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This Month in AJP

    Open AccessPublished:March 05, 2012DOI:https://doi.org/10.1016/j.ajpath.2012.02.005

        Using Fluorescent Q-Dots to 3D-Reconstruct Pick Bodies

        The smooth, spherical shape of Pick bodies differs from Alzheimer disease neurofibrillary tangles. Uematsu et al (Am J Pathol 2012, 180:1394–1397) immunofluorescently labeled tau-positive Pick bodies with quantum dot (QD) nanocrystals for 3D reconstruction via electron microscopy (EM) to identify QD immunolabeling on the same Pick body for comparison in detail. The identity of the QD nanocrystals, which are detectable both by fluorescence light microscopy and by EM, was confirmed via super-resolution scanning transmission EM. The exact comparison of the same structure by EM and 3D light microscopy demonstrated relevance between ultrastructural details and surrounding structures on a 3D basis. This method provides further insights into how molecules woven into specific pathological ultrastructures are at work in situ.

        Full-Genome Dissection of an Epidemic Group A Streptococcus

        An epidemic of severe invasive human infections caused by type emm59 group A Streptococcus (GAS) spread across Canada from 2006 to 2008. By sequencing the genomes of 601 epidemic, historic, and other emm59 organisms, Fittipaldi et al (Am J Pathol 2012, 180:1522–1534) identified a recently emerged, genetically distinct emm59 clone as being responsible for this epidemic, as well as its spread into the United States. Mouse and nonhuman primate models demonstrated that the emerged clone is unusually virulent, with transmission occurring primarily by skin contact. In addition, the emm59 strains had a significantly impaired ability to persist in human saliva, colonized the oropharynx of mice, and seldom caused human pharyngitis. This analysis illustrates how full-genome data can be used to precisely illuminate the landscape of strain dissemination during a bacterial epidemic.

        FTY720 Aids Recovery after Spinal Cord Injury

        Levels of the lysophospholipid mediator sphingosine-1-phosphate (S1P) increase in the spinal cord after contusion injury. To apply S1P receptor modulation to the treatment of spinal cord injury (SCI), Norimatsu et al (Am J Pathol 2012, 180:1625–1635) examined the therapeutic effects of FTY720, an S1P receptor agonist, on locomotor recovery after SCI in mice. FTY720 administered orally shortly after contusion SCI significantly improved motor function recovery, induced lymphopenia, and reduced T-cell infiltration in the spinal cord, but it did not affect early neutrophil infiltration, microglial activation, or expression of inflammatory cytokines. Vascular permeability and astrocyte accumulation were both decreased by FTY720 in the injured spinal cord. FTY720 also ameliorated motor function after SCI in mice with severe combined immunodeficiency. These data highlight the importance of immune-independent functions of FTY720 in promoting locomotor function recovery after SCI.

        APP Is a Biomarker for Transformed Stem Cells

        An important function of the β-amyloid precursor protein (APP) may exist in malignant disease, but its biological basis is unclear. To understand the role of APP in transformed pluripotent stem cells, Venkataraman et al (Am J Pathol 2012, 180:1636–1652) studied its expression levels in human testicular germ cell tumors. The cooperative expression of APP aligned with prominent pluripotency-related genes (Sox2, NANOG, and Oct3/4); however, the closest homologue family member, APLP2, showed no correlation. In addition, treatment with histone deacetylase (HDAC) inhibitors suppressed the levels of APP and stem cell markers. Loss of pluripotency was accompanied by decreased APP protein levels both in vitro and in vivo. Thus, APP represents a novel and specific biomarker in human transformed pluripotent stem cells that can be selectively modulated by HDAC inhibitors.

        EPO Protects Neuroretinal Function in Ischemic Retinopathy

        Retinal ischemia is a common feature of vision loss caused by diabetes, retinal vascular occlusion, and retinopathy of prematurity. Mowat et al (Am J Pathol 2012, 180:1726–1739) investigated the effects of ischemia in murine oxygen-induced retinopathy (OIR) on retinal function and neurodegeneration. OIR was associated with significant neuroretinal dysfunction as well as significantly increased apoptosis and atrophy of the inner retina. Erythropoietin (EPO) deficiency in heterozygous Epo-Tag transgenic mice led to more profound retinal dysfunction after OIR but had no measurable effect on the extent of retinal ischemia, preretinal neovascularization, or neuroretinal degeneration. Systemic administration of recombinant EPO protected EPO-deficient mice, but EPO supplementation in wild-type animals with OIR did not rescue neuroretinal dysfunction or degeneration. Therefore, endogenous EPO can protect neuroretinal function in ischemic retinopathy.

        Linked Article

        • Atomic Identification of Fluorescent Q-Dots on Tau-Positive Fibrils in 3D-Reconstructed Pick Bodies
          The American Journal of PathologyVol. 180Issue 4
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            Pick body disease, characterized by the presence of Pick bodies, is distinguished from neurofibrillary tangles in Alzheimer disease on the basis of their smooth, spherical shape. Quantum dots (QDs) are nanometer-scale, water-soluble fluorophores that are detectable both as a fluorescent signal by light microscopy and as electron-dense particles under electron microscopy. In this study, tau-positive Pick bodies were immunofluorescently labeled with QD nanocrystals composed of cadmium selenide for three-dimensional (3D) reconstruction and subsequently subjected to electron microscopic observation to identify QD immunolabeling on the same Pick body for comparison in detail.
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        • FTY720 Improves Functional Recovery after Spinal Cord Injury by Primarily Nonimmunomodulatory Mechanisms
          The American Journal of PathologyVol. 180Issue 4
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            Spinal cord injury (SCI) is an incapacitating injury that can result in limited functional recovery. We have previously shown increases in the lysophospholipid mediator, sphingosine-1-phosphate (S1P), in the spinal cord after contusion injury. To apply S1P receptor modulation to the treatment of SCI, we examined the therapeutic effects of FTY720, an S1P receptor agonist, on locomotor recovery after SCI in mice. Oral administration of FTY720 shortly after contusion SCI significantly improved motor function recovery, as assessed by both Basso Mouse Scale scores and Rotarod Performance test results.
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        • Amyloid Precursor Protein Is a Biomarker for Transformed Human Pluripotent Stem Cells
          The American Journal of PathologyVol. 180Issue 4
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            Increasing evidence suggests an important function of the β-amyloid precursor protein (APP) in malignant disease in humans; however, the biological basis for this evidence is not well understood at present. To understand the role of APP in transformed pluripotent stem cells, we studied its expression levels in human testicular germ cell tumors using patient tissues, model cell lines, and an established xenograft mouse model. In the present study, we demonstrate the cooperative expression of APP with prominent pluripotency-related genes such as Sox2, NANOG, and POU5F1 (Oct3/4).
          • Full-Text
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        • Full-Genome Dissection of an Epidemic of Severe Invasive Disease Caused by a Hypervirulent, Recently Emerged Clone of Group A Streptococcus
          The American Journal of PathologyVol. 180Issue 4
          • Preview
            Group A Streptococcus (GAS) causes an exceptionally broad range of infections in humans, from relatively mild pharyngitis and skin infections to life-threatening necrotizing fasciitis and toxic shock syndrome. An epidemic of severe invasive human infections caused by type emm59 GAS, heretofore an exceedingly rare cause of disease, spread west to east across Canada over a 3-year period (2006 to 2008). By sequencing the genomes of 601 epidemic, historic, and other emm59 organisms, we discovered that a recently emerged, genetically distinct emm59 clone is responsible for the Canadian epidemic.
          • Full-Text
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        • Endogenous Erythropoietin Protects Neuroretinal Function in Ischemic Retinopathy
          The American Journal of PathologyVol. 180Issue 4
          • Preview
            Because retinal ischemia is a common cause of vision loss, we sought to determine the effects of ischemia on neuroretinal function and survival in murine oxygen-induced retinopathy (OIR) and to define the role of endogenous erythropoietin (EPO) in this model. OIR is a reproducible model of ischemia-induced retinal neovascularization; it is used commonly to develop antiangiogenic strategies. We investigated the effects of ischemia in murine OIR on retinal function and neurodegeneration by electroretinography and detailed morphology.
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          Open Access
        • Corrections
          The American Journal of PathologyVol. 181Issue 1
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            In the article entitled, “Toward Routine Use of 3D Histopathology as a Research Tool” (Volume 180, pages 1835–1842 of the May 2012 issue of The American Journal of Pathology), the support footnote should have included the following: “This work was partially funded through WELMEC, a Centre of Excellence in Medical Engineering funded by the Wellcome Trust and EPSRC (grant WT088908/Z/09/Z ).”
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          Open Access