A Cross-Sectional Study of Hyponatremia Associated with Acute Central Nervous System Infections

Hyponatremia can occur with central nervous system (CNS) infections, but the frequency and severity may depend on the organism and nature of CNS involvement. In this cross-sectional study at a large Australian hospital network from 2015 to 2018, we aimed to determine the prevalence and severity of hyponatremia associated with CNS infection clinical syndromes, and the association with specific organisms. We examined the results of cerebrospinal fluid analysis from lumbar punctures performed in 184 adult patients with a serum sodium below 135 mmol/L who had abnormal cerebrospinal fluid analysis and a clinical syndrome consistent with an acute CNS infection (meningitis or encephalitis). Hyponatremia affected 39% of patients and was more severe and frequent in patients with encephalitis compared to meningitis (odds ratio = 3.03, 95% CI: 1.43–6.39, after adjusting for age). Hyponatremia was present on admission in 85% of cases. Herpes simplex virus infection was associated with the highest odds of hyponatremia (odds ratio = 3.25, 95% CI: 1.13–7.87) while enterovirus infection was associated with the lowest (odds ratio = 0.36, 95% CI: 0.14–0.92), compared to cases without an isolated organism. We concluded that the risk of hyponatremia may vary by the organism isolated but the clinical syndrome was a useful surrogate for predicting the probability of developing hyponatremia

Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules

High-grade brain cancer such as glioblastoma (GBM) remains an incurable disease. A common feature of GBM is the angiogenic vasculature, which can be targeted with selected peptides for payload delivery. We assessed the ability of micelle-tagged, vascular homing peptides RGR, CGKRK and NGR to specifically bind to blood vessels in syngeneic orthotopic GBM models. By using the peptide CGKRK to deliver the tumour necrosis factor (TNF) superfamily member LIGHT (also known as TNF superfamily member 14; TNFSF14) to angiogenic tumour vessels, we have generated a reagent that normalizes the brain cancer vasculature by inducing pericyte contractility and re-establishing endothelial barrier integrity. LIGHT-mediated vascular remodelling also activates endothelia and induces intratumoural high endothelial venules (HEVs), which are specialized blood vessels for lymphocyte infiltration. Combining CGKRK-LIGHT with anti-vascular endothelial growth factor and checkpoint blockade amplified HEV frequency and T-cell accumulation in GBM, which is often sparsely infiltrated by immune effector cells, and reduced tumour burden. Furthermore, CGKRK and RGR peptides strongly bound to blood vessels in freshly resected human GBM, demonstrating shared peptide-binding activities in mouse and human primary brain tumour vessels. Thus, peptide-mediated LIGHT targeting is a highly translatable approach in primary brain cancer to reduce vascular leakiness and enhance immunotherapy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

Invasive Streptococcus anginosus group infection—does the species predict the outcome?

Objective - To determine whether there is an association between the species of Streptococcus anginosus group (SAG) bacteria and the clinical outcome. Methods - Isolates from invasive infections caused by SAG bacteria at our institution between January 2004 and February 2009 were identified phenotypically to the taxonomic level of species. Clinical data from the medical records of the patients from whom these isolates were recovered were obtained retrospectively and analyzed. Results - Patients with invasive Streptococcus intermedius infections had a significantly longer hospital stay than patients infected with S. anginosus (p = 0.024) and a significantly higher 30-day all-cause mortality than patients infected with Streptococcus constellatus (p = 0.049). Conclusion - Identification of SAG bacteria to the taxonomic level of species may be of prognostic importance

Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules

High-grade brain cancer such as glioblastoma (GBM) remains an incurable disease. A common feature of GBM is the angiogenic vasculature, which can be targeted with selected peptides for payload delivery. We assessed the ability of micelle-tagged, vascular homing peptides RGR, CGKRK and NGR to specifically bind to blood vessels in syngeneic orthotopic GBM models. By using the peptide CGKRK to deliver the tumour necrosis factor (TNF) superfamily member LIGHT (also known as TNF superfamily member 14; TNFSF14) to angiogenic tumour vessels, we have generated a reagent that normalizes the brain cancer vasculature by inducing pericyte contractility and re-establishing endothelial barrier integrity. LIGHT-mediated vascular remodelling also activates endothelia and induces intratumoural high endothelial venules (HEVs), which are specialized blood vessels for lymphocyte infiltration. Combining CGKRK-LIGHT with anti-vascular endothelial growth factor and checkpoint blockade amplified HEV frequency and T-cell accumulation in GBM, which is often sparsely infiltrated by immune effector cells, and reduced tumour burden. Furthermore, CGKRK and RGR peptides strongly bound to blood vessels in freshly resected human GBM, demonstrating shared peptide-binding activities in mouse and human primary brain tumour vessels. Thus, peptide-mediated LIGHT targeting is a highly translatable approach in primary brain cancer to reduce vascular leakiness and enhance immunotherapy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.status: publishe

Nuclear actin aggregation is a hallmark of anti-synthetase syndrome-induced dysimmune myopathy

Objective: To analyze antisynthetase syndrome–associated myositis by modern myopathologic methods and to define its place in the spectrum of idiopathic inflammatory myopathies (IIMs). Methods: Skeletal muscle biopsies from antisynthetase syndrome–associated myositis and other IIMs from different institutions worldwide were analyzed by histopathology, quantitative PCR, and electron microscopy. Results: Myonuclear actin filament inclusions were identified as a unique morphologic hallmark of antisynthetase syndrome–associated myositis. Nuclear actin inclusions were never found in dermatomyositis, polymyositis, sporadic inclusion body myositis, autoimmune necrotizing myopathy associated with signal recognition particle or 3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies, or nonspecific myositis associated with other systemic diseases, harboring myositis-associated autoantibodies, and presenting myofiber necrosis. We show that molecules involved in actin filament formation and actin shuttling mechanisms are altered in antisynthetase syndrome, and may thus be involved in pathologic myonuclear actin aggregation. In addition, we have identified a typical topographic distribution of necrotic myofibers predominantly located at the periphery of muscle fascicles accompanied by inflammation and destruction of the perimysial connective tissue. Conclusion: Antisynthetase syndrome–associated myositis is characterized by distinctive myonuclear actin filament inclusions, including rod formations and a typical necrotizing perimysial myositis. This supports the hypothesis that antisynthetase syndrome–associated myositis is unique and should not be grouped among dermatomyositis, polymyositis, sporadic inclusion body myositis, necrotizing autoimmune myositis, or nonspecific myositis. Classification of evidence: This study provides Class II evidence that for patients with IIMs, the presence of myonuclear actin filament inclusions accurately identifies patients with antisynthetase syndrome–associated myositis (sensitivity 81%, specificity 100%)