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Viral hepatitis associated with transplantable mouse leukemia. I. Acute hepatic manifestations following treatment with urethane or methylformamide.

An hepatic disease caused by a filterable agent carried in leukemic mice is described. Ordinarily the virus remains latent and asymptomatic. If, however, the mice are treated with urethane or methylformamide before and after virus inoculation, the disease becomes manifest and is characterized by extremely marked liver necrosis. Infant mice, a large percentage of weanlings, and adult Bagg albino mice are killed when injected with a filtrate from organs of diseased animals. Adult F1 and Swiss mice show signs of the disease but generally recover. They succumb, however, when simultaneously treated with urethane or methylformamide. By continuing the treatment of consecutive transfer generations an acute disease can be induced which finally kills all adult F1 mice without the treatment. At this stage the original leukemia may be lost. Mice which have recovered from the subacute disease are resistant to the acute disease, and mice injected with the latent form of the agent are immune to the subacute disease. However, even immunized animals lose their resistance if they are treated with urethane. The acute or subacute disease can be reduced to the latent stage by passing the agent through several generations of immunized animals. The relationship of this hepatitis virus of mice to viruses causing similar diseases is discussed, as is the possibility that these agents are closely related, if not identical.

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Acute hepatitis associated with mouse leukemia. V. The neurotropic properties of the causal virus.

Observations on the behavior of MHV (Pr) in the cerebral tissue of Princeton and Swiss weanling mice indicated a limited neurotropism. The virus migrated to the brain on intraperitoneal injection and was established there by cranial passage, though with difficulty in Swiss mice. Intracerebral multiplication was rarely followed by outward signs of nervous disorder. A slight pathologic reaction occurred in the brains of intracerebrally injected Princeton mice, but it was negligible compared with that of the ensuing hepatitis. In Swiss mice, injected intracerebrally with a mixture of MHV (Pr) and Eperythrozoon coccoides, a related virus with restricted pathogenicity and host range, possibly a mutant, was isolated from the liver and brain. MHV (C), an actively hepatotropic virus recovered from leukemic Balb C mice, was much more neurotropic than MHV (Pr). Intracerebral injection of Balb C and Swiss weanling mice was attended by marked leptomeningeal and encephalitic lesions. Paralysis of the extremities occurred in some of the animals. The virus was essentially inactive in Princeton mice. During the intracerebral passage of MHV (C) in Swiss mice a pleuropneumonia-like organism was isolated from the brain. In conjunction with the virus this organism produced a vigorous leukocytic reaction.

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Cell-free transmission in adult Swiss mice of a disease having the character of a leukemia.

A disease with the characteristics of a leukemia has been found to be serially transmissible in adult Swiss mice by means of cell-free filtrates. Thus far, the disease has been transmitted through twenty-six serial passages with filtrates as well as cell suspensions. The agent readily passes through Selas 03, Berkefeld N, and gradocol membrane filters-these last having an average pore size of 220 mmicro. Filtrates remain stable when stored for long periods at -70 degrees C. or when lyophilized. Splenic tissue containing the agent, which was subjected to massive doses of x-ray (50,000 r),-far more than sufficient to kill the cells,-show undiminished infectivity. The agent is inactivated by heating to 56 degrees C. for 30 minutes and by exposure to ether or formalin. The disease can be transmitted to adult Swiss mice or DBA/2 mice, but not to adult PRI, C(3)H, A, C(57)B1/6, or F(1)(C(58) x BALB) mice. Intraperitoneal, subcutaneous, intracerebral, and intramuscular injections are all effective.

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Acute hepatitis associated with mouse leukemia. I. Pathological features and transmission of the disease.

On four occasions a naturally occurring mouse leukemia, which was maintained by serial passage in weanlings of the Princeton strain, was superseded by a syndrome typical of acute hepatitis. Once initiated, the disease was regularly transmissible by the injection of liver suspensions of sick mice. It was also passed, though irregularly, by feeding such suspensions, and it also followed cannibalism. The course of the disease after intraperitoneal injection of liver suspensions into normal weanlings was commonly less than 7 days and the mortality rate nearly 100 per cent. Focal or diffuse necrosis of the liver was the only constant lesion at autopsy. On recovery, which occurred only in exceptional cases, cirrhosis was often found. The primary source of the disease was undetermined. Latent carriage by healthy mice was not detectable on direct examination nor by the serial passage of suspensions of normal livers.

Acute Disease↗

Acute hepatitis associated with mouse leukemia. II. Etiology and host range of the causal agent in mice.

The etiological agent of the acute hepatitis encountered in weanling mice of the Princeton strain is a virus found in the liver, spleen, kidneys, heart's blood, urine, and intestinal contents of experimentally infected animals. Older Princeton mice and weanlings from four other strains (Swiss, Webster's BSVS, C albino) and Bagg) proved to be less susceptible than Princeton weanlings. The virus was demonstrable in Berkefeld V filtrates of liver suspensions and in supernatants after centrifugation at 10,000 G. In whole liver suspensions it was detectable in decreasing amounts through a dilution of 10(-7). Aureomycin and terramycin had no detectable effect on the activity of the virus in weanlings.

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Mouse leukemia.

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Animals↗