The Journal of Experimental Medicine

Atkins, Elisha; Allison, Fred; Smith, Mary Ruth; Wood, W. Barry

doi: 10.1084/jem.101.4.353pmid: 14354106

The mode of action of cortisone as an antipyretic has been studied in rabbits challenged with intravenous injections of bacterial pyrogens. The fever induced by pyromen or dextran was found to be markedly suppressed when cortisone was administered in liberal amounts (25 mg. twice daily) for 3 days prior to the challenge. Although the cortisone effectively blocked the febrile response to both pyrogens, it failed to influence the transient but marked leucopenia which characteristically precedes the onset of fever. The antipyretic action of the drug also was shown to bear no relation to the activity of the serum factor recently demonstrated by Farr, Grant, and others to be involved in the production of pyrogen-induced fever. In preliminary experiments with typhoid vaccine as the inciting pyrogen, the presence of serum factor activity in normal blood and its absence in the blood of pyrogen-tolerant rabbits was confirmed. Subsequently the blood of rabbits treated with antipyretically effective doses of cortisone was shown to contain just as much serum factor activity as that of normal rabbits. In addition, previous incubation of the pyrogen with serum factor failed to influence the antipyretic effect of the drug. It is concluded from these findings that in suppressing pyrogen fever, cortisone acts neither upon the leucopenic reaction nor upon the fever-accelerating factor of the serum. By exclusion it would appear that the drug must influence some later stage of the fever-producing process. The mechanisms involved in the later stages of the response to exogenous pyrogen remain undefined, and the need for determining whether they are related to the prefebrile leucopenia is emphasized. Footnotes Submitted: 21 November 1954

Hardy, Paul H.; Nell, E. Ellen

doi: 10.1084/jem.101.4.367pmid: 14354107

A method has been described for the preparation of Treponema pallidum suspensions that are suitable for specific agglutination studies and can be stored at 4°C. for months without loss of agglutinability. Such suspensions have been shown to react with two distinct antibodies in the serum of syphilitic animals and man: Wassermann antibody and a specific treponeme agglutinin. It has been demonstrated that the agglutination of treponemes by specific treponeme agglutinin is enhanced by heat treatment or aging of the suspension, and inhibited by a divalent cation, probably Ca ++ , normally present in serum. This inhibition has been overcome by the use of a chelating agent, ethylene-diamine tetracetate. These findings have been utilized to devise a simple agglutination test for the diagnosis of treponeme infections that is very sensitive and highly specific. This test has been carried out with 430 human sera, and a comparison has been made of the results of the agglutination, treponemal immobilization, and standard serological tests on these sera. The agglutination test appears to have a specificity comparable to the treponemal immobilization test and considerably greater than the standard serological tests. Footnotes Submitted: 29 November 1954

Faber, Harold K.; Dong, Luther

doi: 10.1084/jem.101.4.383pmid: 14354108

1. The effects of viremia on the CNS of cynomolgus monkeys were studied by comprehensive histological examination following inoculations of approximately equal amounts of the same strain of poliomyelitis virus into the femoral vein, carotid artery, and vertebral artery, respectively, of four animals in each case. 2. The intravenous injections failed to produce lesions in the CNS, indicating that an effective mechanism exists for the removal of virus from the blood stream. While not absolute, the degree of protection of the CNS afforded by this mechanism appears to be of major importance. 3. Inoculations into the carotid artery failed to produce significant lesions in the CNS in two animals; only a few minor lesions in one; and bulbar paralysis in one. The neuronal areas supplied by the carotid artery are in general those of low susceptibility to poliomyelitis virus. 4. Inoculations into the vertebral artery, which supplies neuronal areas of high susceptibility, produced in all four animals severe symmetrical and widely distributed lesions in the brainstem, chiefly the motor centers of the pons, medulla, and cord, and maximal in the cord. Involvement of all of the various affected areas appeared to be simultaneous. 5. Viremic invasion of the CNS appears to occur at many points by direct passage of virus from capillary to neuron, and not at a single area of specialized vascular permeability. 6. Comparison of the two routes of arterial inoculation indicates that: ( a ) the localizations of CNS lesions from viremia depend largely upon the susceptibilities of exposed nerve cells in a given region; ( b ) in areas of high neuron susceptibility the blood-neuron "barrier" does not present an obstacle of importance to the passage of virus. 7. Invasion of the CNS from the blood results in a notable difference in the initial localization of lesions from that produced by invasion by way of the peripheral nerves, the latter tending to occur in isolated nuclear groups, usually in the lower brainstem, related to the regional supply. Footnotes Submitted: 5 December 1954

Cole, Leon R.; Favour, Cutting B.

doi: 10.1084/jem.101.4.391pmid: 14354109

Guinea pigs sensitized with tubercle bacilli demonstrate a dual allergic response mediated by two chemically distinct plasma fractions: 1. Antibody to tuberculopolysaccharide is located exclusively in fraction II (gamma globulin). This fraction will passively transfer systemic anaphylaxis and urticarial type skin reactivity to tuberculopolysaccharide, and contains the Middlebrook-Dubos antibody. 2. Antibody to tuberculoprotein is contained exclusively in a new plasma fraction called fraction IV-10. By Cohn's Method X, fraction IV-10 is a part of fraction IV (alpha globulin) and to a lesser extent V (albumin). This fraction will passively transfer to normal guinea pigs a delayed type skin sensitivity to tuberculin PPD which is maximal between 18 and 30 hours, and it contains the Boyden antibody. When fractions II and IV-10 are combined, the antibody to tuberculopolysaccharide inhibits the passive transfer of delayed type reactivity. Combination of these two fractions does not alter their separate in vitro hemagglutinating properties. Adsorption of IV-10 with Boyden sensitized cells removes its ability to transfer delayed type tuberculin sensitivity. Adsorption of II with Middlebrook-Dubos-sensitized cells removes its capacity to effect passive transfer of immediate type reactivity to tuberculopolysaccharides. Footnotes Submitted: 23 November 1954

Stetson, Chandler A.

doi: 10.1084/jem.101.4.421pmid: 14354110

The cutaneous, ophthalmic, and systemic reactions of normal rabbits to Gram-negative bacterial endotoxins have been compared with the classical reactions of bacterial hypersensitivity, and in each case certain similarities have been found. It has also been shown that the Shwartzman phenomenon can be reproduced with tuberculin, in BCG-vaccinated rabbits, and with suspensions or extracts of heat-killed Group A streptococci in rabbits previously sensitized to these bacteria. These considerations suggest the hypothesis that the biologic activity of endotoxins may be based on the existence in "normal" animals of delayed or tuberculin-type hypersensitivity to these materials. Footnotes Submitted: 4 November 1954

Kilbourne, Edwin D.

doi: 10.1084/jem.101.4.437pmid: 14354111

The administration of cortisone to chick embryos inoculated with large quantities of inactive influenza B virus results in a rate of viral increase greater than is concommittantly observed with inocula of comparable infectivity which are devoid of inactive particles. Thus, more than a mere negation of autointerference is effected. It is concluded that in the presence of cortisone reactivation has occurred of non-infective virus to a state in which it can participate in viral synthesis. Cortisone-induced viral reactivation is dependent upon a high partide/cell ratio and is thus analogous to the previously described phenomenon of "multiplicity reactivation." Cortisone does not influence either homologous or heterologous viral interference unless reactivation of the inactive interfering virus occurs. Virus reactivable with cortisone possesses both interfering and enzymatic properties. Reactivation of virus with cortisone cannot be effected in vitro but is mediated by the host cell. Two hypotheses concerning the action of cortisone are presented. Footnotes Submitted: 9 December 1954