SUMMARY:Cynomolgus monkeys (Macaca fascicularis) were exposed by fine-particle aerosol to lethal doses of monkeypox virus, Zaire strain. Death, attributable to fibrinonecrotic bronchopneumonia, occurred 9 to 17 days postexposure. Lower airway epithelium served as the principal target for primary infection. The relative degree of involvement among lymphoid tissues suggested that tonsil, mediastinal, and mandibular lymph nodes were also infected early in the course of the disease, and may have served as additional, although subordinate, sites of primary replication. The distribution of lesions was consistent with lymphatogenous spread to the mediastinal lymph nodes and systemic dissemination of the virus through a monocytic cell-associated viremia. This resulted in lesions affecting other lymph nodes, the thymus, spleen, skin, oral mucosa, gastrointestinal tract, and reproductive system. The mononuclear phagocyte/dendritic cell system was the principal target within lymphoid tissues and may also have provided the means of entry into other systemic sites. Hepatic involvement was uncommon. Lesions at all affected sites were characterized morphologically as necrotizing. Terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining of select lesions suggested that cell death within lymphoid and epithelial tissues was due in large part to apoptosis. Skin and mucosal surfaces of the respiratory and gastrointestinal tracts also exhibited variable proliferation of epithelial cells and subjacent fibroblasts. Epithelial intracytoplasmic inclusion bodies, consistent with Guarnieri bodies, were usually inconspicuous by light microscopy, but when present, were most readily apparent in the stratified squamous epithelium of the oral mucosa and epidermis. Multinucleated syncytial cells were also occasionally observed in the stratified squamous epithelium of the tongue, tonsil, and skin, and in the intestinal mucosa. Monkeypox virus antigen was readily demonstrated by immunohistochemistry using anti-vaccinia mouse polyclonal antibodies as well as anti-monkeypox rabbit polyclonal antibodies. Detectable poxviral antigen was limited to sites exhibiting obvious morphologic involvement and was most prominent within epithelial cells, macrophages, dendritic cells, and fibroblasts of affected tissues. The presence of poxviral antigen, as determined by immunohistochemistry, correlated with ultrastructural identification of replicating virus. Concurrent bacterial septicemia, present in one monkey, was associated with increased dissemination of the virus to the liver, spleen, and bone marrow and resulted in a more rapidly fatal clinical course. (Lab Invest 2001, 81:1581-1600.

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The observed dynamics in polymorphonuclear leukocyte alterations in peripheral blood after OPW exposure were similar to those found recently in clinical observations of nonpenetrating injury and in animal models of infectious insults. Therefore, our data suggest that the main pattern of proinflammatory alterations in the rat model of lung injury induced by exposure to long-duration shock wave is similar to patterns that are characteristic of major trauma. The data further suggest that the expression of polymorphonuclear leukocyte CD11b and the response of iron-transferrin complex can be considered as potential surrogate markers in blood for systemic alterations following OPW-induced injury and, therefore, warrant further investigation in a human pilot study.

Clinical use of modern dextran solutions has been limited by concerns of anaphylactoid reactions. To assess the short-term antigenic response to 7.5% hypertonic saline in 6% Dextran-70 (HSD), sera were obtained from dogs involved in the acute and subacute toxicology testing of HSD and its individual components, and analyzed for IgG, IgM and C3 complement. In separate studies, beagles were infused i.v. with a single dose of HSD or its components at 20 ml kg-1 (the maximum tolerated dose; MTD), or the MTD daily for 14 days, and serum was obtained prior to and at various times after infusion up to 14 days. In both studies, despite serum dextran concentrations exceeding 2000 mg dl-1, no induction of IgG, IgM or C3 complement concentrations were observed. In addition, serum IgG immunoelectrophoretic patterns were of normal curvature, position and intensity; the immunoprecipitin bands were not displaced, bowed, inhibited or thicker than the normal preinfusion immunoelectrophoretograms. The data suggest that single or multiple HSD i.v. injections, as much as five times the proposed therapeutic level for the treatment of hypovolemia, evoked no increase in antibody titers in dogs. Therefore, therapeutic use of HSD in the treatment of hemorrhagic shock should not be associated with widespread concomitant allergic complications.

The presented data suggest that assessment of TRF-[Fe3+] in blunt trauma can provide a good deal of information on severity of injury. The response of TRF-[Fe3+] can be considered as a potential surrogate marker of the systemic alterations in blunt trauma and, therefore, warrants further investigation in a human pilot study.