscesses as a source of infection with M. salivarium ., Competing Interests: The authors declare that there are no conflicts of interest., (© 2021 The Authors.)
- Published
- 2021
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20. Mycoplasma genitalium Biofilms Contain Poly-GlcNAc and Contribute to Antibiotic Resistance.
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Daubenspeck JM, Totten AH, Needham J, Feng M, Balish MF, Atkinson TP, and Dybvig K
- Abstract
Mycoplasma genitalium is an important etiologic agent of non-gonococcal urethritis (NGU), known for chronicity and multidrug resistance, in which biofilms may play an integral role. In some bacterial species capable of forming biofilms, extracellular polymeric substances (EPS) composed of poly- N -acetylglucosamine (PNAG) are a crucial component of the matrix. Monosaccharide analysis of M. genitalium strains revealed high abundance of GlcNAc, suggesting a biofilm-specific EPS. Chromatograms also showed high concentrations of galactose and glucose as observed in other mycoplasma species. Fluorescence microscopy of M. genitalium biofilms utilizing fluor-coupled lectins revealed differential staining of biofilm structures. Scanning electron microscopy (SEM) showed increasing maturation over time of bacterial "towers" seen in biofilm development. As seen with Mycoplasma pneumoniae , organisms within fully mature M. genitalium biofilms exhibited loss of cell polarization. Bacteria associated with disrupted biofilms exhibited decreased dose-dependent viability after treatment with antibiotics compared to bacteria with intact biofilms. In addition, growth index analysis demonstrated decreases in metabolism in cultures with disrupted biofilms with antibiotic treatment. Taken together, these data suggest that M. genitalium biofilms are a contributing factor in antibiotic resistance., (Copyright © 2020 Daubenspeck, Totten, Needham, Feng, Balish, Atkinson and Dybvig.)
- Published
- 2020
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21. Molecular Characterization of Mycoplasma pneumoniae Isolates in the United States from 2012 to 2018.
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Xiao L, Ratliff AE, Crabb DM, Mixon E, Qin X, Selvarangan R, Tang YW, Zheng X, Dien Bard J, Hong T, Prichard M, Brooks E, Dallas S, Duffy LB, Fowler KB, Atkinson TP, and Waites KB
- Subjects
- Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Drug Resistance, Bacterial, Genotype, Humans, Macrolides pharmacology, United States epidemiology, Mycoplasma pneumoniae genetics, Pneumonia, Mycoplasma drug therapy, Pneumonia, Mycoplasma epidemiology
- Abstract
Mycoplasma pneumoniae is a major cause of community-acquired pneumonia. There are limited data in the United States on the molecular epidemiological characteristics of M. pneumoniae We collected 446 M. pneumoniae -positive specimens from 9 states between August 2012 and October 2018. Culture, antimicrobial susceptibility testing, P1 subtyping, and multilocus VNTR (variable-number tandem repeats) analysis (MLVA) were performed to characterize the isolates. Macrolide-resistant M. pneumoniae (MRMp) was detected in 37 (8.3%) specimens. P1 subtype 2 (P1-2) was the predominant P1 subtype (59.8%). P1 subtype distribution did not change significantly chronologically or geographically. The macrolide resistance rate in P1 subtype 1 (P1-1) samples was significantly higher than that in P1-2 (12.9% versus 5.5%). Six P1-2 variants were identified, including two novel types, and variant 2c was predominant (64.6%). P1-2 variants were distributed significantly differently among geographic regions. Classical P1-2 was more frequent in lower respiratory tract specimens and had longer p1 trinucleotide repeats. Classical P1-2 was most common in MRMp (35.7%), while variant 2c was most common in macrolide-susceptible M. pneumoniae (67.5%). Fifteen MLVA types were identified; 3-5-6-2 (41.7%), 4-5-7-2 (35.3%), and 3-6-6-2 (16.6%) were the major types, and four MLVA clusters were delineated. The distribution of MLVA types varied significantly over time and geographic location. The predominant MLVA type switched from 4-5-7-2 to 3-5-6-2 in 2015. MLVA type was associated with P1 subtypes and P1-2 variant types but not with macrolide resistance. To investigate the M. pneumoniae genotype shift and its impact on clinical presentations, additional surveillance programs targeting more diverse populations and prolonged sampling times are required., (Copyright © 2020 Xiao et al.)
- Published
- 2020
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22. Evaluation of Commercial Molecular Diagnostic Methods for Detection and Determination of Macrolide Resistance in Mycoplasma pneumoniae.
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Leal SM Jr, Totten AH, Xiao L, Crabb DM, Ratliff A, Duffy LB, Fowler KB, Mixon E, Winchell JM, Diaz MH, Benitez AJ, Wolff BJ, Qin X, Tang YW, Gonzalez M, Selvarangan R, Hong T, Brooks E, Dallas S, Atkinson TP, Zheng X, Dien Bard J, and Waites KB
- Subjects
- Anti-Bacterial Agents pharmacology, Drug Resistance, Bacterial, Humans, Macrolides pharmacology, Pathology, Molecular, Mycoplasma pneumoniae genetics, Pneumonia, Mycoplasma diagnosis
- Abstract
We evaluated six commercial molecular tests targeting Mycoplasma pneumoniae , namely, the BioFire FilmArray respiratory panel (RP), the Meridian Alethia Mycoplasma Direct, the GenMark ePlex respiratory pathogen panel (RPP), the Luminex NxTAG RPP, the ELITech ELITe InGenius Mycoplasma MGB research use only (RUO) PCR, and the SpeeDx Resistance Plus MP assays. Laboratory-developed PCR assays at the University of Alabama at Birmingham and the Centers for Disease Control and Prevention were used as reference standards. Among 428 specimens, 212 were designated confirmed positives for M. pneumoniae The highest clinical sensitivities were found with the InGenius PCR (99.5%) and the FilmArray RP (98.1%). The Resistance Plus MP identified 93.3% of the confirmed-positive specimens, whereas 83.6, 64.6, and 55.7% were identified by the ePlex RPP, NxTAG RPP, and Mycoplasma Direct assays, respectively. There was no significant difference between the sensitivity of the reference methods and that of the FilmArray RP and InGenius assays, but the remaining four assays detected significantly fewer positive specimens ( P < 0.05). Specificities of all assays were 99.5 to 100%. The Resistance Plus MP assay detected macrolide resistance in 27/33 specimens, resulting in a sensitivity of 81.8%. This study provides the first large-scale comparison of commercial molecular assays for detection of M. pneumoniae in the United States and identified clear differences among their performance. Additional studies are necessary to explore the impact of various test performances on patient outcome., (Copyright © 2020 American Society for Microbiology.)
- Published
- 2020
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23. Benefit of Anakinra in Treating Pediatric Secondary Hemophagocytic Lymphohistiocytosis.
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Eloseily EM, Weiser P, Crayne CB, Haines H, Mannion ML, Stoll ML, Beukelman T, Atkinson TP, and Cron RQ
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- Adolescent, Child, Child, Preschool, Female, Humans, Male, Retrospective Studies, Treatment Outcome, Interleukin 1 Receptor Antagonist Protein therapeutic use, Lymphohistiocytosis, Hemophagocytic drug therapy, Macrophage Activation Syndrome drug therapy
- Abstract
Objective: To assess the benefit of the recombinant human interleukin-1 receptor antagonist anakinra in treating pediatric patients with secondary hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) associated with rheumatic and nonrheumatic conditions., Methods: A retrospective chart review of all anakinra-treated patients with secondary HLH/MAS was performed at Children's of Alabama from January 2008 through December 2016. Demographic, clinical, laboratory, and genetic characteristics, outcomes data, and information on concurrent treatments were collected from the records and analyzed using appropriate univariate statistical approaches to assess changes following treatment and associations between patient variables and outcomes., Results: Forty-four patients with secondary HLH/MAS being treated with anakinra were identified in the electronic medical records. The median duration of hospitalization was 15 days. The mean pretreatment serum ferritin level was 33,316 ng/ml and dropped to 14,435 ng/ml (57% decrease) within 15 days of the start of anakinra treatment. The overall mortality rate in the cohort was 27%. Earlier initiation of anakinra (within 5 days of hospitalization) was associated with reduced mortality (P = 0.046), whereas thrombocytopenia (platelet count <100,000/μl) and STXBP2 mutations were both associated with increased mortality (P = 0.008 and P = 0.012, respectively). In considering patients according to their underlying diagnosis, those with systemic juvenile idiopathic arthritis (JIA) had the lowest mortality rate, with no deaths among the 13 systemic JIA patients included in the study (P = 0.006). In contrast, those with an underlying hematologic malignancy had the highest mortality rate, at 100% (n = 3)., Conclusion: These findings suggest that anakinra appears to be effective in treating pediatric patients with non-malignancy-associated secondary HLH/MAS, especially when it is given early in the disease course and when administered to patients who have an underlying rheumatic disease., (© 2019, American College of Rheumatology.)
- Published
- 2020
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24. Recurrent microdeletions at chromosome 2p11.2 are associated with thymic hypoplasia and features resembling DiGeorge syndrome.
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Bernstock JD, Totten AH, Elkahloun AG, Johnson KR, Hurst AC, Goldman F, Groves AK, Mikhail FM, and Atkinson TP
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- Animals, Chromosomes, Human, Pair 2 immunology, DiGeorge Syndrome immunology, DiGeorge Syndrome pathology, Female, Forkhead Transcription Factors immunology, Humans, Male, Mice, Mice, Mutant Strains, Thymus Gland immunology, Thymus Gland pathology, Chromosome Deletion, Chromosomes, Human, Pair 2 genetics, DiGeorge Syndrome genetics, Forkhead Transcription Factors genetics, Loss of Function Mutation
- Abstract
Background: Thymic hypoplasia/aplasia occurs as a part of DiGeorge syndrome, which has several known genetic causes, and with loss-of-function mutations in forkhead box N1 (FOXN1)., Objective: We sought to determine the cause of selective T-cell lymphopenia with inverted kappa/lambda ratio in several kindreds., Methods: Patients were identified through newborn screening for severe combined immunodeficiency using the T-cell receptor excision circle assay. Those found to have selective T-cell lymphopenia underwent testing with chromosomal microarray analysis. Three-week-old mice heterozygous for a loss-of-function mutation in forkhead box I3 (FOXI3), a candidate gene within the common deleted region found in patients, were compared with wild-type littermates. Assessments included body and organ weights, flow cytometric analysis of thymocytes and splenocytes, and histologic/transcriptomic analyses of thymic tissue., Results: Five kindreds with similar immunophenotypes that included selective T-cell lymphopenia had overlapping microdeletions at chromosome 2p11.2 that spanned FOXI3 and, in most cases, the immunoglobulin kappa light chain locus. Studies in a mouse knockout strain for FOXI3 revealed smaller body weights and relatively lower thymus weights in heterozygous compared with wild-type animals. Histology and flow cytometry on spleens and thymi from 3-week-old pups for T- and B-cell subsets and epithelial cells did not show any significant qualitative or quantitative differences. Transcriptomic analysis of thymic RNA revealed divergence in global transcriptomic signatures, and Ingenuity Pathway Analysis revealed predicted dysfunction in epithelial adherens junctions., Conclusions: Microdeletions at chromosome 2p11.2 are associated with T-cell lymphopenia and probable thymic hypoplasia in human subjects, and haploinsufficiency for FOXI3, a candidate gene within the deleted region, is the likely underlying cause., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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25. Macrolide-Resistant Mycoplasma pneumoniae in the United States as Determined from a National Surveillance Program.
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Waites KB, Ratliff A, Crabb DM, Xiao L, Qin X, Selvarangan R, Tang YW, Zheng X, Dien Bard J, Hong T, Prichard M, Brooks E, Dallas S, Duffy L, Mixon E, Fowler KB, and Atkinson TP
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Epidemiological Monitoring, Female, Humans, Infant, Male, Microbial Sensitivity Tests, Middle Aged, Mutation, Mycoplasma pneumoniae genetics, Pneumonia, Mycoplasma microbiology, Prevalence, RNA, Ribosomal, 23S genetics, United States epidemiology, Young Adult, Anti-Bacterial Agents pharmacology, Drug Resistance, Bacterial genetics, Macrolides pharmacology, Mycoplasma pneumoniae drug effects, Pneumonia, Mycoplasma epidemiology
- Abstract
There are sparse data to indicate the extent that macrolide-resistant Mycoplasma pneumoniae (MRMp) occurs in the United States or its clinical significance. Between 2015 and 2018, hospitals in 8 states collected and stored respiratory specimens that tested positive for M. pneumoniae and sent them to the University of Alabama at Birmingham, where real-time PCR was performed for detection of 23S rRNA mutations known to confer macrolide resistance. MRMp was detected in 27 of 360 specimens (7.5%). MRMp prevalence was significantly higher in the South and East (18.3%) than in the West (2.1%). A2063G was the predominant 23S rRNA mutation detected. MICs for macrolide-susceptible M. pneumoniae (MSMp) were ≤0.008 μg/ml, whereas MICs for MRMp were 16 to 32 μg/ml. Patients with MRMp infection were more likely to have a history of immunodeficiency or malignancy. Otherwise, there were no other significant differences in the clinical features between patients infected with MRMp and those infected with MSMp, nor were there any differences in radiographic findings, hospitalization rates, viral coinfections, the mean duration of antimicrobial treatment, or clinical outcomes. There was no significant change in MRMp incidence over time or according to age, sex, race/ethnicity, or status as an inpatient or an outpatient. Patients with MRMp were more likely to have received a macrolide prior to presentation, and their treatment was more likely to have been changed to a fluoroquinolone after presentation. This is the first national surveillance program for M. pneumoniae in the United States. Additional surveillance is needed to assess the clinical significance of MRMp and to monitor changes in MRMp prevalence., (Copyright © 2019 American Society for Microbiology.)
- Published
- 2019
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26. A novel in situ multiplex immunofluorescence panel for the assessment of tumor immunopathology and response to virotherapy in pediatric glioblastoma reveals a role for checkpoint protein inhibition.
- Author
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Bernstock JD, Vicario N, Rong L, Valdes PA, Choi BD, Chen JA, DiToro D, Osorio DS, Kachurak K, Gessler F, Johnston JM Jr, Atkinson TP, Whitley RJ, Bag AK, Gillespie GY, Markert JM, Maric D, and Friedman GK
- Abstract
Immunotherapy with oncolytic herpes simplex virus-1 therapy offers an innovative, targeted, less-toxic approach for treating brain tumors. However, a major obstacle in maximizing oncolytic virotherapy is a lack of comprehensive understanding of the underlying mechanisms that unfold in CNS tumors/associated microenvironments after infusion of virus. We demonstrate that our multiplex biomarker screening platform comprehensively informs changes in both topographical location and functional states of resident/infiltrating immune cells that play a role in neuropathology after treatment with HSV G207 in a pediatric Phase 1 patient. Using this approach, we identified robust infiltration of CD8
+ T cells suggesting activation of the immune response following virotherapy; however there was a corresponding upregulation of checkpoint proteins PD-1, PD-L1, CTLA-4, and IDO revealing a potential role for checkpoint inhibitors. Such work may ultimately lead to an understanding of the governing pathobiology of tumors, thereby fostering development of novel therapeutics tailored to produce optimal responses., (© 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.)- Published
- 2019
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27. Mycoplasma pneumoniae Carriage With De Novo Macrolide-Resistance and Breakthrough Pneumonia.
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Alishlash AS, Atkinson TP, Schlappi C, Leal SM Jr, Waites KB, and Xiao L
- Subjects
- Anti-Bacterial Agents therapeutic use, Azithromycin therapeutic use, Bronchoalveolar Lavage Fluid microbiology, Child, Preschool, Female, Humans, Levofloxacin therapeutic use, Polymerase Chain Reaction, Precursor Cell Lymphoblastic Leukemia-Lymphoma, RNA, Ribosomal, 23S genetics, Carrier State microbiology, Drug Resistance, Bacterial genetics, Mycoplasma pneumoniae genetics, Pneumonia, Bacterial drug therapy, Pneumonia, Bacterial microbiology
- Abstract
Mycoplasma pneumoniae pneumonia is prevalent in children and can be followed by upper airway carriage for months. Treatment of M pneumoniae pneumonia with macrolides is widespread and can lead to the development of macrolide resistance. The clinical consequences of chronic M pneumoniae carriage are unknown. In this article, we describe a child with acute lymphoblastic leukemia who developed macrolide-susceptible M pneumoniae pneumonia confirmed by nasopharyngeal secretions polymerase chain reaction and culture with good response to azithromycin. Five months later, the patient developed another M pneumoniae pneumonia that was diagnosed with positive macrolide-resistant M pneumoniae polymerase chain reaction and culture from the bronchoalveolar lavage. The child responded well to fluoroquinolones and eventually was discharged from the hospital. The M pneumoniae recovered from the second pneumonia is a novel strain and is genetically identical to the M pneumoniae that caused the first pneumonia, apart from the macrolide-resistance 23S ribosomal RNA gene. Both isolates are identical in both P1 (subtype 2 with a novel variant, 2bv) and multiple-locus variable number tandem repeat analysis type (53662). This is indicative of chronic M pneumoniae carriage with de novo macrolide-resistance mutation and subsequent breakthrough pneumonia that is reported for the first time here. Children with immunosuppression may be at increased risk of life-threatening macrolide-resistant pneumonia after M pneumoniae carriage. Further studies are required to evaluate the impact of this phenomenon. This will then guide strategies to limit the associated morbidity, such as testing for macrolide resistance, treatment of M pneumoniae pneumonia in high-risk children with bactericidal antibiotics (such as fluoroquinolones), and possibly eradication protocols of M pneumoniae carriage to prevent subsequent life-threatening infections., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)
- Published
- 2019
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28. Differential Susceptibility of Mycoplasma and Ureaplasma Species to Compound-Enhanced Copper Toxicity.
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Totten AH, Crawford CL, Dalecki AG, Xiao L, Wolschendorf F, and Atkinson TP
- Abstract
Rationale: Mycoplasmas represent important etiologic agents of many human diseases. Due to increasing antimicrobial resistance and slow rate of novel discovery, unconventional methods of drug discovery are necessary. Copper ions are utilized in host microbial killing, and bacteria must regulate intracellular Cu concentrations to avoid toxicity. We hypothesized that human mollicutes may have susceptibility to Cu-induced toxicity, and compounds that augment copper-dependent killing., Methods: Mycoplasma pneumoniae (Mpn), Ureaplasma parvum (Up), Ureaplasma urealyticum (Uu), and Mycoplasma hominis (Mh) were exposed to CuSO
4 to determine minimal inhibitory concentrations (MICs). Once inhibitory concentrations had been determined, bacteria were treated with an FDA-approved drug disulfiram (DSF), glyoxal bis(4-methyl-3-thiosemicarbazone) (GTSM), and 2,9-dimethyl-1,10-phenanthroline (neocuproine), with or without Cu2+ , to determine compound MICs., Results: Ureaplasma species and Mh were able to tolerate 30-60 μM CuSO4 , while Mpn tolerated over 10-fold higher concentrations (>1 mM). GTSM inhibited growth of all four organisms, but was unaffected by Cu2+ addition. Inhibition by GTSM was reduced by addition of the cell-impermeant Cu chelator, bathocuproine disulfonate (BCS). Neocuproine exhibited Cu-dependent growth inhibition of all organisms. DSF exhibited Cu-dependent growth inhibition against Mh at low micromolar concentrations, and at intermediate concentrations for Mpn., Conclusion: MICs for CuSO4 differ widely among human mollicutes, with higher MICs for Mpn compared to Mh, Uu, and Up. DSF and Neocuproine exhibit Cu-dependent inhibition of mollicutes with copper concentrations between 25 and 50 μM. GTSM has copper-dependent anti-microbial activity at low levels of copper. Drug enhanced copper toxicity is a promising avenue for novel therapeutic development research with Mycoplasma and Ureaplasma species.- Published
- 2019
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29. A unique phenotype of T-cell acute lymphoblastic leukemia in a patient with GATA2 haploinsufficiency.
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Esparza O, Xavier AC, Atkinson TP, Hill BC, and Whelan K
- Subjects
- Child, Female, Humans, Phenotype, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma etiology, Prognosis, GATA2 Deficiency complications, Haploinsufficiency, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology
- Abstract
Germline or acquired mutations involving the GATA-binding protein gene (GATA2) have been linked to a variety of clinical conditions. In addition, patients harboring GATA2 mutations have a striking predisposition to develop myeloid malignancies, such as myelodysplastic syndrome or acute myeloid leukemia, but not acute lymphoblastic leukemia (ALL). We report here a unique occurrence of early T-cell precursor ALL in a young child with GATA2 haploinsufficiency., (© 2019 Wiley Periodicals, Inc.)
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- 2019
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30. Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease.
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Dorjbal B, Stinson JR, Ma CA, Weinreich MA, Miraghazadeh B, Hartberger JM, Frey-Jakobs S, Weidinger S, Moebus L, Franke A, Schäffer AA, Bulashevska A, Fuchs S, Ehl S, Limaye S, Arkwright PD, Briggs TA, Langley C, Bethune C, Whyte AF, Alachkar H, Nejentsev S, DiMaggio T, Nelson CG, Stone KD, Nason M, Brittain EH, Oler AJ, Veltri DP, Leahy TR, Conlon N, Poli MC, Borzutzky A, Cohen JI, Davis J, Lambert MP, Romberg N, Sullivan KE, Paris K, Freeman AF, Lucas L, Chandrakasan S, Savic S, Hambleton S, Patel SY, Jordan MB, Theos A, Lebensburger J, Atkinson TP, Torgerson TR, Chinn IK, Milner JD, Grimbacher B, Cook MC, and Snow AL
- Subjects
- Adult, Female, Humans, Male, Mutation, Phenotype, CARD Signaling Adaptor Proteins genetics, CARD Signaling Adaptor Proteins immunology, Guanylate Cyclase genetics, Guanylate Cyclase immunology, Immune System Diseases genetics, Immune System Diseases immunology
- Abstract
Background: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing., Objectives: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles., Methods: Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants., Results: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein., Conclusion: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity., (Published by Elsevier Inc.)
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- 2019
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31. Allergic airway sensitization impairs antibacterial IgG antibody responses during bacterial respiratory tract infections.
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Totten AH, Xiao L, Luo D, Briles D, Hale JY, Crabb DM, Schoeb TR, Alishlash AS, Waites KB, and Atkinson TP
- Subjects
- Allergens immunology, Animals, Asthma pathology, Asthma physiopathology, Cytokines genetics, Lung pathology, Lung physiopathology, Mice, Inbred BALB C, Mice, Knockout, Ovalbumin immunology, Pneumococcal Infections pathology, Pneumococcal Infections physiopathology, Pneumonia, Mycoplasma pathology, Pneumonia, Mycoplasma physiopathology, Receptors, Cell Surface genetics, Respiratory Tract Infections pathology, Respiratory Tract Infections physiopathology, Asthma immunology, Immunoglobulin G immunology, Pneumococcal Infections immunology, Pneumonia, Mycoplasma immunology, Respiratory Tract Infections immunology
- Abstract
Background: Mycoplasma pneumoniae, an atypical human pathogen, has been associated with asthma initiation and exacerbation. Asthmatic patients have been reported to have higher carriage rates of M pneumoniae compared with nonasthmatic subjects and are at greater risk for invasive respiratory infections., Objective: We sought to study whether prior allergen sensitization affects the host response to chronic bacterial infection., Methods: BALB/cJ and IL-4 receptor α
-/- mice were sensitized with ovalbumin (OVA) and then infected with M pneumoniae or Streptococcus pneumoniae. Immune parameters were analyzed at 30 days postinfection and included cellular profiles in bronchoalveolar lavage fluid (BALF) and serum IgG and IgE antibody levels to whole bacterial lysate, recombinant P1 adhesin, and OVA. Total lung RNA was examined for transcript levels, and BALF was examined for cytokine protein profiles., Results: Anti-M pneumoniae antibody responses were decreased in allergen-sensitized, M pneumoniae-infected animals compared with control animals, but OVA-specific IgG responses were unaffected. Similar decreases in anti-S pneumoniae antibody levels were found in OVA-sensitized animals. However, M pneumoniae, but not S pneumoniae, infection augmented anti-OVA IgE antibody responses. Loss of IL-4 receptor signaling partially restored anti-M pneumoniae antibody responses in IgG2a and IgG2b subclasses. Inflammatory cytokine levels in BALF from OVA-sensitized, M pneumoniae-infected or S pneumoniae-infected animals were reduced compared with those in uninfected OVA-sensitized control animals. Unexpectedly, airway hyperreactivity to methacholine was essentially ablated in M pneumoniae-infected, OVA-sensitized animals., Conclusions: An established type 2-biased host immune response impairs the host immune response to respiratory bacterial infection in a largely pathogen-independent manner. Some pathogens, such as M pneumoniae, can augment ongoing allergic responses and inhibit pulmonary type 2 cytokine responses and allergic airway hyperreactivity., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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32. Clinical Efficacy, Safety and Tolerability of a New Subcutaneous Immunoglobulin 16.5% (Octanorm [Cutaquig®]) in the Treatment of Patients With Primary Immunodeficiencies.
- Author
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Kobayashi RH, Gupta S, Melamed I, Mandujano JF, Kobayashi AL, Ritchie B, Geng B, Atkinson TP, Rehman S, Turpel-Kantor E, and Litzman J
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Humans, Immunoglobulin G administration & dosage, Immunoglobulin G blood, Immunoglobulins, Intravenous administration & dosage, Immunoglobulins, Intravenous pharmacokinetics, Immunoglobulins, Intravenous therapeutic use, Infusions, Subcutaneous, Male, Middle Aged, Young Adult, Immunization, Passive methods, Immunologic Deficiency Syndromes drug therapy
- Abstract
Introduction: Subcutaneously administered immunoglobulin (SCIG) is increasingly used to treat patients with primary immunodeficiencies (PIDs). Octanorm (marketed as cutaquig® in USA and Canada) is a new 16.5% solution of human SCIG, manufactured by a process based on that of the intravenous preparation (IVIG) octagam®. Objectives: To investigate the efficacy, safety and tolerability of octanorm in a prospective, open-label, single-arm phase 3 study involving adult and pediatric patients with PIDs (NCT01888484; clinicaltrials.gov/ct2/show/NCT01888484). Methods: Patients who were previously treated with IVIG received a total of 64 weekly SCIG infusions, including 12 weekly infusions during the wash-in/wash-out period, followed by 52 weekly infusions during the evaluation period. Results: A total of 61 patients aged 2-73 years received 3,497 infusions of octanorm. The mean dose per patient was 0.175 g/kg/infusion. The mean calculated dose conversion factor from the patients' previous IVIG dose for octanorm was 1.37. No serious bacterial infections developed during the study. The rate of other infections per person-year during the primary observation period was 3.43 (upper 95% CI 4.57). All but one non-bacterial infection were mild or moderate in intensity. IgG trough levels were constant during the course of the study. Eleven patients (18.0%) experienced 14 mild or moderate systemic adverse events (AEs) related to octanorm. The rate of related AEs per infusion was 0.004. In 76.7% of infusions, no infusion site reactions were observed and only two (0.3%) reactions were deemed severe. The incidence of site reactions decreased with successive infusions. Conclusion: The new 16.5% SCIG octanorm was shown to be efficacious in preventing infections in PIDs, and was well tolerated.
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- 2019
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33. Epidermodysplasia verruciformis in a young adult with activated PI3Kδ syndrome.
- Author
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Donaldson SL, Purnell JC, Pavlidakey PG, Atkinson TP, and Kissel R
- Published
- 2019
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34. A previously unrecognized 22q13.2 microdeletion syndrome that encompasses TCF20 and TNFRSF13C.
- Author
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Upadia J, Gonzales PR, Atkinson TP, Schroeder HW, Robin NH, Rudy NL, and Mikhail FM
- Subjects
- Alleles, Chromosome Deletion, Chromosomes, Human, Pair 22 genetics, Comparative Genomic Hybridization, Cytogenetic Analysis, Female, Genetic Association Studies, Humans, Infant, Mutation, B-Cell Activation Factor Receptor genetics, Chromosome Disorders diagnosis, Chromosome Disorders genetics, Phenotype, Transcription Factors genetics
- Abstract
Phelan-McDermid syndrome (PMS, OMIM 606232) is a heterozygous contiguous gene microdeletion syndrome occurring at the distal region of chromosome 22q13. This deletion encompasses the SHANK3 gene at 22q13.33, which is thought to be the critical gene for the neurodevelopmental features seen in this syndrome. PMS is typically characterized by intellectual disability, autism spectrum disorder, absent to severely delayed speech, neonatal hypotonia, and dysmorphic features. Two patients presenting with classic clinical features of PMS have been reported to have interstitial microdeletions in the 22q13.2 region that map proximal to the SHANK3 gene (0.54 and 0.72 Mb, respectively). Here, we describe a 13-month-old girl with a de novo 1.16 Mb interstitial deletion in the 22q13.2 region who presented with global developmental delay, subtle dysmorphic features, and immunodeficiency. This deletion overlaps with the two previously published cases and five cases from the DECIPHER database. All eight patients share features common to patients with PMS including developmental delay and language delay, which suggests that this represents a previously unrecognized microdeletion syndrome in the 22q13.2 region. Our patient's deletion encompasses the TCF20 and TNFRSF13C genes, which are thought to play causative roles in the patient's neurodevelopmental and immunological features, respectively., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
- Full Text
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35. A rapid and simple chemical method for the preparation of Ag colloids for surface-enhanced Raman spectroscopy using the Ag mirror reaction.
- Author
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Panneerselvam R, Xiao L, Waites KB, Atkinson TP, and Dluhy RA
- Abstract
Colloidal silver (Ag) nanoparticles (AgNP) have been widely used for surface-enhanced Raman spectroscopy (SERS) applications. We report a simple, rapid and effective method to prepare AgNP colloids for SERS using the classic organic chemistry Ag mirror reaction with Tollens' reagent. The AgNP colloid prepared with this process was characterized using SEM, and the reaction conditions further optimized using SERS measurements. It was found that Ag mirror reaction conditions that included 20 mM AgNO3, 5 min reaction time, and 0.5 M glucose produced AgNP colloids with an average size of 319.1 nm (s.d ±128.1). These AgNP colloids exhibited a significant SERS response when adenine was used as the reporter molecule. The usefulness of these new AgNP colloids was demonstrated by detecting the nucleotides adenosine 5'-monophosphate (AMP), guanosine 5'-monophosphate (GMP), cytidine 5'-monophosphate (CMP), and uridine 5'-monophosphate (UMP). A detection limit of 500 nM for AMP was achieved with the as-prepared AgNP colloid. The bacterium Mycoplasma pneumoniae was also easily detected in laboratory culture with these SERS substrates. These findings attest to the applicability of this AgNP colloid for the sensitive and specific detection of both small biomolecules and microorganisms.
- Published
- 2018
- Full Text
- View/download PDF
36. Reactions to psychological contract breaches and organizational citizenship behaviours: An experimental manipulation of severity.
- Author
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Atkinson TP, Matthews RA, Henderson AA, and Spitzmueller C
- Subjects
- Adult, Contracts, Female, Humans, Male, Middle Aged, Young Adult, Employment psychology, Organizational Culture, Social Behavior
- Abstract
Grounded in affective events theory, we investigated the effects of experimentally manipulated psychological contract breaches on participants' feelings of violation, subsequent perceptions of psychological contract strength, and organizational citizenship behaviours in a sample of working adults. Results support previous findings that pre-existing relational psychological contract strength interacts with severity of unmet promises or expectations. Specifically, individuals with high relational contracts who experience low severity of unmet promises/expectations have the lowest breach perceptions, whereas individuals with high relational contracts who experience more severe levels unmet promises/expectations experience the highest level of breach perceptions. Results also support the concept of a breach spiral in that prior perceptions of breach led to an increased likelihood of subsequent perceptions of breach following the experimental manipulation. Furthermore, consistent with affective events theory, results support the argument that a psychological contract breach's effect on specific organizational citizenship behaviours is mediated by feelings of violation and the reassessment of relational contracts. These effects were present even after controlling for the direct effects of the manipulated severity of unmet promises/expectations., (Copyright © 2018 John Wiley & Sons, Ltd.)
- Published
- 2018
- Full Text
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37. Analysis of the tonsillar microbiome in young adults with sore throat reveals a high relative abundance of Fusobacterium necrophorum with low diversity.
- Author
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Atkinson TP, Centor RM, Xiao L, Wang F, Cui X, Van Der Pol W, Morrow CD, Ratliff AE, Crabb DM, Totten AH, Estrada CA, Faircloth MB, and Waites KB
- Subjects
- Adolescent, Adult, Case-Control Studies, Female, Fusobacterium necrophorum genetics, High-Throughput Nucleotide Sequencing, Humans, Male, RNA, Ribosomal, 16S genetics, Real-Time Polymerase Chain Reaction, Young Adult, Fusobacterium necrophorum physiology, Microbiota, Palatine Tonsil microbiology, Pharyngitis microbiology
- Abstract
Fusobacterium necrophorum (Fn), a gram-negative anaerobe, is increasingly implicated as an etiologic agent in older adolescents and young adults with sore throat. Inadequately treated Fn pharyngitis may result in suppurative complications such as peritonsillar abscess and Lemierre's syndrome. Data from the literature suggest that the incidence of life-threating complications in these age groups from Fn pharyngitis (Lemierre's syndrome) in the United States exceeds those associated with group A beta-hemolytic streptococcal (GAS) pharyngitis (acute rheumatic fever). Using real-time PCR, we previously reported about a 10% prevalence of Fn in asymptomatic medical students and about 20% in students complaining of sore throat at a university student health clinic (p = 0.009). In this study, a comprehensive microbiome analysis of the same study samples confirms that Fn pharyngitis was more common than GAS pharyngitis. Eighteen patients were found to have Fn OTU values exceeding an arbitrary cutoff value of 0.1, i.e. greater than 10% of total sequences, with five subjects reaching values above 0.7. By contrast only 9 patients had GAS OTU values greater than 0.1 and none exceeded 0.6. When the data were analyzed using five separate assessments of alpha diversity, in each case for Fn there were statistically significant differences between Fn positive_high (OTU abundance > 0.1) vs control, Fn positive_high vs Fn negative (OTU abundance = 0), Fn positive_high vs Fn positive_low (OTU abundance > 0 and < 0.1). When the data were analyzed using three beta diversity indexes (Bray-Curtis, weighted unifrac, and unweighted unifrac), there were statistically significant differences between Fn positive_high (OTU abundance ≥ 0.1) vs control for all three. Statistically significant differences remained if we chose somewhat different OTU abundance cutoffs of 0.05 or 0.15. We conclude that Fn appears to play a dominant role in bacterial pharyngitis in the older adolescent and young adult age groups and that the development of a productive mucosal infection with Fn is linked to a significant decrease in the diversity of the associated tonsillar microbiome.
- Published
- 2018
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38. Mycoplasma pneumoniae from the Respiratory Tract and Beyond.
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Waites KB, Xiao L, Liu Y, Balish MF, and Atkinson TP
- Subjects
- Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Drug Resistance, Bacterial, Humans, Molecular Epidemiology, Mycoplasma pneumoniae drug effects, Pneumonia, Mycoplasma drug therapy, Pneumonia, Mycoplasma epidemiology, United States, Mycoplasma pneumoniae physiology, Pneumonia, Mycoplasma microbiology, Respiratory System microbiology
- Abstract
Mycoplasma pneumoniae is an important cause of respiratory tract infections in children as well as adults that can range in severity from mild to life-threatening. Over the past several years there has been much new information published concerning infections caused by this organism. New molecular-based tests for M. pneumoniae detection are now commercially available in the United States, and advances in molecular typing systems have enhanced understanding of the epidemiology of infections. More strains have had their entire genome sequences published, providing additional insights into pathogenic mechanisms. Clinically significant acquired macrolide resistance has emerged worldwide and is now complicating treatment. In vitro susceptibility testing methods have been standardized, and several new drugs that may be effective against this organism are undergoing development. This review focuses on the many new developments that have occurred over the past several years that enhance our understanding of this microbe, which is among the smallest bacterial pathogens but one of great clinical importance., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
- Full Text
- View/download PDF
39. Inter- and intra-strain variability of tandem repeats in Mycoplasma pneumoniae based on next-generation sequencing data.
- Author
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Zhang J, Song X, Ma MJ, Xiao L, Kenri T, Sun H, Ptacek T, Li S, Waites KB, Atkinson TP, Shibayama K, Dybvig K, and Feng Y
- Subjects
- DNA Copy Number Variations, DNA, Bacterial genetics, Genetic Loci, Genetic Markers, Genotyping Techniques, Sequence Analysis, DNA, High-Throughput Nucleotide Sequencing methods, Minisatellite Repeats, Mycoplasma pneumoniae genetics
- Abstract
Aim: To characterize inter- and intra-strain variability of variable-number tandem repeats (VNTRs) in Mycoplasma pneumoniae to determine the optimal multilocus VNTR analysis scheme for improved strain typing., Methods: Whole genome assemblies and next-generation sequencing data from diverse M. pneumoniae isolates were used to characterize VNTRs and their variability, and to compare the strain discriminability of new VNTR and existing markers., Results: We identified 13 VNTRs including five reported previously. These VNTRs displayed different levels of inter- and intra-strain copy number variations. All new markers showed similar or higher discriminability compared with existing VNTR markers and the P1 typing system., Conclusion: Our study provides novel insights into VNTR variations and potential new multilocus VNTR analysis schemes for improved genotyping of M. pneumoniae.
- Published
- 2017
- Full Text
- View/download PDF
40. Ureaplasma infection-mediated release of matrix metalloproteinase-9 and PGP: a novel mechanism of preterm rupture of membranes and chorioamnionitis.
- Author
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Lal CV, Xu X, Jackson P, Atkinson TP, Faye-Petersen OM, Kandasamy J, Waites K, Biggio JR, Gaggar A, and Ambalavanan N
- Subjects
- Amniotic Fluid metabolism, Collagen metabolism, Female, Humans, Mitochondrial Proteins metabolism, Models, Biological, Peptide Fragments metabolism, Pregnancy, Proline metabolism, Serine Endopeptidases metabolism, Spectrometry, Mass, Electrospray Ionization, Tandem Mass Spectrometry, Chorioamnionitis etiology, Chorioamnionitis metabolism, Fetal Membranes, Premature Rupture etiology, Fetal Membranes, Premature Rupture metabolism, Matrix Metalloproteinase 9 metabolism, Oligopeptides metabolism, Pregnancy Complications, Infectious metabolism, Proline analogs & derivatives, Ureaplasma Infections complications, Ureaplasma Infections metabolism
- Abstract
Background: Premature rupture of membranes and preterm delivery are associated with Ureaplasma infection. We hypothesized that Ureaplasma induced extracellular collagen fragmentation results in production of the tripeptide PGP (proline-glycine-proline), a neutrophil chemoattractant. PGP release from collagen requires matrix metalloproteases (MMP-8/MMP-9) along with a serine protease, prolyl endopeptidase (PE)., Methods: Ureaplasma culture negative amniotic fluid (indicated preterm birth, n = 8; spontaneous preterm birth, n = 8) and Ureaplasma positive amniotic fluid (spontaneous preterm birth, n = 8) were analyzed by electro-spray ionization-liquid chromatography tandem mass spectrometry for PGP, and for MMP-9 by zymography. PE was evaluated in lysates of U. parvum serovar 3 (Up3) and U. urealyticum serovar 10 (Uu10) by western blotting and activity assay., Results: PGP and MMP-9 were increased in amniotic fluid from spontaneous preterm birth with positive Ureaplasma cultures, but not with indicated preterm birth or spontaneous preterm birth with negative Ureaplasma cultures. Human neutrophils cocultured with Ureaplasma strains showed increased MMP-9 activity. PE presence and activity were noted with both Ureaplasma strains., Conclusion: Ureaplasma spp. carry the protease necessary for PGP release, and PGP and MMP-9 are increased in amniotic fluid during Ureaplasma infection, suggesting Ureaplasma spp. induced collagen fragmentation contributes to preterm rupture of membranes and neutrophil influx causing chorioamnionitis., Competing Interests: Conflicts of interest/Financial Disclosures: There are no conflicts of interest or financial disclosures (other than funding as stated above) for any of the authors.
- Published
- 2017
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41. Shaken or stirred?: Comparison of methods for dispersion of Mycoplasma pneumoniae aggregates for persistence in vivo.
- Author
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Totten AH, Xiao L, Crabb DM, Ratliff AE, Dybvig K, Waites KB, and Atkinson TP
- Subjects
- Animals, Bacterial Adhesion, Colony Count, Microbial, Disease Models, Animal, Female, Host-Pathogen Interactions, Lung microbiology, Mice, Mice, Inbred BALB C, Microbial Viability, Microscopy, Electron, Scanning Transmission, Mycoplasma pneumoniae classification, Particle Size, Pneumonia, Mycoplasma diagnosis, Pneumonia, Mycoplasma microbiology, RNA, Bacterial genetics, Sonication, Tenericutes isolation & purification, Bacteriological Techniques, Mycoplasma pneumoniae isolation & purification, RNA, Bacterial isolation & purification
- Abstract
Background: Mycoplasma pneumoniae (Mpn), one of the smallest self-replicating prokaryotes, is known to readily adhere to host cells and to form aggregates in suspension. Having only one cell membrane and no cell wall, mycoplasmas present questions as to optimal aggregate disruption method while minimizing cell death in vitro. We compared conventional vortex mixing with other methods for disruption of bacterial aggregates and for its effect on cell viability., Methods: Strain UAB PO1, a clinical Mpn isolate, was dispersed using a conventional vortex mixer with or without nonionic detergent (0.1% and 0.01% Tween-20), a probe-type ultrasonicator, or repeated passage through a 27-gauge needle. The resulting suspensions were assayed for recoverable colony-forming units (CFU). Flow cytometric assays were carried out to examine particle size and membrane integrity with the transmembrane potential dye DiBAC
4 . Wet Scanning Transmission Electron Microscopy (Wet-STEM) was performed for high resolution imaging of the resultant cell suspensions. Additional Mpn strains and other human mollicute species were assayed in a similar manner. Mice were infected with either vortexed or sonicated UAB PO1 and bacterial persistence was examined via Mpn-specific 16S qPCR., Results: Comparison between dispersion methods showed a 10-fold enrichment of recoverable Mpn CFU with sonication compared to other methods. Time-course analysis showed significantly lower bacterial CFU with vortexing compared to sonication at all time points. Flow cytometric analysis showed increased cellular membrane damage via DiBAC4 staining in sonicated suspensions, but a decreased particle size. Wet-STEM imaging showed markedly improved dispersion with sonication compared to conventional vortex treatment, and surprisingly vortexing for 30s produced up to a 100-fold drop in CFU. Results similar to UAB PO1 were obtained with three additional Mpn strains and other Mollicutes species, although they exhibited differential susceptibilities to disaggregation by sonication. Finally, increased persistence of the organism in a mouse model of infection was observed using sonicated suspensions for initial infection., Conclusions: Sonication is superior to vortexing with or without nonionic detergent or repeated 27-gauge needle passage for dispersion of Mpn aggregates while preserving cell viability. Preparation of Mpn suspensions for in vivo experiments is best accomplished using brief sonication due to the dramatic increase in CFU produced by sonication. Dispersion methods may affect the final experimental results and should be an important consideration for future research involving mycoplasma species., (Copyright © 2016 Elsevier B.V. All rights reserved.)- Published
- 2017
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42. Dermatological clues to the diagnosis of atypical complete DiGeorge syndrome.
- Author
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Seminario-Vidal L, Kole L, Knapp C, Fort P, Kankirawatana S, Atkinson TP, McKay KM, and Theos A
- Subjects
- DiGeorge Syndrome complications, Humans, Infant, Male, Skin Diseases etiology, Skin Diseases pathology, DiGeorge Syndrome diagnosis, Skin pathology, Skin Diseases diagnosis
- Abstract
Atypical complete DiGeorge syndrome (DGS) is an extremely rare congenital disease characterized by an eczematous dermatitis, lymphadenopathy, and an oligoclonal T-cell proliferation. Because its initial presentation may be confused with other types of eczematous dermatitis, diagnosis and treatment are usually delayed. We describe herein a case of an infant with atypical complete DGS to draw attention to the clinical and histopathological findings that lead us to the diagnosis.
- Published
- 2016
43. Killer cell immunoglobulin-like receptors are associated with common variable immune deficiency pathogenesis.
- Author
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Wang Y, Hwangpo T, Martin MP, Vince N, Qi Y, Reynolds RJ 4th, Absher D, Gao X, Ballinger CA, Burrows PD, Atkinson TP, Brown EE, Elgavish A, Liu C, Carrington M, and Schroeder HW
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Genes, MHC Class I immunology, Genotype, Humans, Killer Cells, Natural immunology, Male, Middle Aged, T-Lymphocyte Subsets immunology, Young Adult, Common Variable Immunodeficiency genetics, Common Variable Immunodeficiency immunology, Receptors, KIR genetics, Receptors, KIR immunology
- Abstract
Competing Interests: of potential conflict of interests. The authors declare they have no relevant conflicts of interest.
- Published
- 2016
- Full Text
- View/download PDF
44. The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1.
- Author
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Depner M, Fuchs S, Raabe J, Frede N, Glocker C, Doffinger R, Gkrania-Klotsas E, Kumararatne D, Atkinson TP, Schroeder HW Jr, Niehues T, Dückers G, Stray-Pedersen A, Baumann U, Schmidt R, Franco JL, Orrego J, Ben-Shoshan M, McCusker C, Jacob CM, Carneiro-Sampaio M, Devlin LA, Edgar JD, Henderson P, Russell RK, Skytte AB, Seneviratne SL, Wanders J, Stauss H, Meyts I, Moens L, Jesenak M, Kobbe R, Borte S, Borte M, Wright DA, Hagin D, Torgerson TR, and Grimbacher B
- Subjects
- Adult, Candidiasis, Chronic Mucocutaneous genetics, Cells, Cultured, Cytokines metabolism, DNA Mutational Analysis, Female, Humans, Immunologic Deficiency Syndromes genetics, Male, Pedigree, Phenotype, Protein Structure, Tertiary genetics, STAT1 Transcription Factor genetics, Candidiasis, Chronic Mucocutaneous diagnosis, Immunologic Deficiency Syndromes diagnosis, Leukocytes, Mononuclear immunology, Mutation genetics, STAT1 Transcription Factor metabolism
- Abstract
Purpose: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients., Methods: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients., Results: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%). Out of 39 familial cases from 11 families, 26 patients (67%) from 9 families and out of 18 sporadic cases, 9 patients (50%) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients., Conclusion: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.
- Published
- 2016
- Full Text
- View/download PDF
45. LMX, Breach Perceptions, Work-Family Conflict, and Well-Being: A Mediational Model.
- Author
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Hill RT, Morganson VJ, Matthews RA, and Atkinson TP
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Organization and Administration, Psychological Theory, Conflict, Psychological, Employment psychology, Family psychology, Interpersonal Relations, Personal Satisfaction
- Abstract
Despite research advances, work-family scholars still lack an understanding of how leadership constructs relate to an employee's ability to effectively manage the work-family interface. In addition, there remains a need to examine the process through which leadership and work-family conflict influence well-being outcomes. Using a sample of 312 workers, a mediated process model grounded in social exchange theory is tested wherein the authors seek to explain how leaders shape employee perceptions, which, in turn, impact organizational fulfillment of expectations (i.e., psychological contract breach), work-family conflict, and well-being. A fully latent structural equation model was used to test study hypotheses, all of which were supported. Building on existing theory, findings suggest that the supervisor plays a critical role as a frontline representative for the organization and that work-family conflict is reduced and well-being enhanced through a process of social exchange between the supervisor and worker.
- Published
- 2016
- Full Text
- View/download PDF
46. Comparative genome analysis of Mycoplasma pneumoniae.
- Author
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Xiao L, Ptacek T, Osborne JD, Crabb DM, Simmons WL, Lefkowitz EJ, Waites KB, Atkinson TP, and Dybvig K
- Subjects
- China, Comparative Genomic Hybridization, England, Evolution, Molecular, Genetic Variation, Genome, Bacterial, Humans, Mycoplasma pneumoniae genetics, Phylogeny, Sequence Homology, Nucleic Acid, United States, High-Throughput Nucleotide Sequencing methods, Mycoplasma pneumoniae classification, Mycoplasma pneumoniae isolation & purification, Sequence Analysis, DNA methods
- Abstract
Background: Mycoplasma pneumoniae is a common pathogen that causes upper and lower respiratory tract infections in people of all ages, responsible for up to 40% of community-acquired pneumonias. It also causes a wide array of extrapulmonary infections and autoimmune phenomena. Phylogenetic studies of the organism have been generally restricted to specific genes or regions of the genome, because whole genome sequencing has been completed for only 4 strains. To better understand the physiology and pathogenicity of this important human pathogen, we performed comparative genomic analysis of 15 strains of M. pneumoniae that were isolated between the 1940s to 2009 from respiratory specimens and cerebrospinal fluid originating from the USA, China and England., Results: Illumina MiSeq whole genome sequencing was performed on the 15 strains and all genome sequences were completed. Results from the comparative genomic analysis indicate that although about 1500 SNP and indel variants exist between type1 and type 2 strains, there is an overall high degree of sequence similarity among the strains (>99% identical to each other). Within the two subtypes, conservation of most genes, including the CARDS toxin gene and arginine deiminase genes, was observed. The major variation occurs in the P1 and ORF6 genes associated with the adhesin complex. Multiple hsdS genes (encodes S subunit of type I restriction enzyme) with variable tandem repeat copy numbers were found in all 15 genomes., Conclusions: These data indicate that despite conclusions drawn from 16S rRNA sequences suggesting rapid evolution, the M. pneumoniae genome is extraordinarily stable over time and geographic distance across the globe with a striking lack of evidence of horizontal gene transfer.
- Published
- 2015
- Full Text
- View/download PDF
47. Macrolide-Resistant Mycoplasma pneumoniae, United States.
- Author
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Zheng X, Lee S, Selvarangan R, Qin X, Tang YW, Stiles J, Hong T, Todd K, Ratliff AE, Crabb DM, Xiao L, Atkinson TP, and Waites KB
- Subjects
- Adolescent, Adult, Aged, Anti-Bacterial Agents therapeutic use, Child, Child, Preschool, Drug Resistance, Bacterial genetics, Humans, Infant, Middle Aged, Mycoplasma pneumoniae genetics, Mycoplasma pneumoniae immunology, United States epidemiology, Anti-Bacterial Agents pharmacology, Drug Resistance, Bacterial drug effects, Macrolides therapeutic use, Microbial Sensitivity Tests statistics & numerical data, Mycoplasma pneumoniae drug effects, Pneumonia, Mycoplasma epidemiology
- Abstract
Macrolide-resistant Mycoplasma pneumoniae (MRMP) is highly prevalent in Asia and is now being reported from Europe. Few data on MRMP are available in the United States. Using genotypic and phenotypic methods, we detected high-level MRMP in 13.2% of 91 M. pneumoniae--positive specimens from 6 US locations.
- Published
- 2015
- Full Text
- View/download PDF
48. Subcutaneous Immunoglobulin Replacement Therapy with Hizentra® is Safe and Effective in Children Less Than 5 Years of Age.
- Author
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Patel NC, Gallagher JL, Ochs HD, Atkinson TP, Wahlstrom J, Dorsey M, Bonilla FA, Heimall J, Kobrynski L, Morris D, and Haddad E
- Subjects
- Adult, Child, Child, Preschool, Female, Humans, Immunologic Deficiency Syndromes immunology, Infant, Injections, Subcutaneous, Male, Retrospective Studies, Weight Gain drug effects, Immunoglobulin G administration & dosage, Immunologic Deficiency Syndromes therapy
- Abstract
Background: Hizentra® (IGSC 20%) is a 20% liquid IgG product approved for subcutaneous administration in adults and children 2 years of age and older who have primary immunodeficiency disease (PIDD). There is limited information about the use of IGSC 20 % in very young children including those less than 5 years of age., Methods: A retrospective chart review involved 88 PIDD infants and children less than 5 years of age who received Hizentra®., Results: The mean age at the start of Hizentra® was 34 months (range 2 to 59 months). IGSC 20 % was administered weekly to 86 infants (two additional infants received twice weekly and three times weekly infusions, respectively) and included an average of 63 infusions (range 6-182) for an observation period up to 45.5 months. Infusion by manual delivery occurred in 15 patients. The mean dose was 674 mg/kg/4 weeks. The mean IgG level was 942 mg/dL while on IGSC 20 %, compared to a mean trough IgG level of 794 mg/dL (p < 0.0001) during intravenous or subcutaneous IgG administration prior to IGSC 20 %. Average infusion time was 47 (range 5-120) minutes, and the median number of infusion sites was 2 (range 1-4). Local reactions were mostly mild and observed in 36/88 (41%) children. No serious adverse events were reported. A significant increase in weight percentile (7 % ± 19.2, p = 0.0012) among subjects was observed during IGSC 20% administration. The rate of serious bacterial infections was 0.067 per patient-year while receiving IGSC 20%, similar to previously reported efficacy studies., Conclusions: Hizentra® is effective in preventing infections, and is well tolerated in children less than age 5 years.
- Published
- 2015
- Full Text
- View/download PDF
49. Specificity and Strain-Typing Capabilities of Nanorod Array-Surface Enhanced Raman Spectroscopy for Mycoplasma pneumoniae Detection.
- Author
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Henderson KC, Benitez AJ, Ratliff AE, Crabb DM, Sheppard ES, Winchell JM, Dluhy RA, Waites KB, Atkinson TP, and Krause DC
- Subjects
- Humans, Limit of Detection, Mycoplasma pneumoniae genetics, Sensitivity and Specificity, Mycoplasma pneumoniae pathogenicity, Nanotubes, Pneumonia, Mycoplasma microbiology, Spectrum Analysis, Raman methods
- Abstract
Mycoplasma pneumoniae is a cell wall-less bacterial pathogen of the human respiratory tract that accounts for > 20% of all community-acquired pneumonia (CAP). At present the most effective means for detection and strain-typing is quantitative polymerase chain reaction (qPCR), which can exhibit excellent sensitivity and specificity but requires separate tests for detection and genotyping, lacks standardization between available tests and between labs, and has limited practicality for widespread, point-of-care use. We have developed and previously described a silver nanorod array-surface enhanced Raman Spectroscopy (NA-SERS) biosensing platform capable of detecting M. pneumoniae with statistically significant specificity and sensitivity in simulated and true clinical throat swab samples, and the ability to distinguish between reference strains of the two main genotypes of M. pneumoniae. Furthermore, we have established a qualitative lower endpoint of detection for NA-SERS of < 1 genome equivalent (cell/μl) and a quantitative multivariate detection limit of 5.3 ± 1 cells/μl. Here we demonstrate using partial least squares- discriminatory analysis (PLS-DA) of sample spectra that NA-SERS correctly identified M. pneumoniae clinical isolates from globally diverse origins and distinguished these from a panel of 12 other human commensal and pathogenic mycoplasma species with 100% cross-validated statistical accuracy. Furthermore, PLS-DA correctly classified by strain type all 30 clinical isolates with 96% cross-validated accuracy for type 1 strains, 98% cross-validated accuracy for type 2 strains, and 90% cross-validated accuracy for type 2V strains.
- Published
- 2015
- Full Text
- View/download PDF
50. Disseminated Primary Herpes Simplex Virus Type 2 Infection in a 22-Year-Old male.
- Author
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Erdmann N, Hewitt BA, Atkinson TP, and Van Wagoner N
- Abstract
We present a case of primary disseminated herpes simplex virus type 2 (HSV-2) cutaneous disease in a 22-year-old male. We discuss the immune response to HSV-2 infection as well as the extragenital manifestations of HSV-2 observed in immune-competent and immune-suppressed persons.
- Published
- 2015
- Full Text
- View/download PDF
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