Sex differences in the relative lengths of metacarpals and metatarsals in gorillas and chimpanzees

Sex differences other than the simple dimorphism in size were documented for the metapodials of two primate species. Lengths of metacarpals and metatarsals were obtained from the skeletons of 64 gorillas and 42 chimpanzees. Length ratios were constructed for all possible pairings of the five bones in each individual hand and foot. For both species, several of these length ratios exhibited substantial differences between the sexes. Body size was not the basis for these sex differences; when specimens of similar size were compared, the sex differences remained. In humans, length ratios for the fingers and toes also have previously been demonstrated to exhibit sex differences, and the length ratio for the index and ring fingers (the 2D:4D ratio) has been shown to correlate with various medical conditions. Various facts suggest that length ratios in human digits are associated with androgen exposure, probably during prenatal development. For gorillas, the metacarpal length ratio showing the largest sex difference was 4Mc:5Mc in both hands, and the metatarsal length ratio showing the largest sex difference was 1Mt:2Mt in the left foot. Sex differences in length ratios also existed for chimpanzees, but they were generally smaller than for gorillas. Apparently, both gorillas and chimpanzees are affected by developmental mechanisms, possibly androgenic mechanisms, similar to those in humans. Analyses of previous measurements [Susman, R.L., 1979 Comparative and functional morphology of hominoid fingers. Am. J. Phys. Anthropol. 50, 215-236] revealed that all components of the rays are not affected equally by whatever mechanisms are responsible for the sex differences in length ratios.     

Naproxen affects Ca(2+) fluxes in mitochondria, microsomes and plasma membrane vesicles

There is substantial evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) affect cellular processes regulated by Ca(2+) ions, including the metabolic responses of the liver to Ca(2+)-dependent hormones. The aim of the present study was to determine whether the effects of naproxen are mediated by a direct action on cellular Ca(2+) fluxes. The effects of naproxen on 45Ca(2+) fluxes in mitochondria, microsomes and inside-out plasma membrane vesicles were examined. Naproxen strongly impaired the mitochondrial capacity to retain 45Ca(2+) and inhibited also ATP-dependent 45Ca(2+) uptake by microsomes. Naproxen did not modify 45Ca(2+) uptake by inside-out plasma membrane vesicles, but it inhibited the hexokinase/glucose-induced Ca(2+) efflux from preloaded vesicles. Additional assays performed in isolated mitochondria revealed that naproxen causes mitochondrial uncoupling and swelling in the presence of Ca(2+) ions. These effects were prevented by EGTA, ruthenium red and cyclosporin A, indicating that naproxen acts synergistically with Ca(2+) ions by promoting the mitochondrial permeability transition. The experimental results suggest that naproxen may impair the metabolic responses to Ca(2+)-dependent hormones acting by at least two mechanisms: (1) by interfering with the supply of external Ca(2+) through a direct action on the plasma membrane Ca(2+) influx, and (2) by affecting the refilling of the agonist-sensitive internal stores, including endoplasmic reticulum and mitochondria.     

Flow rates in the isolated perfused rat liver by pulse labeling with radioactive substrates and mathematical analysis of the wash-out kinetics

The multiple indicator dilution technique (Goresky and Bach) is critically evaluated and its application to the isolated, hemoglobin-free perfused rat liver is described. From the results of pulse labelling experiments using indicator substances for the total aqueous space of the liver ([3H]water and [14C]urea) an for the extracellular space ([14C]sucrose, [3H]-inulin and [3H]dextrane), it is concluded that the mathematical model of the liver in situ according to Goresky and Bach is sufficient to also describe the hemodynamics of the isolated liver perfused with a saline solution. The data indicate that the multiple indicator dilution technique in combination with the available mathematical basis is applicable to the study of transport across the liver cell membrane. The method, however, is restricted to compounds which are metabolized very slowly, such as D-lactate. A possible extension of this method to metabolic processes is discussed in view of pulse labelling experiments with [3H]-and [1-14C]L-lactate. Since the involvement of metabolism in the available mathematical model is not differentiated and the release of products is not taken into consideration, the method in its present state is not applicable to studies of metabolism. Moreover, even the parameters of transport derived by this technique are of limited value, when the transported compounds are rapidly metabolized by reversible reactions. Despite these uncertainties, the present data indicate that the transport of L-lactate is ten times faster than that of D-lactate.     

Bivascular liver perfusion in the anterograde and retrograde modes: Zonation of the response to inhibitors of oxidative phosphorylation

The action of cyanide (500 μM ), 2,4-dinitrophenol (50 μM ) and atractyloside (100 μM ) on glycogen catabolism and oxygen uptake was investigated in the bivascularly perfused liver of fed rats. Cyanide, 2,4-dinitrophenol and atractyloside were infused at identical rates into the hepatic artery in either the anterograde or retrograde perfusion. The accessible aqueous cell spaces were determined by means of the multiple-indicator dilution technique. Glucose release, oxygen uptake and glycolysis were measured as metabolic parameters. Oxygen uptake changes per unit cell space caused by atractyloside (inhibition) and 2,4-dinitrophenol (stimulation) were equal in the retrograde perfusion (periportal cells) and the anterograde perfusion (space enriched in perivenous cells); the decreases caused by cyanide were higher in the retrograde perfusion. Glucose release from periportal cells was not increased upon inhibition of oxidative phosphorylation, a phenomenon which was independent of the mechanism of action of the inhibitor. There were nearly identical changes in glycolysis in the periportal and perivenous cells. It was concluded that: (1) oxygen concentration in the perfused rat liver, if maintained above 100 μM , had little influence on the zonation of the respiratory activity; (2) in spite of the lower activities of the key enzymes of glycolysis in the periportal hepatocytes, as assayed under standard conditions, these cells were as effective as the perivenous ones in generating ATP in the cytosol when oxidative phosphorylation was impaired; (3) the key enzymes of glycogenolysis and glycolysis in periportal and perivenous cells responded differently to changes in the energy charge.     

The action of zymosan on octanoate transport and metabolism in the isolated perfused rat liver

The effects of zymosan on transport, distribution, and metabolism of octanoate in the perfused rat liver were investigated using the multiple‐indicator dilution technique. Livers were perfused with 300 µM octanoate in the absence or in the presence of 100 µg/mL zymosan. Tracer amounts of [1‐¹⁴C]octanoate, [³H] water, and [¹³¹I]albumin were injected into the portal vein, and the effluent perfusate was fractionated. The normalized dilution curves were analyzed by means of a space‐distributed variable transit time model. Zymosan decreased the space into which octanoate undergoes flow‐limited distribution, possibly the first cellular exchanging pool represented by plasma membranes and their adjacencies. However, the rate of transfer of octanoate from the plasma membrane into the rest of the cell was not modified as indicated by the similar values of the influx rates and also the net uptake of octanoate per unit of accessible cellular volume. However, when referred to the wet weight of the liver, the net uptake of octanoate was 37.5% reduced, a value corresponding to the diminution of the cellular accessible space. It can be concluded that an exclusion of a fraction of the liver parenchyma from the microcirculation is the main mechanism by which zymosan reduces the metabolism of exogenous octanoate. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:155–165, 2009; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/jbt.20269     

Ex vivo activated OVA specific and non-specific CD4+CD25+ regulatory T cells exhibit comparable suppression to OVA mediated T cell responses

CD4+CD25+ regulatory T cells (Tr) are important in maintaining immune tolerance to self-antigen (Ag) and preventing autoimmunity. Reduced number and inadequate function of Tr are observed in chronic autoimmune diseases. Adoptively transferred Tr effectively suppress ongoing autoimmune disease in multiple animal models. Therefore, strategies to modulate Tr have become an attractive approach to control autoimmunity. Activation of Tr is necessary for their optimal immune regulatory function. However, due to the low ratio of Tr to any given antigen (Ag) and the unknown nature of Ag in many autoimmune diseases, specific activation is not practical for potential therapeutic intervention. It has been shown in animal models that once activated, Tr can exhibit immune suppression in a bystander Ag-non-specific fashion, suggesting the effector phase of Tr is Ag independent. To investigate whether the immune suppression by activated bystander Tr is as potent as that of the Ag specific Tr, Tr cells were isolated from BALB/c or ovalbumin (OVA) specific T cell receptor (TCR) transgenic mice (DO11.10) and their immune suppression of an OVA specific T cell response was compared. We found that once activated ex vivo, Tr from BALB/c and DO11.10 mice exhibited comparable inhibition on OVA specific T cell responses as determined by T cell proliferation and cytokine production. Furthermore, their immune suppression function was compared in a delayed type hypersensitivity (DTH) model induced by OVA specific T cells. Again, OVA specific and non-specific Tr exhibited similar inhibition of the DTH response. Taken together, the results indicate that ex vivo activated Ag-non-specific Tr are as efficient as Ag specific Tr in immune suppression, therefore our study provides additional evidence suggesting the possibility of applying ex vivo activated Tr therapy for the control of autoimmunity.     

Diltiazem inhibits fatty acid oxidation in the isolated perfused rat liver

The effects of diltiazem on fatty acid metabolism were measured in the isolated perfused rat liver and in isolated mitochondria. In the perfused rat liver diltiazem inhibited oxygen uptake and ketogenesis from endogenous substrates. Ketogenesis from exogenously supplied palmitate was also inhibited. The β-hydroxybutyrate/acetoacetate ratio in the presence of palmitate alone was equal to 3·2. When the fatty acid and diltiazem were present simultaneously this ratio was decreased to 0·93, suggesting that, in spite of the inhibition of oxygen uptake, the respiratory chain was not rate limiting for the oxidation of the reducing equivalents coming from β-oxidation. In experiments with isolated mitochondria, incubated in the presence of all intermediates of the Krebs cycle, pyruvate or glutamate, no significant inhibition of oxygen uptake by diltiazem was detected. Inhibition of oxygen uptake in isolated mitochondria was found only when palmitoyl CoA was the source of the reducing equivalents. It was concluded that a direct effect on β-oxidation may be a major cause for the inhibition of oxygen uptake caused by diltiazem in the perfused liver. © 1997 John Wiley & Sons, Ltd.     

Effects of norepinephrine on the metabolism of fatty acids with different chain lengths in the perfused rat liver

The effects of norepinephrine on ketogenesis in isolated hepatocytes have been reported as ranging from stimulation to inhibition. The present work was planned with the aim of clarifying these discrepancies. The experimental system was the once-through perfused liver from fasted and fed rats. Fatty acids with chain lengths varying from 8-18 were infused. The effects of norepinephrine depended on the metabolic state of the rat and on the nature of the fatty acid. Norepinephrine clearly inhibited ketogenesis from long-chain fatty acids (stearate > palmitate > oleate), but had little effect on ketogenesis from medium-chain fatty acids (octanoate and laureate). With palmitate the decrease in oxygen uptake was restricted to the substrate stimulated portion; with stearate, the decrease exceeded the substrate stimulated portion; with oleate, oxygen uptake was transiently inhibited. Withdrawal of Ca²⁺ attenuated the inhibitory effects. ¹⁴CO₂ production from [1-¹⁴C]oleate was inhibited. Net uptake of the fatty acids was not affected by norepinephrine. In livers from fed rats, oxygen uptake and ketogenesis from stearate were only transiently inhibited. The conclusions are: (a) in the fasted state norepinephrine reduces ketogenesis and respiration by means of a Ca²⁺-dependent mechanism; (b) the degree of inhibition varies with the chain length and the degree of saturation of the fatty acids; (c) norepinephrine favours esterification of the activated long-chain fatty acids in detriment to oxidation; (d) in the fed state the stimulatory action of norepinephrine on glycogen catabolism induces conditions which are able to reverse inhibition of ketogenesis and oxygen uptake.