Comparative multifactorial analysis of combined administration of injection and peroral forms of an antibiotic with a microbial immunomodulator in experimental anthrax

Comparative efficacy of the use of injection and oral dosage forms of rifampicin in the subtherapeutic doses in combination with peptidoglycan , an immunomodulator of microbial origin, was studied in respect to experimental anthracic infection with application of multifactorial analysis. It was shown that the antibiotic and immunomodulator had a pronounced synergistic effect. Polynomial statistic models were developed and nomograms or equal level curves defining the survival rate and average life-span (ALS) of the experimental animals within a wide range of the antibiotic and immunomodulator doses and the peptidoglycan dosing time were plotted. The combined use of the injection rifampicin in the subtherapeutic doses and the immunomodulator provided a significant increase in the survival rate and ALS, whereas the use of the oral antibiotic in combination with the immunomodulator increased only the ALS and not the survival rate. Multifactorial analysis proved to be an optimal methodical approach to comparative study of various antibiotic dosage forms used in combination with immunomodulators under experimental conditions.     

Effectiveness of phosphomycin and its combinations with amikacin and cefotaxime in experimental plague infection]

When administered intramuscularly in doses of 8 and 16 mg/mouse, phosphomycin was highly active in the treatment of albino mice with experimental plague infection (80-100-percent protection of the animals from death). Combinations of phosphomycin with cefotaxime in inefficient or not sufficiently efficient doses had a synergistic effect. When the albino mice were treated with combinations of phosphomycin and amikacin, the percentage of the survived animals significantly increased in comparison to that after the use of the antibiotics alone.     

Role of antibodies and effect of BCG vaccination in experimental candidiasis in mice

The role of humoral antibodies and the effect of BCG vaccination were studied in the experimental candidiasis in mice. The antibody suppressed, B-cell deficient animals were prepared by repeated administration of rabbit anti-mouse--antiserum to the new born mice from birth onwards. Such immunodeficient animals along with controls were infected intravenously with Candida albicans, to study the course of candidal infection. It was observed that B-cell-deficient animals were found to be more susceptible to candidal infection than the controls, as indicated by their steady loss of body weight, longer mean time to death and higher viable counts of candidal cells in different organs. The anti-candidal antibodies were absent in all B-cell-deficient animals but present in the controls. These results suggest that antibodies make a contribution in protection against candidal infection in mice. The BCG vaccinated animals were prepared by repeated intravenous administration of BCG to mice and these vaccinated animals along with unvaccinated controls were challenged intravenously with C. albicans, to study the course of candidal infection. It was observed that BCG vaccination prolonged meantime to death and reduced the number of candidal cells in their kidneys.     

Immunomodulating action of levamisole in influenzal infection in mice

The time of the activation of the regulatory lymphocyte subpopulation in the spleen and the influence of levamisole on the course of influenza infection in mice were studied in parallel. The study revealed that the final effect of the immunomodulating action of levamisole was determined by the concrete phase of the regulatory activity of lymphocytes. At the same time the injection of the preparation at the peak of helper activity induced a transitory decrease in antibody formation and, in the fatal form of the infection, a rise in the death rate among the animals. The probable role of levamisole-activated macrophages in the transitory suppression of immune response in mice during influenza infection is discussed.     

Systemic candidiasis in mice immunized with Candida albicans ribosomes

In view of our previous findings that vaccination of mice with Candida albicans ribosomes protects them against experimental systemic candidiasis, the aim of this study was to investigate the effect of this vaccination on the course of infection in immunized animals. Since the kidney is the maj or target in systemic candidal infection, we concentrated in this research on studying the histopathology and determining quantitatively the candidal colonization of this organ. The experiments were carried out at various time intervals after intravenous inoculation with live C. albicans. The colonization of kidneys in immunized mice was markedly lower than that in controls. The maximal difference in renal colonization between immunized and non immunized animals was observed when relatively low challenge doses were used. The inhibition of candidal multiplication in immunized mice seemed to be correlated to their increased resistance against lethal challenge, as expressed by a significantly higher survival rate. Histopathological changes and fungal elements were found in kidneys of control mice as early as 20 h post infection, while the kidneys of immunized mice did not seem affected by the disease. Moreover, even 3 days post infection, the kidneys of vaccinated animals still seemed normal. In conclusion, apparently the ribosomal vaccination leads to diminished colonization of the major site of infection in candidiasis, thus affording protection to the immunized animals against these infections.     

Development of the controlled model of persisting infection , caused by Pseudomonas aeruginosa and bacteria of the complex Burkholderia cepacia

As the result of testing three different variants, the experimental models of persisting infection for P. aeruginosa and B. cepacia have been developed. These doses differ in the time of administration, doses of antibiotics and the infective doses of the microorganisms. The administration of the sub-inhibiting concentration of antibiotics for 5 days and the subsequent infection of laboratory animals (non-inbred mice) B. cepacia strains in a dose of LD50 leads to a considerable increase in the survival rate of mice and to a longer period (up to 20 days) of obtaining inoculative material from the spleen. The isolated cultures are characterized by a sharply slower growth on artificial culture media (up to 5-7 days as compared with 24-48 hours for the initial culture). The newly developed models have made it possible to control different stages of the infectious process in the induced increase or decrease of the virulent properties of the infective agent and in changes in the immune status of the host. As the result of these studies, in some mice (10%) infected with B. cepacia after the injection of gamma-hydroxybutyric acid lactone the infection has taken the acute form, while in the mice infected with P. aeruginosa no such effect has been observed. On the contrary, in the mice infected with P. aeruginosa and then receiving cyclophosphamide the transition of the infection into the acute form has been observed in 30% of the animals. In the mice infected with B. cepacia no such effect has been noted after the injection of this preparation. Different effects produced by cyclophosphamide and lactone are discussed from the positions of "quorum sensing" in pathogenic bacteria.     

山羊单纯与复合全身麻醉效果的比较

目的对比山羊单纯麻醉与复合麻醉的效果,探讨一种安全高效便捷的山羊麻醉方法。方法选取山羊30只,随机分为A、B、C三组,A组给予单纯戊巴比妥钠麻醉,B组给予单纯氯胺酮麻醉,C组给予地西泮、戊巴比妥钠和氯胺酮复合麻醉,记录三种麻醉方法的起效时间、麻醉维持时间、麻醉药物用量及麻醉死亡率。结果地西泮、戊巴比妥钠和氯胺酮复合麻醉,起效快、麻醉维持时间长、动物死亡率低、麻醉效果好。结论安定、戊巴比妥钠和氯胺酮复合麻醉优于单纯麻醉,是一种高效、便捷、安全山羊全身麻醉方法。     

Host Parasite Relations in Initiation of Infection: II. Hyperglycemia and Stress in Experimental Infection with L. Monocytogenes

The effects of applied stimuli on the initiation of experimental infection were studied on lemmings, rabbits, hamsters, and guinea pigs. Stress was simulated by injection of cortisone acetate, or by trauma, heat, or cold. L. monocytogenes was the organism used for experimental infection. The results showed that the course of the infection was influenced in favour of the invading microorganism by the stress agents used. Hyperglycemia was present in the animals that developed the infection to overt disease. This suggests that hyperglycemia may be the trigger mechanism.     

Protective effect of a commercial vaccine, poludan and their combinations in an experimental herpes infection

The antiviral action of herpes vaccine and poludan, an interferon-inducing agent, has been studied in experimental herpes infection, and the synergic effect of these preparations has been obtained. The best result (survival rate equal to 100% after the intraperitoneal inoculation of herpes simplex virus and 85.7% after its intracerebral inoculation) has been registered after the multiple vaccination of experimental animals and the injection of poludan 1 day before the challenge of the animals with the virus. The protective effect of the synergic action of the preparations under study coincides with the period of the maximum content of antibodies in the blood sera of the animals.     

The chemoluminescence of the primary focus of a suppurative infection and of isolated neutrophils exposed to dimephosphon]

The influence of dimephosphone at concentrations of 0.001 M-0.75 M on the chemiluminescence of tissues at the focus of purulent infection in the ear of a guinea pig, on the survival rate of the experimental animals injected with the lethal dose of Staphylococcus aureus, as well as on the spontaneous and stimulated chemiluminescence of blood neutrophils in patients with wound infection, was studied. The study showed that different concentrations of dimephosphone oppositely influenced the intensity of the chemiluminescence of neutrophil suspensions and tissues at the focus of infection: low concentrations were found to produce stimulating action and high concentrations, suppressive action. At the highest concentration used in this study (0.75 M) dimephosphone prevented the death of the animals receiving lethal doses of S. aureus.     

Investigations on the efficacy of monovalent Pseudomonas aeruginosa vaccine for oral administration in Pseudomonas aeruginosa experimental infection

Therapeutic efficacy of Pseudomonas aeruginosa vaccine for oral use (10(10) killed germs/ml), prepared from strain 4922, belonging to serotype XV, by Meitert-Meitert scheme, on 4 experimental models in mice (pneumonia, infected burn, septicaemia and urinary tract infection) was studied in comparison with monovalent Ps. aeruginosa vaccine serotype XV (10(9) killed germs/ml) for subcutaneous use and also with associated administration of the two vaccine variants. Mice immunization by using vaccine for oral use was performed by 0.5 ml vaccine per day, for 10 days and vaccine for subcutaneous use was administrated in a volume of 0.5 ml x 2, at 3 days interval. Mice immunization by using the two vaccine types, in association was concomitantly performed and in the same quantity as for separate immunization. In experimental pneumonia, Ps. aeruginosa vaccine for oral use protected mice in 35% of cases, those with infected burns were protected in 33.3% of cases, those with septicemia--in 96.6% of cases and those with urinary tract infection in 50% of cases. As compared to Ps. aeruginosa vaccine for subcutaneous use, the results obtained by vaccine for oral use are less favourable but associated administration of both vaccine variants led to superior results. Thus, in experimental pneumonia, it was obtained a surviving rate of 65% for animals immunized with both vaccine types, in comparison with 50% for animals immunized with vaccine for subcutaneous use only, and in Ps. aeruginosa infected burn, it was obtained a recovering rate of 79.1% for the animals immunized by using both vaccines, in comparison with 70.8% surviving for animals immunized with vaccine for subcutaneous use. In experimental septicaemia and urinary tract infection, combined use of both vaccine variants determined animals surviving and recovering in percents similar to those obtained by separate administration of vaccine for subcutaneous use (in septicemia--100% protection; in urinary tract infection--75% protection).     

Interferon type I in protective body reactions in an experimental Klebsiella infection]

The study on mice with experimental generalized Klebsiella infection, carried out with the use of microbiologic, immunologic and pathomorphologic methods, revealed that the intraperitoneal injection of type I interferon into the animals prevented their death and led to the rapid elimination of the infective agent from their body, enhanced the phagocytic and metabolic activity of polymorphonuclear lymphocytes of their peritoneal exudate, decreased the manifestation of microcirculatory and dystrophic changes in the parenchyma of their internal organs.     

Study of immunological mechanisms of action of temperature and emotional stress factors in experimental flavivirus infections

The influence of two stress factors, sharp changes in temperature and hypokinesia, on the course of experimental tick-borne encephalitis and Langat virus infections in mice has been studied. The data obtained in this study indicate that both factors produce defects in T- and B-cell-mediated immunity, accompanied by the activation of asymptomatic infection and the decrease of the mean survival time in acute infection. These two stress factors, differing in their intensity and nature (physical and emotional), have been shown to produce the same effect on the course of acute and asymptomatic flavivirus infections. In the former case the mean survival time of the animals decreases, and in the latter case clinically manifest infection develops. Under the conditions of hypokinesia (or changes in temperature), the death rate among the animals infected with langat virus has been found to increase 3- to 4-fold in comparison with the controls, the mortality level in the groups subjected to different stress factors being the same.     

Changes in lymphocyte and macrophage subsets due to morphine and ethanol treatment during a retrovirus infection causing murine AIDS

Infection by LP-BM5 murine leukemia virus (MuLV) suppressed significantly the percentage of peripheral blood cells showing surface markers for macrophages, lymphocytes and activated lymphoid cells. Chronic administration of a 7% (36% calories) ethanol diet or injection of 1.9 mg/mouse/day of morphine for a 7 day period were followed by 3 week periods of abstinence and then 1 week periods of consumption of 5% ethanol diets or morphine injection to female C57BL/6 mice resulted in changes in the numbers of macrophages and lymphocyte subsets. The number of lymphocytes of various subsets were not significantly changed by the ethanol exposure except those showing activation markers which were reduced. The percentage of peripheral blood cells showing markers for macrophage functions and their activation were significantly reduced after "binge" use of ethanol. Ethanol retarded suppression of cells by retroviral infection. However by 25 weeks of infection there was a 8.6% survival in the ethanol fed mice infected with retrovirus which was much less than virally infected controls (45.0%). Morphine treatment also increased the percentage of cells with markers for macrophages and activated macrophages in virally infected mice, while suppressing them in uninfected mice. The second and third morphine injection series suppressed lymphocyte T-helper and T-suppressor cells, but not total T cells. However, suppression by morphine was significantly less during retroviral disease than suppression caused by the virus only. At 25 weeks of infection 44.8% of morphine treated, infected mice survived. Morphine treatment also caused deaths such that the survival in morphine treated, retrovirally infected was higher than would have been expected if the death rate in virally infected, and morphine injected animals were combined during combined treatment. Thus these drugs of abuse can modulate peripheral blood lymphoid subsets, suppression caused by retroviral infection, and survival.     

Pathomorphological picture of the liver in mice administered antitumor antibiotics intraperitoneally and its comparative assessment]

A single administration of carminomycin, ribomycin or olivomycin in LD50 or treatment of the experimental animals with these antibiotics for 10 days in the therapeutic doses equal to 10 per cent of the LD50 induced distrophic and necrobiotic changes in the liver. The use of bruneomycin in the equivalent doses induced sclerotic process in addition to the above doses resulted in a decrease in the colour intensity of DNA, RNA and protein as compared to the control, the content of glycogen and a marked increase in the amount of lipids in the hepatocyte cytoplasm. The most pronounced shifts were observed with the use of carminomycin, rubomycin and especially bruneomycin in single doses. With the use of olivomycin in a single dose the shifts were less pronounced. It should be noted that with the use of carminomycin and rubomycin the damages were of the same character by their intensity. The changes in the liver on the use of carminomycin, rubomycin and olivomycin in single doses or during the treatment course were reversible, while on the use of bruneomycin they preserved to the end of the experiment.     

Quantitative regularities of development of endogenous infection in irradiated organism (survey of literature)

Statistical analysis of data from the literature and the author's own experimental results was carried out in order to reveal functional dependence between the dose of irradiation and the development of endogenous infection in an irradiated organism. Direct linear dependence was established between the dose of irradiation and the severity of endogenous infection at doses causing death from the "bone-marrow" syndrome in acute radiation sickness. In the case of death from the "intestinal" syndrome, inverse linear dependence can be observed between the dose of irradiation and the culture yield of microbes from internal organs. In this case, the pathological effect on the organism is due to bacterial endotoxins formed during disintegration of microbial cells in the organism. Endogenous infection and endotoxinaemia essentially aggravate the course of acute radiation disease. The importance of endogenous infection in death of the organism is neutralized after irradiation in doses causing death "under the ray".     

The therapeutic use of diucifon-activated immunocytes in adoptive transfer in mice with burn trauma complicated by Pseudomonas aeruginosa infection]

The effectiveness of the therapeutic use of diucyphone-stimulated syngeneic spleen cells was studied in mice with a burn trauma complicated by P. aeruginosa infection. For this purpose CBA mice were subjected to a burn of degree IIIa, covering 30% of their body surface, the wound was infected with P. aeruginosa strain, and 24 hours later spleen cells were taken from some of these animals. The spleen cells, incubated for 3 hours with or without diucyphone at a concentration of 10-100 micrograms/ml, were washed and reinfused intravenously to the remaining animals. The injection of diucyphone-treated spleen cells was shown to greatly increase the survival rate of the animals, to accelerate healing processes and to enhance the proliferative response of spleen cells to mitogens (phytohemagglutinin, concanavalin A) and interleukin-2. A conclusion was made on the efficacy of the therapeutic use of diucyphone-activated immunocompetent cells in cases of immunodeficiency induced by burn infection.     

Theileria parva: Kinetics of infection in the lymphoid system of cattle

The kinetics of infection with Theileria parva in cattle were studied by examining the total cellularity and numbers of parasites in a range of lymphoid organs from animals killed at intervals during the course of the infection. With the dose of T. parva stabilate used, macroschizonts were initially detected in the drainage lymph node about 7 days after inoculation and death of the host resulted on Day 18–19. Associated with the initial detection of parasites, there was a marked increase in cellularity of the drainage lymph node and a more gradual and less pronounced increase in cellularity of the other lymphoid organs. From about Day 12 onward, there was a gradual decrease in the cellularity in all of the lymphoid organs, so that in animals examined in the terminal stages of the infection there was often cellular depletion. The pattern of these cellular changes was similar in groups of Boran and Friesian cattle, although both the increase in cellularity and the terminal depletion were more marked in the Friesians. Blood leukocyte counts in infected Boran started to drop as early as Day 7 of infection and by Day 14 had reached values less than 25% of normal. Quantitation of parasitic schizonts indicated that the numbers of parasites in the lymphoid organs do not increase in a simple exponential manner. Rather, there appears to be an early rapid increase in parasite numbers followed by a phase of less rapid multiplication. Because of the marked changes which occured in total cellularity of the lymphoid organs during the course of the infection, a significant discrepancy was found between the replication rate of the parasite as calculated using total numbers of parasites and that obtained using schizont index (SI). These results indicated that the use of SI, as described in previous studies, is not a reliable method of determining the replication rate of the parasite.     

Callithrix penicillata as a nonhuman primate model for strongyloidiasis

In order to better understand experimental strongyloidiasis in small New World primates, and to evaluate aspects of reinfection and immunosuppression induced by glucocorticoids, nine specimens of Callithrix penicillata (Primates: Cebidae) were administered (by subcutaneous injection, sc) 3000 infective larvae of a strain of Strongyloides venezuelensis (Rhabditida: Strongyloididae) that had been maintained in successive passages through AKR/J mice since 1987. The mean prepatent period was 5.6 ± 0.7 days post-infection (DPI). The mean patent period of infection among the untreated animals (marmosets 1-7) was 123.4 ± 61.4 DPI. Two animals (marmosets 8 and 9) received dexamethasone (2.5 mg/kg, sc) for five consecutive days starting on the 20th day after infection, but this treatment did not alter the course of the infection, and the patent period for these animals was 100.5 ± 58.7 DPI (59 and 142, respectively). Stool examination showed that the highest quantities of parasite eggs were expelled between the 8th and 19th days after inoculation of the larvae. Thereafter, there was a gradual reduction in the number of parasite eggs in feces of all marmosets. During the chronic phase of the infection, before completely negative parasitological findings were obtained, the parasitological examinations were intermittently positive. Reinfection of three of these animals did not result in new positive examinations. However, given the receptiveness of these animals to initial infection with S. venezuelensis and their similarities to human beings, it is proposed that C. penicillata could be used as a nonhuman primate model for experimental strongyloidiasis.     

A method of reproduction in mice of chronic sacculated staphylococciasis the deeply tissues]

The intranasal method of infeciton of mice proved to be of no avail in search of a model of prolonged staphylococciasis in animals. Intraorbital infection by Badenski's method - by high staphylococcus doses - produced a severe septico-pyemic process with a high percentage of animal death during the first days of the disease. Intraorbital administration to mice of the pathogenic staphylococci in a dose of 300,000-500,000 microbial cells led to formation (in 60 to 80% cases of the sacculated purulent foci with a preponderant localization of the abscesses in the area of the chest, their prolonged persistance and progressive development. The suggested modification of Badenski's method consisting in the use of a 200 times lower infective dose served as a convenient model for studying the pathogenesis of chronic staphylococcus infection and for testing the therapeutic antistaphylococcus preparations.