Key Points• In canine S aureus pneumonia, first randomized blinded trial showing blood transfused at end of storage period increases mortality.• Increased in vivo hemolysis, cell-free hemoglobin, pulmonary hypertension, tissue damage, and gas exchange abnormalities each contributed.Two-year-old purpose-bred beagles (n ؍ 24) infected with Staphylococcus aureus pneumonia were randomized in a blinded fashion for exchange transfusion with either 7-or 42-day-old canine universal donor blood (80 mL/kg in 4 divided doses). Older blood increased mortality (P ؍ .0005), the arterial alveolar oxygen gradient (24-48 hours after infection; P < .01), systemic and pulmonary pressures during transfusion (4-16 hours) and pulmonary pressures for ϳ 10 hours afterward (all P < .02). Further, older blood caused more severe lung damage, evidenced by increased necrosis, hemorrhage, and thrombosis (P ؍ .03) noted at the infection site postmortem. Plasma cell-free hemoglobin and nitric oxide (NO) consumption capability were elevated and haptoglobin levels were decreased with older blood during and for 32 hours after transfusion (all P < .03). The low haptoglobin (r ؍ 0.61; P ؍ .003) and high NO consumption levels at 24 hours (r ؍ ؊0.76; P < .0001) were associated with poor survival. Plasma nontransferrin-bound and labile iron were significantly elevated only during transfusion (both P ؍ .03) and not associated with survival (P ؍ NS). These data from canines indicate that older blood after transfusion has a propensity to hemolyze in vivo, releases vasoconstrictive cell-free hemoglobin over days, worsens pulmonary hypertension, gas exchange, and ischemic vascular damage in the infected lung, and thereby increases the risk of death from transfusion. (Blood. 2013;121(9):1663-1672) IntroductionTransfusion of red blood cells (RBCs) is one of the most commonly used, potentially lifesaving medical therapies. Each year, some 80.7 million units of blood are collected in 167 countries worldwide, and approximately 15 million units are collected and transfused in the United States alone. 1,2 RBCs can be stored for up to 42 days to meet inventory needs, and by standard practice the oldest blood is usually used first ("first in, first out"). Food and Drug Administration (FDA) regulations only stipulate that at the end of the storage period 75% of the cells remain in the circulation at 24 hours after transfusion and that hemolysis in the storage bag does not exceed 1%, 3 no other product specification of quality is required. Although 6-week-old stored blood meets current FDA standards, laboratory and clinical studies have raised concerns that "older" blood may not be as safe as blood stored for a shorter duration. [4][5][6][7][8] Refrigerated storage of blood results in a "storage lesion" characterized by rheologic changes, metabolic derangements, changes in oxygen affinity and delivery, oxidative injury to lipids and proteins, RBC shape change, loss of membrane carbohydrates, and reduced RBC lifespan. [8][9][10] The storage lesion resu...
The fungus Cryptococcus is a major cause of meningoencephalitis in HIV-infected as well as HIV-uninfected individuals with mortalities in developed countries of 20% and 30%, respectively. In HIV-related disease, defects in T-cell immunity are paramount, whereas there is little understanding of mechanisms of susceptibility in non-HIV related disease, especially that occurring in previously healthy adults. The present description is the first detailed immunological study of non-HIV-infected patients including those with severe central nervous system (s-CNS) disease to 1) identify mechanisms of susceptibility as well as 2) understand mechanisms underlying severe disease. Despite the expectation that, as in HIV, T-cell immunity would be deficient in such patients, cerebrospinal fluid (CSF) immunophenotyping, T-cell activation studies, soluble cytokine mapping and tissue cellular phenotyping demonstrated that patients with s-CNS disease had effective microbiological control, but displayed strong intrathecal expansion and activation of cells of both the innate and adaptive immunity including HLA-DR+ CD4+ and CD8+ cells and NK cells. These expanded CSF T cells were enriched for cryptococcal-antigen specific CD4+ cells and expressed high levels of IFN-γ as well as a lack of elevated CSF levels of typical T-cell specific Th2 cytokines -- IL-4 and IL-13. This inflammatory response was accompanied by elevated levels of CSF NFL, a marker of axonal damage, consistent with ongoing neurological damage. However, while tissue macrophage recruitment to the site of infection was intact, polarization studies of brain biopsy and autopsy specimens demonstrated an M2 macrophage polarization and poor phagocytosis of fungal cells. These studies thus expand the paradigm for cryptococcal disease susceptibility to include a prominent role for macrophage activation defects and suggest a spectrum of disease whereby severe neurological disease is characterized by immune-mediated host cell damage.
Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V) are axonal neuropathies characterized by a phenotype that is more severe in the upper extremities. We previously implicated mutations in the gene encoding glycyl-tRNA synthetase (GARS) as the cause of CMT2D and dSMA-V. GARS is a member of the family of aminoacyl-tRNA synthetases responsible for charging tRNA with cognate amino acids; GARS ligates glycine to tRNA Gly . Here, we present functional analyses of disease-associated GARS mutations and show that there are not any significant mutation-associated changes in GARS expression levels; that the majority of identified GARS mutations modeled in yeast severely impair viability; and that, in most cases, mutant GARS protein mislocalizes in neuronal cells. Indeed, four of the five mutations studied show loss-of-function features in at least one assay, suggesting that tRNAcharging deficits play a role in disease pathogenesis. Finally, we detected endogenous GARS-associated granules in the neurite projections of cultured neurons and in the peripheral nerve axons of normal human tissue. These data are particularly important in light of the recent identification of CMT-associated mutations in another tRNA synthetase gene [YARS (tyrosyl-tRNA synthetase gene)]. Together, these findings suggest that tRNA-charging enzymes play a key role in maintaining peripheral axons.
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