114 results on '"Didier ES"'
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2. Inconclusive quantum measurements and decisions under uncertainty
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Vyacheslav I. Yukalov and Didier eSornette
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Decision Theory ,quantum measurements ,decoy effect ,quantum probability ,non-informative priors ,inconclusive events ,Physics ,QC1-999 - Abstract
We give a mathematical definition for the notion of inconclusive quantum measurements.In physics, such measurements occur at intermediate stages of a complex measurement procedure, with the final measurement result being operationally testable. Since the mathematical structure of Quantum Decision Theory has been developed in analogy withthe theory of quantum measurements, the inconclusive quantum measurements correspond,in Quantum Decision Theory, to intermediate stages of decision making in the process of taking decisions under uncertainty. The general form of the quantum probability for a composite event is the sum of a utility factor, describing a rational evaluationof the considered prospect, and of an attraction factor, characterizing irrational,subconscious attitudes of the decision maker. Despite the involved irrationality, the probability of prospects can be evaluated. This is equivalent to the possibility of calculating quantum probabilities without specifying hidden variables. We formulate a general way of evaluation, based on the use of non-informative priors. As an example,we suggest the explanation of the decoy effect. Our quantitative predictions are in very good agreement with experimental data.
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- 2016
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3. Application of modified-alginate encapsulated carbonate producing bacteria in concrete: a promising strategy for crack self-healing
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Jianyun eWang, Arn eMignon, Didier eSnoeck, Virginie eWiktor, Nico eBoon, and Nele eDe Belie
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Oxygen Consumption ,Crack self-healing ,modified-alginate hydrogel ,B. sphaericus spores ,bacterial CaCO3 ,in-situ activity ,Microbiology ,QR1-502 - Abstract
Self-healing concrete holds promising benefits to reduce the cost for concrete maintenance and repair as cracks are autonomously repaired without any human intervention. In this study, the application of a carbonate precipitating bacterium Bacillus sphaericus was explored. Regarding the harsh condition in concrete, B. sphaericus spores were first encapsulated into a modified-alginate based hydrogel (AM-H) which was proven to have a good compatibility with the bacteria and concrete regarding the influence on bacterial viability and concrete strength. Experimental results show that the spores were still viable after encapsulation. Encapsulated spores can precipitate a large amount of CaCO3 in/on the hydrogel matrix (around 70% by weight). Encapsulated B. sphaericus spores were added into mortar specimens and bacterial in-situ activity was demonstrated by the oxygen consumption on the mimicked crack surface. Specimens with free spores added showed no oxygen consumption. This indicates the efficient protection of the hydrogel for spores in concrete. To conclude, the AM-H encapsulated carbonate precipitating bacteria have great potential to be used for crack self-healing in concrete applications.
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- 2015
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4. Preference reversal in quantum decision theory
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Vyacheslav I. Yukalov and Didier eSornette
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uncertainty ,Decision Theory ,Preference reversal ,Planning paradox ,behavioral quantum probability ,Psychology ,BF1-990 - Abstract
We consider the psychological effect of preference reversal and showthat it finds a natural explanation in the frame of quantum decisiontheory. When people choose between lotteries with non-negative payoffs, they prefer a more certain lottery because of uncertainty aversion. But when people evaluate lottery prices, e.g. for selling to others the right to play them, they do this more rationally, being less subject to behavioral biases. This difference can be explained bythe presence of the attraction factors entering the expression of quantumprobabilities. Only the existence of attraction factors can explain why,considering two lotteries with close utility factors, a decision maker prefers one of them when choosing, but evaluates higher the other one when pricing. We derive a general quantitative criterion for the preference reversal to occur that relates the utilities of the two lotteries to the attraction factors under choosing versus pricing and test successfully its application on experiments by Tversky et al.We also show that the planning paradox can be treated as a kind of preference reversal.
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- 2015
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5. Psychiatric stigma in treatment seeking adults with personality problems: evidence from a sample of 214 patients.
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Kirsten eCatthoor, Didier eSchrijvers, Joost eHutsebaut, Dineke eFeenstra, and Bernard eSabbe
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Personality Disorders ,Psychotherapy ,stigma ,Adult patients ,Mental health burden ,Psychiatry ,RC435-571 - Abstract
Stigmatization is a major hindrance in adult psychiatric patients with Axis-I diagnoses, as shown consistently in most studies. Significantly fewer studies on the emergence of psychiatric stigma in adult patients with personality disorders exist, although the resulting evidence is conclusive. Some authors consider patients with personality disorders at risk for severe stigmatization because of intense difficulties during interpersonal contact, even in a psychotherapeutic relationship. The aim of this study was primarily the assessment of pre-existing stigma in patients referred for intensive treatment for personality disorders. The study enrolled 214 patients admitted to the adult department of a highly specialized mental health care institute offering psychotherapy for patients with severe and complex personality pathology. All patients underwent a standard assessment with self-report questionnaires and a semi-structured interview to measure Axis II personality disorders. The Stigma Consciousness Questionnaire (SCQ) and the Perceived Devaluation-Discrimination Questionnaire (DDQ), both validated instruments, were used to measure perceived and actual experiences of stigma. Independent sample t-tests were used to investigate differences in the mean total stigma scores for patients both with and without a personality disorder. One-way ANOVA’s were performed to assess the differences between having a borderline personality disorder, another personality disorder, or no personality disorder diagnosis.Multiple regression main effect analyses were conducted in order to explore the impact of the different personality disorder diagnosis on the level of stigma. The mean scores across all patient groups were consistent with rather low stigma. No differences were found for patients with or without a personality disorder diagnosis. Level of stigma in general was not associated with an accumulating number of personality disorders.
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- 2015
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6. Psychomotor Retardation in untreated depressed elderly
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Lieve Lia Beheydt, Didier eSchrijvers, Lise eDocx, Filip eBouckaert, Wouter eHulstijn, and Bernard eSabbe
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Cognition ,neuropsychological assessment ,Elderly ,major depression ,psychomotor retardation ,Copying Tasks ,Psychiatry ,RC435-571 - Abstract
Background: Psychomotor retardation (PR) is one of the core features in depression according to 17 DSM V1, but also aging in itself causes cognitive and psychomotor slowing. This is the first study 18 investigating psychomotor retardation in relation to cognitive functioning and to the concomitant 19 effect of depression and aging in a geriatric population ruling out contending effects of psychotropic 20 medication. Methods: A group of 28 non-demented depressed elderly is compared to a matched 21 control group of 20 healthy elderly. All participants underwent a test battery containing clinical 22 depression measures, cognitive measures of processing speed, executive function and memory, 23 clinical ratings of psychomotor retardation and objective computerized fine motor skill-tests. 24 Statistical analysis consisted of a General Linear Method (GLM) multivariate analysis of variance to 25 compare the clinical, cognitive and psychomotor outcomes of the two groups. Results: Patients 26 performed worse on all clinical, cognitive and psychomotor retardation measures. Both groups 27 showed an effect of cognitive load on fine motor function but the influence was significantly larger 28 for patients than for healthy elderly except for the initiation time. Limitations: due to the restrictive 29 inclusion criteria, only a relatively limited sample size could be obtained. Conclusion: With a 30 medication free sample, an additive effect of depression and aging on cognition and PR in geriatric 31 patients was found,. As this effect was independent of demand of effort (by varying the cognitive 32 load), it was apparently not a motivational slowing effect of depression.
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- 2015
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7. NHP BurkPx: A multiplex serodiagnostic bead assay to monitor Burkholderia pseudomallei exposures in non-human primates.
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Celona KR, Shannon AB, Sonderegger D, Yi J, Monroy FP, Allender C, Hornstra H, Barnes MB, Didier ES, Bohm RP, Phillippi-Falkenstein K, Sanford D, Keim P, and Settles EW
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- Animals, Humans, Antibodies, Bacterial, Antigens, Bacterial, Primates, Burkholderia pseudomallei, Melioidosis diagnosis, Melioidosis veterinary, Melioidosis epidemiology
- Abstract
Background: Melioidosis is a disease caused by the bacterium Burkholderia pseudomallei, infecting humans and non-human primates (NHP) through contaminated soil or water. World-wide there are an estimated 165,000 human melioidosis cases each year, but recordings of NHP cases are sporadic. Clinical detection of melioidosis in humans is primarily by culturing B. pseudomallei, and there are no standardized detection protocols for NHP. NHP are an important animal model for melioidosis research including clinical trials and development of biodefense countermeasures., Methodology/principle Findings: We evaluated the diagnostic potential of the multiple antigen serological assay, BurkPx, in NHP using two sera sets: (i) 115 B. pseudomallei-challenged serum samples from 80 NHP collected each week post-exposure (n = 52) and at euthanasia (n = 47), and (ii) 126 B. pseudomallei-naïve/negative serum samples. We observed early IgM antibody responses to carbohydrate antigens followed by IgG antibody recognition to multiple B. pseudomallei protein antigens during the second week of infection. B. pseudomallei negative serum samples had low to intermediate antibody cross reactivity to the antigens in this assay. Infection time was predicted as the determining factor in the variation of antibody responses, with 77.67% of variation explained by the first component of the principal component analysis. A multiple antigen model generated a binary prediction metric ([Formula: see text]), which when applied to all data resulted in 100% specificity and 63.48% sensitivity. Removal of week 1 B. pseudomallei challenged serum samples increased the sensitivity of the model to 95%., Conclusion/significance: We employed a previously standardized assay for humans, the BurkPx assay, and assessed its diagnostic potential for detection of B. pseudomallei exposure in NHP. The assay is expected to be useful for surveillance in NHP colonies, in investigations of suspected accidental releases or exposures, and for identifying vaccine correlates of protection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Celona et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2023
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8. Comparison of predictors for terminal disease progression in simian immunodeficiency virus/simian-HIV-infected rhesus macaques.
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Takahashi N, Ardeshir A, Holder GE, Cai Y, Sugimoto C, Mori K, Araínga M, He Z, Fukuyo Y, Kim WK, Didier ES, and Kuroda MJ
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- Animals, Disease Progression, Humans, Macaca mulatta, Retrospective Studies, Viral Load, HIV Infections complications, Simian Acquired Immunodeficiency Syndrome, Simian Immunodeficiency Virus
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Objectives: CD4+ T-cell decline and increasing virus levels are considered hallmarks of HIV/AIDS pathogenesis but we previously demonstrated in rhesus macaques that tissue macrophage destruction by simian immunodeficiency virus (SIV) infection associated with increased monocyte turnover also appear to impact pathogenesis. It remains unclear, however, which factors best predict onset of terminal disease progression and survival time. The objective of this study, therefore, was to directly compare these co-variates of infection for predicting survival times in retrospective studies of SIV/simian-HIV (SHIV)-infected adult rhesus macaques., Methods: Rhesus macaques were infected with various strains of SIV/SHIV and evaluated longitudinally for monocyte turnover, CD4+ T-cell loss, plasma viral load, and SIV/SHIV strain. Correlation analyses and machine learning algorithm modeling were applied to compare relative contributions of each of the co-variates to survival time., Results: All animals with AIDS-related clinical signs requiring euthanasia exhibited increased monocyte turnover regardless of CD4+ T-cell level, viral strain, or plasma viral load. Regression analyses and machine learning algorithms indicated a stronger correlation and contribution between increased monocyte turnover and reduced survival time than between CD4+ T-cell decline, plasma viral load, or virus strain and reduced survival time. Decision tree modeling categorized monocyte turnover of 13.2% as the initial significant threshold that best predicted decreased survival time., Conclusion: These results demonstrate that monocytes/macrophages significantly affect HIV/SIV pathogenesis outcomes. Monocyte turnover analyses are not currently feasible in humans, so there is a need to identify surrogate biomarkers reflecting tissue macrophage damage that predict HIV infection disease progression., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2021
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9. Declining neutrophil production despite increasing G-CSF levels is associated with chronic inflammation in elderly rhesus macaques.
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He Z, Fahlberg MD, Takahashi N, Slisarenko N, Rout N, Didier ES, and Kuroda MJ
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- Age Factors, Animals, Chronic Disease, Cytokines metabolism, Disease Susceptibility, Hematopoiesis, Inflammation Mediators metabolism, Macaca mulatta, Myeloid-Derived Suppressor Cells immunology, Myeloid-Derived Suppressor Cells metabolism, Neutrophils immunology, Granulocyte Colony-Stimulating Factor biosynthesis, Inflammation etiology, Inflammation metabolism, Neutrophils metabolism
- Abstract
Aging is characterized by a loss of bone marrow hematopoietic tissue, systemic chronic inflammation, and higher susceptibility to infectious and noninfectious diseases. We previously reported the tightly regulated kinetics and massive daily production of neutrophils during homeostasis in adult rhesus macaques aged 3 to 19 yr (equivalent to approximately 10 to 70 yr of age in humans). In the current study, we observed an earlier release of recently dividing neutrophils from bone marrow and greater in-group variability of neutrophil kinetics based on in vivo BrdU labeling in a group of older rhesus macaques of 20-26 yr of age. Comparing neutrophil numbers and circulating cytokine levels in rhesus macaques spanning 2 to 26 yr of age, we found a negative correlation between age and blood neutrophil counts and a positive correlation between age and plasma G-CSF levels. Hierarchic clustering analysis also identified strong associations between G-CSF with the proinflammatory cytokines, IL-1β and MIP-1α. Furthermore, neutrophils from older macaques expressed less myeloperoxidase and comprised higher frequencies of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) compared to the young adult macaques. In summary, we observed an earlier release from bone marrow and a reduced production of neutrophils despite the increased levels of plasma G-CSF, especially in the elderly rhesus macaques. This lower neutrophil production capacity associated with increased production of proinflammatory cytokines as well as an earlier release of less mature neutrophils and PMN-MDSCs may contribute to the chronic inflammation and greater susceptibility to infectious and noninfectious diseases during aging., (©2021 Society for Leukocyte Biology.)
- Published
- 2021
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10. A subtype of cerebrovascular pericytes is associated with blood-brain barrier disruption that develops during normal aging and simian immunodeficiency virus infection.
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Bohannon DG, Okhravi HR, Kim J, Kuroda MJ, Didier ES, and Kim WK
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- Actins metabolism, Adult, Animals, Brain blood supply, Humans, Macaca mulatta, Microvessels cytology, Myosin Heavy Chains metabolism, Pericytes metabolism, Receptor, Platelet-Derived Growth Factor beta metabolism, Simian Acquired Immunodeficiency Syndrome virology, Young Adult, Aging pathology, Blood-Brain Barrier pathology, Pericytes classification, Pericytes physiology, Simian Acquired Immunodeficiency Syndrome pathology, Simian Immunodeficiency Virus
- Abstract
Lax phenotypic characterization of these morphologically distinct pericytes has delayed our understanding of their role in neurological disorders. We herein establish markers which uniquely distinguish different subpopulations of human brain microvascular pericytes and characterize them independently from cerebrovascular smooth muscle cells. Furthermore, we begin to elucidate the roles of these subsets in blood-brain barrier (BBB) breakdown by studying natural aging and simian immunodeficiency virus (SIV) infection in rhesus macaques. We demonstrate that the main type-1 pericyte subpopulation in the brain of young uninfected adults is positive for platelet-derived growth factor receptor-β (PDGFRB) and negative for α-smooth muscle actin (SMA) and myosin heavy chain 11 (MYH11), whereas PDGFRB+/SMA+/MYH11- (type-2) pericytes are found more frequently in older adults and are associated with SIV infection and progression. Interestingly, we find a strong positive correlation between the degree of BBB breakdown and the percentage of type-2 pericytes regardless of age or SIV status. Taken together, our findings suggest that type-2 pericytes may be a cellular biomarker related to BBB disruption independent of disease status., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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11. Clinical and Immunological Metrics During Pediatric Rhesus Macaque Development.
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Merino KM, Slisarenko N, Taylor JM, Falkenstein KP, Gilbert MH, Bohm RP, Blanchard JL, Ardeshir A, Didier ES, Kim WK, and Kuroda MJ
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Background: Clinical measurements commonly used to evaluate overall health of laboratory animals including complete blood count, serum chemistry, weight, and immunophenotyping, differ with respect to age, development, and environment. This report provides comprehensive clinical and immunological reference ranges for pediatric rhesus macaques over the first year of life. Methods: We collected and analyzed blood samples from 151 healthy rhesus macaques, aged 0-55 weeks, and compared mother-reared infants to two categories of nursery-reared infants; those on an active research protocol and those under derivation for the expanded specific-pathogen-free breeding colony. Hematology was performed on EDTA-anticoagulated blood using a Sysmex XT2000i, and serum clinical chemistry was performed using the Beckman AU480 chemistry analyzer. Immunophenotyping of whole blood was performed with immunofluorescence staining and subsequent flow cytometric analysis on a BD LSRFortessa. Plasma cytokine analysis was performed using a Millipore multiplex Luminex assay. Results: For hematological and chemistry measurements, pediatric reference ranges deviate largely from adults. Comparison of mother-reared and nursery-reared animals revealed that large differences depend on rearing conditions and diet. Significant differences found between two nursery-reared cohorts (research and colony animals) indicate large influences of experimental factors and anesthetic events on these parameters. Immune cells and cytokine responses presented with distinct patterns for infants depending on age, birth location, and rearing conditions. Conclusions: Our results illustrate how the immune system changed over time and that there was variability among pediatric age groups. Reference ranges of results reported here will support interpretations for how infection and treatment may skew common immune correlates used for assessment of pathology or protection in research studies as well as help veterinarians in the clinical care of infant non-human primates. We highlighted the importance of using age-specific reference comparisons for pediatric studies and reiterated the utility of rhesus macaques as a model for human studies. Given the rapid transformation that occurs in multiple tissue compartments after birth and cumulative exposures to antigens as individuals grow, a better understanding of immunological development and how this relates to timing of infection or vaccination will support optimal experimental designs for developing vaccines and treatment interventions., (Copyright © 2020 Merino, Slisarenko, Taylor, Falkenstein, Gilbert, Bohm, Blanchard, Ardeshir, Didier, Kim and Kuroda.)
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- 2020
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12. Correction to: Inflammaging phenotype in rhesus macaques is associated with a decline in epithelial barrier-protective functions and increased pro-inflammatory function in CD161-expressing cells.
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Walker EM, Slisarenko N, Gerrets GL, Kissinger PJ, Didier ES, Kuroda MJ, Veazey RS, Jazwinski SM, and Rout N
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Unfortunately, the original version of this article was published with error in the materials and methods section.
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- 2020
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13. Development of a Geropathology Grading Platform for nonhuman primates.
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Olstad KJ, Imai DM, Keesler RI, Reader R, Morrison JH, Roberts JA, Capitanio JP, Didier ES, Kuroda MJ, Simmons H, Salimi S, Mattison JA, Ikeno Y, and Ladiges W
- Abstract
A geropathology grading platform (GGP) for assessing age-related lesions has been established and validated for in inbred strain of mice. Because nonhuman primates (NHPs) share significant similarities in aging and spontaneous chronic diseases with humans, they provide excellent translational value for correlating histopathology with biological and pathological events associated with increasing age. Descriptive age-associated pathology has been described for rhesus macaques and marmosets, but a grading platform similar to the mouse GGP does not exist. The value of these NHP models is enhanced by considerable historical data from clinical, bio-behavioral, and social domains that align with health span in these animals. Successful adaptation of the mouse GGP for NHPs will include 1) expanding the range of organs examined; 2) standardizing necropsy collection, tissue trimming, and descriptive lesion terminology; 3) expanding beyond rhesus macaques and marmosets to include other commonly used NHPs in research; and 4) creating a national resource for age-related pathology to complement the extensive in-life datasets. Adaptation of the GGP to include translational models other than mice will be crucial to advance geropathology designed to enhance aging research., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest.
- Published
- 2020
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14. Characterization of heart macrophages in rhesus macaques as a model to study cardiovascular disease in humans.
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Petkov DI, Liu DX, Allers C, Didier PJ, Didier ES, and Kuroda MJ
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- Age Factors, Animals, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Biomarkers, Cardiovascular Diseases etiology, Cardiovascular Diseases metabolism, Cardiovascular Diseases pathology, Disease Models, Animal, Disease Susceptibility, Female, Humans, Immunohistochemistry, Immunophenotyping, Lymphocytes immunology, Lymphocytes metabolism, Macaca mulatta, Male, Muscle, Skeletal immunology, Muscle, Skeletal metabolism, Myocardium pathology, Organ Specificity immunology, Receptors, Cell Surface metabolism, Macrophages immunology, Macrophages metabolism, Myocardium immunology, Myocardium metabolism
- Abstract
Rhesus macaques are physiologically similar to humans and, thus, have served as useful animal models of human diseases including cardiovascular disease. The purpose of this study was to characterize the distribution, composition, and phenotype of macrophages in heart tissues of very young (fetus: 0.5 years, n = 6), young adult (2-12 years, n = 12), and older adult (13-24 years, n = 9) rhesus macaques using histopathology and immunofluorescence microscopy. Results demonstrated that macrophages were uniformly distributed throughout the heart in animals of all age groups and were more prevalent than CD3-positve T-cells and CD20-positive B-cells. Macrophages comprised approximately 2% of heart tissue cells in the younger animals and increased to a mean of nearly 4% in the older adults. CD163-positive macrophages predominated over HAM56-positive and CD206-positive macrophages, and were detected at significantly higher percentage in the animals between 13 and 24 years of age, as well as in heart tissues exhibiting severe histopathology or inflammation in animals of all age groups. In vivo dextran labeling and retention indicated that approximately half of the macrophages were longer lived in healthy adult heart tissues and may comprise the tissue-resident population of macrophages. These results provide a basis for continued studies to examine the specific functional roles of macrophage subpopulations in heart tissues during homeostasis and in cardiovascular disease for then developing intervention strategies., (©2019 Society for Leukocyte Biology.)
- Published
- 2019
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15. Inflammaging phenotype in rhesus macaques is associated with a decline in epithelial barrier-protective functions and increased pro-inflammatory function in CD161-expressing cells.
- Author
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Walker EM, Slisarenko N, Gerrets GL, Kissinger PJ, Didier ES, Kuroda MJ, Veazey RS, Jazwinski SM, and Rout N
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- Animals, Chronic Disease, Cytokines metabolism, Disease Models, Animal, Epithelium immunology, Epithelium pathology, Flow Cytometry, Inflammation metabolism, Inflammation pathology, Macaca mulatta, Phenotype, Th17 Cells metabolism, Th17 Cells pathology, Aging immunology, Epithelium metabolism, Immunity, Innate, Inflammation immunology, NK Cell Lectin-Like Receptor Subfamily B biosynthesis, Th17 Cells immunology
- Abstract
The development of chronic inflammation, called inflammaging, contributes to the pathogenesis of age-related diseases. Although it is known that both B and T lymphocyte compartments of the adaptive immune system deteriorate with advancing age, the impact of aging on immune functions of Th17-type CD161-expressing innate immune cells and their role in inflammaging remain incompletely understood. Here, utilizing the nonhuman primate model of rhesus macaques, we report that a dysregulated Th17-type effector function of CD161
+ immune cells is associated with leaky gut and inflammatory phenotype of aging. Higher plasma levels of inflammatory cytokines IL-6, TNF-α, IL-1β, GM-CSF, IL-12, and Eotaxin correlated with elevated markers of gut permeability including LPS-binding protein (LBP), intestinal fatty acid binding protein (I-FABP), and sCD14 in aging macaques. Further, older macaques displayed significantly lower frequencies of circulating Th17-type immune cells comprised of CD161+ T cell subsets, NK cells, and innate lymphoid cells. Corresponding with the increased markers of gut permeability, production of the type-17 cytokines IL-17 and IL-22 was impaired in CD161+ T cell subsets and NK cells, along with a skewing towards IFN-γ cytokine production. These findings suggest that reduced frequencies of CD161+ immune cells along with a specific loss in Th17-type effector functions contribute to impaired gut barrier integrity and systemic inflammation in aging macaques. Modulating type-17 immune cell functions via cytokine therapy or dietary interventions towards reducing chronic inflammation in inflammaging individuals may have the potential to prevent or delay age-related chronic diseases and improve immune responses in the elderly population.- Published
- 2019
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16. Shifting Dynamics of Intestinal Macrophages during Simian Immunodeficiency Virus Infection in Adult Rhesus Macaques.
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Takahashi N, Sugimoto C, Allers C, Alvarez X, Kim WK, Didier ES, and Kuroda MJ
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- Animals, Antigens, CD immunology, Antigens, Differentiation, Myelomonocytic immunology, Cell Survival immunology, Colon pathology, Colon virology, Female, Flow Cytometry, Intestinal Mucosa pathology, Intestinal Mucosa virology, Lectins, C-Type immunology, Macaca mulatta, Macrophages pathology, Male, Mannose Receptor, Mannose-Binding Lectins immunology, Receptors, Cell Surface immunology, Simian Acquired Immunodeficiency Syndrome pathology, Colon immunology, Intestinal Mucosa immunology, Macrophages immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus immunology
- Abstract
The intestinal tract is a primary barrier to invading pathogens and contains immune cells, including lymphocytes and macrophages. We previously reported that CD163
+ CD206- (single-positive [SP]) interstitial macrophages of the lung are short-lived and succumb early to SIV infection. Conversely, CD163+ CD206+ (double-positive [DP]) alveolar macrophages are long-lived, survive after SIV infection, and may contribute to the virus reservoir. This report characterizes analogous populations of macrophages in the intestinal tract of rhesus macaques ( Macaca mulatta ) with SIV/AIDS. By flow cytometry analysis, immunofluorescence staining, and confocal microscopy, CD163+ CD206+ DP macrophages predominated in the lamina propria of uninfected animals, compared with CD163+ CD206- SP macrophages, which predominated in the lamina propria in animals with SIV infection that were exhibiting AIDS. In submucosal areas, CD163+ CD206+ DP macrophages predominated in both SIV-infected and uninfected macaques. Furthermore, BrdU-labeled CD163+ CD206+ DP and CD163+ CD206- SP macrophages recently arriving in the colon, which are both presumed to be shorter-lived, were observed to localize only in the lamina propria. Conversely, longer-lived CD163+ CD206+ DP macrophages that retained dextran at least 2 mo after in vivo administration localized exclusively in the submucosa. This suggests that CD163+ CD206+ DP intestinal macrophages of the lamina propria were destroyed after SIV infection and replaced by immature CD163+ CD206- SP macrophages, whereas longer-lived CD163+ CD206+ DP macrophages remained in the submucosa, supporting their potential role as an SIV/HIV tissue reservoir. Moreover, the DP macrophages in the submucosa, which differ from lamina propria DP macrophages, may be missed from pinch biopsy sampling, which may preclude detecting virus reservoirs for monitoring HIV cure., (Copyright © 2019 by The American Association of Immunologists, Inc.)- Published
- 2019
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17. Encephalitozoon cuniculi and Vittaforma corneae (Phylum Microsporidia) inhibit staurosporine-induced apoptosis in human THP-1 macrophages in vitro.
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Sokolova YY, Bowers LC, Alvarez X, and Didier ES
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- Apoptosis genetics, Encephalitozoonosis microbiology, Gene Expression Regulation, Humans, Microsporidiosis microbiology, THP-1 Cells, Apoptosis drug effects, Encephalitozoon cuniculi physiology, Staurosporine pharmacology, Vittaforma physiology
- Abstract
Obligately intracellular microsporidia regulate their host cell life cycles, including apoptosis, but this has not been evaluated in phagocytic host cells such as macrophages that can facilitate infection but also can be activated to kill microsporidia. We examined two biologically dissimilar human-infecting microsporidia species, Encephalitozoon cuniculi and Vittaforma corneae, for their effects on staurosporine-induced apoptosis in the human macrophage-differentiated cell line, THP1. Apoptosis was measured after exposure of THP-1 cells to live and dead mature organisms via direct fluorometric measurement of Caspase 3, colorimetric and fluorometric TUNEL assays, and mRNA gene expression profiles using Apoptosis RT2 Profiler PCR Array. Both species of microsporidia modulated the intrinsic apoptosis pathway. In particular, live E. cuniculi spores inhibited staurosporine-induced apoptosis as well as suppressed pro-apoptosis genes and upregulated anti-apoptosis genes more broadly than V. corneae. Exposure to dead spores induced an opposite effect. Vittaforma corneae, however, also induced inflammasome activation via Caspases 1 and 4. Of the 84 apoptosis-related genes assayed, 42 (i.e. 23 pro-apoptosis, nine anti-apoptosis, and 10 regulatory) genes were more affected including those encoding members of the Bcl2 family, caspases and their regulators, and members of the tumour necrosis factor (TNF)/TNF receptor R superfamily.
- Published
- 2019
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18. Rapid Turnover and High Production Rate of Myeloid Cells in Adult Rhesus Macaques with Compensations during Aging.
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He Z, Allers C, Sugimoto C, Ahmed N, Fujioka H, Kim WK, Didier ES, and Kuroda MJ
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- Animals, Basophils physiology, Bone Marrow Cells physiology, Eosinophils physiology, Half-Life, Homeostasis physiology, Macaca mulatta, Male, Monocytes physiology, Neutrophils physiology, Aging physiology, Myeloid Cells physiology
- Abstract
Neutrophils, basophils, and monocytes are continuously produced in bone marrow via myelopoiesis, circulate in blood, and are eventually removed from circulation to maintain homeostasis. To quantitate the kinetics of myeloid cell movement during homeostasis, we applied 5-bromo-2'-deoxyuridine pulse labeling in healthy rhesus macaques ( Macaca mulatta ) followed by hematology and flow cytometry analyses. Results were applied to a mathematical model, and the blood circulating half-life and daily production, respectively, of each cell type from macaques aged 5-10 y old were calculated for neutrophils (1.63 ± 0.16 d, 1.42 × 10
9 cells/l/d), basophils (1.78 ± 0.30 d, 5.89 × 106 cells/l/d), and CD14+ CD16- classical monocytes (1.01 ± 0.15 d, 3.09 × 108 cells/l/d). Classical monocytes were released into the blood circulation as early as 1 d after dividing, whereas neutrophils remained in bone marrow 4-5 d before being released. Among granulocytes, neutrophils and basophils exhibited distinct kinetics in bone marrow maturation time and blood circulation. With increasing chronological age, there was a significant decrease in daily production of neutrophils and basophils, but the half-life of these granulocytes remained unchanged between 3 and 19 y of age. In contrast, daily production of classical monocytes remained stable through 19 y of age but exhibited a significant decline in half-life. These results demonstrated relatively short half-lives and continuous replenishment of neutrophils, basophils, and classical monocytes during homeostasis in adult rhesus macaques with compensations observed during increasing chronological age., (Copyright © 2018 by The American Association of Immunologists, Inc.)- Published
- 2018
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19. Hydrocephalus after Intrathecal Administration of Dextran to Rhesus Macaques ( Macaca mulatta ).
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Dufour JP, Russell-Lodrigue KE, Doyle-Meyers L, Falkenstein KP, Blair RV, Didier ES, Slisarenko N, Williams KC, and Kuroda MJ
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- Animals, Central Nervous System cytology, Central Nervous System drug effects, Dextrans administration & dosage, Dextrans therapeutic use, Injections, Spinal adverse effects, Macrophages physiology, Retrospective Studies, Saline Solution administration & dosage, Time Factors, Dextrans adverse effects, Hydrocephalus etiology, Injections, Spinal veterinary, Macaca mulatta, Saline Solution adverse effects
- Abstract
Dextrans have been used extensively as medical therapies and labeling agents in biomedical research to investigate the blood-brain barrier and CSF flow and absorption. Adverse effects from dextrans include anaphylactic reaction and dilation of the cerebral ventricles due to administration into the subarachnoid space. This retrospective study describes 51 rhesus macaques (Macaca mulatta) that received dextran intrathecally. The purpose of intrathecal administration was to enable detection of long-lived, dextran-labeled macrophages and to study monocyte-macrophage turnover in the CNS of SIV- or SHIV- infected and uninfected animals by using immunofluorescence. Of the 51 dextran-treated macaques, 8 that received dextran diluted in saline developed hydrocephalus; 6 of these 8 animals exhibited neurologic signs. In contrast, none of the macaques that received intrathecal dextran diluted in PBS developed hydrocephalus. These data suggest the use of saline diluent and the duration of dextran exposure as potential factors contributing to hydrocephalus after intrathecal dextran in rhesus macaques.
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- 2018
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20. High Turnover of Tissue Macrophages Contributes to Tuberculosis Reactivation in Simian Immunodeficiency Virus-Infected Rhesus Macaques.
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Kuroda MJ, Sugimoto C, Cai Y, Merino KM, Mehra S, Araínga M, Roy CJ, Midkiff CC, Alvarez X, Didier ES, and Kaushal D
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- Animals, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes microbiology, CD4-Positive T-Lymphocytes virology, Coinfection immunology, Coinfection microbiology, Coinfection virology, Disease Models, Animal, Latent Tuberculosis microbiology, Latent Tuberculosis virology, Lymphocyte Depletion methods, Macaca mulatta, Macrophages, Alveolar microbiology, Macrophages, Alveolar virology, Male, Monocytes microbiology, Monocytes virology, Mycobacterium tuberculosis immunology, Simian Acquired Immunodeficiency Syndrome microbiology, Simian Acquired Immunodeficiency Syndrome virology, Tuberculosis microbiology, Tuberculosis virology, Viral Load immunology, Latent Tuberculosis immunology, Macrophages, Alveolar immunology, Monocytes immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus immunology, Tuberculosis immunology
- Abstract
Background: Tuberculosis (TB) and human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) profoundly affect the immune system and synergistically accelerate disease progression. It is believed that CD4+ T-cell depletion by HIV is the major cause of immunodeficiency and reactivation of latent TB. Previous studies demonstrated that blood monocyte turnover concurrent with tissue macrophage death from virus infection better predicted AIDS onset than CD4+ T-cell depletion in macaques infected with simian immunodeficiency virus (SIV)., Methods: In this study, we describe the contribution of macrophages to the pathogenesis of Mycobacterium tuberculosis (Mtb)/SIV coinfection in a rhesus macaque model using in vivo BrdU labeling, immunostaining, flow cytometry, and confocal microscopy., Results: We found that increased monocyte and macrophage turnover and levels of SIV-infected lung macrophages correlated with TB reactivation. All Mtb/SIV-coinfected monkeys exhibited declines in CD4+ T cells regardless of reactivation or latency outcomes, negating lower CD4+ T-cell levels as a primary cause of Mtb reactivation., Conclusions: Results suggest that SIV-related damage to macrophages contributes to Mtb reactivation during coinfection. This also supports strategies to target lung macrophages for the treatment of TB.
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- 2018
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21. Role of Monocyte/Macrophages during HIV/SIV Infection in Adult and Pediatric Acquired Immune Deficiency Syndrome.
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Merino KM, Allers C, Didier ES, and Kuroda MJ
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Monocytes/macrophages are a diverse group of cells that act as first responders in innate immunity and then as mediators for adaptive immunity to help clear infections. In performing these functions, however, the macrophage inflammatory responses can also contribute to pathogenesis. Various monocyte and tissue macrophage subsets have been associated with inflammatory disorders and tissue pathogeneses such as occur during HIV infection. Non-human primate research of simian immunodeficiency virus (SIV) has been invaluable in better understanding the pathogenesis of HIV infection. The question of HIV/SIV-infected macrophages serving as a viral reservoir has become significant for achieving a cure. In the rhesus macaque model, SIV-infected macrophages have been shown to promote pathogenesis in several tissues resulting in cardiovascular, metabolic, and neurological diseases. Results from human studies illustrated that alveolar macrophages could be an important HIV reservoir and humanized myeloid-only mice supported productive HIV infection and viral persistence in macrophages during ART treatment. Depletion of CD4+ T cells is considered the primary cause for terminal progression, but it was reported that increasing monocyte turnover was a significantly better predictor in SIV-infected adult macaques. Notably, pediatric cases of HIV/SIV exhibit faster and more severe disease progression than adults, yet neonates have fewer target T cells and generally lack the hallmark CD4+ T cell depletion typical of adult infections. Current data show that the baseline blood monocyte turnover rate was significantly higher in neonatal macaques compared to adults and this remained high with disease progression. In this review, we discuss recent data exploring the contribution of monocytes and macrophages to HIV/SIV infection and progression. Furthermore, we highlight the need to further investigate their role in pediatric cases of infection.
- Published
- 2017
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22. Correction for Sugimoto et al., "Critical Role for Monocytes/Macrophages in Rapid Progression to AIDS in Pediatric Simian Immunodeficiency Virus-Infected Rhesus Macaques".
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Sugimoto C, Merino KM, Hasegawa A, Wang X, Alvarez XA, Wakao H, Mori K, Kim WK, Veazey RS, Didier ES, and Kuroda MJ
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- 2017
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23. Critical Role for Monocytes/Macrophages in Rapid Progression to AIDS in Pediatric Simian Immunodeficiency Virus-Infected Rhesus Macaques.
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Sugimoto C, Merino KM, Hasegawa A, Wang X, Alvarez XA, Wakao H, Mori K, Kim WK, Veazey RS, Didier ES, and Kuroda MJ
- Subjects
- Animals, Disease Models, Animal, Disease Progression, HIV Infections immunology, HIV Infections pathology, Humans, Macaca mulatta virology, Macrophages virology, Monocytes virology, RNA, Viral blood, Simian Acquired Immunodeficiency Syndrome pathology, Viral Load, CD4-Positive T-Lymphocytes immunology, Macrophages immunology, Monocytes immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus immunology
- Abstract
Infant humans and rhesus macaques infected with the human or simian immunodeficiency virus (HIV or SIV), respectively, express higher viral loads and progress more rapidly to AIDS than infected adults. Activated memory CD4
+ T cells in intestinal tissues are major primary target cells for SIV/HIV infection, and massive depletion of these cells is considered a major cause of immunodeficiency. Monocytes and macrophages are important cells of innate immunity and also are targets of HIV/SIV infection. We reported previously that a high peripheral blood monocyte turnover rate was predictive for the onset of disease progression to AIDS in SIV-infected adult macaques. The purpose of this study was to determine if earlier or higher infection of monocytes/macrophages contributes to the more rapid progression to AIDS in infants. We observed that uninfected infant rhesus macaques exhibited higher physiologic baseline monocyte turnover than adults. Early after SIV infection, the monocyte turnover further increased, and it remained high during progression to AIDS. A high percentage of terminal deoxynucleotidyltransferase dUTP nick end label (TUNEL)-positive macrophages in the lymph nodes (LNs) and intestine corresponded with an increasing number of macrophages derived from circulating monocytes (bromodeoxyuridine positive [BrdU+ ] CD163+ ), suggesting that the increased blood monocyte turnover was required to rapidly replenish destroyed tissue macrophages. Immunofluorescence analysis further demonstrated that macrophages were a significant portion of the virus-producing cells found in LNs, intestinal tissues, and lungs. The higher baseline monocyte turnover in infant macaques and subsequent macrophage damage by SIV infection may help explain the basis of more rapid disease progression to AIDS in infants. IMPORTANCE HIV infection progresses much more rapidly in pediatric cases than in adults; however, the mechanism for this difference is unclear. Using the rhesus macaque model, this work was performed to address why infants infected with SIV progress more quickly to AIDS than do adults. Earlier we reported that in adult rhesus macaques, increasing monocyte turnover reflected tissue macrophage damage by SIV and was predictive of terminal disease progression to AIDS. Here we report that uninfected infant rhesus macaques exhibited a higher physiological baseline monocyte turnover rate than adults. Furthermore, once infected with SIV, infants displayed further increased monocyte turnover that may have facilitated the accelerated progression to AIDS. These results support a role for monocytes and macrophages in the pathogenesis of SIV/HIV and begin to explain why infants are more prone to rapid disease progression., (Copyright © 2017 American Society for Microbiology.)- Published
- 2017
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24. Microsporidia-Emergent Pathogens in the Global Food Chain (Trends in Parasitology 32, 336-348; April 2, 2016).
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Stentiford GD, Becnel JJ, Weiss LM, Keeling PJ, Didier ES, Williams BAP, Bjornson S, Kent ML, Freeman MA, Brown MJF, Troemel ER, Roesel K, Sokolova Y, Snowden KF, and Solter LF
- Published
- 2016
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25. Five-Antigen Fluorescent Bead-Based Assay for Diagnosis of Lyme Disease.
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Embers ME, Hasenkampf NR, Barnes MB, Didier ES, Philipp MT, and Tardo AC
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- Animals, Humans, Immunoglobulin G blood, Macaca mulatta, Male, Sensitivity and Specificity, Antibodies, Bacterial blood, Antigens, Bacterial immunology, Borrelia burgdorferi immunology, Immunoassay methods, Lyme Disease diagnosis, Serologic Tests methods
- Abstract
The systematically difficult task of diagnosing Lyme disease can be simplified by sensitive and specific laboratory tests. The currently recommended two-tier test for serology is highly specific but falls short in sensitivity, especially in the early acute phase. We previously examined serially collected serum samples from Borrelia burgdorferi-infected rhesus macaques and defined a combination of antigens that could be utilized for detection of infection at all phases of disease in humans. The five B. burgdorferi antigens, consisting of OspC, OspA, DbpA, OppA2, and the C6 peptide, were combined into a fluorescent cytometric bead-based assay for the detection of B. burgdorferi antigen-specific IgG antibodies. Samples from Lyme disease patients and controls were used to determine the diagnostic value of this assay. Using this sample set, we found that our five-antigen multiplex IgG assay exhibited higher sensitivity (79.5%) than the enzyme immunoassay (EIA) (76.1%), the two-tier test (61.4%), and the C6 peptide enzyme-linked immunosorbent assay (ELISA) (77.2%) while maintaining specificity over 90%. When detection of IgM was added to the bead-based assay, the sensitivity improved to 91%, but at a cost of reduced specificity (78%). These results indicate that the rational combination of antigens in our multiplex assay may offer an improved serodiagnostic test for Lyme disease., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
- Published
- 2016
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26. Specific pathogen free macaque colonies: a review of principles and recent advances for viral testing and colony management.
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Yee JL, Vanderford TH, Didier ES, Gray S, Lewis A, Roberts J, Taylor K, and Bohm RP
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- Algorithms, Animals, Betaretrovirus isolation & purification, Deltaretrovirus Infections diagnosis, Deltaretrovirus Infections veterinary, Herpesviridae Infections diagnosis, Herpesviridae Infections veterinary, Herpesvirus 1, Cercopithecine isolation & purification, Models, Animal, Monkey Diseases virology, Quality Control, Retroviridae Infections diagnosis, Retroviridae Infections veterinary, Simian Acquired Immunodeficiency Syndrome diagnosis, Simian Immunodeficiency Virus isolation & purification, Simian T-lymphotropic virus 1 isolation & purification, Specific Pathogen-Free Organisms, Virus Diseases diagnosis, Macaca, Monkey Diseases diagnosis, Virus Diseases veterinary
- Abstract
Specific pathogen free (SPF) macaques provide valuable animal models for biomedical research. In 1989, the National Center for Research Resources [now Office of Research Infrastructure Programs (ORIP)] of the National Institutes of Health initiated experimental research contracts to establish and maintain SPF colonies. The derivation and maintenance of SPF macaque colonies is a complex undertaking requiring knowledge of the biology of the agents for exclusion and normal physiology and behavior of macaques, application of the latest diagnostic technology, facilitiy management, and animal husbandry. This review provides information on the biology of the four viral agents targeted for exclusion in ORIP SPF macaque colonies, describes current state-of-the-art viral diagnostic algorithms, presents data from proficiency testing of diagnostic assays between laboratories at institutions participating in the ORIP SPF program, and outlines management strategies for maintaining the integrity of SPF colonies using results of diagnostic testing as a guide to decision making., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2016
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27. Encephalitozoon hellem infection in aviary passerine and psittacine birds in Spain.
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Rosell J, Máinez M, Didier ES, Bowers LC, Marco A, and Juan-Sallés C
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- Agapornis parasitology, Animals, Bird Diseases diagnosis, Bird Diseases pathology, Canaries parasitology, Encephalitozoon physiology, Encephalitozoonosis diagnosis, Encephalitozoonosis parasitology, Encephalitozoonosis pathology, Female, Finches parasitology, Intestines parasitology, Intestines pathology, Male, Spain, Bird Diseases parasitology, Encephalitozoonosis veterinary
- Abstract
A European goldfinch (Carduelis carduelis), a canary (Serinus canaria), and a lovebird (Agapornis roseicollis) captive-bred at three different private aviaries in Spain were submitted for necropsy with a history of weakness and ruffled feathers, weight loss associated with glossitis, and respiratory disease, respectively. Microscopically, enterocytes in the jejunum and ileum contained colonies of gram- and Stamp-positive, oval to elliptical microorganisms within parasitophorous vacuoles in the apical cytoplasm. Nested PCR using MSP primers that target microsporidian RNA genes produced amplicons of expected size for Encephalitozoon species, and analysis of forward and reverse DNA sequences confirmed the presence of Encephalitozoon hellem in all cases. The main cause of death of all three birds consisted of concurrent infections. However, intestinal encephalitozoonosis may have contributed to exacerbated catabolism. Encephalitozoonosis (or microsporidiosis) has been rarely described in passerine birds., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2016
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28. Contributions of Nonhuman Primates to Research on Aging.
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Didier ES, MacLean AG, Mohan M, Didier PJ, Lackner AA, and Kuroda MJ
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- Aging genetics, Animals, Humans, Macaca fascicularis, Macaca mulatta, Models, Animal, Primates genetics, Aging pathology, Primates physiology, Research
- Abstract
Aging is the biological process of declining physiologic function associated with increasing mortality rate during advancing age. Humans and higher nonhuman primates exhibit unusually longer average life spans as compared with mammals of similar body mass. Furthermore, the population of humans worldwide is growing older as a result of improvements in public health, social services, and health care systems. Comparative studies among a wide range of organisms that include nonhuman primates contribute greatly to our understanding about the basic mechanisms of aging. Based on their genetic and physiologic relatedness to humans, nonhuman primates are especially important for better understanding processes of aging unique to primates, as well as for testing intervention strategies to improve healthy aging and to treat diseases and disabilities in older people. Rhesus and cynomolgus macaques are the predominant monkeys used in studies on aging, but research with lower nonhuman primate species is increasing. One of the priority topics of research about aging in nonhuman primates involves neurologic changes associated with cognitive decline and neurodegenerative diseases. Additional areas of research include osteoporosis, reproductive decline, caloric restriction, and their mimetics, as well as immune senescence and chronic inflammation that affect vaccine efficacy and resistance to infections and cancer. The purpose of this review is to highlight the findings from nonhuman primate research that contribute to our understanding about aging and health span in humans., (© The Author(s) 2016.)
- Published
- 2016
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29. Fast Technology Analysis Enables Identification of Species and Genotypes of Latent Microsporidia Infections in Healthy Native Cameroonians.
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Ndzi ES, Asonganyi T, Nkinin MB, Xiao L, Didier ES, Bowers LC, Nkinin SW, and Kaneshiro ES
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- Adolescent, Adult, Base Sequence, Biodiversity, Cameroon epidemiology, Child, Child, Preschool, Cross-Sectional Studies, Encephalitozoon cuniculi classification, Encephalitozoon cuniculi genetics, Encephalitozoon cuniculi isolation & purification, Encephalitozoonosis epidemiology, Encephalitozoonosis microbiology, Enterocytozoon classification, Enterocytozoon genetics, Enterocytozoon isolation & purification, Feces microbiology, Female, Genotype, Humans, Infant, Infant, Newborn, Male, Microsporidia classification, Microsporidiosis epidemiology, Middle Aged, Polymerase Chain Reaction methods, Sequence Analysis, DNA, Young Adult, Microsporidia genetics, Microsporidia isolation & purification, Microsporidiosis microbiology
- Abstract
Several enteric microsporidia species have been detected in humans and other vertebrates and their identifications at the genotype level are currently being elucidated. As advanced methods, reagents, and disposal kits for detecting and identifying pathogens become commercially available, it is important to test them in settings other than in laboratories with "state-of-the-art" equipment and well-trained staff members. In the present study, we sought to detect microsporidia DNA preserved and extracted from FTA (fast technology analysis) cards spotted with human fecal suspensions obtained from Cameroonian volunteers living in the capital city of Yaoundé to preclude the need for employing spore-concentrating protocols. Further, we tested whether amplicon nucleotide sequencing approaches could be used on small aliquots taken from the cards to elucidate the diversity of microsporidia species and strains infecting native residents. Of 196 samples analyzed, 12 (6.1%) were positive for microsporidia DNA; Enterocytozoon bieneusi (Type IV and KIN-1), Encephalitozoon cuniculi, and Encephalitozoon intestinalis were identified. These data demonstrate the utility of the FTA cards in identifying genotypes of microsporidia DNA in human fecal samples that may be applied to field testing for prevalence studies., (© 2015 The Author(s) Journal of Eukaryotic Microbiology © 2015 International Society of Protistologists.)
- Published
- 2016
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30. Preferential Destruction of Interstitial Macrophages over Alveolar Macrophages as a Cause of Pulmonary Disease in Simian Immunodeficiency Virus-Infected Rhesus Macaques.
- Author
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Cai Y, Sugimoto C, Arainga M, Midkiff CC, Liu DX, Alvarez X, Lackner AA, Kim WK, Didier ES, and Kuroda MJ
- Subjects
- Animals, Cell Death immunology, Humans, Lung pathology, Lung Diseases pathology, Macaca mulatta, Macrophages, Alveolar pathology, Simian Acquired Immunodeficiency Syndrome pathology, Lung immunology, Lung Diseases immunology, Macrophages, Alveolar immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus immunology
- Abstract
To our knowledge, this study demonstrates for the first time that the AIDS virus differentially impacts two distinct subsets of lung macrophages. The predominant macrophages harvested by bronchoalveolar lavage (BAL), alveolar macrophages (AMs), are routinely used in studies on human lung macrophages, are long-lived cells, and exhibit low turnover. Interstitial macrophages (IMs) inhabit the lung tissue, are not recovered with BAL, are shorter-lived, and exhibit higher baseline turnover rates distinct from AMs. We examined the effects of SIV infection on AMs in BAL fluid and IMs in lung tissue of rhesus macaques. SIV infection produced massive cell death of IMs that contributed to lung tissue damage. Conversely, SIV infection induced minimal cell death of AMs, and these cells maintained the lower turnover rate throughout the duration of infection. This indicates that SIV produces lung tissue damage through destruction of IMs, whereas the longer-lived AMs may serve as a virus reservoir to facilitate HIV persistence., (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Published
- 2015
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31. Differentiation Kinetics of Blood Monocytes and Dendritic Cells in Macaques: Insights to Understanding Human Myeloid Cell Development.
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Sugimoto C, Hasegawa A, Saito Y, Fukuyo Y, Chiu KB, Cai Y, Breed MW, Mori K, Roy CJ, Lackner AA, Kim WK, Didier ES, and Kuroda MJ
- Subjects
- Animals, Antigens, CD metabolism, Bone Marrow Cells cytology, Bone Marrow Cells metabolism, CD11c Antigen metabolism, Humans, Immunophenotyping, Macaca, Myeloid Cells cytology, Myeloid Cells metabolism, Phenotype, Cell Differentiation, Dendritic Cells cytology, Dendritic Cells metabolism, Monocytes cytology, Monocytes metabolism
- Abstract
Monocyte and dendritic cell (DC) development was evaluated using in vivo BrdU pulse-chase analyses in rhesus macaques, and phenotype analyses of these cells in blood also were assessed by immunostaining and flow cytometry for comparisons among rhesus, cynomolgus, and pigtail macaques, as well as African green monkeys and humans. The nonhuman primate species and humans have three subsets of monocytes, CD14(+)CD16(-), CD14(+)CD16(+), and CD14(-)CD16(+) cells, which correspond to classical, intermediate, and nonclassical monocytes, respectively. In addition, there exist presently two subsets of DC, BDCA-1(+) myeloid DC and CD123(+) plasmacytoid DC, that were first confirmed in rhesus macaque blood. Following BrdU inoculation, labeled cells first appeared in CD14(+)CD16(-) monocytes, then in CD14(+)CD16(+) cells, and finally in CD14(-)CD16(+) cells, thus defining different stages of monocyte maturation. A fraction of the classical CD14(+)CD16(-) monocytes gradually expressed CD16(+) to become CD16(+)CD14(+) cells and subsequently matured into the nonclassical CD14(-)CD16(+) cell subset. The differentiation kinetics of BDCA-1(+) myeloid DC and CD123(+) plasmacytoid DC were distinct from the monocyte subsets, indicating differences in their myeloid cell origins. Results from studies utilizing nonhuman primates provide valuable information about the turnover, kinetics, and maturation of the different subsets of monocytes and DC using approaches that cannot readily be performed in humans and support further analyses to continue examining the unique myeloid cell origins that may be applied to address disease pathogenesis mechanisms and intervention strategies in humans., (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Published
- 2015
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32. Increased monocyte turnover is associated with interstitial macrophage accumulation and pulmonary tissue damage in SIV-infected rhesus macaques.
- Author
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Cai Y, Sugimoto C, Liu DX, Midkiff CC, Alvarez X, Lackner AA, Kim WK, Didier ES, and Kuroda MJ
- Subjects
- Animals, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes pathology, CD4-Positive T-Lymphocytes virology, Calcium Ionophores pharmacology, Immunohistochemistry, Interleukin-6 biosynthesis, Leukocyte Count, Lipopolysaccharides pharmacology, Lung immunology, Lung virology, Lung Diseases, Interstitial complications, Lung Diseases, Interstitial immunology, Lung Diseases, Interstitial virology, Macaca mulatta, Macrophages, Alveolar drug effects, Macrophages, Alveolar immunology, Macrophages, Alveolar virology, Male, Monocytes immunology, Monocytes virology, Pulmonary Edema complications, Pulmonary Edema immunology, Pulmonary Edema virology, Severity of Illness Index, Simian Acquired Immunodeficiency Syndrome complications, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus immunology, Viral Load, Lung pathology, Lung Diseases, Interstitial pathology, Macrophages, Alveolar pathology, Monocytes pathology, Pulmonary Edema pathology, Simian Acquired Immunodeficiency Syndrome pathology
- Abstract
We recently reported that increasing blood monocyte turnover that was associated with tissue macrophage death better predicts terminal disease progression in adult SIV-infected macaques than does declining CD4(+) T cell levels. To understand better mechanisms of pathogenesis, this study relates severity of lung-tissue damage to the ratio, distribution, and inflammatory responses of lung macrophage subsets during SIV infection in rhesus macaques exhibiting varying rates of monocyte turnover. In vivo BrdU incorporation was used to evaluate kinetics of monocyte/tissue macrophage turnover. Tissue damage was scored microscopically from H&E-stained lung-tissue sections, and cytokine expression was examined via immunohistochemistry and confocal microscopy. Increased monocyte turnover in SIV-infected rhesus macaques significantly correlated with severity of lung-tissue damage, as exhibited by perivasculitis, vasculitis, interstitial pneumonia, alveolar histiocytosis, foamy macrophages, multinucleated giant cells, fibrin, and edema in the alveoli. In addition, the higher monocyte turnover correlated with declining AI ratio, increased accumulation of IM in the perivascular region of the lung, and higher expression of IL-6 in the IM of the lung tissue exposed to a LPS, calcium ionophore, and tumor promoter combination stimulation ex vivo. Accumulation of IM associated with increasing monocyte turnover during SIV infection appears to contribute to chronic pulmonary inflammation and tissue damage during disease progression to AIDS., (© Society for Leukocyte Biology.)
- Published
- 2015
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33. Encephalitozoon cuniculi -Associated Equine Encephalitis: A Case Report.
- Author
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Hollyer JA, McGuinness E, Bowers LC, Didier ES, Giudice C, Perl DP, and Fogarty U
- Abstract
A case of encephalitis of unknown origin in the horse was investigated. Postmortem examination findings revealed a nonsuppurative granulomatous meningoencephalitis in the right hemisphere of the cerebral cortex. Testing for West Nile virus, equine herpes virus, equine infectious anemia, Toxoplasma gondii , Neospora caninum , and Sarcocystis neurona were negative. The horse had a titer for Encephalitozoon cuniculi , and sections from the affected area of the brain tested positive for the organism using both polymerase chain reaction (PCR) and immunohistochemistry. Amplicons generated using PCR were sequenced, and E. cuniculi genotype II was identified. This is the first case of E. cuniculi genotype II associated with encephalitis in the horse.
- Published
- 2014
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34. In vivo characterization of alveolar and interstitial lung macrophages in rhesus macaques: implications for understanding lung disease in humans.
- Author
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Cai Y, Sugimoto C, Arainga M, Alvarez X, Didier ES, and Kuroda MJ
- Subjects
- Animals, Antigens, CD immunology, Antigens, CD metabolism, Apoptosis immunology, Bronchoalveolar Lavage Fluid cytology, Bronchoalveolar Lavage Fluid immunology, Flow Cytometry, Humans, Immunophenotyping, In Situ Nick-End Labeling, Interferon-gamma immunology, Interferon-gamma pharmacology, Lipopolysaccharides immunology, Lipopolysaccharides pharmacology, Lung cytology, Lung metabolism, Lung Diseases immunology, Lung Diseases metabolism, Lung Diseases pathology, Macrophages drug effects, Macrophages metabolism, Macrophages, Alveolar drug effects, Macrophages, Alveolar metabolism, Male, Microscopy, Confocal, Monocytes drug effects, Monocytes immunology, Monocytes metabolism, Tumor Necrosis Factor-alpha immunology, Tumor Necrosis Factor-alpha metabolism, Lung immunology, Macaca mulatta immunology, Macrophages immunology, Macrophages, Alveolar immunology
- Abstract
Alveolar macrophages (AMs) obtained by bronchoalveolar lavage (BAL) are commonly used to study lung macrophage-mediated immune responses. Questions remain, however, about whether AMs fully represent macrophage function in the lung. This study was performed to determine the contribution of interstitial macrophages (IMs) of lung tissue to pulmonary immunity and that are not present in BAL sampling. In vivo BrdU injection was performed to evaluate the kinetics and monocyte/tissue macrophage turnover in Indian rhesus macaques (Macaca mulatta). Lung macrophage phenotype and cell turnover were analyzed by flow cytometry and immunohistochemistry. AMs and IMs in lungs of rhesus macaques composed ∼70% of immune response cells in the lung. AMs represented a larger proportion of macrophages, ∼75-80%, and exhibited minimal turnover. Conversely, IMs exhibited higher turnover rates that were similar to those of blood monocytes during steady-state homeostasis. IMs also exhibited higher staining for TUNEL, suggesting a continuous transition of blood monocytes replacing IMs undergoing apoptosis. Although AMs appear static in steady-state homeostasis, increased influx of new AMs derived from monocytes/IMs was observed after BAL procedure. Moreover, ex vivo IFN-γ plus LPS treatment significantly increased intracellular expression of TNF-α in IMs, but not in AMs. These findings indicate that the longer-lived AMs obtained from BAL may not represent the entire pulmonary spectrum of macrophage responses, and shorter-lived IMs may function as the critical mucosal macrophage subset in the lung that helps to maintain homeostasis and protect against continuous pathogen exposure from the environment.
- Published
- 2014
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35. Optimization of PCR for quantification of simian immunodeficiency virus genomic RNA in plasma of rhesus macaques (Macaca mulatta) using armored RNA.
- Author
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Monjure CJ, Tatum CD, Panganiban AT, Arainga M, Traina-Dorge V, Marx PA Jr, and Didier ES
- Subjects
- Animals, Genome, Viral, RNA, Viral blood, Reproducibility of Results, Sensitivity and Specificity, Simian Acquired Immunodeficiency Syndrome virology, Viral Load, Macaca mulatta, RNA, Viral genetics, Real-Time Polymerase Chain Reaction methods, Simian Acquired Immunodeficiency Syndrome blood, Simian Immunodeficiency Virus genetics
- Abstract
Introduction: Quantification of plasma viral load (PVL) is used to monitor disease progression in SIV-infected macaques. This study was aimed at optimizing of performance characteristics of the quantitative PCR (qPCR) PVL assay., Methods: The PVL quantification procedure was optimized by inclusion of an exogenous control hepatitis C virus armored RNA (aRNA), a plasma concentration step, extended digestion with proteinase K, and a second RNA elution step. Efficiency of viral RNA (vRNA) extraction was compared using several commercial vRNA extraction kits. Various parameters of qPCR targeting the gag region of SIVmac239, SIVsmE660, and the LTR region of SIVagmSAB were also optimized., Results: Modifications of the SIV PVL qPCR procedure increased vRNA recovery, reduced inhibition and improved analytical sensitivity. The PVL values determined by this SIV PVL qPCR correlated with quantification results of SIV RNA in the same samples using the 'industry standard' method of branched-DNA (bDNA) signal amplification., Conclusions: Quantification of SIV genomic RNA in plasma of rhesus macaques using this optimized SIV PVL qPCR is equivalent to the bDNA signal amplification method, less costly and more versatile. Use of heterologous aRNA as an internal control is useful for optimizing performance characteristics of PVL qPCRs., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2014
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36. Testing predictions of the oxidative stress hypothesis of aging using a novel invertebrate model of longevity: the giant clam (Tridacna derasa).
- Author
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Ungvari Z, Csiszar A, Sosnowska D, Philipp EE, Campbell CM, McQuary PR, Chow TT, Coelho M, Didier ES, Gelino S, Holmbeck MA, Kim I, Levy E, Sonntag WE, Whitby PW, Austad SN, and Ridgway I
- Subjects
- Animals, Antioxidants metabolism, Biological Evolution, Bivalvia, Catalase metabolism, Free Radical Scavengers metabolism, Hydrogen Peroxide metabolism, Life Expectancy, Models, Biological, Seawater, Species Specificity, Superoxide Dismutase metabolism, Temperature, Tissue Survival physiology, Aging physiology, Longevity physiology, Oxidative Stress physiology, Protein Carbonylation, tert-Butylhydroperoxide pharmacology
- Abstract
Bivalve species with exceptional longevity are newly introduced model systems in biogerontology to test evolutionarily conserved mechanisms of aging. Here, we tested predictions based on the oxidative stress hypothesis of aging using one of the tropical long-lived sessile giant clam species, the smooth giant clam (Tridacna derasa; predicted maximum life span: >100 years) and the short-lived Atlantic bay scallop (Argopecten irradians irradians; maximum life span: 2 years). The warm water-dwelling giant clams warrant attention because they challenge the commonly held view that the exceptional longevity of bivalves is a consequence of the cold water they reside in. No significant interspecific differences in production of H2O2 and O2- in the gills, heart, or adductor muscle were observed. Protein carbonyl content in gill and muscle tissues were similar in T derasa and A i irradians. In tissues of T derasa, neither basal antioxidant capacities nor superoxide dismutase and catalase activities were consistently greater than in A i irradians. We observed a positive association between longevity and resistance to mortality induced by exposure to tert-butyl hydroperoxide (TBHP). This finding is consistent with the prediction based on the oxidative stress hypothesis of aging. The findings that in tissues of T derasa, proteasome activities are significantly increased as compared with those in tissues of A i irradians warrant further studies to test the role of enhanced protein recycling activities in longevity of bivalves.
- Published
- 2013
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37. Transcriptome analysis of the parasite Encephalitozoon cuniculi: an in-depth examination of pre-mRNA splicing in a reduced eukaryote.
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Grisdale CJ, Bowers LC, Didier ES, and Fast NM
- Subjects
- Genome, Fungal, Introns, Open Reading Frames, RNA Splicing, RNA, Messenger genetics, Sequence Analysis, RNA, Spliceosomes metabolism, Encephalitozoon cuniculi genetics, Gene Expression Profiling, RNA, Messenger metabolism
- Abstract
Background: The microsporidian Encephalitozoon cuniculi possesses one of the most reduced and compacted eukaryotic genomes. Reduction in this intracellular parasite has affected major cellular machinery, including the loss of over fifty core spliceosomal components compared to S. cerevisiae. To identify expression changes throughout the parasite's life cycle and also to assess splicing in the context of this reduced system, we examined the transcriptome of E. cuniculi using Illumina RNA-seq., Results: We observed that nearly all genes are expressed at three post-infection time-points examined. A large fraction of genes are differentially expressed between the first and second (37.7%) and first and third (43.8%) time-points, while only four genes are differentially expressed between the latter two. Levels of intron splicing are very low, with 81% of junctions spliced at levels below 50%. This is dramatically lower than splicing levels found in two other fungal species examined. We also describe the first case of alternative splicing in a microsporidian, an unexpected complexity given the reduction in spliceosomal components., Conclusions: Low levels of splicing observed are likely the result of an inefficient spliceosome; however, at least in one case, splicing appears to be playing a functional role. Although several RNA decay genes are encoded in E. cuniculi, the lack of a few key players could be reducing decay levels and therefore increasing the proportion of unspliced transcripts. Significant proportions of genes are differentially expressed in the first forty-eight hours but not after, indicative of genetic changes that precede the intracellular to infective stage transition.
- Published
- 2013
- Full Text
- View/download PDF
38. Microsporidian genome analysis reveals evolutionary strategies for obligate intracellular growth.
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Cuomo CA, Desjardins CA, Bakowski MA, Goldberg J, Ma AT, Becnel JJ, Didier ES, Fan L, Heiman DI, Levin JZ, Young S, Zeng Q, and Troemel ER
- Subjects
- Animals, Caenorhabditis parasitology, Chromatin Assembly and Disassembly, Chromosome Mapping, DNA, Fungal genetics, Databases, Genetic, Gene Deletion, Genes, Tumor Suppressor, Genetic Variation, Heterozygote, Hexokinase metabolism, Microsporidia classification, Microsporidia pathogenicity, Multigene Family, Phylogeny, Polymorphism, Single Nucleotide, Retinoblastoma genetics, Sequence Analysis, RNA, Evolution, Molecular, Genome, Fungal, Microsporidia genetics, Microsporidia growth & development
- Abstract
Microsporidia comprise a large phylum of obligate intracellular eukaryotes that are fungal-related parasites responsible for widespread disease, and here we address questions about microsporidia biology and evolution. We sequenced three microsporidian genomes from two species, Nematocida parisii and Nematocida sp1, which are natural pathogens of Caenorhabditis nematodes and provide model systems for studying microsporidian pathogenesis. We performed deep sequencing of transcripts from a time course of N. parisii infection. Examination of pathogen gene expression revealed compact transcripts and a dramatic takeover of host cells by Nematocida. We also performed phylogenomic analyses of Nematocida and other microsporidian genomes to refine microsporidian phylogeny and identify evolutionary events of gene loss, acquisition, and modification. In particular, we found that all microsporidia lost the tumor-suppressor gene retinoblastoma, which we speculate could accelerate the parasite cell cycle and increase the mutation rate. We also found that microsporidia acquired transporters that could import nucleosides to fuel rapid growth. In addition, microsporidian hexokinases gained secretion signal sequences, and in a functional assay these were sufficient to export proteins out of the cell; thus hexokinase may be targeted into the host cell to reprogram it toward biosynthesis. Similar molecular changes appear during formation of cancer cells and may be evolutionary strategies adopted independently by microsporidia to proliferate rapidly within host cells. Finally, analysis of genome polymorphisms revealed evidence for a sexual cycle that may provide genetic diversity to alleviate problems caused by clonal growth. Together these events may explain the emergence and success of these diverse intracellular parasites.
- Published
- 2012
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39. Immune correlates of aging in outdoor-housed captive rhesus macaques (Macaca mulatta).
- Author
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Didier ES, Sugimoto C, Bowers LC, Khan IA, and Kuroda MJ
- Abstract
Background: Questions remain about whether inflammation is a cause, consequence, or coincidence of aging. The purpose of this study was to define baseline immunological characteristics from blood to develop a model in rhesus macaques that could be used to address the relationship between inflammation and aging. Hematology, flow cytometry, clinical chemistry, and multiplex cytokine/chemokine analyses were performed on a group of 101 outdoor-housed captive rhesus macaques ranging from 2 to 24 years of age, approximately equivalent to 8 to 77 years of age in humans., Results: These results extend earlier reports correlating changes in lymphocyte subpopulations and cytokines/chemokines with increasing age. There were significant declines in numbers of white blood cells (WBC) overall, as well as lymphocytes, monocytes, and polymorphonuclear cells with increasing age. Among lymphocytes, there were no significant declines in NK cells and T cells, whereas B cell numbers exhibited significant declines with age. Within the T cell populations, there were significant declines in numbers of CD4+ naïve T cells and CD8+ naïve T cells. Conversely, numbers of CD4+CD8+ effector memory and CD8+effector memory T cells increased with age. New multiplex analyses revealed that concentrations of a panel of ten circulating cytokines/chemokines, IFNγ, IL1b, IL6, IL12, IL15, TNFα, MCP1, MIP1α, IL1ra, and IL4, each significantly correlated with age and also exhibited concordant pairwise correlations with every other factor within this group. To also control for outlier values, mean rank values of each of these cytokine concentrations in relation to age of each animal and these also correlated with age., Conclusions: A panel of ten cytokines/chemokines were identified that correlated with aging and also with each other. This will permit selection of animals exhibiting relatively higher and lower inflammation status as a model to test mechanisms of inflammation status in aging with susceptibility to infections and vaccine efficacy.
- Published
- 2012
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- View/download PDF
40. Increased cellular immune responses and CD4+ T-cell proliferation correlate with reduced plasma viral load in SIV challenged recombinant simian varicella virus - simian immunodeficiency virus (rSVV-SIV) vaccinated rhesus macaques.
- Author
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Pahar B, Gray WL, Phelps K, Didier ES, deHaro E, Marx PA, and Traina-Dorge VL
- Subjects
- Animals, Cell Proliferation, Cytokines metabolism, Macaca mulatta, Plasma virology, SAIDS Vaccines administration & dosage, SAIDS Vaccines genetics, Simian Immunodeficiency Virus immunology, Vaccines, Synthetic administration & dosage, Vaccines, Synthetic genetics, Vaccines, Synthetic immunology, CD4-Positive T-Lymphocytes immunology, SAIDS Vaccines immunology, Simian Immunodeficiency Virus genetics, Varicellovirus genetics, Viral Load, Viremia prevention & control
- Abstract
Background: An effective AIDS vaccine remains one of the highest priorities in HIV-research. Our recent study showed that vaccination of rhesus macaques with recombinant simian varicella virus (rSVV) vector - simian immunodeficiency virus (SIV) envelope and gag genes, induced neutralizing antibodies and cellular immune responses to SIV and also significantly reduced plasma viral loads following intravenous pathogenic challenge with SIVMAC251/CX1., Findings: The purpose of this study was to define cellular immunological correlates of protection in rSVV-SIV vaccinated and SIV challenged animals. Immunofluorescent staining and multifunctional assessment of SIV-specific T-cell responses were evaluated in both Experimental and Control vaccinated animal groups. Significant increases in the proliferating CD4+ T-cell population and polyfunctional T-cell responses were observed in all Experimental-vaccinated animals compared with the Control-vaccinated animals., Conclusions: Increased CD4+ T-cell proliferation was significantly and inversely correlated with plasma viral load. Increased SIV-specific polyfunctional cytokine responses and increased proliferation of CD4+ T-cell may be crucial to control plasma viral loads in vaccinated and SIVMAC251/CX1 challenged macaques.
- Published
- 2012
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41. The adjuvanticity of an O. volvulus-derived rOv-ASP-1 protein in mice using sequential vaccinations and in non-human primates.
- Author
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Wang J, Tricoche N, Du L, Hunter M, Zhan B, Goud G, Didier ES, Liu J, Lu L, Marx PA, Jiang S, and Lustigman S
- Subjects
- Animals, Antibody Formation, Female, HEK293 Cells, Hemagglutinins immunology, Humans, Mice, Mice, Inbred BALB C, Primates immunology, Severe acute respiratory syndrome-related coronavirus immunology, Vaccination methods, Adjuvants, Immunologic pharmacology, Antigens, Helminth immunology, Helminth Proteins immunology, Influenza Vaccines immunology, Onchocerca volvulus immunology, Onchocerca volvulus metabolism, Recombinant Proteins immunology
- Abstract
Adjuvants potentiate antigen-specific protective immune responses and can be key elements promoting vaccine effectiveness. We previously reported that the Onchocerca volvulus recombinant protein rOv-ASP-1 can induce activation and maturation of naïve human DCs and therefore could be used as an innate adjuvant to promote balanced Th1 and Th2 responses to bystander vaccine antigens in mice. With a few vaccine antigens, it also promoted a Th1-biased response based on pronounced induction of Th1-associated IgG2a and IgG2b antibody responses and the upregulated production of Th1 cytokines, including IL-2, IFN-γ, TNF-α and IL-6. However, because it is a protein, the rOv-ASP-1 adjuvant may also induce anti-self-antibodies. Therefore, it was important to verify that the host responses to self will not affect the adjuvanticity of rOv-ASP-1 when it is used in subsequent vaccinations with the same or different vaccine antigens. In this study, we have established rOv-ASP-1's adjuvanticity in mice during the course of two sequential vaccinations using two vaccine model systems: the receptor-binding domain (RBD) of SARS-CoV spike protein and a commercial influenza virus hemagglutinin (HA) vaccine comprised of three virus strains. Moreover, the adjuvanticity of rOv-ASP-1 was retained with an efficacy similar to that obtained when it was used for a first vaccination, even though a high level of anti-rOv-ASP-1 antibodies was present in the sera of mice before the administration of the second vaccine. To further demonstrate its utility as an adjuvant for human use, we also immunized non-human primates (NHPs) with RBD plus rOv-ASP-1 and showed that rOv-ASP-1 could induce high titres of functional and protective anti-RBD antibody responses in NHPs. Notably, the rOv-ASP-1 adjuvant did not induce high titer antibodies against self in NHPs. Thus, the present study provided a sound scientific foundation for future strategies in the development of this novel protein adjuvant.
- Published
- 2012
- Full Text
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42. Microsporidiosis: not just in AIDS patients.
- Author
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Didier ES and Weiss LM
- Subjects
- Antiprotozoal Agents therapeutic use, Humans, Immunocompromised Host, Microsporidiosis diagnosis, Microsporidiosis therapy, AIDS-Related Opportunistic Infections microbiology, Microsporidiosis epidemiology
- Abstract
Purpose of Review: Microsporidia have emerged as causes of opportunistic infections associated with diarrhea and wasting in AIDS patients. This review describes recent reports of microsporidiosis in HIV-infected individuals and the growing awareness of microsporidiosis in non-HIV-infected populations., Recent Findings: Microsporidia were only rarely recognized as causes of disease in humans until the AIDS pandemic. Implementation of combination antiretroviral therapy (cART) to curtail HIV replication and restore immune status drastically reduced the occurrence of opportunistic infections, including those due to microsporidia, in HIV-infected individuals. In developing countries where cART is not always accessible, microsporidiosis continues to be problematic. Improvement of diagnostic methods over the previous 25 years led to identification of several new species of microsporidia, many of which disseminate from enteric to systemic sites of infection and contribute to some unexpected lesions. Among non-HIV-infected but immune-suppressed individuals, microsporidia have infected organ transplant recipients, children, the elderly, and patients with malignant disease and diabetes. In otherwise healthy immune-competent HIV seronegative populations, self-limiting diarrhea occurred in travelers and as a result of a foodborne outbreak associated with contaminated cucumbers. Keratitis due to microsporidiosis has become problematic and a recent longitudinal evaluation demonstrated that non-HIV-infected individuals seropositive for microsporidia who had no clinical signs continued to intermittently shed organisms in feces and urine., Summary: Greater awareness and implementation of better diagnostic methods are demonstrating that microsporidia contribute to a wide range of clinical syndromes in HIV-infected and non-HIV-infected people. As such, microsporidia should be considered in differential diagnoses if no other cause can be defined.
- Published
- 2011
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43. Extreme longevity is associated with increased resistance to oxidative stress in Arctica islandica, the longest-living non-colonial animal.
- Author
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Ungvari Z, Ridgway I, Philipp EE, Campbell CM, McQuary P, Chow T, Coelho M, Didier ES, Gelino S, Holmbeck MA, Kim I, Levy E, Sosnowska D, Sonntag WE, Austad SN, and Csiszar A
- Subjects
- Animals, Antioxidants metabolism, Hydrogen Peroxide metabolism, Longevity drug effects, Mercenaria drug effects, Reactive Oxygen Species metabolism, Aging metabolism, Apoptosis, Longevity physiology, Mercenaria physiology, Oxidative Stress physiology, tert-Butylhydroperoxide pharmacology
- Abstract
We assess whether reactive oxygen species production and resistance to oxidative stress might be causally involved in the exceptional longevity exhibited by the ocean quahog Arctica islandica. We tested this hypothesis by comparing reactive oxygen species production, resistance to oxidative stress, antioxidant defenses, and protein damage elimination processes in long-lived A islandica with the shorter-lived hard clam, Mercenaria mercenaria. We compared baseline biochemical profiles, age-related changes, and responses to exposure to the oxidative stressor tert-butyl hydroperoxide (TBHP). Our data support the premise that extreme longevity in A islandica is associated with an attenuated cellular reactive oxygen species production. The observation of reduced protein carbonyl concentration in A islandica gill tissue compared with M mercenaria suggests that reduced reactive oxygen species production in long-living bivalves is associated with lower levels of accumulated macromolecular damage, suggesting cellular redox homeostasis may determine life span. Resistance to aging at the organismal level is often reflected in resistance to oxidative stressors at the cellular level. Following TBHP exposure, we observed not only an association between longevity and resistance to oxidative stress-induced mortality but also marked resistance to oxidative stress-induced cell death in the longer-living bivalves. Contrary to some expectations from the oxidative stress hypothesis, we observed that A islandica exhibited neither greater antioxidant capacities nor specific activities than in M mercenaria nor a more pronounced homeostatic antioxidant response following TBHP exposure. The study also failed to provide support for the exceptional longevity of A islandica being associated with enhanced protein recycling. Our findings demonstrate an association between longevity and resistance to oxidative stress-induced cell death in A islandica, consistent with the oxidative stress hypothesis of aging and provide justification for detailed evaluation of pathways involving repair of free radical-mediated macromolecular damage and regulation of apoptosis in the world's longest-living non-colonial animal.
- Published
- 2011
- Full Text
- View/download PDF
44. Emerging microsporidian infections in Russian HIV-infected patients.
- Author
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Sokolova OI, Demyanov AV, Bowers LC, Didier ES, Yakovlev AV, Skarlato SO, and Sokolova YY
- Subjects
- Adult, Communicable Diseases, Emerging microbiology, DNA, Fungal chemistry, DNA, Fungal genetics, DNA, Ribosomal Spacer chemistry, DNA, Ribosomal Spacer genetics, Enterocytozoon classification, Feces microbiology, Female, Histocytochemistry methods, Humans, Male, Microsporidia, Unclassified classification, Microsporidiosis microbiology, Middle Aged, Molecular Sequence Data, Polymerase Chain Reaction methods, Russia epidemiology, Sequence Analysis, DNA, Communicable Diseases, Emerging epidemiology, Enterocytozoon isolation & purification, HIV Infections complications, Microsporidia, Unclassified isolation & purification, Microsporidiosis epidemiology
- Abstract
Microsporidia were identified in stool specimens by histochemistry and PCR of 30 (18.9%) of 159 HIV-infected patients presenting to the S. P. Botkin Memorial Clinical Hospital of Infectious Diseases, St. Petersburg, Russia. The higher prevalence of Encephalitozoon intestinalis, in 21 (12.8%) patients, than of Enterocytozoon bieneusi, in 2 patients (1.2%), was unexpected. Encephalitozoon cuniculi was detected in three patients: one with strain I and two with strain II. Encephalitozoon hellem was detected in one patient, and two patients were identified as being infected by Microsporidium species. One patient was infected with both E. intestinalis and E. cuniculi. In two patients, the microsporidian species were not identifiable. No statistically significant differences in gender, age, and stage of AIDS were observed between the microsporidian-positive and -negative HIV-infected patients. HIV-infected patients diagnosed with microsporidian infection, however, were significantly more likely to exhibit ≤ 100 CD4(+) T cells/μl blood (20/30 patients [67%]; odds ratio [OR], 3.150; 95% confidence interval [CI(95)], 1.280 to 7.750; P = 0.0116) and weight loss of >10% of the baseline (19/30 patients [63%]; odds ratio, 2.995; CI(95), 1.100 to 8.158; P = 0.0352) than HIV-infected patients not diagnosed with microsporidian infection. In summary, this is the first report describing the diagnosis of microsporidian infection of HIV-infected patients in Russia and the first detection of E. cuniculi strain II in a human.
- Published
- 2011
- Full Text
- View/download PDF
45. Reactive nitrogen and oxygen species, and iron sequestration contribute to macrophage-mediated control of Encephalitozoon cuniculi (Phylum Microsporidia) infection in vitro and in vivo.
- Author
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Didier ES, Bowers LC, Martin AD, Kuroda MJ, Khan IA, and Didier PJ
- Subjects
- Animals, Female, Macrophages, Peritoneal metabolism, Mice, Peritoneum immunology, Peritoneum microbiology, Reactive Nitrogen Species toxicity, Reactive Oxygen Species toxicity, Survival Analysis, Encephalitozoon cuniculi immunology, Encephalitozoonosis immunology, Iron metabolism, Macrophages, Peritoneal immunology, Reactive Nitrogen Species metabolism, Reactive Oxygen Species metabolism
- Abstract
Encephalitozoon cuniculi (Phylum Microsporidia) infects a wide range of mammals, and replicates within resting macrophages. Activated macrophages, conversely, inhibit replication and destroy intracellular organisms. These studies were performed to assess mechanisms of innate immune responses expressed by macrophages to control E. cuniculi infection. Addition of reactive oxygen and nitrogen species inhibitors to activated murine peritoneal macrophages statistically significantly, rescued E. cuniculi infection ex vivo. Mice deficient in reactive oxygen species, reactive nitrogen species, or both survived ip inoculation of E. cuniculi, but carried significantly higher peritoneal parasite burdens than wild-type mice at 1 and 2 weeks post inoculation. Infected peritoneal macrophages could still be identified 4 weeks post inoculation in mice deficient in reactive nitrogen species. L-tryptophan supplementation of activated murine peritoneal macrophage cultures ex vivo failed to rescue microsporidia infection. Addition of ferric citrate to supplement iron, however, did significantly rescue E. cuniculi infection in activated macrophages and further increased parasite replication in non-activated macrophages over non-treated resting control macrophages. These results demonstrate the contribution of reactive oxygen and nitrogen species, as well as iron sequestration, to innate immune responses expressed by macrophages to control E. cuniculi infection., (Copyright © 2010 Institut Pasteur. Published by Elsevier SAS. All rights reserved.)
- Published
- 2010
- Full Text
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46. The complete sequence of the smallest known nuclear genome from the microsporidian Encephalitozoon intestinalis.
- Author
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Corradi N, Pombert JF, Farinelli L, Didier ES, and Keeling PJ
- Subjects
- Encephalitozoon genetics, Genome, Fungal genetics
- Abstract
The genome of the microsporidia Encephalitozoon cuniculi is widely recognized as a model for extreme reduction and compaction. At only 2.9 Mbp, the genome encodes approximately 2,000 densely packed genes and little else. However, the nuclear genome of its sister, Encephalitozoon intestinalis, is even more reduced; at 2.3 Mbp, it represents a 20% reduction from an already severely compacted genome, raising the question, what else can be lost? In this paper, we describe the complete sequence of the E. intestinalis genome and its comparison with that of E. cuniculi. The two species share a conserved gene content, order and density over most of their genomes. The exceptions are the subtelomeric regions, where E. intestinalis chromosomes are missing large gene blocks of sequence found in E. cuniculi. In the remaining gene-dense chromosome 'cores', the diminutive intergenic sequences and introns are actually more highly conserved than the genes themselves, suggesting that they have reached the limits of reduction for a fully functional genome.
- Published
- 2010
- Full Text
- View/download PDF
47. Overview of the presentations on microsporidia and free-living amebae at the 10th International Workshops on Opportunistic Protists.
- Author
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Didier ES, Weiss LM, Cali A, and Marciano-Cabral F
- Subjects
- Animals, Humans, Opportunistic Infections drug therapy, Opportunistic Infections epidemiology, International Cooperation, Lobosea drug effects, Lobosea genetics, Lobosea physiology, Microsporidia drug effects, Microsporidia genetics, Microsporidia physiology, Opportunistic Infections microbiology, Opportunistic Infections parasitology
- Published
- 2009
- Full Text
- View/download PDF
48. Microsporidian infection is prevalent in healthy people in Cameroon.
- Author
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Nkinin SW, Asonganyi T, Didier ES, and Kaneshiro ES
- Subjects
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Cameroon epidemiology, Child, Child, Preschool, Enterocytozoon isolation & purification, Feces microbiology, Female, Fluorescent Antibody Technique, Indirect, HIV Infections complications, Humans, Infant, Infant, Newborn, Male, Middle Aged, Prevalence, Tuberculosis complications, Microsporidiosis epidemiology
- Abstract
Most studies of opportunistic infections focus on those with weak immune systems, such as human immunodeficiency virus (HIV)/AIDS patients and children. However, there is a lack of information on these infectious agents in healthy people worldwide. In the present study, stool samples from both HIV patients and healthy people were examined to begin filling in this serious gap in the understanding of human microsporidiosis, particularly the enteric parasite Enterocytozoon bieneusi. Specimens were obtained from 191 individuals living in Yaoundé, the capital city of Cameroon, in sub-Sahara Africa, including 28 HIV-positive patients who also had tuberculosis (TB). E. bieneusi prevalence was 35.7% among the HIV(+) TB patients, whereas it was only 24.0% among 25 HIV(-) TB patients in the same hospital. Unexpectedly, the prevalence (67.5%) of microsporidiosis was found to be even higher for 126 immunocompetent individuals than for those with TB (healthy people compared to HIV(+) TB and HIV(-) TB patients; P < 0.001). The immunocompetent group included people ranging from 2 to 70 years of age living in four different neighborhoods in Yaoundé. The highest prevalence (81.5%) was among teenagers, and the highest mean infection score (+2.5) was among children. Additional studies of immunocompetent people in other parts of Cameroon, as well as in other countries, are needed to better understand microsporidiosis epidemiology. There is still much more to be learned about the natural history of microsporidia, the pathogenicity of different strains, and the role of enteric microsporidia as opportunistic infections in immunodeficient people.
- Published
- 2007
- Full Text
- View/download PDF
49. Disseminated encephalitozoonosis in captive, juvenile, cotton-top (Saguinus oedipus) and neonatal emperor (Saguinus imperator) tamarins in North America.
- Author
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Juan-Sallés C, Garner MM, Didier ES, Serrato S, Acevedo LD, Ramos-Vara JA, Nordhausen RW, Bowers LC, and Parás A
- Subjects
- Adrenal Glands parasitology, Adrenal Glands pathology, Animals, Animals, Newborn, Animals, Zoo, Antibodies, Protozoan blood, Blotting, Western veterinary, Brain parasitology, Brain pathology, DNA, Protozoan chemistry, DNA, Protozoan genetics, Encephalitozoon cuniculi genetics, Encephalitozoonosis parasitology, Encephalitozoonosis pathology, Enzyme-Linked Immunosorbent Assay veterinary, Female, Liver parasitology, Liver pathology, Male, Microscopy, Electron, Transmission veterinary, Monkey Diseases pathology, North America epidemiology, Polymerase Chain Reaction veterinary, Sequence Analysis, DNA, Encephalitozoon cuniculi growth & development, Encephalitozoonosis veterinary, Monkey Diseases parasitology, Saguinus
- Abstract
Disseminated encephalitozoonosis was diagnosed in 2 sibling, juvenile, cotton-top tamarins (Saguinus oedipus) and 3 sibling, neonatal, emperor tamarins (S. imperator) by use of histologic examination, histochemical analysis, electron microscopy, and polymerase chain reaction (PCR) analysis with nucleotide sequencing. All tamarins were captive born at zoos in North America and died with no premonitory signs of disease. The main pathologic findings were myocarditis (4/5), hepatitis (3/5), interstitial pneumonia (3/5), skeletal myositis (3/5), meningoencephalitis (2/5), adrenalitis (2/5), tubulointerstitial nephritis (1/5), myelitis (1/5), sympathetic ganglioneuritis (1/5), and retinitis (1/5). Central nervous system lesions were the most prominent findings in cotton-top tamarins. The inflammation was predominantly lymphocytic and suppurative in cotton-top tamarins, whereas emperor tamarins had granulomatous or lymphoplasmacytic lesions. Intralesional periodic acid-Schiff-, gram-, or acid-fast (or all 3)-positive, oval-to-elliptical shaped organisms were found in 1 cotton-top and the 3 emperor tamarins. By electron microscopy, these organisms were consistent with microsporidia of the genus Encephalitozoon. E. cuniculi genotype III was detected by PCR analysis and sequencing in paraffin-embedded brain, lung, and bone marrow specimens from the cotton-top tamarins. Although PCR results were negative for one of the emperor tamarins, their dam was seropositive for E. cuniculi by ELISA and Western blot immunodetection. These findings and recent reports of encephalitozoonosis in tamarins in Europe suggest that E. cuniculi infection may be an emerging disease in callitrichids, causing high neonatal and juvenile mortality in some colonies. The death of 2 less than 1-day-old emperor tamarins from a seropositive dam supports the likelihood of vertical transmission in some of the cases reported here.
- Published
- 2006
- Full Text
- View/download PDF
50. Antimicrosporidial activities of fumagillin, TNP-470, ovalicin, and ovalicin derivatives in vitro and in vivo.
- Author
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Didier PJ, Phillips JN, Kuebler DJ, Nasr M, Brindley PJ, Stovall ME, Bowers LC, and Didier ES
- Subjects
- Animals, Cyclohexanes, Drug Evaluation, Preclinical, Encephalitozoon drug effects, Encephalitozoon growth & development, In Vitro Techniques, Male, Mice, Mice, Nude, O-(Chloroacetylcarbamoyl)fumagillol, Time Factors, Vittaforma drug effects, Vittaforma growth & development, Fatty Acids, Unsaturated pharmacology, Microsporidia drug effects, Microsporidiosis drug therapy, Sesquiterpenes pharmacology
- Abstract
Therapies for microsporidiosis in humans are limited, and fumagillin, which appears to be the most broadly effective antimicrosporidial drug, is considered to be moderately toxic. The purpose of this study was to apply an in vitro drug screening assay for Encephalitozoon intestinalis and Vittaforma corneae and an in vivo athymic mouse model of V. corneae infection to assess the efficacy of TNP-470 (a semisynthetic analogue of fumagillin), ovalicin, and eight ovalicin derivatives. TNP-470, ovalicin, and three of the ovalicin derivatives inhibited both E. intestinalis and V. corneae replication by more than 70% in vitro. Another three of the ovalicin derivatives inhibited one of the two microsporidian species by more than 70%. None of the treated athymic mice survived the V. corneae infection, but they did survive statistically significantly longer than the untreated controls after daily treatment with fumagillin administered at 5, 10, and 20 mg/kg of body weight subcutaneously (s.c.), TNP-470 administered at 20 mg/kg intraperitoneally (i.p.), or ovalicin administered at 5 mg/kg s.c. Of two ovalicin derivatives that were assessed in vivo, NSC 9665 given at 10 mg/kg i.p. daily also statistically significantly prolonged survival of the mice. No lesions associated with drug toxicity were observed in the kidneys or livers of uninfected mice treated with these drugs at the highest dose of 20 mg/kg daily. These results thus support continued studies to identify more effective fumagillin-related drugs for treating microsporidiosis.
- Published
- 2006
- Full Text
- View/download PDF
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