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Within 24 hr after injection of mice on day 10 of pregnancy, embryos exposed to a teratogenic dose of 3H-bromodeoxyuridine (3H-BrdU) have smaller wet weights than control embryos exposed to a trace dose of 3H-thymidine (3H-TdR) or a trace dose of 3H-BrdU. This difference increased by 48 hr after injection. Measurements of total embryo DNA content indicate that these lighter embryos contain fewer cells than controls. If cell death plays a role in the observed growth retardation following administration of 3H-BrdU, one would expect label to be lost from the embryo DNA fraction. Following injection of a trace dose of 3H-TdR or 3H-BrdU, total embryo DNA label rapidly reached peak levels and remained at those levels for at least 48 hr after injection. However, within 48 hr of administering a teratogenic dose of 3H-BrdU, total embryo DNA label had decreased to 25% of peak levels. Histological evidence of cell death was found in the embryos, although it is not yet clear whether cell death was sufficiently extensive to account for the amount of label lost from the DNA fraction. Since none of these BrdU-induced cytotoxic effects were found in the maternal liver, spleen, kidney, or placenta, it is concluded that BrdU probably exerts its teratogenic effects directly on the embryo.

A pedigree control line of mice (ICR stock) with a mean effective population size [Formula: see text] of 110.52 was evaluated over 26 generations. Control lines, sampled from the ICR stock, of 16, 8, 4, 2 and 1 pairs, replicated 2, 2, 4, 8 and 16 times, respectively, were maintained for 15 generations. Mean inbreeding coefficients (F) were 0.10 in the ICR stock and 0.12, 0.20, 0.42, 0.76 and 0.95 in the respective control lines. Traits evaluated were per cent females littering (PFL), number born (NB), 12-day litter weight (W12), body weights at 3 (WK3), 6 (WK6) and 8 (WK8) weeks, gain from 3 to 6 weeks (PWG) and 6-week tail length (TAIL). The significant (P etended to show greater average divergence among replicates. For about 70% of the Ne-trait combinations the observed variance among replicates exceeded the predicted drift variance. Linear regressions of control line means for each trait on F, within generations, were significantly (P

The postnatal development and involution of the X zone in the mouse adrenal cortex of both sexes were examined using the light and electron microscopes. At 0–5 days of age, no special cell group could be distinguished for the developing X zone in the inner cortex. The inner cortical cells contained spherical or ellipsoidal mitochondria with vesiculotubular cristae, vesiculotubular smooth endoplasmic reticulum (sER) and electron-lucent lipid droplets. The first sign of the developing X zone was the appearance of small groups of cells in juxtamedullary region differing from the cells in other part of inner cortex at 8 days. The electron microscopy showed that such cells contained nuclei of somewhat irregular outline and some parallel stacks of flattened sER. At 10–11 days, a thin layer of small eosinophilic cells were clearly identified as the developing X zone light microscopically in both sexes. Electron microscopically, the X zone cells showed a much dense cytoplas, which contained abundant sER, many mitochondria and numerous ribosomes. The typical X zone cells were characterized by the formation of peculiar mitochondrial complexes and whorled pattern of the sER. Mitoses were often found in the X zone, where mitotic cells even contained the whorled sER and bizarre mitochondria characteristic of the typical X zone cells. In the male the X zone rapidly involuted and might disappear by 30 days of age, whereas in the female X zone persisted as a thicker layer with the earlist sign of fatty degeneration. The origin of the X zone cell and the process of formation of its characteristic organelles are discussed.

The fine structure and the cytochemical activity of the liver, the duodenum and the jejunum of adult mice have been studied after phenobarbital (P.B.) treatment. A smooth endoplasmic reticulum proliferation has been observed in the centrolobular hepatocytes after 3 injections of P.B. and in the apical cells of the intestinal villi after 1 to 7 injections of P.B. The distribution of glucose-6-phosphatase remained unchanged but the specific activity decreased. Biochemical measurements of alkaline phosphatase activity have shown a differential response in the duodenum and in the jejunum.

SummaryN-Acetylprocainamide has been detected in the plasma samples of each of four patients receiving procainamide. The metabolite was identified from tlc data and its identity confirmed by gas chomatographic-mass spectroscopic analysis. The metabolite was also detected in the whole blood of Sprague-Dawley rats after administration of PA. NAPA · HCI when injected ip into 42- to 49- day-old ICR male mice prevented coarse ventricular fibrillation caused by deep chloroform anesthesia and resultant hypoxia. NAPA · HCl reduced aconitine-induced arrhythmia to atrial flutter or atrial tachycardia with varying degrees of A-V block in three dogs. Analysis by tlc indicated that the mice, dogs, and rats did not deacetylate NAPA during the period of pharmacologic testing. NAPA was found to cause less ferrihemoglobin in Sprague-Dawley rats than did PA.

A total of 25 hydroxyurea derivatives have been screened on mouse vaginal mucosa for antimitotic effect. Antimitotic properties are preserved in derivatives where a methyl or ethyl group is substituted for hydrogen at position 1 or a method group at position 3. Higher alkyl and carbonyl groups at position 1 or 3 are correlated with loss of antimitotic activity. Loss of antimitotic property is interpretable on the basis of steric and inductive-effects. The hydroxyl proton may not be substituted by an alkyl group but can be replaced by labile substituents such as carbamoyl or trimethylsilyl which permit formation of hydroxyurea itself in vivo.

The effect of 2 urease inhibitors, hydroxyurea and thiourea, on experimental ascending pyelonephritis by P. mirabilis was studied in mice undergoing water diuresis. It was found tha

The results of our studies indicated that the avirulent Neff strain of Acanthamoeba was more susceptible to the activity of the anti-metabolite 5-fluorocytosine (5-FC) than was the virulent A-1 strain or a mouse brain reisolate of this strain, designated A-3. Results of competition experiments in which cultures were exposed simultaneously to 5-FC and either uracil, thymidine, or both uracil and thymidine demonstrated that the drug was directed against both deoxyribonucleic acid and ribonucleic acid in the avirulent strain, whereas ribonucleic acid was mainly affected in the virulent amebas. Concentrations >10 μg of 5-FC per ml were amebicidal to the avirulent strain; lower concentrations of the drug, which only affected growth slightly, significantly impaired the capacity of the cells to spontaneously encyst in stationary-phase cultures. On the other hand, the virulent strains were capable of growing in the presence of 5-FC (40 μg/ml) after an initial period of susceptibility. After a few transfers in growth medium lacking the drug, 5-FC-treated virulent amebas exhibited growth parameters typical of untreated cells. However, after successive subcultures in drug-free medium, 5-FC-treated cells lost their resistance and were again susceptible to the drug. This result suggested that the capacity of the cells to develop resistance resulted from a drug-induced mechanism. Spontaneous encystment, which was normally minimal in stationary-phase A-1 or A-3 cultures, was enhanced in A-3 but not A-1 cultures treated with 5-FC (>30 μg/ml). Results obtained from experiments to determine the effectiveness of 5-FC in protecting mice experimentally infected with either A-1 or A-3 amebas indicated that the clinical usefulness of 5-FC may be limited by the capacity of the amebas to develop resistance.

Optimum conditions for the determination of 5-phosphoribosyl 1-pyrophosphate (PP-ribose-P) in mouse liver are described. PP-Ribose-P is extracted from frozen liver powder with a solution of 182 μ m [ 14 C]adenine (10 μCi/μmole), 3.36 m m 2,3-diphosphoglycerate and 21.3 m m Tris-Cl buffer (pH 7.4) for 20 sec at 100°C. The amount of PP-ribose-P in the extract is calculated from the radioactivity incorporated into AMP, ADP, and ATP during a 60 min incubation at 37°C with adenine phosphoribosyltransferase and 2.5 m m CaCl 2 .

The effect of benzene on erythropoiesis was evaluated in mice using the erythrocyte 59Fe utilization method. After the normal rate of 59Fe accumulation in circulating red blood cells was estimated, mice were given single doses of benzene sc and its effect on 59Fe uptake was evaluated after 5 specific time intervals. The earliest time at which bone marrow suppression could be detected was 24 hr after benzene administration (440 or 2200 mg/kg). No suppression was found after 1 and 12 hr whereas maximum suppression was seen after 48 hr and complete recovery was observed after 72 hr. The evidence suggests that benzene inhibits the multiplication of erythrocyte precursor cells but does not interfere with the incorporation of iron into heme.

The binding of 3 H-naloxone (spec. act. 5.2 Ci/mmol) in a crude mitochondrial fraction of the whole mouse brain was examined. Binding was reversed by the narcotic agonists levorphanol, morphine and 1-methadone but not by dextrorphan. Levorphanol sensitive (specific) 3 H-naloxone binding was blocked by Na+, Li+, Ca++, Mg++ and Mn++ but not by K+. When the crude mitochondrial fraction was separated on a discontinuous sucrose gradient, the highest activity of specific binding was found in the nerve ending particle fraction. Animals made physically dependent by 3 day morphine pellet implantation did not show an increased binding affinity for 3 H-nalovxone. The implantation of a 10 mg naloxone pellet increased the apparent total number of binding sites on the second and third day of implantation.

Summary The differential effects produced in culture by silver, platinum, and stainless steel were studied. After 24 h, mouse marrow cultured on silver showed a significant decrease in the percentages of immature granulocytic and erythroid cells, and a significant increase in the percentage of mature granulocytic cells. The effect, which was not observed at 72 h, was unrelated to the equilibrium potential assumed by silver.

Alcohol withdrawal reactions were induced in mice using an established technique. Mice, administered 1.0 mmole/kg pyrazole daily were exposed for 3 days to 10 mg/l ethanol vapor and withdrawal was brought about by discontinuation of the exposure. Diphenylhydantoin administered in doses of 12, 20 or 50 mg/kg by either of two routes (i.p. or p.o.), failed to have any discernable effect on the withdrawal. A 100 mg/kg dose of diphenylhydantoin increased seizure scores. Chloral hydrate administration in doses of 175, 244 or 350 mg/kg, on the other hand, lowered seizure scores in a manner which was dose related and prompt. These findings suggest that the clinical use of diphenylhydantoin for control of the seizures seen in alcohol withdrawal should be re-evaluated. The seizure scores of mice not exposed to ethanol but administered 1.0 mmole/kg pyrazole daily for 3 days were negligible and well within values obtained with naive control mice not exposed to any pharmacological agent.

Swiss ICR adult male mice were used to analyse regional morphologic differences in the mucosa of the colon. The three cell types recently described in the descending colon of the mouse were also observed in the transverse and in the ascending colon. However the vacuolated cells of the crypts have presented different morphological characteristics depending on their localisation. In the ascending colon, they exhibited small supranuclear vesicles in contrast to the large vesicles observed in the descending colon. Several cell combining features of argentaffin-vacuolated, goblet-vacuolated and goblet-argentaffin cells have been observed. Furthermore a special type of granule referred to as a secondary lysosome was observed in the peripheral area of the typical goblet cells.

IV. ANTIMYCOPLASMA ACTIVITY OF ASPICULAMYCIN in vitro AND IN VIVOkn-subtitle=en-abstract=Aspiculamycin, a new cytosine nucleoside antibiotic produced by Streptomyces toyocaensis var. aspiculamyceticus, showed strong activity against various strains of Mycoplasma in vitro and in vivo. The minimal inhibitory concentration of the antibiotic ranged between 50 to 0.05mcg/ml by agar dilution, broth dilution or microtiter method. No influences of inoculum size and pH of the medium on the activity were observed. A number of strains of Mycoplasma gallisepticum showing resistance to macrolide antibiotics were all susceptible to the antibiotic. L-Forms derived from Staphylococcus aureus and Proteus vulgaris were insensitive to the antibiotic. After administration of 0.04% (w/w) of aspiculamycin in the basal diet for seven days, the lung and trachea of mice infected intranasally with Mycoplasma pulmonis were free of pathogen. In the experimental mice arthritis induced with M. pulmonis, the Mycoplasma could not be detected in joints of the mice after treatment with aspiculamycin at a dose of 0.05% (w/w) in the diet for ten days.

THE membranes of lymphoid cells from tumours induced by oncornaviruses are antigenically altered. The new surface antigen(s) are readily recognised by isologous (histocompatible) hosts which mount both cellular and humoral immune responses1,2. It is essential to know whether or not antigens induced by the various strains of murine leukaemia viruses (MuLV) are cross-reacting immunologically.

Genetic effects of saccharin were studied in mice by the dominant lethal test and the cytological analysis of changes induced in the stage of spermatogonia formation.

A myelogenous leukemia-inducing virus (MyLV) has been isolated from a chloroleukemic C57Bl mouse, injected neonatally with the lymphatic leukemia virus (LLV)-containing helper component of the Friend virus (FV) complex. MyLV, free of detectable spleen focus-forming virus (SFFV), consistently induced only myelogenous leukemia in neonatally infected C57Bl, Ha/ICR, C3H and BALB/c mice, within 5 months (including chloroleukemias in C57Bl and Ha/ICR). The leukemia involved chiefly the spleen, liver, lymph nodes and bone marrow, and tumor cells could be recovered from the marrow to grow in the solid (subcutaneous) or ascites (intraperitoneal) form. MyLV preparations had ample helper activity for SFFV in restrictive hosts, and could be used to prepare a MyLV pseudotype of SFFV which was antigenically indistinguishable from native FV complex. MyLV could have arisen by selection of a pre-existing variant in the LLV population, by a genetic interaction between LLV and the C57Bl chloroleukemic host cell, or could have arisen from the original host C57Bl mice as a result of activation following the infection with LLV.

A potent anti-inflammatory compound, TAI-284, and its optical isomers were subjected to the pharmacological, toxicological and metabolic studies in rats, mice and guinea-pigs. In anti-inflammatory, analgesic and antipyretic activities examined in rats and mice, the d-isomer was the most potent, followed by the racemate, and the l-isomer was the lowest. Similar results were obtained regarding toxicity and ulcerogenicity. The d-isomer maintained the highest plasma level, followed in decreasing order by the racemate and the l-isomer, when they were administered orally to rats. In the same experiment, the plasma level of the l-isomer's metabolites was the highest, followed in decreasing order by that of the racemate's metabolites and that of the disomer's metabolites. In Vitro, the l-isomer was most rapidly transformed into the metabolites while the d-isomer was most slowly transformed. On the other hand, the d-isomer was as potent as the l-isomer in the anti-inflammatory activity in guineapigs. In this species TAI-284 is hardly biotransformed into the metabolites. It is postulated that the rate of biotransformation of these compounds has a great influence on their pharmacological activities.

Mouse eggs were parthenogenetically stimulated with hyaluronidase and osmotic shock and the resulting two-, four- and eight-cell stage embryos examined with the electron microscope. The ultrastructure of parthenogenones during cleavage showed numerous differences when compared with normal development. Cortical reaction was absent and there were no microvilli on the cell surface of developing blastomeres. The cytoplasm contained numerous bundles of fibrous material, vacuoles and lipid droplets, multivesicular bodies, and agglomerates of vesicles sometimes connected with cortical granules. Cortical granules and vacuolated mitochondria were numerous and usually situated near the cell membrane. The number of free ribosomes was very small and agglomerates of ribosomes or rough endoplasmic reticulum were not observed. Nucleoli in almost all cells were so-called primary nucleoli consisting of a dense, osmiophilic core and narrow ring of granular material. In only a few cells was reticulation of nucleoli and formation of fibrillar and granular parts noticed. Nuclear fragments and nuclei with broken membranes were present in some cells. Primary nucleoli persisted during mitosis and were in close contact with chromosomes. Cytokinesis was irregular and small and large fragments of cytoplasm surrounded by membrane were often observed between dividing cells. Our results suggested that failure of parthenogenones to develop normally is probably caused by numerous disturbances during early cleavage. Incomplete cortical reaction, persistence of primary nucleoli, a probable disturbance in RNA and protein synthesis, and irregularities during nuclear and cellular division were observed in all embryos.

Mouse brains, cell cultures of mouse brains, and spleens from mice with scrapie were examined by electron microscopy. Brains and spleens of 10 scrapie-inoculated and control mice were studied. Seven brain-cell cultures, four of which were from mice inoculated intracerebrally or subcutaneously with scrapie, were examined. Status spongiosus and vacuolated neurons were found in the brains. Structures 35 nm in diameter were seen in the brains of mice inoculated intracerebrally. They were not evident in cell cultures, although a vacuolated structure was found in one such culture. No significant changes were found in the spleens. Through electron microscopy, investigators have sought to show scrapie virus and its associated changes. The established histological diagnostic cri­ teria - neuronal vacuolation, astrocytic hypertrophy and status spongiosus ­ have been studied also by this means. Natural cases of scrapie have neuronal vacuolation and intravacuolar budding of vesicles and cytoplasmic processes, with some vacuolated neurons containing membrane-bound accumulations of 35-nm particles (2). There are other reports of similar findings without the intravacuolar budding (4), and particles 15-26 X 75 nm were found both in astrocytic processes and nerve cell terminals (20). Electron microscopic examination of experimentally infected animals has included studies of the mouse and rat. Reports on mice indicated areas of sta­ tus spongiosus, ruptured plasma membranes and curled fragments of mem­ branes in areas of presynaptic and postsynaptic neuronal terminals, and 35­ nm vesicular and tubular structures suggestive of viral particles (10, 17). One report suggested that the small vesicles found within a nerve cell were formed by dilatation of endoplasmic reticulum (13). In rats, neurons were found that contained small inclusion bodies composed of a folded membrane and accu

The effects of several i.p. administered, centrally active cholinergic agonists and antagonists on the naloxone-induced jumping behavior of morphine tolerant and dependent mice were studied in an effort to differentiate muscarinic and nicotinic modification of the withdrawal jumping behavior. Nicotine, tremorine, oxotremorine, arecoline and physostigmine significantly inhibited jumping, whereas atropine, benzotropine, pempidine and mecamylamine significantly potentiated jumping. Quaternary cholinergic drugs did not modify jumping. These drug effects were obtained generally without an alteration of the amount of naloxone or morphine in the brain. Cholinergic drugs also modified the jumping incidence in mice undergoing abrupt morphine abstinence. It is concluded that the inhibition of withdrawal jumping in morphine dependent mice by both muscarinic and nicotinic agonists and its enhancement by muscarinic and nicotinic antagonists reflect cholinergic modifications of the jumping response by a central mechanism(s).

Histidyl transfer ribonucleic acid (tRNA) from 17 day mouse placenta was fractionated into six components by reversed-phase plaskon chromatography. Codon specificity of three components (tRNA2His, tRNA4His and tRNA6His) was studied by binding to mouse liver ribosomes in the presence of poly(AC) and poly(ACU). All three tRNAs respond equally to each polymer indicating a dual in vitro recognition of CAC and CAU. At present the data do not support changes in coding as a rationale for the quantitative variation shown by placental His-tRNAs during pregnancy.

The LD50 values for l -dopa and l -dopa-N-methyl ester hydrochloride in mice, rats and rabbits administered by various routes are compiled from various sources and given in tabular form.

Ovariotomy in 8 week-old, specific pathogen free ICR/JCL mice was effective in securing a marked thymus regeneration following a single whole body irradiation with 300 rads of X-ray. Recovery of the bone marrow cell counts, especially of the lymphoid cells, preceded the thymus regeneration and was more marked in spayed mice than in the sham-operated. On the basis of these results, it is suggested that ovarian hormones play a role in the thymic lymphopoiesis by affecting the dynamics of the lymphoid stem cells in the bone marrow and/or the lymphopoietic microenvironments in the thymic cortex.

Cytophilic macroglobulin was eluted (by heating at 56 C for 60 min) from lymphoid cells of mice immunized with subfractions of virulent Salmonella typhimurium SR-11 or vaccinated with an attenuated strain of S. typhimurium (RIA). No such macroglobulin was present on comparable cell populations from normal or adjuvant-injected mice. Cytophilic macroglobulin was also present in the sera of immunized mice. In mice immunized with RNA and protein-containing subfractions extracted from lysates of S. typhimurium SR-11, the cytophilic macroglobulin was present by 14 days after immunization, whereas it was present by 10 days in mice injected with living attenuated S. typhimurium RIA. This macroglobulin reacts specifically with protein-rich components present in the immunogenic subfractions of the whole bacterial cells and has been demonstrated to facilitate phagocytic uptake of virulent S. typhimurium SR-11. Moreover, a similar protein material was present in broth culture media in which the salmonellae were cultivated. Greater amounts were detectable in older (4 day) cultures.

The effect of high oxygen pressure on the in vivo turnover of NE in mouse and rat brain, and the turnover of 5-HT in mouse brain was investigated. Turnover of NE and 5-HT was determined by steady-state kinetic methods. In mice, synthesis of NE was inhibited by the administration of α-MPT. In rats NE turnover was determined from the decline in intracisternally administered H 3 NE. Steady-state kinetic methods also were used to determine 5-HT turnover in mice, utilizing probenecid to block the transport of 5-HIAA. In these studies, 100% oxygen at 1 and 3 atmospheres had no effect on either NE turnover in mice and rats or 5-HT turnover in mice. These studies suggest that changes in NE and 5-HT turnover do not appear to be implicated in the onset of oxygen-induced convulsions.

Thiopeptin is a new antibiotic, produced by Streptomyces tateyamensis and developed solely for animal use as a feed additive. The antibiotic content in animal tissue and feed was assayed in terms of the antimicrobial activity against Mycoplasma laidlawii A. This antibiotic was found to be relatively nontoxic in rats and mice. In chickens, this antibiotic is excreted into feces within 48 hr of administration and is not absorbed in tissue. It is well tolerated in both broilers and swine and is highly stable in animal feed. Thiopeptin-supplemented feed contributes to the improvement of weight gain, feed efficiency in chickens and swine, and the egg performance in layers. Thus, thiopeptin, when used as a feed additive, is quite suitable for supplementing animal nutrition.

Tobramycin, an aminoglycoside antibiotic, has been administered to mice, rats, cats and dogs for toxicologic evaluation. The sc LD50 values in mice and rats were 441 and 969 mg/kg, respectively. Deaths were preceded by CNS depression and occurred within 1 hr of treatment. A 100 mg/kg iv dose in chloralose-anesthetized cats produced a moderate, transient decrease in blood pressure and a significant decrease in inspiratory volume and soleus twitch force. Rats were given daily sc doses of 15–120 mg/kg for 3 months. Renal tissue change, the only drug effect evident histologically, ranged in degree from a slight reparative nephrosis at the lowest dose to cortical tubular necrosis in some rats that received the highest dose. In a 1-month study, a daily im dose of 7.5 mg/kg had no apparent effect on dogs, but a 30 mg/kg dose produced severe renal damage. Vestibular injury occurred within less than 30 days in all cats that received daily sc doses of 50 mg/kg, but no vestibular changes were observed in cats that were given 65 doses of 25 mg/kg. The toxicologic effects observed in tobramycin-treated animals were qualitatively and quantitatively similar to those observed with gentamicin.

1.Candida albicans readily establishes in the gastrointestinal tract of germfree mice either alone or in the presence ofE. coli. 2. Noninhibitory and inhibitory groups ofE. coli have been separated by their actionin vitro againstC. albicans. 3. The inhibitoryE. coli significantly lowers the levels ofC. albicans in stools of gnotobiotic mice. A dialysate of the inhibitoryE. coli also lowers theCandida levels in the stool of other gnotobiotic mice. 4. Gentamicin therapy and a 10% third degree burn had no effect on theCandida levels in the stool of germfree mice nor did it cause invasive infection or mortality in the animals.

Latent corynebactenai infection occurs naturally in many strains of mice. It can be evoked into the active disease, pseudotuberculosis, by a single injection of 10 mg of cortisone. The cortisone effect was tested in 21 colonies, representing 11 genetically different strains of mice. Animals of the C57B1/6, DBA/2, and RIII strains were shown to be latently infected with Corynebacterium kutscheri by the fact that they developed fatal pseudotuberculosis following cortisone treatment. Virulent C. kutscheri could not be isolated from homogenates of organs obtained from latently infected animals before cortisone administration; however, these homogenates yielded small translucent colonies of avirulent organisms. Recovery of these atypical colonies was facilitated by preincubating the organ homogenates before plating. The organisms constituting such colonies differed morphologically and immunologically from C. kutscheri, but had similar biochemical properties with the exception that they lacked urease and catalase activity. Mice treated with cortisone yielded both the avirulent bacteria and virulent C. kutscheri. The latter was the predominant organism present in the organs at the height of infection. Injection of avirulent organisms into Swiss Lynch mice, which are normally free of latent corynebacteria, occasionally established a latent infection which could be converted into corynebacterial pseudotuberculosis by cortisone. Cultures of fully virulent C. kutscheri were then obtained from the lesions. Latency was produced experimentally with a streptomycin-resistant strain of virulent C. kutscheri (CKsr) derived from the stock culture. When sublethal doses of CKsr were injected into NCS mice (Institut Pasteur colony), they induced a latent infection characterized by the presence of avirulent organisms possessing the streptomycin resistance marker. These were isolated in the form of small translucent colonies from the livers of the infected animals. Administration of cortisone to these animals subsequently evoked active infection from which virulent CKsr could be obtained. Injection of the avirulent streptomycin-resistant organisms into normal NCS mice established a latent infection which could be uniformly converted into corynebacterial pseudotuberculosis by cortisone. The virulent C. kutscheri obtained from the lesions bore the genetic marker of streptomycin resistance, thus being identical with CKsr. Except for streptomycin resistance, the avirulent organisms isolated from the experimentally induced latent infections were identical with those found in the naturally occurring latent infections. These results suggest that C. kutscheri can persist in vitro in an avirulent form which is resistant to the defense mechanisms of the host, and can thus establish a latent infection. Treatment of the animal with cortisone results in the conversion of the avirulent form into virulent C. kutscheri, and of the latent infection into active corynebacterial pseudotuberculosis. The findings are discussed with regard to their relevance to infection immunity, and to the conversion of latent infection into overt disease.

SummarySuppression of corticosteroid production by inhibitors effected a tenfold increase in susceptibility of mice to death from endotoxin shock. Amphenone B and metyrapone caused some increase in susceptibility, but if given more than 1 hr before the endotoxin afforded protection to the test animals. Aminoglutethimide exerted a deleterious effect for at least 24 hr. The effect of the aminoglutethimide was reversed by pregnenolone, progesterone and deoxycorticosterone, although the LD50 remained lower than in the control animals. Corticosterone, cortisone and hydrocortisone afforded marked protection in both the endotoxin treated mice as well as the endotoxin-inhibitor treated mice. Andros-tenedione caused a decrease in the LD50 value in both the control and aminoglutethimidetreated mice. By contrast 17-a-hydroxyprogesterone afforded no protection against endotoxin in the control mice and a significant, but miniscule, degree of protection in the inhibitor-treated mice.This investigation was supported by ...

SummaryAn agent has been isolated from Ha/ICR Swiss mice which induces lymphocytic leukemia in approximately 80% of Swiss mice injected at birth with cell-free filtrates. This agent retains its infectivity after storage at room temperature for 24 hours, at 4°C for 48 hours, at —20°C for 1 month, and in the CO2 deep freeze for 1 month. There is some loss of infectivity under all storage conditions, greatest at —20°C for 1 month. Storage in the CO2 deep freeze for 6 months reduces infectivity to about one-third. In all instances, latency is extended. The agent is inactivated at 56°C for 30 minutes, but is not destroyed by exposure to ether overnight. It can be neutralized by incubation with specific antiserum produced in rabbits. Sprague-Dawley rats and Rf strain mice are susceptible to infection when injected at birth; weanling Swiss mice are resistant to infection. Similarities and differences between this agent and other murine leukemia viruses are discussed.

The gut flora of 4- and 24-month-old ICR mice has been studied in the following groups: (a) conventional mice held in the open environment, (b) conventional mice in germ-free-type isolators and (c) germ-free mice in similar conditions after they have been associated with normal mouse flora following a single microbial exposure. The results indicate that elements of the autochthonous flora populate the gut in young mice, irrespective of the type of housing. Pathogenic organisms (e.g. clostridia, E. coli) were rejected. In older mice held in the open environment – i.e. when re-seeding from the external environment was permitted – these pathogens were established in the gut, while this did not occur in mice protected by the isolator. Age-induced impairment of body defenses might be responsible for this phenomenon.

Dibutyryl cyclic adenosine 3′,5′-monophosphate (DBcAMP), 25 mg/kg, administered intraperitoneally 25 minutes prior to testing produced a significant decrease in spontaneous locomotor activity (SLMA) to 58 percent of control and in exploratory behavior to 64 percent of control but failed to alter rotarod performance of mice. DBcAMP did not decrease activity when mice were pretreated with the nucleotide 24 hours prior to its subsequent administration. The results of time-response studies of DBcAMP and SLMA showed that the effects were present as early as 2 minutes after administration and persisted for approximately 90 minutes. Dose-response experiments showed a significant decrease in SLMA with 10 mg/kg and an 86 percent decrease with 75 mg/kg. The results suggest that DBcAMP acts centrally to alter several behavioral patterns in mice and that tolerance rapidly develops to its effects.

— Assays of citric acid cycle substrates and metabolites of the second stage of the glycolytic pathway have completed a series of studies of glucose metabolism in brains of mice rapidly frozen at intervals during electrically-induced, tonic-clonic convulsions. Citric acid cycle metabolism reached a new equilibrium at a significantly higher rate. However, oxidative metabolism did not keep up with the demand for energy supplies, as indicated by an increasing lactate level and an increasing lactate: pyruvate ratio. Administration of a sub-anaesthetic but anticonvulsant dose of phenobarbitone prior to convulsive electrical stirnulation was associated with as great an increase in anaerobic glycolysis as in mice given no drug prior to stimulation; but oxidative metabolism was not enhanced, as reflected by even greater lactate: pyruvate ratios in mice given phenobarbitone than in mice given no drug prior to convulsive stimulation.

A total of 174 test agents, including pharmaceuticals, food additives, pesticides and organic extracts of air and water pollutants, was tested for mutagenicity in mice using the modified dominant lethal assay. In concurrent control populations, the mean weekly pregnancy rate was 66% and exceeded 30% in 99% of all weeks; the distribution of weekly mean total implants per pregnancy was symmetrical around a peak of 11.5–11.9 and was never less than 8; mean early fetal deaths per pregnancy were

A significant loss of protective activity of BALB/c spleen homogenate against cell-free transmission of HIPA plasmacytoma was noted by pretreatment with mineral oil of spleen donor mice. No decrease of protection was found in ICR mice, when they received intraperitoneally spleen homogenate from oil-pre-treated BALB/c mice. A strain specific immunosuppression, combined with virus activation, could be the mechanism of this effect.

The effect of goldthioglucose (GTG) obesity on development of diabetes was investigated in genetically diabetic (KK) and normal (ICR and C57BL) mice. GTG obesity intensified diabetic traits in KK mice from chemical diabetes to overt diabetes, as was already demonstrated in obesity induced by either dietary or genetical means. GTG obesity caused diabetic changes likewise in ICR mice as manifested by hyperglycemia, glucosuria, hyperinsulinemia, and depressed insulin sensitivity. In vitro glucose oxidation was also decreased to about half of the untreated controls and became less sensitive to added insulin in the epididymal adipose tissue from GTG-obese ICR mice. Hypertrophy of pancreatic islets associated with degranulation of B cells was also recognized in the obese mice. By contrast, either hyperglycemia or glucosuria did not develop in GTG-obese C57BL mice, although the other diabetic changes observed in GTG-obese ICR mice were induced but only in lesser extents. These results indicate that mice inherit their own diabetic potentials and add further experimental evidence for the concept that obesity accelerates the development of diabetes.