scholarly journals EXPERIMENTAL STUDIES ON YELLOW FEVER IN NORTHERN PERU

1921 ◽  
Vol 33 (2) ◽  
pp. 239-252 ◽  
Author(s):  
Hideyo Noguchi ◽  
I. J. Kligler
Keyword(s):  
New York ◽  
Yellow Fever ◽  
Guinea Pigs ◽  
Culture Media ◽  
Experimental Studies ◽  
Dark Field ◽  
Practical Significance ◽  
Rabbit Serum ◽  
Laboratory Facilities ◽  
Northern Peru

Fourteen typical cases of yellow fever were studied in northern Peru during an epidemic occurring in 1920, nine in Payta in March and April, and five in Morropon and Piura in April and May. The method of investigation was similar to that previously employed, but as the laboratory facilities were very meager certain changes were required. Although in Payta the work was handicapped by the lack of electric light, the scarcity of water and animal food, the unsuitability of the guinea pigs for inoculation, and the changes in culture media due to age, the results obtained under these adverse conditions were by no means negative. While in no instance was there a typical infection produced in animals, either by direct inoculation of blood or with culture materials, yet certain guinea pigs in each series showed temporary febrile reactions or definite hemorrhagic lesions of the lungs indicative of a mild leptospira infection. Direct search for Leptospira icteroides in the blood of patients or in culture materials was not made because the dark-field microscope could not be used. Subsequently, at Piura, the laboratory facilities were vastly, improved, the use of the dark-field microscope was made possible by means of a storage battery, and a fresh stock of young healthy guinea pigs was received from New York, and fresh rabbit serum obtained in Piura. In the study of the materials obtained from five cases of yellow fever in Morropon all these added facilities were taken advantage of, with the result that the outcome was positive and convincing. Cultures from the five cases were examined after 11, 12, and 13 days, and in those from three cases living leptospiras were found. By inoculation into suitable guinea pigs of culture material from these five cases, irrespective of whether or not leptospiras were detected under the dark-field microscope, a typical Leptospira icteroides infection was produced from four of the five cases. In one of these no leptospira had been detected in the culture tubes. Thus one case only yielded negative results, in that no leptospiras were found under the dark-field microscope and the animal inoculation was negative. The leptospira was demonstrated in the blood or organ emulsions of the infected guinea pigs, and further transmission of each strain to other guinea pigs was obtained and pure cultures were secured. A few points of practical significance appeared in the course of the present investigation. One is the importance of using fresh rabbit serum for culture media. Old rabbit serum, whether in pure form or incorporated with agar, etc., which had been kept for several months in a tropical climate, proved to be unsatisfactory for obtaining a growth of Leptospira icteroides. A second point of interest is the variation in susceptibility of guinea pigs to infection with Leptospira icteroides. In two of four series of positive animal inoculations with the Morropon culture materials only one-half of the guinea pigs inoculated with given materials developed typical symptoms. The other half either suffered from a transient mild infection, as evidenced by a few hemorrhagic foci in the lungs, or escaped infection altogether. From these facts it is highly probable that the lung lesions and febrile reactions observed in certain guinea pigs inoculated with the Payta materials were due to a mild leptospira infection. In a comparative experiment the native guinea pigs procured in Payta were found to be more resistant to the leptospira infection than those recently brought from New York. In fact, only a small portion of the former succumbed to typical infection even when inoculated with a virulent strain of Leptospira icteroides obtained from the Morropon epidemic. In conclusion it may be stated that of fourteen cases of yellow fever studied in Peru, a typical leptospira infection, together with the demonstration of the organism in experimentally infected guinea pigs, was obtained in four, while in the majority of instances indications of a mild, non-fatal leptospira infection were observed. In a few cases only were the results entirely negative. The leptospira isolated from Morropon cases of yellow fever, which is morphologically and culturally identical with the Guayaquil and Merida strains of Leptospira icteroides, was also shown by immunity test to be indistinguishable from the Guayaquil organism.

scholarly journals EXPERIMENTAL STUDIES ON YELLOW FEVER OCCURRING IN MERIDA, YUCATAN

1920 ◽  
Vol 32 (5) ◽  
pp. 601-625 ◽  
Author(s):  
Hideyo Noguchi ◽  
I. J. Kligler
Keyword(s):  
Guinea Pig ◽  
Yellow Fever ◽  
Guinea Pigs ◽  
Secondary Infection ◽  
Fatal Case ◽  
Primary Cultures ◽  
Experimental Studies ◽  
Dark Field ◽  
Liver And Kidney ◽  
Positive Direct

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

scholarly journals IMMUNOLOGY OF THE PERUVIAN STRAINS OF LEPTOSPIRA ICTEROIDES

1921 ◽  
Vol 33 (2) ◽  
pp. 253-260 ◽  
Author(s):  
Hideyo Noguchi ◽  
I. J. Kligler
Keyword(s):  
New York ◽  
Guinea Pig ◽  
Incubation Period ◽  
Yellow Fever ◽  
Guinea Pigs ◽  
Lethal Dose ◽  
Fatal Outcome ◽  
Rabbit Serum ◽  
Minimum Lethal Dose ◽  
Lethal Doses

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.

scholarly journals ETIOLOGY OF OROYA FEVER

1926 ◽  
Vol 43 (6) ◽  
pp. 851-864 ◽  
Author(s):  
Hideyo Noguchi ◽  
Telémaco S. Battistini
Keyword(s):  
New York ◽  
Culture Media ◽  
Dark Field ◽  
Intradermal Injection ◽  
Initial Growth ◽  
Bartonella Bacilliformis ◽  
Animal Blood ◽  
Gram Staining ◽  
Pathogenic Action ◽  
Staining Methods

A pure culture of a microorganism resembling in morphology and pathogenic action Bartonella bacilliformis has been obtained from blood taken during life from a case of Oroya fever which ended fatally. The blood taken at Lima into citrate solution and transported to New York at refrigerator temperature yielded positive cultures 28 days after its withdrawal from the patient. The strain of Bartonella bacilliformis thus isolated grows well on the semisolid leptospira medium, and also on slant agar containing animal blood. The initial growth is not readily recognizable to the naked eye, but the presence of the organisms can be determined by means of the dark-field microscope and by Giemsa and Gram staining methods. No growth has been obtained on the more ordinary culture media. The organism is an obligate aerobe, is Gram-negative, and under certain cultural conditions motile. All the forms which have been described as occurring in human red corpuscles may be found in the cultures, and in addition many granular and coarsely irregular forms have been met with. The inoculation of cultures of Bartonella bacilliformis into Macacus rhesus produces infection and gives rise to effects which differ with the mode of inoculation. The intravenous injection of the culture into young macaques induces a prolonged irregularly remittent fever. The organism can be cultivated from the blood over a long period, and it has been detected within the red corpuscles of the monkeys, reproducing the precise appearances observed in human cases of Oroya fever. The intradermal injection of the culture into the eyebrow of young macaques gives rise to nodular formations rich in new blood vessels and showing the bacilliform organism within the endothelial cells. From the experimentally induced nodules cultures of the organism are readily recovered.

scholarly journals ETIOLOGY OF YELLOW FEVER

1919 ◽  
Vol 30 (1) ◽  
pp. 13-29 ◽  
Author(s):  
Hideyo Noguchi
Keyword(s):  
Yellow Fever ◽  
Pure Culture ◽  
Guinea Pigs ◽  
Culture Media ◽  
Morphological Characteristics ◽  
Biological Properties ◽  
Freezing And Thawing ◽  
Highly Sensitive ◽  
Favorable Conditions ◽  
Aerobic And Anaerobic

By the employment of methods designed to promote the growth both of aerobic and anaerobic organisms, particularly those belonging to the class of spirochetes, it was possible to obtain a pure culture of a delicate organism, the morphological features of which place it in the genus Leptospira. On three occasions, that is, from three out of eleven cases of yellow fever, the organism was directly cultivated. These three strains were found to induce the characteristic symptoms and lesions when tested on guinea pigs. The organism was designated Leptospira icteroides. Leptospira icteroides was also obtained in pure culture from the blood of guinea pigs which succumbed to infection after being inoculated with the blood or organ emulsions from patients suffering from yellow fever. These cultures also proved to be virulent when tested on susceptible animals. The morphological characteristics and certain biological properties of the organism were considered in detail. It is invisible under translucent illumination and is difficult to stain by most aniline dyes. It is highly sensitive to the presence of bacteria and is rapidly destroyed in a medium in which certain other organisms are present. The presence of blood serum (man, sheep, horse, rabbit, etc.) seems to be essential for its growth. It grows well at a temperature of about 25–26°C. and more quickly at 37°C., though at the latter temperature it dies out within a few weeks. At 25°C. under favorable conditions and in suitable culture media it remains viable for several months without losing its virulence. Leptospira icteroides multiplies by transverse division. The virulence attained by some strains was such that 0.00001 cc. of a culture could induce typical fatal infection in guinea pigs. There exists a considerable variation among guinea pigs in their susceptibility to Leptospira icteroides. The organism is killed within 10 minutes at a temperature of 55°C. and is also destroyed by complete desiccation or freezing and thawing. Bile and bile salts dissolve it in certain concentrations, but not saponin. Leptospira icteroides passes through the pores of Berkefeld filters V and N, and there is a possibility of its having a granular phase of life under certain conditions.

scholarly journals ETIOLOGY OF YELLOW FEVER

1919 ◽  
Vol 30 (2) ◽  
pp. 87-93 ◽  
Author(s):  
Hideyo Noguchi
Keyword(s):  
Yellow Fever ◽  
Experimental Infection ◽  
Guinea Pigs ◽  
Dark Field ◽  
Blood Film ◽  
Fresh Blood ◽  
The Third ◽  
Fresh State ◽  
Liver And Kidney ◽  
Made In

Examinations of fresh blood from yellow fever patients by means of the dark-field microscope, made in more than twenty-seven cases, revealed in three cases the presence of Leptospira icteroides. In no instance was a large number of organisms found, a long search being required before one was encountered. The injection of the blood into guinea pigs from two of the three positive cases induced in the animals a fatal infection, while the blood from the third positive case failed to infect the guinea pigs fatally. Careful but by no means exhaustive dark-field searches for the leptospira with fresh specimens of blood from the remaining cases of yellow fever ended without positive findings, although four of the specimens, when injected into guinea pigs, caused a fatal leptospira infection. Stained blood film preparations from the corresponding cases were also examined, but the percentage showing the leptospira in the blood was no greater than that found by examination in the fresh state with the dark-field microscope. In fact, owing to the defective stains that were available at the time of the investigation a great many slides did not take the proper coloration with Giemsa's or Wright's stain and could not be relied upon. Regarding the presence of Leptospira icteroides in various organs both dark-field and stained films were examined. In only one instance so far a few organisms were detected in the emulsion of liver taken shortly after death from a case dying on the 4th day of yellow fever. This part of the work will be reported later upon completion. Examinations of the urine from different cases of yellow fever were made both by dark-field microscope and by inoculation into guinea pigs. The results were totally negative in thirteen cases, including many convalescents, but in one case one of the guinea pigs inoculated with 10 cc. of the urine came down on the 15th day with suggestive symptoms (suspicion of jaundice, and some hemorrhagic and parenchymatous lesions of the lungs and kidneys). This specimen showed no leptospira by dark-field examination. In experimental infection of guinea pigs with Leptospira icteroides the blood became infective in many instances 48 hours after inoculation, and was always infective after 72 hours. The liver and kidney become infective simultaneously with the blood. Detection of the organism by means of the dark-field microscope has seldom been accomplished before the 5th day. The organisms are most abundant on the 6th to the 7th day, but become fewer or completely disappear before death. In the meanwhile the number of organisms increases in the liver and kidney, from which they disappear as the jaundice and other symptoms become aggravated. When death occurs these organs seem to have lost most of the leptospira) and positive transfer by means of them is less certain. At the later stage of the disease the blood is often free from the organisms and ceases to be infective. Positive transmission with blood obtained from moribund animals is not impossible, however, even when no leptospira can be detected under the dark-field microscope.

scholarly journals ETIOLOGY OF YELLOW FEVER

1919 ◽  
Vol 30 (2) ◽  
pp. 95-107 ◽  
Author(s):  
Hideyo Noguchi
Keyword(s):  
New York ◽  
Yellow Fever ◽  
Guinea Pigs ◽  
Subsequent Infection ◽  
Rat Strains ◽  
Wild Rats ◽  
Different Strains ◽  
Rats And Mice

By the inoculation of guinea pigs intraperitoneally with the emulsions of kidneys from wild rats and mice captured in Guayaquil, it was found that 67 per cent of the wild rats tested harbored in their kidneys a leptospira which produced in guinea pigs symptoms and lesions identical with those produced by Leptospira icterohamorrhagia derived either from patients suffering from infectious jaundice in Japan or Europe, or from wild rats caught in New York. Immune sera were prepared in rabbits by injecting different strains of the Guayaquil leptospira. These sera had a marked agglutinating and disintegrating influence upon the homologous strains, and also, but often to a less pronounced degree, upon the strains of Leptospira icterohœmorrhagiœ from other sources. Pfeiffer's phenomenon was also found to be positive, and protection was demonstrated against infection with virulent cultures of strains of Leptospira icterohœmorrhagiœ. The same sera had no effect, or at most a very slight one, upon Leptospira icteroides. Guinea pigs inoculated with icteroides strains were not noticeably protected by the use of the immune sera prepared with the Guayaquil rat strains. Guinea pigs inoculated with killed cultures of the Guayaquil strains of leptospira proved to be resistant to a subsequent infection with heterologous as well as homologous strains of Leptospira icterohœmorrhagiœ. It is concluded, therefore, that the leptospira isolated from the kidneys of wild rats and mice in Guayaquil belongs to the group of Leptospira icterohœmorrhagiœ, and differs from Leptospira icteroides in its immunity reactions. No positive transmission was obtained with kidney material from bats and an opossum.

Multi-Head Spatio-Temporal Attention Mechanism for Urban Anomaly Event Prediction

2021 ◽  
Vol 5 (3) ◽  
pp. 1-21
Author(s):  
Huiqun Huang ◽  
Xi Yang ◽  
Suining He
Keyword(s):  
New York ◽  
Experimental Studies ◽  
Attention Mechanism ◽  
City Management ◽  
Temporal Attention ◽  
Spatial Correlations ◽  
Time Step ◽  
Event Prediction ◽  
Spatio Temporal ◽  
Prediction Approach

Timely forecasting the urban anomaly events in advance is of great importance to the city management and planning. However, anomaly event prediction is highly challenging due to the sparseness of data, geographic heterogeneity (e.g., complex spatial correlation, skewed spatial distribution of anomaly events and crowd flows), and the dynamic temporal dependencies. In this study, we propose M-STAP, a novel Multi-head Spatio-Temporal Attention Prediction approach to address the problem of multi-region urban anomaly event prediction. Specifically, M-STAP considers the problem from three main aspects: (1) extracting the spatial characteristics of the anomaly events in different regions, and the spatial correlations between anomaly events and crowd flows; (2) modeling the impacts of crowd flow dynamic of the most relevant regions in each time step on the anomaly events; and (3) employing attention mechanism to analyze the varying impacts of the historical anomaly events on the predicted data. We have conducted extensive experimental studies on the crowd flows and anomaly events data of New York City, Melbourne and Chicago. Our proposed model shows higher accuracy (41.91% improvement on average) in predicting multi-region anomaly events compared with the state-of-the-arts.

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