Decreased liver and lung drug-metabolizing activity in mice treated with Corynebacterium parvum.
Injections of killed suspensions of Corynebacterium parvum (i.p.) in young male mice were followed by time- and dose-dependent decreases in the drug-metabolizing activity of liver microsomes and lung homogenates. In vitro assays with model substrates [aminopyrine, aniline, p-nitroanisole, and benzo(a)pyrene] were used to quantitate drug-metabolizing activity. It is likely that such decreases in mixed function oxidases activity will act to significantly alter the pharmacokinetics of concurrently or subsequently administered drugs. The results provide a possible mechanism to explain several previously reported immunochemotherapeutic interactions. (+info)
Ambiguity of the thymidine index.
The observed thymidine indices of seven experimental tumor lines are compared as a function of duration of emulsion exposure. The effects of dose level of tritiated thymidine and background threshold are also evaluated. The results indicate that an arbitrary high background threshold discriminates against "lightly" labeled cells at short periods of exposure but that the chosen threshold becomes less critical with longer exposure. The observed thymidine index increases with increasing duration of emulsion exposure but appears to approach a plateau for all tumor systems. The "thymidine index curves" are significantly different for each tumor. There is an inverse relationship between the dose of tritiated thymidine and the duration of exposure required to recognize the same fraction of cells as labeled in a given tumor. Similar experimental conditions do not necessarily guarantee a valid basis for comparison of observed thymidine indices among tumors. (+info)
The developmental basis for allometry in insects.
Within all species of animals, the size of each organ bears a specific relationship to overall body size. These patterns of organ size relative to total body size are called static allometry and have enchanted biologists for centuries, yet the mechanisms generating these patterns have attracted little experimental study. We review recent and older work on holometabolous insect development that sheds light on these mechanisms. In insects, static allometry can be divided into at least two processes: (1) the autonomous specification of organ identity, perhaps including the approximate size of the organ, and (2) the determination of the final size of organs based on total body size. We present three models to explain the second process: (1) all organs autonomously absorb nutrients and grow at organ-specific rates, (2) a centralized system measures a close correlate of total body size and distributes this information to all organs, and (3) autonomous organ growth is combined with feedback between growing organs to modulate final sizes. We provide evidence supporting models 2 and 3 and also suggest that hormones are the messengers of size information. Advances in our understanding of the mechanisms of allometry will come through the integrated study of whole tissues using techniques from development, genetics, endocrinology and population biology. (+info)
Lung weight parallels disease severity in experimental coccidioidomycosis.
Evidence provided by histopathological study of lesions is a valuable adjunct for evaluating chemotherapeutic efficacy in experimental animal models, In addition, this should be correlated with a measure of disease severity in the same animal. The latter could be obtained by homogenization of infected organs and quantitative enumeration of viable cells of the etiological agent, but this would preclude histopathological studies in the same animal. Progression of disease in pulmonary infection is associated with replacement of air space by fluid, cells, and cellular debris. Therefore, an increase in lung weight should reflect severity of disease. Results with the murine model of coccidioidomycosis demonstrate that increasing lung weight parallels the increasing census of fungus cells in the lungs of both treated and nontreated infected mice. This was supported with evidence obtained from microscopic studies of lesions indicating that specific chemotherapy limited spread of the infection and inhibited multiplication of the fungus in the lung. Therefore, lung weight can be used as a measure of disease severity in the murine model of coccidioidomycosis. (+info)
Cardiomegaly in the juvenile visceral steatosis (JVS) mouse is reduced with acute elevation of heart short-chain acyl-carnitine level after L-carnitine injection.
The long-term administration of L-carnitine was very effective in preventing cardiomegaly in juvenile visceral steatosis (JVS) mice, which was confirmed by heart weight as well as the lipid contents in heart tissue. After i.p. injection of L-carnitine, the concentration of free carnitine in heart remained constant, although serum free carnitine level increased up to 80-fold. On the other hand, a significant increase in short-chain acyl-carnitine level in heart was observed. These results suggest that increased levels of short-chain acyl-carnitine, not free carnitine, might be a key compound in the protective effect of L-carnitine administration in JVS mice. (+info)
Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion.
Uncoupling protein 2 (UCP2) uncouples respiration from oxidative phosphorylation and may contribute to obesity through effects on energy metabolism. Because basal metabolic rate is decreased in obesity, UCP2 expression is predicted to be reduced. Paradoxically, hepatic expression of UCP2 mRNA is increased in genetically obese (ob/ob) mice. In situ hybridization and immunohistochemical analysis of ob/ob livers demonstrate that UCP2 mRNA and protein expression are increased in hepatocytes, which do not express UCP2 in lean mice. Mitochondria isolated from ob/ob livers exhibit an increased rate of H+ leak which partially dissipates the mitochondrial membrane potential when the rate of electron transport is suppressed. In addition, hepatic ATP stores are reduced and these livers are more vulnerable to necrosis after transient hepatic ischemia. Hence, hepatocytes adapt to obesity by up-regulating UCP2. However, because this decreases the efficiency of energy trapping, the cells become vulnerable to ATP depletion when energy needs increase acutely. (+info)
Modulation of oestrogenic effects by progesterone antagonists in the rat uterus.
Antiprogestins can modulate oestrogenic effects in various oestrogen-dependent tissues, dependent on species, tissue, dose and duration of treatment. Enhanced oestrogenic responses to mifepristone and onapristone occur in vitro and in vivo. However, the antiprogestins mifepristone, onapristone, and ZK 137 316 can block the ability of oestradiol to increase endometrial growth in non-human primates. Our purposes were firstly, to decide whether mifepristone and onapristone had direct oestrogenic activity in vitro and in the uterus of spayed and immature rats, and secondly, to discover whether antiprogestins exhibit inhibitory effects on oestrogen action in the uterus in spayed, oestrogen-substituted rats. In transactivation assays, mifepristone induced oestrogenic response, whereas onapristone had only marginal effects on reporter gene transcription. In immature rats, onapristone and mifepristone markedly increased uterine weights, and onapristone, but not mifepristone significantly enhanced endometrial luminal epithelial height, a sensitive oestrogen parameter. Conversely, in spayed and adrenalectomized rats, neither onapristone nor mifepristone changed uterine weights or endometrial morphology, indicating that their effects in immature rats were indirect. In spayed, oestrogen-substituted rats, antiprogestins did not block oestradiol-stimulated endometrial growth and luminal and glandular epithelium were stimulated more after antiprogestin plus oestrogen, than after oestradiol alone. All compounds induced compaction of the uterine stroma. In spayed rats, onapristone and some other 13alpha-configured (type 1) antagonists (ZK 135 569, ZK 131 535) reduced oestradiol-stimulated myometrial proliferation and induced an overall uterine weight reduction in animals treated with oestrogen and antiprogestins, in comparison with oestradiol-treated controls. 13beta- configured (type II) antagonists, including mifepristone, lilopristone and ZK 112 993, were not effective. In the uteri of spayed rats, onapristone was also found to enhance the oestradiol-stimulatory effect on expression of the oestrogen-dependent proto-oncogene, c-fos. In conclusion, antiprogestins do not inhibit, but rather enhance, oestrogen-induced uterine glandular and luminal epithelium in spayed rats, contrary to their effects in primates. The rat model is unsuitable to study endometrial antiproliferative effects of antiprogestins in primate uteri. (+info)
Investigation of distal aortic compliance and vasodilator responsiveness in heart failure due to proximal aortic stenosis in the guinea pig.
Hypotension and syncope are recognized features of chronic aortic stenosis. This study examined vasomotor responses and dynamic compliance in isolated abdominal aortae after chronic constriction of the ascending aorta. Guinea pigs underwent constriction of the ascending aorta or sham operation. Sections of descending aorta were removed for studies of contractile performance and compliance. Dynamic compliance was measured using a feedback-controlled pulsatile pressure system at frequencies of 0.5, 1.5 and 2.5 Hz and mean pressures from 40 to 100 mmHg. Chronic (149+/-6 days) aortic constriction resulted in significant increases in organ weight/body weight ratios for left ventricle (58%), right ventricle (100%) and lung (61%). The presence of heart failure was indicated by increased lung weights, left ventricular end-diastolic pressure and systemic vascular resistance, reduced cardiac output and increased levels of plasma atrial natriuretic peptide (166%), adrenaline (x20), noradrenaline (106%) and dopamine (x3). Aortic rings showed similar constrictor responses to phenylephrine and angiotensin II, but maximal vasodilator responses to acetylcholine and isoprenaline were significantly increased (144% and 48% respectively). Dilator responses to sodium nitroprusside, forskolin and cromokalim were unchanged. Compliance of all vessels decreased with increasing pulsatile frequency and to a lesser extent with increased mean pressure, but were similar in aortic-constricted and control groups. Chronic constriction of the ascending aorta resulted in heart failure and increased vasodilator responses to acetylcholine and isoprenaline in the distal aorta while dynamic compliance was unchanged. We hypothesize that increased endothelium-mediated vasodilatation may contribute to hypotension and syncope in patients with left ventricular outflow obstruction. (+info)