Hypersegmented megakaryocytes and megakaryocytes with multiple separate nuclei in dogs treated with PNU-100592, an oxazolidinone antibiotic.

Megakaryocytes in normal dogs have a variety of nuclear forms. The most common variations are a single large multilobed nucleus or a segmented nucleus consisting of irregular nuclear lobes joined by strands of chromatin. Exaggerated segmentation (hypersegmentation) of the nucleus occurs in a small number of megakaryocytes. Megakaryocytes with multiple separate nuclei are infrequently observed. In a 1-mo toxicology study in young adult beagle dogs with PNU-100592, a new oxazolidinone antibacterial agent, a large increase in the number of megakaryocytes with hypersegmented nuclei and multiple separate nuclei was observed. The group mean platelet count was slightly decreased for most PNU-100592-treated groups. Siderocytes were observed on peripheral blood smears, and ring sideroblasts were present on bone marrow smears. Minimal to mild toxicologic lesions were observed in the large intestine, rectum, kidneys, liver, and testes, primarily in the high-dose group. PNU-100592 may be useful in the study of the regulation of endomitosis during megakaryocytopoiesis in the dog.

Clinical and epidemiological features of simian parvovirus infection in cynomolgus macaques with severe anemia.

We recently identified a simian parvovirus (SPV) in cynomolgus monkeys with severe anemia. We describe here the clinical and epidemiological findings in the original outbreak and in a second episode of anemia involving monkeys in a drug safety study at a separate facility. The major clinical findings associated with SPV infection were a severe normocytic, normochromic anemia. In the original episode the anemia was predominantly nonregenerative, whereas in the second outbreak there was an initial strong, regenerative response. In the absence of predisposing factors, SPV infection was mild or inapparent. However, the presence of concurrent acute infection with type D simian retrovirus in the original episode is believed to have been a major predisposing factor for the development of immunodeficiency and persistent SPV infection, culminating in severe anemia. It is unclear whether simian retrovirus infection played a role in the second episode, but it is possible that the drug used may have been a factor, because severely anemic monkeys were in the high drug dosage group. We conclude that SPV should be considered in the differential diagnosis of severe anemia in monkeys.

Induction of neutral proteinase and prostanoid production in bovine nasal chondrocytes by interleukin-1 and tumor necrosis factor alpha: modulation of these cellular responses by interleukin-6 and platelet-derived growth factor.

We have previously reported that recombinant human interleukin-1 (IL-1) stimulates matrix erosion in bovine nasal cartilage explants (R. J. Smith et al., Inflammation 13, 367-382, 1989). This action of IL-1 is believed to be caused by matrix-degrading neutral proteinases produced by activated chrondrocytes. Accordingly, we investigated the effects of recombinant human interleukin-1 alpha (IL-1 alpha), recombinant human interleukin-1 beta (IL-1 beta), and recombinant human tumor necrosis factor alpha (TNF alpha) on bovine nasal chondrocyte (BNC) responsiveness. IL-1 alpha and IL-1 beta stimulated a time (0-72 hr) and concentration-dependent (0.01-10 ng/ml) production of collagenase, gelatinase, caseinase, and prostaglandin E2 (PGE2) in BNC monolayer cultures. Neutral proteinase and PGE2 production by BNC was also induced by TNF alpha (0.2-200 ng/ml) in a time-dependent (0-72 hr) manner. Recombinant human interleukin-6 (IL-6) caused a concentration-dependent (6-200 ng/ml) potentiation of IL-1-stimulated neutral proteinase and PGE2 production by BNC. However, recombinant human platelet-derived growth factor homodimer BB suppressed BNC responsiveness to IL-1. A recombinant human IL-1 receptor antagonist protein inhibited BNC activation by IL-1 but not TNF alpha.

Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene.

The fibrinolytic potential of the vasculature is modulated primarily by the availability and activity of plasminogen activators, which convert the zymogen plasminogen into the active fibrin-degrading enzyme plasmin. The activities of these key regulatory enzymes are directly neutralized by their primary endogenous inhibitor, plasminogen activator inhibitor-1 (PAI-1). Although some individuals with a tendency to develop thrombotic disorders exhibit elevated levels of PAI-1 in their plasma, the cause-and-effect relationship between increased PAI-1 and thrombosis is still unclear. Specifically, it is not known whether chronic depression of fibrinolytic activity results in the development of thrombosis. To address this question we developed transgenic mice in which the contribution of PAI-1 to thrombus formation could be evaluated. The results presented in this report indicate that elevated levels of PAI-1 contribute to the development of venous but not arterial occlusions.

Retinopathy from inhaling 4,4'-methylenedianiline aerosols.

4,4'-Methylenedianiline (MDA) is an important chemical intermediate in the production of isocyanates and polyurethane elastomers and polymers. The health hazards from acute inhalation exposure to the aerosols were evaluated. Guinea pigs of albino and pigmented strains were exposed nose-only to the aerosols of MDA in polyethylene glycol 200 (PEG) solution. The exposure was 4 hr per day, 5 days per week for a total of 10 exposures in 2 weeks. The time-weighted average aerosol concentration was 0.44 +/- 0.09 mg/liter and the optical number length mean diameter of the aerosol particle was 2.4 micron with sigma g of 2.1. During exposures, no overt respiratory distress was observed. Two weeks after the exposures, the guinea pigs were tested for possible dermal sensitization by being challenged with dermal application of MDA-PEG solutions at concentrations of 0, 2, 20, and 200 mg/ml. Neither dermal irritation nor allergic response was detected under this experimental condition. Thereafter, the animals were tracheostomized for measurements of changes in lung insufflation pressure for detecting possible changes in the distensibility of the lungs from a challenge dose of an aerosol of MDA-PEG at a concentration of 200 mg/ml. No significant changes were observed under this testing condition. Finally, the animals were euthanized for histopathologic examinations of eye, lung, liver, and kidney. The most remarkable findings was the degeneration of the inner and outer segments of the photoreceptor cells and the pigmented epithelial cell layer of the retinas of both albino and pigmented strains of guinea pigs.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies of the pathogenesis of anemia of inflammation: mechanism of impaired erythropoiesis.

Cats with induced sterile abscesses developed a hematologic disorder consistent with anemia of inflammation. Serum iron concentrations decreased while the abscess was present, but erythropoietin concentrations did not change significantly. Cobalt administration to control (healthy) cats resulted in polycythemia, reticulocytosis, and hyperferremia. Cats with abscesses responded to cobalt similarly; however, magnitudes of the polycythemia and reticulocytosis were less. Constant infusion of ferric citrate (IV) into cats with sterile abscesses maintained serum iron concentration in the normal to high range. The iron infusion did not prevent the anemia, but did enable the bone marrow to respond to the anemia.

Morphologic and biochemical effects of intratracheally administered oil shale in rats.

Young adult rats were given three weekly intratracheal instillations of 30 mg of raw oil shale or spent oil shale suspended in 1.0 ml sterile physiological saline. Positive control groups received similar instillations of 30 mg or 5 mg of quartz. Animals were sacrificed and tissue samples taken for histopathology and biochemical analyses at 3 weeks, 7 weeks, 4 months, and 8 months following the first instillation. Rats exposed to raw shale, spent shale or quartz had increased lung weights compared with controls. Microscopically, all exposed groups developed granulomatous pneumonia and alveolar lipoproteinosis; pulmonary fibrosis was most severe in the quartz-exposed groups and progressed with time in these groups. Total amounts of pulmonary hydroxyproline, prolyl hydroxylase, total protein, and lipid phosphate were increased in shale or quartz-exposed groups; however, concentration of these substances on a per gram of lung tissue basis was not different from control groups.

Mycobacteriosis in mountain whitefish (Prosopium williamsoni) from the Yakima River, Washington.

Mycobacteriosis was found in mountain whitefish (Prosopium williamsoni) taken from the Yakima River near Richland, Washington in 1975 and 1976. The disease appeared to affect about 8% of the population sampled. Gross lesions were present in most visceral organs, but were most common in the kidney, liver and pyloric caeca. Microscopically, the lesions consisted of large numbers of macrophages containing numerous intracellular bacilli. An organism was isolated and has been tentatively classified as Mycobacterium sp., Runyon group III.

Lesions of tuberculosis in mountain whitefish (Prosopium williamsoni).

Lesions of tuberculosis in mountain whitefish (Prosopium williamsoni) were present in all visceral organs. The tubercles were composed of large rounded macrophages which contained numerous intracytoplasmic acid-fast bacilli. The lesions were not encapsulated and mineralization was not observed.

Focal mastocytosis in lymph nodes from a Beagle dog.

An 11-year-old Beagle dog had focal mastocytosis in the midtracheobronchial and left tracheobronchial lymph nodes. The cells were well-differentiated and were arranged in well-defined follicles. There were neither skin tumors nor mast-cell accumulations in other tissues.

Bone tumors induced by inhalation of 238PuO2 in dogs.

Plutonium-238, an alpha-emitting radionuclide, is used as a heat source in thermoeleltric power generators such as have been employed on lunar expeditions of communications satellites and in cardiac pacemakers. It has an 86.4 year half-life and emits 5.5 MeV alpha particles. Beagle dogs were given single 10-30 minute exposures to 238PuO2 aerosols to study the long-term translocation of plutonium and biological effects. Dogs with a terminal body burden ranging from 7-260 muCi were euthanized due to respiratory insufficiency related to plutonium-induced pneumonitis during the first 3 years after exposure. Nine of the 11 dogs euthanized during the 4-6 year postexposure period had osteosarcomas. The terminal plutonium body burden in the tumor-bearing dogs ranged from 0.5-2.6 muCi with 30-55% of the plutonium in the skeleton. Experiments are in progress to further define the dose-effect relationship of inhaled 238PuO2 and investigate the mechanisms of plutonium-induced neoplasia.