scholarly journals ETIOLOGY OF YELLOW FEVER

1920 ◽  
Vol 31 (2) ◽  
pp. 159-168 ◽  
Author(s):  
Hideyo Noguchi

The use ot a polyvalent immune serum ot nign potency in tne treatment of an experimental infection of guinea pigs with Leptospira icteroides was found to be of definite advantage in checking the progress of the infection. When administered during the period of incubation the serum was found capable of completely preventing the development of the disease, although on subsequent examination hemorrhagic lesions of greater or less number and extent were found in the lungs of the guinea pigs which survived. Moreover, the serum modified the course of the disease and when used in the early stages of infection prevented a fatal outcome. Employed at a later stage, however, when jaundice and nephritis had been present for several days and the animal was near collapse, the serum had no perceptible beneficial effect. This was, of course, to be expected in view of the incidence of various pathological phases of this disease—nephritis, hepatitis, and other toxic symptoms in succession. In man the clinical manifestations are more gradual and distinct than in the guinea pig, yet the yellow fever patient whose temperature is sub-normal, and who has reached the stage of hemorrhages from the gums, nose, stomach, and intestines, and of uremia and cholemia, would seem to have little or no chance of deriving benefit from the use of a specific immune serum. This latter assumption would probably hold irrespective of the relation which Leptospira icteroides proves to have to the etiology of yellow fever.

1921 ◽  
Vol 33 (2) ◽  
pp. 253-260 ◽  
Author(s):  
Hideyo Noguchi ◽  
I. J. Kligler

Serum from yellow fever convalescents from Payta, Piura, and Morropon gave a positive Pfeiffer reaction with the strains of Leptospira icteroides isolated in Guayaquil and Merida. The serum also protected the guinea pigs from these strains in the majority of instances. The Pfeiffer reaction was complete with all recent convalescents (7 to 36 days) but slight or partial in some instances with serum derived from individuals who had had the attack of yellow fever 10 months previously. The virulence of the Morropon strains was found to be approximately the same as that of the Guayaquil or Merida strains. With one strain the minimum lethal dose for the guinea pig was less than 0.00001 cc. of a kidney emulsion from an infected guinea pig. Suitable quantities of the anti-icteroides serum administered to guinea pigs inoculated with 2,000 to 20,000 minimum lethal doses of infective material prevented the development of the infection, or a fatal outcome, according as the serum was given during the incubation period or after fever had appeared. The earlier the administration of the serum the smaller was the quantity needed; during the incubation period 0.0001 to 0.001 cc. was sufficient, during the febrile period 0.01 to 0.1 cc. was required to check the progress of the disease, and even at the time when jaundice had already appeared, the injection of 0.1 to 1 cc. saved three out of four animals inoculated with Strain 3 and one out of three inoculated with Strain 1. The native guinea pigs secured in Payta proved to be unusually refractory to infection with Leptospira icteroides as compared with normal guinea pigs recently imported from New York. Fresh rabbit serum is recommended for culture work with Leptospira icteroides.


1919 ◽  
Vol 29 (6) ◽  
pp. 585-596 ◽  
Author(s):  
Hideyo Noguchi

Studies are reported on the type of disease induced in guinea pigs, dogs, and monkeys by inoculating them (1) with the blood or organ emulsions of guinea pigs or other susceptible animals experimentally infected with Leptospira icteroides, and (2) with a pure culture of the organism. Particular attention has been given in these experiments to the clinical features of the experimental infection in the various animals and to the pathological changes resulting from the infection. The symptoms and pathological lesions induced in guinea pigs are much more pronounced than those observed in dogs or marmosets. The period of incubation is nearly the same in all three species, 72 to 96 hours with intraperitoneal or subcutaneous inoculation, and a day or more longer when the infection is induced percutaneously or per os. The febrile reaction in the guinea pig and marmoset is about the same; in the dog there is less fever. The amount of albumin, casts, and bile pigments in the urine is more abundant in the guinea pig and marmoset than in the dog, and these animals also appear on the whole to become more intensely icteric. The black or bilious vomit, however, though occurring frequently in dogs during life, is observed in the guinea pig and marmoset at autopsy. The hemorrhagic diathesis is most pronounced in guinea pigs, less so in marmosets, and least in dogs. In dogs) for example, subcutaneous hemorrhages almost never occur, and the lungs usually show only a few minute ecchymoses. The pleurse, pericardium, and other serous surfaces of the thorax and abdomen remain free from ecchymoses, which, however, with hyperemia, are very marked along the gastrointestinal tract. The symptoms and lesions observed in animals experimentally infected with Leptospira icteroides closely parallel those of human yellow fever. The pathological changes occurring in human cases of yellow fever are similar to those induced by inoculation in guinea pigs and marmosets and in respect to their intensity stand intermediate between those arising in the two animals mentioned.


1920 ◽  
Vol 32 (5) ◽  
pp. 601-625 ◽  
Author(s):  
Hideyo Noguchi ◽  
I. J. Kligler

Injections into guinea pigs of the blood and the emulsions of liver and kidney obtained at autopsy from a fatal case of yellow fever in Merida induced in some of these animals, after a period of several days incubation, a rise of temperature which lasted 1, 2, or more days. When killed for examination at this febrile stage the animals invariably showed hemorrhagic areas of various size, sometimes few and sometimes numerous, in the lungs, and also, though less constantly, in the gastrointestinal mucosa, together with general hyperemia of the liver and kidneys. In a guinea pig (No. 6) inoculated with the liver emulsion of Case 1 there was a trace of jaundice on the 9th day. Injections of the blood or liver and kidney emulsions from such animals into normal guinea pigs reproduced the febrile reactions and the visceral lesions. The majority of the animals which were allowed to live and complete the course of the infection rapidly returned to normal (within several days). Examinations of these surviving guinea pigs after 2 weeks revealed the presence of rather old hemorrhagic foci in the lungs. In the course of further attempts to transfer the passage strain, a secondary infection by a bacillus of the paratyphoid group caused many deaths among the guinea pigs and resulted finally in the loss of the strain from Case 1. Most of the cultures made with the heart's blood taken at autopsy from Case 1 proved to be contaminated with a bacillus of the coli group. The contents of the apparently uncontaminated tubes were inoculated into guinea pigs, but the results were for the most part negative or vitiated by a secondary infection. Dark-field search for the leptospira with the autopsy materials was negative, although prolonged and thorough examination was not practicable at the time of these experiments. Our efforts were concentrated on obtaining positive animal transmission rather than on the time-consuming demonstration of the leptospira, which when unsuccessful does not necessarily exclude the presence of the organism in small numbers. Likewise, the dark-field work with the material from guinea pigs was confined to a brief examination and was omitted in many instances. Under these circumstances no leptospira was encountered in any of the material from Case 1. On the other hand, the results obtained with the specimens of blood from Case 2 were definitely positive, not only in the transmission of the disease directly, or indirectly by means of cultures, into guinea pigs, but also in the demonstration of the leptospira in the primary cultures and in the blood and organ emulsions of guinea pigs experimentally infected with such cultures. Definite positive direct transmissions were obtained with the specimens of blood drawn on the 2nd and 3rd days. No blood was taken on the 4th or 6th days. There were indications of abortive or mild leptospira infection in the guinea pigs inoculated with the blood taken on the 5th day. Regarding the inoculation of cultures from Case 2, it may be stated that only the cultures (leptospira +) made with the blood drawn on the 2nd day caused a definite fatal infection in guinea pigs. From this series a continuous passage in the guinea pig has been successfully accomplished. One of the guinea pigs (No. 48) inoculated with the culture 5 days old (leptospira +) made from the blood taken on the 3rd day presented typical symptoms, and a positive transfer from this to another animal (No. 98) was also made. Cultures of the blood drawn on the 5th and 7th days gave unsatisfactory results, owing to a secondary contamination. Leptospiras were detected in some of the culture tubes containing 2nd and 3rd day specimens of blood from Case 2; they were few in number and for the most part immotile, owing perhaps to some unfavorable cultural condition such as a fungus contamination. Charts 17, 18, and 19 give a summary of the experiments. See PDF for Structure


2004 ◽  
Vol 72 (1) ◽  
pp. 489-497 ◽  
Author(s):  
Anna I. Bakardjiev ◽  
Brian A. Stacy ◽  
Susan J. Fisher ◽  
Daniel A. Portnoy

ABSTRACT Feto-placental infections represent a major cause of pregnancy complications, and yet the underlying molecular and cellular mechanisms of vertical transmission are poorly understood. Listeria monocytogenes, a facultative intracellular pathogen, is one of a group of pathogens that are known to cause feto-placental infections in humans and other mammals. The purpose of this study was to evaluate possible mechanisms of vertical transmission of L. monocytogenes. Humans and guinea pigs have a hemochorial placenta, where a single layer of fetally derived trophoblasts separates maternal from fetal circulation. We characterized L. monocytogenes infection of the feto-placental unit in a pregnant guinea pig model and in primary human trophoblasts and trophoblast-derived cell lines. The clinical manifestations of listeriosis in the pregnant guinea pigs and the tropism of L. monocytogenes to the guinea pig placenta resembled those in humans. Trophoblast cell culture systems were permissive for listerial growth and cell-to-cell spread and revealed that L. monocytogenes deficient in internalin A, a virulence factor that mediates invasion of nonphagocytic cells, was 100-fold defective in invasion. However, crossing of the feto-placental barrier in the guinea pig model was independent of internalin A, suggesting a negligible role for internalin-mediated direct invasion of trophoblasts in vivo. Further understanding of vertical transmission of L. monocytogenes will help in designing more effective means of treatment and disease prevention.


2015 ◽  
Vol 90 (1) ◽  
pp. 392-399 ◽  
Author(s):  
Gary Wong ◽  
Shihua He ◽  
Haiyan Wei ◽  
Andrea Kroeker ◽  
Jonathan Audet ◽  
...  

ABSTRACT Infections with Sudan virus (SUDV), a member of the genus Ebolavirus , result in a severe hemorrhagic fever with a fatal outcome in over 50% of human cases. The paucity of prophylactics and therapeutics against SUDV is attributed to the lack of a small-animal model to screen promising compounds. By repeatedly passaging SUDV within the livers and spleens of guinea pigs in vivo , a guinea pig-adapted SUDV variant (SUDV-GA) uniformly lethal to these animals, with a 50% lethal dose (LD 50 ) of 5.3 × 10 −2 50% tissue culture infective doses (TCID 50 ), was developed. Animals infected with SUDV-GA developed high viremia and died between 9 and 14 days postinfection. Several hallmarks of SUDV infection, including lymphadenopathy, increased liver enzyme activities, and coagulation abnormalities, were observed. Virological analyses and gross pathology, histopathology, and immunohistochemistry findings indicate that SUDV-GA replicates in the livers and spleens of infected animals similarly to SUDV infections in nonhuman primates. These developments will accelerate the development of specific medical countermeasures in preparation for a future disease outbreak due to SUDV. IMPORTANCE A disease outbreak due to Ebola virus (EBOV), suspected to have emerged during December 2013 in Guinea, with over 11,000 dead and 28,000 infected, is finally winding down. Experimental EBOV vaccines and treatments were administered to patients under compassionate circumstances with promising results, and availability of an approved countermeasure appears to be close. However, the same range of experimental candidates against a potential disease outbreak caused by other members of the genus Ebolavirus , such as Sudan virus (SUDV), is not readily available. One bottleneck contributing to this situation is the lack of a small-animal model to screen promising drugs in an efficient and economical manner. To address this, we have generated a SUDV variant (SUDV-GA) that is uniformly lethal to guinea pigs. Animals infected with SUDV-GA develop disease similar to that of SUDV-infected humans and monkeys. We believe that this model will significantly accelerate the development of life-saving measures against SUDV infections.


1919 ◽  
Vol 30 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Hideyo Noguchi

The majority of guinea pigs inoculated with the blood of yellow fever patients escaped a fatal infection. There were a number of instances in which the inoculation of yellow fever blood induced in these animals a temporary febrile reaction on the 4th or 5th day, followed in some cases by slight jaundice, but with a rapid return to normal. Most of these guinea pigs when later inoculated with an organ emulsion of a passage strain of Leptospira icteroides resisted the infection. On the other hand, the animals which had previously been inoculated with the blood of malaria patients or normal guinea pigs died of the typical experimental infection after being inoculated with the infectious organ emulsion. It appears from the results just described that a number of nonfatal, mild, or abortive infections follow the inoculation of blood of yellow fever patients into guinea pigs. The fact that such animals manifested refractoriness to a subsequent attempt to infect with a highly virulent passage strain of Leptospira icteroides is an indication, judging from the reciprocal immunity reaction, that they actually passed through an infection with the same organism, or a strain closely related to it, as that which was used for the second infection experiment


1922 ◽  
Vol 36 (3) ◽  
pp. 357-364 ◽  
Author(s):  
Hideyo Noguchi

Analysis of the records of instances in which non-immune persons contracted yellow fever notwithstanding vaccination shows that the onset of disease occurs soon after vaccination, the longest period being 13 days. Since the average incubation period in yellow fever is 6 days, it seems that infection must have taken place in some instances during the period while protection was developing. These instances led to a study of the possibility of immediate protection by means of the anti-icteroides serum. It had already been shown that the immune serum protects at once against experimental Leptospira icteroides infection, but it remained to determine how long the protection would last. Guinea pigs were given different quantities of the immune serum and subsequently injected, at various intervals, with a virulent strain of Leptospira icteroides. Complete protection enduring 5 days was obtained with as minute a quantity of serum as 0.002 cc. per 1,000 gm. of body weight. After 5 days, however, the immune substance rapidly diminished, and to keep the animal protected for as long as 10 days it was necessary to give 100 times as much, or 0.2 cc. For a man weighing 80 kilos, 0.16 cc. (0.002 x 80) would theoretically be sufficient to protect for at least 5 days, 1.6 cc. for 7 days, and 16 cc. for 10 days. This temporary protection may be a valuable antecedent to that furnished by vaccination, since the final effect of the latter cannot be expected until at least 9 to 10 days have passed.


1919 ◽  
Vol 30 (1) ◽  
pp. 9-12 ◽  
Author(s):  
Hideyo Noguchi

The serum from a number of persons recovering from yellow fever in Guayaquil was studied with a view to establishing its possible immunological relationship with a strain of Leptospira icteroides derived from one of the yellow fever patients. For this purpose the serum of convalescents was mixed either with an organ emulsion of a passage strain, or with a culture of the organism, and inoculated intraperitoneally into guinea pigs. The Pfeiffer reaction was first studied, and then the animals were allowed to live until the controls, inoculated with the same emulsion or culture of Leptospira icteroides but without the serum, or with serum from patients suffering from other diseases than yellow fever, had died of the experimental infection with typical symptoms A positive Pfeiffer phenomenon was observed in fifteen of the eighteen convalescent cases studied, or approximately 83 per cent. Sera from ten non-immune soldiers and from two malaria patients gave uniformly negative results. Protection from an ultimate fatal infection was afforded some of the guinea pigs which received the serum of yellow fever convalescents, while the control animals succumbed to the infection with typical symptoms. In one instance, in which the serum was tested on the 2nd and the 10th days of disease, a Pfeiffer reaction was demonstrated, as well as protective property against the infection, in the specimen from the 10th but not in that from the 2nd day. From the foregoing observations of immunity reactions it appears highly probable that Leptospira icteroides is etiologically related to yellow fever.


1936 ◽  
Vol 63 (4) ◽  
pp. 491-507 ◽  
Author(s):  
Louise Pearce ◽  
Paul D. Rosahn ◽  
Ch'uan-K'uei Hu

The white mouse, the guinea pig, the calf, and probably the rat, were found to be susceptible to infection with the virus of rabbit pox. Serial transmission of the virus in mice by brain to brain passage was characterized by a fatal outcome usually on the 5th or 6th day after inoculation. Infection of the guinea pig was accomplished by intratesticular injection and the virus was continued to the 2nd passage in this species. Guinea pigs developed a well marked cutaneous reaction from the intradermal injection of both rabbit and guinea pig tissue virus. Active virus was demonstrated in the testicles of rats 8 days after intratesticular injection by rabbit subinoculation. In the calf inoculation of the scarified skin was followed by the development of large papular lesions with marked hemorrhage and necrosis. The results of the investigations on the etiology of rabbit pox and of the experimentally induced infection reported in this and the four preceding papers (1–4) are discussed with special reference to the relation of pox virus to other viruses and of rabbit pox to other pock diseases.


2008 ◽  
Vol 32 (2) ◽  
pp. 68-79
Author(s):  
Ibrahim Z. I.

This work aimed to study the pathological changes induced in theurinary organs after infection with K.pneumoniae. Two laboratory femaleanimal species ,white rat&guinea pig ,were infected by tworoutes,ascending (first group) and direct(intra renal-second group).The infection was examined in different periods through the bacterialculture of urine & kidney samples as well as the pathological changes(gross&microscopic) were examined after post mortum.The resultes of both groups showed a positive bacteriologic culture ofthe urine & kidney samples concomitant with the gross andhistopathological changes of the kidneys which revealed different degreesof inflammation between the two groups as well as within the indivisualsof the same group, especially the kidney specimens which showedpyelonephritis in rats & guinea pigs of both infection routes (ascendingand intrarenal


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