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      The significance of tubuloreticular inclusions as a marker of systemic stimulation by interferons in a case of focal and segmental glomerulosclerosis associated with cytomegalovirus (CMV) infection

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          Abstract

          The identification of large numbers of tubuloreticular inclusions (TRIs) in renal biopsies may be useful to raise diagnostic suspicion for certain clinical entities, particularly autoimmune diseases and viral infections. We report a case of a 65-year-old female with a 2-week history of malaise, massive proteinuria and lower extremity edema of acute onset. A renal biopsy was performed and the diagnosis of non-human immunodeficiency virus (HIV) tip-located, early focal segmental glomerulosclerosis (FSGS) was established. The electron microscopy examination was remarkable for the presence of diffuse foot process effacement and frequent TRIs in the endothelial cells of the glomerular capillary loops, endothelium of arterioles and cytoplasm of fibroblasts in the interstitium, highly suggestive of an underlying etiology. Patient clinical and laboratory workup revealed the absence of an autoimmune disease but the presence of a subclinical cytomegalovirus (CMV) infection. Therefore, we highlight that the identification of TRIs is a useful indicator of systemic interferon activity. In the present case, the unusual location of numerous TRIs was associated with a subclinical CMV infection in an immunocompetent patient.

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          The immune response to human CMV.

          This review will summarize and interpret recent literature regarding the human CMV immune response, which is among the strongest measured and is the focus of attention for numerous research groups. CMV is a highly prevalent, globally occurring infection that rarely elicits disease in healthy immunocompetent hosts. The human immune system is unable to clear CMV infection and latency, but mounts a spirited immune-defense targeting multiple immune-evasion genes encoded by this dsDNA β-herpes virus. Additionally, the magnitude of cellular immune response devoted to CMV may cause premature immune senescence, and the high frequencies of cytolytic T cells may aggravate vascular pathologies. However, uncontrolled CMV viremia and life-threatening symptoms, which occur readily after immunosuppression and in the immature host, clearly indicate the essential role of immunity in maintaining asymptomatic co-existence with CMV. Approaches for harnessing the host immune response to CMV are needed to reduce the burden of CMV complications in immunocompromised individuals.
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            Pathologic classification of focal segmental glomerulosclerosis.

            Focal segmental glomerulosclerosis (FSGS) is defined as a clinical-pathologic syndrome manifesting proteinuria and focal and segmental glomerular sclerosis with foot process effacement. The pathologic approach to the classification of FSGS is complicated by the existence of primary (idiopathic) forms and multiple subcategories with etiologic associations, including human immunodeficiency virus (HIV)-associated nephropathy, heroin nephropathy, familial forms, drug toxicities, and a large group of secondary FSGS mediated by structural-functional adaptations to glomerular hyperfiltration. A number of morphologic variants of primary and secondary focal sclerosis are now recognized, including FSGS not otherwise specified (NOS), perihilar, cellular, tip, and collapsing variants. The defining features of these morphologic variants and of the major subcategories of FSGS are discussed with emphasis on distinguishing light microscopic patterns and clinical-pathologic correlations. Copyright 2003 Elsevier Inc. All rights reserved.
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              Panax ginseng induces production of proinflammatory cytokines via toll-like receptor.

              Ginseng radix, the dried root of Panax ginseng C. A. Meyer, has been shown to enhance the ability to resist microbial infections. Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and interferon-gamma (IFN-gamma) are produced by macrophages treated with ginseng radix extract (GRE) in vitro as well as in vivo. However, the molecular mechanisms of the production are still not clear. In the present study, we demonstrated that production of TNF-alpha and IFN-gamma was induced by GRE in spleen cells and peritoneal macrophages from C3H/HeN mice but was impaired in C3H/HeJ mice carrying a defective toll-like receptor-4 (TLR-4) gene. In addition to these cytokines, the expression of IFN-beta and inducible nitric oxide synthase (iNOS) mRNAs was also increased in GRE-treated C3H/HeN spleen cells. We investigated the possibility that GRE contains a lipopolysaccharide (LPS)-like component. However, GRE induced production of TNF-alpha and IFN-gamma in the presence of polymyxin B, an LPS inhibitor. Furthermore, a Limulus amebocyte lysate assay showed that the endotoxin content of GRE was below the threshold level of 1 ng/ml LPS. These results suggest that GRE contains a non-LPS agent that enhances innate immunity through production of proinflammatory cytokines via TLR-4.
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                Author and article information

                Journal
                Clin Kidney J
                Clin Kidney J
                ckj
                ndtplus
                Clinical Kidney Journal
                Oxford University Press
                2048-8505
                2048-8513
                April 2014
                6 February 2014
                6 February 2014
                : 7
                : 2
                : 174-178
                Affiliations
                [1 ]Department of Pathology, Toronto General Hospital, University Health Network, University of Toronto , Toronto ON, Canada
                [2 ]Department of Nephrology, Toronto General Hospital, University Health Network, University of dfToronto , Toronto ON, Canada
                Author notes
                Correspondence and offprint requests to: Carmen Avila-Casado; E-mail: carmen.avila-casado@ 123456uhn.ca
                Article
                sft156
                10.1093/ckj/sft156
                4377766
                25852866
                c547bf0c-acde-4aba-afcf-1ca3618399c0
                © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For permissions, please email: journals.permissions@oup.com.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 27 June 2013
                : 5 December 2013
                Page count
                Pages: 5
                Categories
                Original Contributions
                Exceptional Cases

                Nephrology
                cmv infection,fsgs,interferon footprints,tubuloreticular structures
                Nephrology
                cmv infection, fsgs, interferon footprints, tubuloreticular structures

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