THE EFFECTS OF X-RAYS AND BETA RAYS (TRITIUM) ON THE GROWTH OF RICKETTSIA MOOSERI AND RICKETTSIA AKARI IN EMBRYONATE EGGS

The growth of Rickettsia mooseri was accelerated and quantitatively increased in embryonate eggs containing tritium oxide at levels of 180, 90, and 45 mc./egg during the growth period. The eggs of a group containing 22.5 mc./egg showed only a slight increase in the rate of growth of organisms; the infections in the eggs of a group given 11.2 mc./egg did not differ significantly from those of the control group. On the other hand, growth of R. akari was inhibited in embryonate eggs containing tritium oxide at levels of 180, 90, and 45 mc./egg, and partially inhibited in groups containing 22.5 and 11.2 mc./egg. The patterns of growth of R. mooseri and of R. akari exposed to tritium oxide for 6 hours prior to inoculation into embryonate eggs did not differ significantly from that of the control group. Single and divided doses of x-rays to the host resulted in partial inhibition of the growth of R. akari.     

Antimicrobial agents in the prevention of dietary hepatic injury (necrosis,cirrhosis) in rats

The effect of various antimicrobial agents, such as aureomycin, terramycin, streptomycin, chloromycetin, penicillin, polymyxin, and sulfaguanidine on the development of massive dietary necrosis of the liver in rats has been studied. Delay in the production of hepatic necrosis was obtained from aureomycin and, to a lesser extent, from terramycin and streptomycin. Indication of temporary protection was shown by sulfaguanidine, whereas chloromycetin, polymyxin, and penicillin were not protective. B₁₂, added alone, or in combination with aureomycin, to the basal experimental diet had no influence on the development of hepatic necrosis. A combination of pectin with streptomycin enhanced the protective effect of the antibiotic. All the antimicrobial agents tested, without relation to their effect on hepatic necrosis, produced temporary stimulation of growth in the experimental animals. The beneficial effect of aureomycin was not limited to the delay of hepatic necrosis but manifested itself also in the prevention of hepatic cirrhosis in rats fed a low protein (casein)-high fat diet. In contrast to control animals showing the usual combination of cirrhosis and renal changes, the rats receiving supplements of aureomycin were free of both cirrhosis and renal changes. The rats receiving aureomycin took more food in and gained weight. No microscopic alterations were seen in the pancreas of the control rats with cirrhosis. In both groups of experiments (necrosis and cirrhosis) the antimicrobial agents, with the exception of penicillin, were given mixed with the food. Their possible effect on the intestinal flora is discussed.     

EFFECT OF ENZYME INHIBITORS AND ACTIVATORS ON THE MULTIPLICATION OF TYPHUS RICKETTSIAE : I. PENICILLIN,PARA-AMINOBENZOIC ACID,SODIUM FLUORIDE,AND VITAMINS OF THE B GROUP

By injection into typhus-infected yolk sacs, a number of agents were tested for possible inhibition or acceleration of rickettsial growth. The previously reported rickettsiostatic activity of penicillin was further confirmed. Para-aminobenzoic acid, in single injections of 6.6 mg. and 3.3 mg. giving initial concentrations of approximately 1:6000 and 1:12,000 was found to have rickettsiostatic activity approximately equal to that of penicillin. No conclusion could be drawn regarding the possibility of a synergistic action of para-aminobenzoic acid and penicillin. Para-aminobenzoic acid neutralized with sodium hydroxide was found to be as effective as the acid itself, when given in single injections of 6.6 mg. Sodium benzoate, as Well as the ortho and meta forms of aminobenzoic acid were found to be ineffective when given in similar amounts. Para-aminobenzoic acid, when added to the food in a concentration of 3 per cent, was shown to have a remarkably effective chemotherapeutic action on murine typhus infection in mice. Sodium fluoride was found at times to accelerate the growth of rickettsiae in the yolk sac, and to cause heavy infection under conditions such that the controls showed practically no multiplication of the organism. When rickettsiostatic substances (penicillin and para-aminobenzoic acid) were combined with sodium fluoride, their rickettsiostatic activity was not demonstrably changed. Other agents studied and found not to affect rickettsial multiplication are listed. The possible mechanisms involved in the observed inhibition and stimulation of rickettsial growth under these conditions are discussed.     

EFFECT OF ENZYME INHIBITORS AND ACTIVATORS ON THE MULTIPLICATION OF TYPHUS RICKETTSIAE : II. TEMPERATURE,POTASSIUM CYANIDE,AND TOLUIDIN BLUE

The time of blending the rickettsial inoculum, as also the strain of hen''s egg employed, influenced the degree of infection which developed in fertile eggs after the injection of typhus rickettsiae into the yolk sac. By varying these factors, maximal or minimal infections could be obtained. Eggs incubated at 40°C. developed only minimal rickettsial infection, whereas control eggs incubated at 37.5°C. became heavily infected. Potassium cyanide markedly enhanced rickettsial growth in experiments in which the control eggs developed only minimal infection. Under circumstances such that the control eggs became heavily infected, KCN had no appreciable effect. Toluidin blue and methylene blue delayed the development of rickettsial infection in the yolk sac, but their rickettsiostatic action under the conditions of these experiments was less marked than that of penicillin and para-aminobenzoic acid. The rickettsiostatic action resulting from temperature elevation was neutralized by KCN, and hence is believed to be due to the increased activity of the cyanide-sensitive respiratory enzyme (cytochrome oxidase) in the entodermal cells in which the rickettsiae multiply. The rickettsiostatic action of toluidin blue and methylene blue, though probably also resulting from increased metabolic activity in the entodermal cells, was not neutralized by KCN. This observation is in harmony with the reported observation that dyes of this type furnish an alternative mechanism for intracellular oxidation which is cyanide-insensitive. The rickettsiostatic action of para-aminobenzoic acid was not neutralized by KCN. No conclusions can be reached at present concerning the mechanism of action of this compound. Dinitrophenol and several compounds related to para-aminobenzoic acid gave negative results.     

Effect of enzyme inhibitors and activators on the multiplication of typhus rickettsiae; correlation of effects of PABA and KCN with oxygen consumption in embryonate eggs

A technique is described for measuring the oxygen uptake of embryonate eggs. Statistical analysis has shown that the method is reliable and accurate. Determinations were made on groups of 15 to 20 eggs, in order to average out individual biological variations. Reduction of the CO(2) tension and relative humidity to approximately zero previous to analysis has been found to be desirable. The oxygen consumption of normal and typhus-infected eggs, untreated and treated with agents previously found to inhibit or enhance rickettsial growth has been studied. Rickettsial infection caused a slight but significant increase in the rate of oxygen consumption on the 4th day after inoculation, followed by a rapid drop in the rate as the infection developed. The evidence suggests that low concentrations of rickettsial toxins may stimulate respiration, while higher concentrations depress respiration and lead eventually to embryonic death. PABA, which is rickettsiostatic, markedly increased the oxygen uptake of normal eggs, the effect appearing 4 days after injection and lasting for about 4 days. Thereafter, the rate fell below that of the untreated eggs. In typhus-infected eggs, PABA had similar effects, but the oxygen consumption reached much higher levels. A possible explanation of this fact is suggested. MABA and OABA, which are not rickettsiostatic, did not increase oxygen uptake; in fact they depressed cellular respiration moderately, OABA being more active in this way than MABA. These two compounds may compete with PABA for a position in some respiratory enzyme system. Potassium cyanide, which enhances rickettsial growth, caused, in concentrations not lethal to the embryos, a moderate drop in the oxygen consumption of normal eggs, the effect starting almost immediately after injection and lasting usually for 9 days. In infected eggs, its effect was more striking. It is probable that rickettsial toxins and KCN act synergistically to depress cellular respiration. When PABA and KCN were injected simultaneously, the stimulating effect of PABA on respiration predominated. The resulting level of oxygen consumption, though lower than that resulting from PABA alone, was still high enough to inhibit rickettsial growth. As far as our results go, they support the hypothesis that, within certain limits, rickettsial growth is inversely proportional to the respiratory rate of the host cells, regardless of the factors which determine that rate. It is not yet clear that PABA owes its rickettsiostatic action to its ability to increase cellular respiration, but this assumption seems reasonable as a working hypothesis. The respiratory mechanism in which PABA participates is not as yet known. Although PABA forms part of the folic acid molecule, folic acid itself, in concentrations corresponding to effective doses of PABA, did not increase cellular respiration or show rickettsiostatic action.     

Further studies on the effects of x-radiation on the multiplication of Rickettsia mooseri in embryonate eggs

The effect of x-rays on the growth of rickettsiae in the embryonate egg was investigated. The intensifying effect of x-radiation of the host on rickettsial growth can be attributed to alterations of the cells of the host that persist at least 7 days. The greatest enhancement of the growth of rickettsiae occurred when moderately infected cells were irradiated. These experiments indicate that x-rays may neutralize or reverse changes in the host that are unfavorable to the growth of rickettsiae. Explanations of the observed phenomena in terms of biochemical and biological alterations of the cells of the host are discussed.     

Antimicrobial therapy of experimental endocarditis caused by nutritionally variant viridans group streptococci.

Rabbits with nutritionally variant viridans group streptococcal experimental endocarditis were treated three times daily for 3 days with procaine penicillin (1.2 X 10(6) U) alone or together with low-dose streptomycin (2 mg/kg), high-dose streptomycin (8 mg/kg), low-dose gentamicin (0.32 mg/kg), or high-dose gentamicin (1.05 mg/kg). The mean 0.5-h serum concentrations of streptomycin were 5.3 and 22.5 micrograms/ml in the low- and high-dose group, respectively, and the concentrations of gentamicin were 0.7 and 2.5 micrograms in the low- and high-dose groups, respectively. The combination of procaine penicillin with each dose of aminoglycoside was significantly more effective (P less than 0.001) than was procaine penicillin alone. In combination with procaine penicillin, the higher dose of streptomycin was significantly more effective (P less than 0.02) than the lower dose of streptomycin. The higher dose of streptomycin was not significantly more effective than either dose of gentamicin. The results of treatment with the high or low dose of gentamicin were virtually identical.     

Treatment of streptomycin-susceptible enterococcal experimental endocarditis with combinations of penicillin and low- or high-dose streptomycin.

We used two strains of streptomycin-susceptible enterococci (MIC, 64 and 128 micrograms of streptomycin per ml, respectively) isolated from patients with infective endocarditis. When combined with penicillin, 20 micrograms of streptomycin per ml killed both strains synergistically in vitro whereas combinations of 5 and 10 micrograms of streptomycin per ml did not act synergistically against either strain. By using the rabbit model of enterococcal experimental endocarditis, animals were treated for 3 days with procaine penicillin (1.2 X 10(6) U intramuscularly three times daily) together with low-dose streptomycin (3.5 mg/kg) or high-dose streptomycin (10 mg/kg) intramuscularly three times daily. The peak concentrations of streptomycin in serum at 0.5 h were 9.2 and 26.8 micrograms/ml in the low- or high-dose group, respectively. When combined with procaine penicillin, both dosages of streptomycin were more effective (P less than 0.01) than procaine penicillin alone for the treatment of enterococcal experimental endocarditis. There was no significant difference in the efficacy of procaine penicillin plus low-dose streptomycin versus procaine penicillin plus high-dose streptomycin therapy of enterococcal experimental endocarditis.     

Therapeutic significance of penicillin tolerance in experimental streptococcal endocarditis.

Tolerance to penicillin exists among the viridans group of streptococci, but its therapeutic significance is unknown. We studied the effect of penicillin alone and in combination with streptomycin, in vivo and in vitro, on three strains of dextran-producing Streptococcus sanguis serotype II which possess widely various degrees of penicillin tolerance. In rabbits with experimental endocarditis, treatment with procaine penicillin (250 mg/kg intramuscularly twice daily for 5 days) decreased the number of viable organisms in valvular vegetations from 8.82 log10 +/- 0.98 CFU/g in untreated controls to 5.31 +/- 1.19 for a highly tolerant strain, 4.22 +/- 1.05 for a less tolerant strain, and 1.79 +/- 1.72 for a nontolerant strain (P less than or equal to 0.01 for comparison between any of the four groups). None of 36 rabbits infected with tolerant strains were cured by 5 days of treatment with penicillin, but 10 of 23 animals infected with the nontolerant strain were cured (P = 0.00002). When streptomycin was given in combination with penicillin, rabbits infected with the nontolerant strain were cured within 3 days, and rabbits infected with the tolerant strain were cured within 5 days. These findings indicate that tolerance can exert a critical influence on the response of S. sanguis to penicillin therapy in vivo and that the combination of penicillin plus streptomycin exerts a synergistic effect against tolerant as well as nontolerant organisms.     

Aminoglycoside-Inactivating Enzymes in Clinical Isolates of Streptococcus Faecalis: AN EXPLANATION FOR RESISTANCE TO ANTIBIOTIC SYNERGISM

Clinical isolates of enterococci (Streptococcus faecalis) with high-level resistance to both streptomycin and kanamycin (minimal inhibitory concentration >2,000 mug/ml), and resistant to synergism with penicillin and streptomycin or kanamycin were examined for aminoglycoside-inactivating enzymes. All of the 10 strains studied had streptomycin adenylyltransferase and neomycin phosphotransferase activities; the latter enzyme phosphorylated amikacin as well as its normal substrates, such as kanamycin. Substrate profiles of the neomycin phosphotransferase activity suggested that phosphorylation occurred at the 3'-hydroxyl position, i.e., aminoglycoside 3'-phosphotransferase. A transconjugant strain, which acquired high-level aminoglycoside resistance and resistance to antibiotic synergism after mating with a resistant clinical isolate, also acquired both enzyme activities. Quantitative phosphorylation of amikacin in vitro by a sonicate of the transconjugant strain inactivated the antibiotic, as measured by bioassay, and the phosphorylated drug failed to produce synergism when combined with penicillin against a strain sensitive to penicillin-amikacin synergism.No differences were found in the sensitivity of ribosomes from a sensitive and resistant strain when examined in vitro using polyuridylic acid directed [(14)C]-phenylalanine incorporation in the presence of streptomycin, kanamycin, or amikacin. Therefore, we conclude that aminoglycoside-inactivating enzymes are responsible for the aminoglycoside resistance, and resistance to antibiotic synergism observed in these strains.     

Chemotherapy of experimental streptococcal endocarditis. IV. Further observations on prophylaxis.

The ability of antibiotics to prevent Streptococcus sanguis endocarditis was tested in rabbits. Only vancomycin or a combination of penicillin G plus streptomycin always prevented infection when administered as a single dose. A loading dose of 30 mg/kg of phenoxymethyl penicillin (penicillin V) followed by additional 7.5 mg/kg doses for 48 h proved to be the only successful prophylactic program that could be given orally to man. Cefazolin alone or with streptomycin in multiple doses was also an effective alternative to penicillin or penicillin derivatives. Erythromycin uniformly failed to protect animals from bacterial endocarditis but showed greater prophylactic efficacy when a low inoculum of streptococci was used.     

Penicillin-induced effects on streptomycin uptake and early bactericidal activity differ in viridans group and enterococcal streptococci.

In vitro studies with penicillin and [3H]streptomycin in four strains of streptococci (S. faecalis, S. sanguis, and S. mitis) were performed by simultaneously measuring the rates of bacterial killing and uptake of streptomycin. In S. faecalis, penicillin stimulated streptomycin uptake, as has been shown by Moellering and Weinberg (R. C. Moellering, Jr., and A. N. Weinberg, J. Clin. Invest. 50:2580-2584, 1971). Moreover, the antibiotic combination was associated with an enhanced bactericidal rate which temporally correlated with beta-lactam-induced aminoglycoside uptake. In contrast, in viridans group streptococci (S. sanguis and S. mitis) penicillin had no effect on streptomycin uptake and a minimal effect on bactericidal rate when compared with either drug alone. These data suggested that the stimulation of streptomycin uptake in streptococci by penicillin is strain or species specific and that important differences exist between enterococci and viridans group streptococci regarding the mechanisms of beta-lactam-aminoglycoside potentiation.     

Bactericidal activity of netilmicin compared with gentamicin and streptomycin, alone and in combination with penicillin, against penicillin tolerant viridans streptococci and enterococci

Netilmicin was compared with gentamicin and streptomycin for in-vitro activity against 30 strains of penicillin-tolerant streptococci including 16 strains of enterococci. Both netilmicin and gentamicin tested alone at 4 mg/l caused 99.9% kill of more than half of the 13 strains of viridans streptococci tested, whereas streptomycin, 4 mg/l, had no bactericidal effect against these strains. Netilmicin, gentamicin and streptomycin tested alone at 8.0 mg/l against 10 strains of Streptococcus faecalis resulted in 99.9% kill of six, one and zero strains respectively. Combinations of penicillin with 2 mg/l of either netilmicin or gentamicin resulted in bactericidal synergy against 12 of 13 strains of viridans streptococci and all 10 strains of S. faecalis after 18 to 24 h incubation. Parallel experiments showed that higher concentration of penicillin were required to obtain 99.9% kill of 10 streptococcal strains when 4 mg/l streptomycin was compared with 2 mg/l of the other aminoglycosides. Killing curves showed similar bactericidal synergy for netilmicin-penicillin and gentamicin-penicillin combinations against most streptococci tested after 24 h incubation but there was sometimes a greater bactericidal effect noted with netilmicin after only 6 h incubation of the broth or after 48 h incubation. The results of this in-vitro study suggest that netilmicin is at least as effective as gentamicin as a bactericidal synergic agent with penicillin against penicillin-tolerant viridans streptococci and S. faecalis strains isolated from patients with endocarditis. Neither gentamicin or netilmicin were effective as bactericidal synergic agents with penicillin against 4 of 6 strains of S. faecium tested.     

Streptococcus pneumoniae resistance to erythromycin and penicillin in relation to macrolide and beta-lactam consumption in Spain (1979-1997)

Streptococcus pneumoniae resistance to penicillin and erythromycin in relation to beta-lactam and macrolide consumption in Spain over 19 years (1979-1997) was studied from resistance data collected by a search of the literature. Antibiotic consumption was expressed in defined daily dosage (DDD)/1000 inhabitants/day. A significant relationship (P: < 0.001) between erythromycin resistance (MIC >/= 1 mg/L) and global macrolide consumption (r = 0.942), as well as between high-level penicillin resistance (MIC >/= 2 mg/L) and global beta-lactam consumption (r = 0.948) was observed. The relationship between erythromycin resistance and macrolide consumption was due mainly to consumption of macrolides taken twice a day (adjusted r(2) = 0.886). Prevalence of high-level penicillin resistance correlated with consumption of oral cephalosporins (adjusted r(2) = 0.877); however, there appeared to be no correlation of consumption of oral or parenteral aminopenicillins, narrow-spectrum penicillins or cephalosporins with intermediate-level penicillin resistance (MIC 0. 12-1 mg/L). The prevalence of high-level penicillin and of erythromycin resistance were also strongly correlated with each other (r = 0.903, P: < 0.001). In addition to global consumption, different categories of resistance (high or intermediate), and the differential capability of antibiotics to select resistance, must be taken into account when studying antibiotic impact on bacterial populations. Although this ecological analysis is not able to demonstrate a causal relationship between antibiotic consumption and development of resistance, it suggests that overuse of certain specific antibiotics is more likely to be related to the increase in drug-resistant strains of S. pneumoniae.     

Evidence for genetic interaction between non-infectious and infectious influenza A viruses

Influenza virus rendered non-infectious by ultraviolet irradiation retained ability to "exchange" genetic traits with related virus, resulting in recombined forms. Sedimentation studies indicated association of recombinining activity with particles approximately the size of influenza virus. Genetic activity was not demonstrated when virus was more severely disrupted in attempts to observe phenomena analogous to bacterial transformation. Irradiated virus was also shown to remain capable of genetic exchange for at least 4 days after inoculation into embryonate eggs. In contrast infectious virus becomes insusceptible to genetic exchange after 1 hour incubation in eggs. The importance of this delayed recombination phenomenon to processes of virus evolution and influenza strain variation was discussed.     

Effect of concentration and time upon inactivation of tobramycin, gentamicin, netilmicin and amikacin by azlocillin, carbenicillin, mecillinam, mezlocillin and piperacillin

Carbenicillin and ticarcillin have been shown to inactivate aminoglycoside antibiotics. This study evaluated the effect of time upon in vitro interaction between mixtures of four aminoglycoside antibiotics at two concentrations with azlocillin, mecillinam, mezlocillin, piperacillin and carbenicillin at three concentrations. By linear regression analysis, the inactivation of each aminoglycoside antibiotic was shown to be directly proportional to the concentration of the semisynthetic penicillin. Aminoglycoside inactivation was greater after 72 hr of incubation with the penicillins than after 24 hr of incubation. Inactivation by each semisynthetic penicillin was greater for tobramycin and gentamicin than for netilmicin and amikacin, especially at higher concentrations of the penicillins. At concentrations of 500 microgram/ml, significantly less inactivation of amikacin occurred when compared to netilmicin. There was little difference in inactivation of a specific aminoglycoside by any of the semisynthetic penicillin antibiotics. No significant change in aminoglycoside activity occurred when the aminoglycosides were stored with the semisynthetic penicillin derivatives at -70 degrees C for 30 days. Conclusions from this study are: 1) serum specimens containing aminoglycoside-penicillin combinations should be tested immediately or frozen before antibiotic assay and 2) aminoglycoside inactivation by the newer semisynthetic penicillins may be important in patients with renal failure who are receiving these antimicrobial agents.     

Reactivation of peptidoglycan synthesis in ether-permeabilized Escherichia coli after inhibition by beta-lactam antibiotics.

The recovery of peptidoglycan-synthesizing activity after inhibition by beta-lactam antibiotics was investigated in ether-permeabilized cells of Escherichia coli B. Such cells synthesize sodium dodecyl sulfate-insoluble peptidoglycan when provided with UDP-linked precursors and Mg2+. The ability of beta-lactam antibiotics to inhibit the synthesis of peptidoglycan was correlated with their affinity for penicillin-binding proteins 1A and 1Bs. Penicillin-binding protein 1Bs is thought to be the major peptidoglycan synthetase in E. coli and is a major lethal target for beta-lactam antibiotics. Ether-treated bacteria were preincubated with concentrations of beta-lactams sufficient to completely inhibit peptidoglycan synthesis and then treated with beta-lactamases to inactivate free antibiotic prior to measurement of peptidoglycan synthesis. At 40 min after beta-lactamase treatment, the rate of peptidoglycan synthesis was about 74% of the control rate in cells pretreated with ampicillin, but only 15% of the control in cells pretreated with penicillin G or azlocillin. Reversal of inhibition by several other antibiotics fell between these extremes. When cross-linking of peptidoglycan was measured specifically, reversal of inhibition by ampicillin also occurred more readily than that by penicillin G. Reactivation of peptidoglycan synthesis was not due to de novo synthesis of penicillin-binding proteins since it occurred under conditions that did not allow incorporation of [14C]leucine. We conclude that there is considerable variation in the stability of the inactive acyl enzymes formed between various beta-lactams and penicillin-binding protein 1Bs, with those formed by penicillin G being relatively long-lived.     

Antimicrobial Therapy of Experimental Enterococcal Endocarditis

The successful therapy of enterococcal endocarditis requires prolonged administration of synergistic antibiotic combinations. Controversy has arisen regarding optimal therapy (i) when the organism possesses high-level streptomycin resistance, and (ii) when the patient is allergic to penicillin. This study examines these questions in vitro and in a rabbit model of enterococcal endocarditis. The combination of penicillin with either streptomycin or gentamicin increased the rate of bacterial killing in vitro and in vivo when compared with penicillin alone (P < 0.05) when the test strain was relatively susceptible to streptomycin (minimal inhibitory concentration, 128 mug/ml). Only the combination of penicillin and gentamicin was consistently more effective than penicillin alone (P < 0.01) when the test strain was highly resistant to streptomycin (minimal inhibitory concentration > 150,000 mug/ml). The combination of vancomycin and streptomycin was more rapidly bactericidal than vancomycin alone in vitro and in the animal model against the streptomycin-susceptible strain (P < 0.01). The relative rate of in vitro bacterial killing by various antibiotics and combinations was predictive of the efficacy of these drugs in eradicating enterococci from cardiac vegetation in experimental endocarditis.     

Activity of 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine against Schistosomiasis mansoni in mice

The activity of the acyclic nucleotide analogue 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine [(S)-HPMPA] against Schistosoma mansoni was investigated in mice. The compound was injected intraperitoneally, usually on two or five consecutive days, at 10 to 20 mg/kg of body weight/day. The treatment started before, at the time of, and after the onset of egg laying (oviposition) by S. mansoni. The animals were killed from 7 to 40 days after the cessation of treatment. Significant reductions in the total numbers of female and coupled worms were found. Female fecundity and both hepatic and intestinal egg loads were suppressed. These effects were more pronounced with dosing regimens launched before the time of oviposition. The complete disappearance of immature eggs and a significant reduction to the complete absence of mature eggs, with 99 to 100% of the eggs being dead, were produced. No hepatic egg-induced granulomas were present in mice treated at the time of oviposition, and the granulomas were smaller in mice treated before S. mansoni oviposition. These preliminary findings extend the knowledge of the antiparasitic properties of (S)-HPMPA.     

Induced and spontaneous diabetes mellitus and suppression of cell-mediated immunologic responses. Granuloma formation, delayed dermal reactivity and allograft rejection.

These investigations delineate the recently described suppression of a form of cellular hypersensitivity in mice with streptozotocin-induced diabetes mellitus using a variety of cell-mediated immunologic responses in animals with several different forms of diabetes. Streptozotocin- and alloxan-induced diabetic mice and db/db genetically determined diabetic mice showed reductions in the areas of inflammation around Schistosoma mansoni eggs injected into the pulmonary vasculature of 68, 70, 77%, respectively. In contrast, streptozotocin-induced diabetes had no effect on the nonimmunologic foreign body granuloma around divinyl benzene copolymer beads injected into the pulmonary arterioles. Animals protected from diabetes by treatment with nicotinamide before streptozotocin administration did not develop hyperglycemia and had normal areas of immunologic granuloma formation around schistosome eggs. Treatment with insulin reversed the suppression of schistosome egg granuloma formation in both streptozotocin- and alloxan-diabetic animals. Two additional in vivo parameters of cellular immunologic reactivity were examined in streptozotocin-induced diabetes: delayed footpad swelling was essentially eliminated; skin graft survival across the H-2 area was significantly prolonged from 10.2 days in the controls to 14.4 days in moderately diabetic A/J mice. These observations suggest that diabetes mellitus is associated with suppression of cell-mediated reactions in vivo and that the defect is reversible with insulin treatment.