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PubMed1958

Studies on the pathogenesis of fever. V. The relation of circulating endogenous pyrogen to the fever of acute bacterial infections.

An endogenous pyrogen, which is indistinguishable from leucocytic pyrogen, has been demonstrated in the blood streams of rabbits with fevers caused by experimental pneumococcal and streptococcal infections. Like the endogenous pyrogen previously detected in the serum of animals with fever produced by the intravenous injection of typhoid vaccine, the newly discovered circulating factor acts directly upon the thermoregulatory centers of the brain. Its origin from polymorphonuclear leucocytes at the site of infection appears to have been established. The possible relationship of this circulating endogenous pyrogen to the pathogenesis of other forms of fever is discussed.

Animals↗
PubMed1958

The effect of bacterial constituents on the resistance of mice to heterologous infection and on the activity of their reticulo-endothelial system.

Administration of small amounts of salmonella endotoxin (20 microg.) or of acetone-extracted BCG cells (100 microg.) increases the resistance of mice to infection with Myco. fortuitum as well as their ability to clear carbon particles from their blood stream. Whereas the increased resistance to infection persists for many weeks, the clearing power returns to a normal level within a few days. When normal mice are infected with Myco. fortuitum, there occurs during the first phase of the infectious process a rise in clearing power for carbon particles followed by a fall during the terminal phase of the disease. The rise occurs more rapidly and is more pronounced in animals previously treated with salmonella endotoxin or with killed BCG cells. This acceleration and intensification of the phagocytic response to infection can be detected even in animals which exhibit a normal phagocytic index when tested several weeks after administration of endotoxin or of BCG. Although increase in resistance to infection is correlated with activation of the so called reticulo-endothelial system, there is no evidence of any direct causal relationship between the two phenomena.

Animals↗
PubMed1958

Effect of dietary proteins and amino acids on the susceptibility of mice to bacterial infections.

Groups of young albino mice were fed continuously four different types of diets and were compared with regard to (1) rate of weight gain; (2) resistance to experimental bacterial infections. The protein content of the four diets was as follows: (a) pellets: a minimum of 21 per cent "crude" protein (according to the manufacturer); (b) diet 20 C: 20 per cent casein; (c) diet 8 C: 8 per cent casein; (d) diet 8 C + AA: 8 per cent casein supplemented with 12 per cent of a mixture of essential amino acids. All diets provided an adequate supply of minerals and vitamins. They were administered ad lib. Three strains of pathogens virulent for mice were used for the infection tests, namely: Staphylococcus aureus, Mycobacterium fortuitum, and Mycobacterium tuberculosis bovis. The bacteria were injected by the intravenous route. The experimental regimens were begun at different times before infection, and were continued until death of the animal, or until termination of the experiment. It was found that mice on the 8 C diet exhibited much greater susceptibility to infection than did mice on the 20 C diet; mice receiving pellets were intermediate between these two groups. The infection-enhancing effect of the 8 C diet could be entirely corrected by amino acid supplementation (diet 8 C + AA). Indeed, mice fed diet 8 C + AA proved the most resistant to infection. The fact that animals fed pellets (which contain a minimum of 21 per cent protein) consistently died faster following infection than did animals fed diets 20 C or 8 C + AA suggests that qualitative characteristics of the protein in the regimen are as important as the quantity of protein fed in determining susceptibility to infection. The differences in susceptibility exhibited by the mice on the four experimental diets were the same whatever the species of bacterial pathogen used for the infection test, the size of the infective dose, and the duration of the disease. There was no apparent relation between the effects of the diets on the weight curves of the animals, and on resistance to infection. Mice on diet 8 C (which were most susceptible) gained weight as rapidly as those on 20 C and more rapidly than those fed 8 C + AA (which were most resistant). All the tests reported in the present paper were carried out with young mice, which were placed on experimental diets within 1 to 2 weeks after weaning. Preliminary experiments suggest that the relation between dietary factors and susceptibility to infection was more difficult to bring out in older animals. There was evidence also that this relation was most apparent during the first weeks that the animals were fed the experimental diets, and became less striking after several weeks.

Amino Acids↗
PubMed1959

Effect of dietary proteins and amino acids on the susceptibility of mice to bacterial infections.

Young mice were maintained for periods of 1 to 6 weeks on experimental diets containing all known growth factors, but differing in their protein and amino acid contents. All diets were supplemented with L-cystine. The effect of the nutritional regimen on infection was tested by inoculating the animals with either one of four pathogens (Mycobacterium tuberculosis var. bovis, Mycobacterium fortuitum, Staphylococcus aureus, Klebsiella pneumoniae type C), and by observing the survival time. The infective dose was administered by either one of three routes: intravenous, intraperitoneal, or air-borne (aerosol). In some experiments, the animals were maintained in groups of five throughout the tests. In other experiments they were housed in individual cages. This difference in housing did not affect the results in a detectable manner. Mice fed diets containing 5 or 8 per cent casein as sole source of amino acid (except for cystine supplementation) proved more susceptible to the experimental diseases than did mice fed diets containing 15 or 20 per cent of the same protein. Susceptibility to infection developed when wheat gluten, or soybean alpha-protein, was substituted for casein-even in high concentrations (15 or 20 per cent). In one experiment, mice were fed a diet containing as sole source of amino acids a mixture of soybean and rice flour, so designed as to provide a protein concentration of 15 per cent, with an amino acid pattern similar to that of casein. These animals gained weight at the same rate as those fed a diet containing 15 per cent casein and they exhibited a satisfactory level of resistance to bacterial infection. The infection-enhancing effect of low casein concentration (5 and 8 per cent) could be corrected by supplementing the diet with the proper mixture of amino acids. This could be done using either synthetic or natural amino acids. In contrast, susceptibility to infection developed when low casein diets were supplemented with unbalanced mixtures of amino acids. The infection-enhancing effect of gluten diets could not be corrected by supplementing the latter with lysine even though this supplementation markedly improved weight gains in uninfected animals. It appears in conclusion that the relative proportion of the various amino acids in the diet is as important a factor as their total amount in conditioning resistance to bacterial infections. This effect of nutrition on resistance can be detected irrespective of the route of infection: intravenous, intraperitoneal, or air-borne. Moreover, the effect has been observed with two strains of mice differing markedly in their natural resistance to bacterial infection.

Amino Acids↗
PubMed1959

Effect of nutrition on the resistance of mice to endotoxin and on the bactericidal power of their tissues.

Mice on inadequate nutritional regimens were found to be more susceptible to various bacterial diseases than mice fed a complete diet containing 15 to 20 per cent casein. The tests of susceptibility included: (a) infections with virulent bacteria; (b) injection of large doses of avirulent coagulase-negative staphylococci; and (c) lethal effects of bacterial endotoxins. The infection-enhancing effect of nutritional deficiencies could be rendered even more striking by administering the infective inoculum simultaneously with a sublethal dose of endotoxin. Despite their great susceptibility to infection, malnourished animals retained much of their ability to eliminate bacteria from the blood, liver, spleen, kidneys, and lungs, at least during the early phases of the infectious processes. This was true even when the animals had received endotoxin simultaneously with the infective dose. The results suggest that under the conditions of the present study, the nutritional state influenced the outcome of infection not primarily by affecting the fate of the pathogens in vivo, but rather by modifying the ability of the host to resist their toxic effects.

Animals↗
PubMed1960

The effect of the intestinal flora on the growth rate of mice, and on their susceptibility to experimental infections.

Mice delivered by Caesarian section were used to develop a new mouse colony which has been maintained in an environment protected from contact with common mouse pathogens, but not in the germ-free state. These mice, designated as NCS, were compared with animals of the same sex and age coming from the parent colony maintained under ordinary conditions. The NCS mice grew more rapidly than ordinary mice on complete diets; moreover, they continued to gain weight-although at a slower rate-when fed deficient diets which caused ordinary mice to stop growing, or to lose weight. The NCS mice proved much more susceptible than ordinary mice to certain experimental bacterial infections. In contrast, they were much more resistant than ordinary mice to the lethal effect of large doses of endotoxins. However, they responded to injection of minute amounts of these endotoxins by a marked increase in susceptibility to staphylococcal infection. Bacteriological studies revealed striking qualitative differences between the intestinal flora of NCS and ordinary mice. When NCS mice were contaminated-either by contact or by feeding-with a strain of Escherichia coli recovered from the intestine of ordinary mice, they acquired the characteristics of the latter animals with regard to weight gain on various diets, and to response to bacterial pathogens and endotoxins. NCS mice have been found well suited to the study of several nutritional, bacteriological, and immunological problems and it appears that their production on a large scale will not present unsurmountable difficulties.

Animals↗
PubMed1960

Studies on susceptibility to infection following ionizing radiation. V. Comparison of intraperitoneal and intravenous challenge at intervals following different doses of x-radiation.

Ten week old female CF-1 mice were subjected to a single total body exposure of x-radiation in one of the following doses: 300, 400, and 500 r. At intervals thereafter, susceptibility to bacterial infection was determined by intraperitoneal challenge with graded inocula of Pseudomonas aeruginosa. Mice exposed to 400 or 500 r were also challenged by intravenous inoculation. The LD(50) of the test microorganism in each challenge was estimated from the mortality data. Exposure to 300 r caused little increase in susceptibility to this experimental infection. 400 r caused a moderate increase on the 3rd day post-irradiation with return to normal on the 17th. Leucocyte counts (geometric means) following this dose of radiation did not fall below 1200. 500 r caused a marked increase in susceptibility which lasted from the 3rd to 11th day, during which period the leucocyte counts were below 800. On the 20th day, susceptibility to infection was normal, although the geometric mean of leucocyte counts was only 2200. Comparison of mortalities resulting from equivalent inocula introduced by the two routes (intravenous and intraperitoneal) showed no difference in unirradiated mice. However, among mice irradiated with 400 or 500 r, higher mortalities resulted from intravenous inoculation. The difference was found to be due to the establishment of a small focus of infection at the site of intravenous injection as a result of leakage of a minute fraction of inoculum into the perivenous tissues of the tail. Bacterial multiplication occurred in such foci in irradiated (leucopenic) mice, but not in unirradiated mice, nor at the site of intraperitoneal inoculation even in irradiated mice.

Animals↗
PubMed1961

Changes produced in mouse plasma proteins by acute bacterial infections.

The immunoelectrophoretic patterns of plasma proteins from mice are altered significantly by acute infections. Some proteins are dissociated into two or more components, some showed striking increase in plasma concentration, others are depleted, and certain ones appear which are undetectable in normal samples. beta(1)-C dissociated into two electrophoretic components under a variety of conditions in addition to infections. Endotoxins and killed organisms in vivo, and specific precipitate absorption, heat and aging in vitro produced this change. Endotoxins injected into mice also induced a rise in haptoglobin though not as sharply or predictably as acute infection. Preliminary results with samples from hospital patients with acute diseases are discussed. It was concluded that study of experimental diseases in laboratory animals by these techniques could provide a fruitful basis for the investigation of the plasma protein changes in similar human diseases.

Animals↗
PubMed1961

The role of opsonins in the clearance of living and inert particles by cells of the reticuloendothelial system.

An investigation of the clearance of bacteria and colloids from the blood stream of mice has shown that both living and inert particles require serum factors (opsonins) in order that they may be phagocytosed by the macrophages of the reticuloendothelial system. It has been demonstrated that after the injection of a large dose of colloid there is a depletion of these serum opsonins which appears to account for the reduced rate of clearance of a second dose of colloid or living bacteria, since replacement of these factors leads to normal clearance. The significance of these results is discussed and it is suggested that in "blockaded" animals there is a depletion of serum opsonins rather than a saturation of phagocytic cells.

Animals↗