Kinetics In Mice Research Articles

Ethanol inhalation on 1-[14C]-pyruvate kinetics in mice using a six-compartment closed model.

1-[14C]-pyruvate kinetics were studied in mice with and without inhalation of vaporised ethanol. The 1-[14C]-pyruvate kinetics were modelled by a six-compartment closed model, i.e. injected site, blood, periphery, expired 14CO2 in air, eliminated 14C in urine and faeces, using the system of differential equations. The results show that the inhalation of vaporised ethanol can stimulate expiration of 14CO2. The completely analytical solution of the six-compartment closed model was found using Laplace transform. The kinetic parameters were estimated using the analytical solutions for the fourth, fifth and sixth compartments to fit eliminated 14CO2, and 14C in urine and faeces. The compartmental analysis showed that the inhalation of vaporised ethanol can stimulate 1-[14C]-pyruvate transmembrane process from injected site to blood and 14C trans-tissue process from periphery to blood.

Proliferation of goblet cells and vacuolated cells in the rabbit distal colon.

Previous studies of colonic epithelial cell kinetics in mice and rats revealed a pattern similar to small intestine, where basally located stem cells proliferate, differentiating as they migrate towards the surface epithelium. Vacuolated and goblet cells are assumed to co-migrate at the same rate. The present study indicates that rabbit distal colon has more complicated epithelial cell kinetics. The zone of proliferation was detected immunohistochemically using proliferating cell nuclear antigen (PCNA) and confirmed with the use of colchicine to arrest dividing cells in metaphase. Migrating cells were tracked from the zero-hour position (PCNA labeling, mitosis) to positions 24, 48, 72 hrs by monitoring cell migration with the thymidine analog 5-Bromo-2-Deoxyuridine (BrdU). PCNA revealed a major proliferative zone in the upper third of the crypt column and the presence of mitotic figures after colchicine corroborated these results. Differentiated vacuolated cell proliferation was detected at three crypt sites: base, middle, and top of the crypt, while columnar cells arose from a population of dividing cells at the top of the crypt. Turnover of columnar and vacuolated cells occurred within 72 hrs. Goblet cells exhibited maximal proliferation at the crypt base and migrated at a much slower rate than the other cell types. In rabbit distal colon, populations of proliferating cells exist at multiple levels of the crypt column. Vacuolated and goblet cells differ in their labeling indices and migration rates, suggesting that the two cell types arise and migrate independently.

Proliferation of goblet cells and vacuolated cells in the rabbit distal colon

Previous studies of colonic epithelial cell kinetics in mice and rats revealed a pattern similar to small intestine, where basally located stem cells proliferate, differentiating as they migrate towards the surface epithelium. Vacuolated and goblet cells are assumed to co-migrate at the same rate. The present study indicates that rabbit distal colon has more complicated epithelial cell kinetics. The zone of proliferation was detected immunohistochemically using proliferating cell nuclear antigen (PCNA) and confirmed with the use of colchicine to arrest dividing cells in metaphase. Migrating cells were tracked from the zero-hour position (PCNA labeling, mitosis) to positions 24, 48, 72 hrs by monitoring cell migration with the thymidine analog 5-Bromo-2-Deoxyuridine (BrdU). PCNA revealed a major proliferative zone in the upper third of the crypt column and the presence of mitotic figures after colchicine corroborated these results. Differentiated vacuolated cell proliferation was detected at three crypt sites: base, middle, and top of the crypt, while columnar cells arose from a population of dividing cells at the top of the crypt. Turnover of columnar and vacuolated cells occurred within 72 hrs. Goblet cells exhibited maximal proliferation at the crypt base and migrated at a much slower rate than the other cell types. In rabbit distal colon, populations of proliferating cells exist at multiple levels of the crypt column. Vacuolated and goblet cells differ in their labeling indices and migration rates, suggesting that the two cell types arise and migrate independently. Anat. Rec. 252:41–48, 1998. © 1998 Wiley-Liss, Inc.

Using a four-compartment closed model to describe inhalation of vaporised ethanol on 1-14C-pyruvate kinetics in mice.

A four-compartment closed model was set up by means of a system of differential equations. A completely analytical solution of the four-compartment closed model was found by means of Laplace transform and Cramer's rule. 1-14C-pyruvate kinetics were studied in mice without and with inhalation of vaporised ethanol. The 1-14C-pyruvate kinetics were modelled by the four-compartment closed model, i.e. injected site, blood, 14CO2 expired in air, and 14C eliminated in urine. The kinetic parameters were estimated using the analytical solution of the four-compartment closed model to fit expired 14CO2 and 14C eliminated in urine simultaneously. Although the results showed that the inhalation of vaporised ethanol increased the expired 14CO2, the compartmental analysis revealed that the increase of expired 14CO2 is mainly attributed to increased 1-14C-pyruvate transmembrane process. The developed model is useful for toxicokinetic analysis when blood is not easy to obtain. Moreover, the developed model can also be used to model two compartments as urine and faeces when the toxin is not eliminated through air.

A pneumolysin-negative mutant of Streptococcus pneumoniae causes chronic bacteremia rather than acute sepsis in mice

Pneumolysin is a cytoplasmic virulence factor of Streptococcus pneumoniae that can interfere with phagocyte function in vitro. We have examined the effects of pneumolysin in vitro and in vivo and have found that it protects intravenously injected pneumococci against infection-induced host resistance. We employed a virulent capsular type 2 pneumococcal strain, D39, and its isogenic pneumolysin-negative mutant, PLN. Strain D39 exhibited exponential net growth in mice (doubling time, 1.4 h); 24 to 28 h after infection with 10(4) CFU, the numbers of pneumococci reached 10(9) to 10(10) CFU/ml and the mice died. Strain PLN yielded identical net growth in mice until reaching 10(6) to 10(7) CFU/ml at 12 to 18 h postinfection. At this time, the increase in the level of PLN CFU per milliliter ceased and remained constant for several days. PLN exhibited wild-type growth kinetics in mice when coinfected simultaneously with strain D39. This observation suggests that pneumolysin exerts its effects at a distance. By 12 to 18 h postinfection with PLN, mice exhibited the following evidence of an induced inflammatory response: (i) elevated plasma interleukin-6, (ii) a halt in the net growth of PLN, and (iii) control of the net growth of pneumolysin-producing D39 pneumococci upon subsequent challenge. Our data suggest that pneumolysin plays a critical role in sepsis during the first few hours after infection by enabling pneumococci to cause acute sepsis rather than a chronic bacteremia. However, once chronic bacteremia was established, it appeared that pneumolysin was no longer able to act as a virulence factor.

A cytolysin encoded by Salmonella is required for survival within macrophages.

A Salmonella gene encoding a cytolysin has been identified by screening for hemolysis on blood agar. DNA sequence analyses together with genetic mapping in Salmonella suggest that it is unrelated to other toxins or hemolysins. The gene (slyA) is present in every strain of Salmonella examined, in Shigella, and in enteroinvasive Escherichia coli but not in other Enterobacteriaceae. SlyA (salmolysin) purified from a derivative of the original clone has hemolytic and cytolytic activity and has a molecular weight predicted by the DNA sequence. The median lethal dose and infection kinetics in mice suggest that the toxin is required for virulence and facilitates Salmonella survival within mouse peritoneal macrophages.

Bupivacaine kinetic changes induced by diltiazem in mice

This study was designed to document possible changes in bupivacaine and its main metabolite, desbutylbupivacaine (PPX) kinetics in mice after a single 5 mg/kg injection of diltiazem. After a single 20 mg/kg i.p. dose of bupivacaine, kinetic parameters of bupivacaine were not statistically different but the ratio AUC PPX/AUC bupivacaine was significantly lower when bupivacaine was associated with diltiazem: thus, it may indicate an influence of diltiazem on bupivacaine metabolism i.e. an inhibition. Diltiazem also seems to increase the free fraction of bupivacaine and thus to decrease the percentage of protein binding. These effects may contribute to the enhanced toxicity previously observed.

Lack of bupivacaine kinetic changes induced by flumazenil in mice

This study was designed to document possible changes in bupivacaine kinetics in mice after a single 1 mg/kg injection of flumazenil. After a single 20 mg/kg i.p. dose of bupivacaine, C max, Vd, C1 and AUC were not significantly modified by flumazenil; even if T max was shown to be significantly shorter when flumazenil was associated, bupivacaine bioavailability did not seem to be modified and thus may not be involved in the explanation of previously reported increasing bupivacaine-induced mortality by flumazenil.

Effects of Isolation Housing and Timing of Drug Administration on Theophylline Kinetics in Mice.

ICR mice were grouped according to 1) housing environment: individual (I) or aggregated (A) and 2) timing of drug administration: midlight (L) or middark (D), i.e. I-L, I-D, A-L, A-D groups. Theophylline was orally administered at midlight or middark. The results showed that both social environment and timing of drug administration exerted significant influence on the pharmacokinetics of theophylline. These data may suggest the importance of considering many non-drug factors in toxicological studies with experimental animals.

Effects of Isolation Housing and Timing of Drug Administration on Theophylline Kinetics in Mice

ICR mice were grouped according to 1) housing environment: individual (I) or aggregated (A) and 2) timing of drug administration: midlight (L) or middark (D), i.e. I-L, I-D, A-L, A-D groups. Theophylline was orally administered at midlight or middark. The results showed that both social environment and timing of drug administration exerted significant influence on the pharmacokinetics of theophylline. These data may suggest the importance of considering many non-drug factors in toxicological studies with experimental animals.

Myeloid Cell Kinetics in Mice Treated With Recombinant Interleukin-3, Granulocyte Colony-Stimulating Factor (CSF), or Granulocyte-Macrophage CSF In Vivo

Myeloid cell kinetics in mice treated with pure hematopoietic growth factors have been investigated using tritiated thymidine labeling and autoradiography. Mice were injected subcutaneously with 125 μg/kg granulocyte colony-stimulating factor (G-CSF) (in some cases 5 μg/kg), or 10 μg/kg of granulocyte-macrophage CSF (GM-CSF), or interleukin-3 (IL-3) every 12 hours for 84 hours. 3HTdR labeling was performed in vivo after 3 days of treatment. G-CSF increased the peripheral neutrophil count 14-fold and increased the proportion and proliferation rate of neutrophilic cells in the marrow, suppressing erythropoiesis at the same time. Newly produced mature cells were released into the circulation within 24 hours of labeling, compared with a normal appearance time of about 96 hours. By contrast, GM-CSF and IL-3 had little effect on either marrow cell kinetics or on the rate of release of mature cells, although GM-CSF did stimulate a 50% increase in peripheral neutrophils. Monocyte production was also increased about eightfold by G-CSF and 1.5-fold by GM-CSF, but their peak release was only slightly accelerated. While the peripheral half-lives of the neutrophilic granulocytes were normal, those of the monocytes were dramatically reduced, perhaps due to sequestration in the tissues for functional purposes. The stimulated monocyte production in the case of G-CSF required an additional five cell cycles, a level that might have repercussions on the progenitor compartments.

Myeloid cell kinetics in mice treated with recombinant interleukin-3, granulocyte colony-stimulating factor (CSF), or granulocyte-macrophage CSF in vivo

Myeloid cell kinetics in mice treated with pure hematopoietic growth factors have been investigated using tritiated thymidine labeling and autoradiography. Mice were injected subcutaneously with 125 micrograms/kg granulocyte colony-stimulating factor (G-CSF) (in some cases 5 micrograms/kg), or 10 micrograms/kg of granulocyte-macrophage CSF (GM-CSF), or interleukin-3 (IL-3) every 12 hours for 84 hours. 3HTdR labeling was performed in vivo after 3 days of treatment. G-CSF increased the peripheral neutrophil count 14-fold and increased the proportion and proliferation rate of neutrophilic cells in the marrow, suppressing erythropoiesis at the same time. Newly produced mature cells were released into the circulation within 24 hours of labeling, compared with a normal appearance time of about 96 hours. By contrast, GM-CSF and IL-3 had little effect on either marrow cell kinetics or on the rate of release of mature cells, although GM-CSF did stimulate a 50% increase in peripheral neutrophils. Monocyte production was also increased about eightfold by G-CSF and 1.5-fold by GM-CSF, but their peak release was only slightly accelerated. While the peripheral half- lives of the neutrophilic granulocytes were normal, those of the monocytes were dramatically reduced, perhaps due to sequestration in the tissues for functional purposes. The stimulated monocyte production in the case of G-CSF required an additional five cell cycles, a level that might have repercussions on the progenitor compartments.

Lymphocyte kinetics in mice with alloxan diabetes

Lymphocyte kinetics in mice with alloxan diabetes

Iron Kinetics in Individual Bone Marrow Regions (Bones) in Mice

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In vitro and in vivo mutagenic activity of ECH as regards to its in vivo metabolism and kinetics in mice

In vitro and in vivo mutagenic activity of ECH as regards to its in vivo metabolism and kinetics in mice

The Internal Iron Kinetics in Mice

Vacha J., V. Znojil, J. Hola, J. Dungel: The Internal Iron Kinetics in Mice. Acta vet. Bmo, 51, 1982: 3-22. Using mice of the strain C57BL/I0ScSnPh a three-week study was made of radio­ activity in the plasma, erythrocytes, liver and haeme and non-haeme iron of the bone marrow and spleen, and of the urine and faeces following·oPe administration. On the basis of the experimental data obtained a mathematical model was used to determine the rates of flows between the assumed iron compartments of the organism. By means of the chemical determination of the haeme and non-haelne iron of these or­ gans it was possible to express these flows in absolute values, thus forming an over­ all model picture of the ferrokinetics of mice. It is clear from the model that the central ferrokinetic pool in mice consists not only of the plasma but also of a further space of considerable size and rate of exchange, identifiable with considerable certainty with the extravascular and lymphatic spaces. Non-haeme pools of considerable sizes were also found in the erythropoietic organs. The one with the faster rate of exchange has a mostly pre-haeme character; the se­ cond, of approximately ten times the size, characterized by a slower rate of exchange, does not have any immediate relation as a whole to erythropoiesis and is thus the main cause of discrepancies between the results of ··Pe incorporation into the erythropoie­ tic organs and the actual intensity of erythropoiesis. Ferrokinetics, iron compartments, haeme and non-haeme iron, bone marrow, spleen, .oFe-incorporation method.

Synthesis of a 11C-labelled neuroleptic drug: Pimozide

Pimozide, a neuroleptic drug which is one of the best ligands for brain dopaminergic receptors in mice in vivo, was labelled with 11C for eventual investigation in man. This synthesis was carried out in 30 min from phosgene as the 11C precursor. The synthesis, resulting specific activity and the tissue distribution kinetics in mice are presented and discussed.

Comparative investigations on the biokinetics of colloidal thorium, zirconium, and hafnium dioxides in animals

The aim of the investigations is to establish biophysical data as a basis for dose calculations of realized and projected long-term animal experiments devoted to the problem radiation and nonradiation effect of Thorotrast. For this purpose a Thorotrast-equivalent thorium dioxide aquasol as well as dextrin-stabilized aquasols of zirconium and hafnium dioxides (Zirconotrast, Hafnotrast) of our own production have been injected intravascularly into rats. The animals subdivided in four subgroups have been administered 60 to 600 μl of any colloid per rat. Four subgroups were sacrificed at different times between 1 and 100 days after injection. The whole-body kinetics of Thorotrast and Hafnotrast have been studied by single whole-body counting of altogether 10 animals during the total time of exposure. Both the distribution of the colloids and the activity ratios between 232Th and daughters have been determined. Supplementary to these investigations studies were performed on the Thorotrast kinetics in mice and in one dog.

Effect of hyperthyroidism on haemopoietic stem cell kinetics in mice.

Changes in the pool of haemopoietic colony-forming units (CFUs) of bone marrow and spleen were studied in experiments with mice fed dried thyroid gland (TH) for 21 days, and during the 13 days that followed feeding. After HU treatment, the number of CFUs in DNA synthesis was estimated. As early as the second day of TH treatment, the pool of CFUs is gradually increased, leading to an increase in the total number of splenic and bone marrow CFUs persisting after TH treatment for the period examined. Simultaneously, the numbers of nucleated cells in the bone marrow and spleen are increased. During TH feeding and following its termination, the total number of erythrocytes and the haematocrit values did not change significantly, whereas an increased number of leucocytes was observed in the peripheral blood after TH treatment. Elevation of the proliferative activity of CFUs occurred early in the period of TH treatment, with the maximum attained by end of the first week of TH feeding. This suggests a rapid response of the haemopoietic stem cell compartment to the administration of TH hormones. The participation of humoral factors controlling CFUs compartments in the mechanism of the stimulatory effect of TH hormones on haemopoietic stem cells is discussed.

The effects of high and low fluoride diets on the frequencies of sister chromatid exchanges

A recent report suggests that fluoride has mutagenic activity in mice. To examine the potential clastogenic effect of ingested fluoride, we examined the frequencies of baseline SCE and mitomycin C induced SCE as well as baseline chromosomal aberrations and cell-cycle kinetics in mice raised on high and low fluoride diets. The lack of significant differences in any of these parameters between the two groups of animals indicates that dietary fluoride is not clastogenic and supports the continued use of water fluoridation.