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PubMed1983

The consequences of base-pair substitution mutations in AT- and GC-rich bacteria.

The likely consequences, in terms of premature stop codons, detectable missense mutants, silent missense mutants, and degenerate codon changes, have been determined for all 12 individual base substitution changes. This has been done for the full, 61 sense codon, genetic code and also for the much more limited codon availabilities of AT- or GC-rich DNA. The specificities and outcomes of individual base substitutions are likely to be rather different at AT- or GC-rich extremes, and also from the situation at an intermediate DNA base-ratio where all 61 sense codons are available. In particular, at DNA base-ratio extremes many mutations will be to non-utilized codons, which may well act as nonsense mutants. These in turn will give novel classes of suppressor-containing revertants. Even in bacteria with intermediate DNA base-ratios, particular codons for a given amino acid may be favoured, over alternatives, because their use maximizes, or minimizes, the mutational consequences of one, or more, base substitution changes.

Adenine↗
PubMed1984

Flunarizine and verapamil: effects on central nervous system and peripheral consequences of cytotoxic hypoxia in rats.

Flunarizine is a calcium entry blocking drug possessing antihypoxic activity in animal models of cerebral and peripheral ischemia-anoxia and has clinical usefulness in circulatory disorders of both central and peripheral origin. This report compares the activity of flunarizine and verapamil, another calcium entry blocking drug, on the central nervous system (CNS) and peripheral consequences of cytotoxic hypoxia induced by high and low doses of KCN. The lethal effect of KCN (6 mg/kg, i.p.) in rats was prevented by orally administered flunarizine (ED50 = 12 mg/kg with four-hr pretreatment) but not by verapamil (at oral doses up to 80 mg/kg with one-hr pretreatment). Since the lethal effect of KCN involves failure of respiration at the CNS level, these results suggest that flunarizine protects against the hypoxic effect of the cyanide ion by an action in brain tissue. We found also that the stimulant effect of low intravenous doses (0.5 mg/kg/min) of KCN upon respiration rate was not altered in pentobarbital- and chloralose-anesthetized rats treated with oral doses of flunarizine up to 80 mg/kg (with four hr pretreatment). In contrast, KCN-stimulated respiration rate in pentobarbital anesthetized rats was significantly attenuated by verapamil (20 and 40 mg/kg, p.o. with one hr pretreatment). Since low doses of the cyanide ion render respiration quicker and deeper by an action on chemoreceptive cells in peripheral arteries, the effect of verapamil against the hypoxic effect of KCN is mediated by an action in the periphery. In summary, we have shown that the physiological consequences of cytotoxic hypoxia can be affected by calcium entry blocking drugs having site-specific activities. Based on our results, flunarizine is more effective than verapamil against cellular anoxia involving the CNS.

Animals↗
PubMed1992

The physiological consequences of glutathione variations.

The major low molecular weight thiol inside cells, the tripeptide glutathione (GSH), is of importance for protection of the cell against oxidative challenge, for thiol homeostasis required to guarantee basic functions, and for defence mechanisms against xenobiotics. Since the pathophysiological significance of a perturbed GSH status in human disease is less clear, this review evaluates the consequences of in vivo variations of GSH. Owing to intracellular GSH concentrations above 2 mM depletion of GSH as such has little metabolic consequences unless an additional stress is superimposed. The kinetic properties of GSH-dependent enzymes imply that loss of up to 90% of intracellular GSH may still be compatible with cellular integrity. Mitochondrial GSH, which accounts for about 10% of total cellular GSH, may define the threshold beyond that toxicity commences. Thus, in cases of severe GSH-depletion a substitution of GSH as a therapeutic measure seems justified. Such a severe depletion of GSH has been described for some diseases such as liver dysfunction, AIDS or pulmonary fibrosis.

Animals↗
PubMed1994

Possible consequences of human antibody responses on the biodistribution of fragments of human, humanized or chimeric monoclonal antibodies: a note of caution.

The effect of anti-combining site antibody responses on the biodistribution of monoclonal antibodies intended for diagnostic or therapeutic purposes is considered. The new generation of chimeric, humanized or human antibodies may well still be immunogenic in man, due to reaction against their combining sites. The likely consequence of this immunogenicity is clearance of antibodies from the circulation. This is already appreciated, and can be modelled in animal studies. However the effect of such anti-combining site responses on the biodistribution of F(ab')2 or Fab fragments of chimeric or human antibodies, or the new generation of fragments such as Fv, is a yet unknown. Animal modelling studies suggest that anti-combining site responses may have totally unexpected consequences. They may not lead to clearance of fragments. Indeed survival of fragments can be greatly prolonged, but target recognition prevented.

Animals↗
PubMed1995

"It's the genes, stupid". Molecular bases and clinical consequences of genetic cytochrome P450 2D6 polymorphism.

In this review we highlight the information available on the genetic polymorphism of cytochrome P4502D6 expression in man. An absent function of this enzyme is observed in 7-10 percent of the Caucasian population which are referred to as Poor metabolizers as opposed to the remainder of the population (Extensive Metabolizers). More than 30 widely used drugs have been identified as substrates for CYP2D6. Disposition and action of these compounds depend on the individual phenotype. Both the molecular bases of the variable enzyme activity and the consequences for drug therapy are outlined. While mutations on the DNA level have been investigated in great detail larger scale clinical trials are lacking and information on therapeutic consequences of CYP2D6 mediated polymorphic drug oxidation is restricted to case reports. Besides these implications for drug metabolism several lines of evidence indicate that CYP2D6 could be involved in biotransformation of endogenous compounds.

Animals↗
PubMed1984

Long-term consequences of antagonism by neuroleptics of behavioural events occurring during mesolimbic dopamine infusion.

Rats selected as low-activity responders to peripherally administered (-)N-n-propylnorapomorphine [(-)NPA] were subjected to a 13-day continuous infusion of dopamine bilaterally into the nucleus accumbens (0.48 microliter/hr, 25 micrograms in 24 hr). This caused biphasic increases in spontaneous levels of hyperactivity with peaks occurring between days 2-5 and 8-12 of infusion. Two weeks after the infusion was withdrawn the low-activity status of the animals, to (-)NPA challenge, converted to high-activity and remained at this changed level for 18 to 20 weeks. The effects of sulpiride (2.5 mg/kg, i.p. daily) or haloperidol (0.025 mg/kg, i.p. daily) on the behavioural changes during infusion and after its withdrawal were assessed by administration on days 1-4 to inhibit the first peak of the enhanced spontaneous locomotion, on days 8-11 to inhibit the second peak, on days 1-4 and 8-11 to inhibit both peaks, on days 6-9 to influence the "trough" of behavioural responding between the peaks of hyperactivity, and on days 1-11 to modify all components of hyperactivity responding to infusion of dopamine. The usual consequence of infusion, the conversion of low-activity to high-activity responders to (-)NPA, was not prevented by any treatment with neuroleptic. It is concluded that the long-term consequences (up to 1 year) of a brief period (13 days) of overactivity induced by mesolimbic infusion of dopamine cannot be prevented by daily treatment with haloperidol or sulpiride in doses adequate to prevent the behavioural expression of the effects of the dopamine stimulation during its infusion.

Animals↗
PubMed1991

Sex differences in the behavioral consequences of inescapable footshocks depend on time since shock.

In two experiments, the effects of inescapable shock on subsequent shuttle-box escape performance were studied in male and female rats. Effects of treatment with short-duration shocks (2 s) were studied after 1- and 24-hour intervals (Experiment 1), and effects of long-duration shocks (6 s) were studied after 24- and 72-hour intervals (Experiment 2). Experience with inescapable shock resulted in a serious disruption of escape performance in both males and females. A large increment in escape latencies was found both during fixed ratio 1 and fixed ratio 2 escape training; however, effects of inescapable shock were more pronounced in males than in females. In Experiment 1, sex differences were most obvious after the short 1-hour interval whereas, in Experiment 2, sex differences were only present after 24 hours and not after 72 hours. Shuttle activity during 2-min adaptation prior to shock-escape training was reduced in both males and females treated with IS, and this effect was somewhat stronger in males than in females. The data of these experiments show that male rats are more sensitive to the consequences of exposure to inescapable aversive stimulation than female rats. It is proposed that the time-dependency of the sex differences in behavioral consequences of treatment with inescapable shock may be related to sex differences in transient neurochemical or hormonal changes induced by inescapable shock.

Animals↗
PubMed1993

The postingestive consequences of fat condition preferences for flavors associated with high dietary fat.

To investigate whether children acquire conditioned preferences for flavors associated with high dietary fat content, 27 3- and 4-year-old children participated in a series of 12 conditioning or mere exposure sessions. Following an overnight fast, children who participated in conditioning trials consumed fixed quantities of a flavored yogurt drink that on half the days was high in fat and energy (954 kJ, 18 g fat/150 g serving) or contained no fat (277 kJ, 0 g fat/150 g serving). Children in the conditioning group consumed 150 g servings, children in the mere exposure group tasted 16 g or less of these same stimuli. Preferences were assessed before and after conditioning when the children were hungry and also postconditioning when the children were satiated. Results provided evidence for conditioned preferences based on the postingestive consequences of dietary fat. Children in the conditioning group learned to prefer the high-density paired flavor over the low-density paired flavor, and increased their preference for the high-density paired flavor from pre- to postconditioning. Children in the mere exposure group showed positive shifts in preference for both the fat-free and the high-fat paired flavors. In the conditioning group, preferences for the high-fat flavor was depressed by satiety, whereas the preference of the mere exposure group did not vary with hunger state. Conditioned flavor preferences, based on the postingestive consequences of fat intake, may contribute to children's preferences for foods high in dietary fat.

Association Learning↗
PubMed1996

Flavor-postingestive consequence associations incorporate the behaviorally opposing effects of positive reinforcement and anticipated satiety: implications for interpreting two-bottle tests.

Rats consuming distinctively flavored solutions containing different numbers of calories learn to associate each flavor with the ensuing postingestive effects ("flavor-postingestive consequence learning"). The hallmark of such learning is preferential consumption of one of the flavors in two-bottle tests (both flavors presented in nutrient-identical solutions). Two experiments were conducted to characterize the relationship between the number of calories associated with flavors and subsequent preferences in two-bottle tests. In Experiment 1, three groups of rats each associated distinctive flavors with real-fed sugar and with sham-fed sugar. The groups differed in the concentration of sucrose (8%, 14%, 24%) with which they were trained. In two-bottle tests rats trained with 8% sucrose preferred the real-fed flavor, whereas rats trained with 24% sucrose preferred the sham-fed flavor. Rats trained with 14% sucrose were intermediate to the other groups. In Experiment 2, two groups of rats associated distinctive flavors with two concentrations of real-fed sucrose. In two-bottle tests, the group trained with 1% and 5% sucrose preferred the flavor paired with the higher concentration, whereas the group trained with 5% and 30% sucrose preferred the flavor paired with the lower concentration. These findings suggest that flavor-postingestive consequence learning incorporates both positive reinforcement, which has the behavioral effect of increasing intake of the associated flavor, and anticipated satiety, which has the behavioral effect of suppressing intake of the associated flavor. When a flavor is associated with relatively few calories, the positive reinforcing effect predominates over anticipated satiety. However, when a flavor is associated with a greater number of calories, anticipated satiety predominates over the positive reinforcing effect.

Animals↗
PubMed1984

Depression of histone acetylation by alkylating antitumor agents: significance for antitumor activity and possible biological consequences.

Treatment of Ehrlich ascites tumor cells with the alkylating antitumor agents triaziquonum, N-mustard and cyclophosphamide leads to a reduction in the posttranslational incorporation of 3H-acetate into histones and the extent of histone acetylation in Ehrlich ascites tumor cells. All core histones are affected. The depression of histone acetylation is not the result of a decrease in acetyl-CoA. Evidence is presented for an activation of histone deacetylase by alkylating agents. A reduction of histone deacetylation is observed after exposure to all concentrations of alkylating agents which inhibit cell proliferation. In order to evaluate the biological consequences of a reduction of histone acetylation, the extent of acetylation was modulated by either chemical acetylation or treatment with butyrate. In all cases an increase in histone acetylation leads to an enhancement of the rate of transcription. In accord with previous reports from our laboratory (1), it is concluded that the reduction of histone acetylation affects RNA synthesis. It is emphasized, however, that besides a regulation of transcription, histone acetylation may be involved in other cell functions. Thus, the complete biological consequences of the reduction of histone acetylation remain to be elucidated. In view of the antitumor activity of the alkylating agents it seems noteworthy that hepatoma AS30D cells are characterized by a remarkably higher extent of histone H4-acetylation compared to normal, adult, fetal, or regenerating liver.

Alkylation↗
PubMed1982

Stress and its timing: critical factors in determining the consequences of dopaminergic agents.

Dopaminergic agonists and antagonists can have opposite effects, depending on the state of the organism involved. The importance of prior state in determining the consequences of treatment with dopaminergic agents is illustrated in Serra's recent experiments. Although repeated treatment with DA antagonists enhanced the hypokinetic effects of 10 micrograms/kg of apomorphine, they obviated the influence of 25 micrograms/kg. In the former case, chronic DA-receptor blockade induced supersensitivity of DA autoreceptors; in the latter it resulted in subsensitivity. Since autoreceptor subsensitivity typically occurs after repeated treatment with DA agonists these experiments illustrate that neuroleptics caN behave like DA agonists. We discuss these and similar studies, emphasizing the role of stress and time in determining the consequences of dopaminergic agents.

Animals↗
PubMed1995

Stressors, stress and stress consequences during long-duration manned space missions: a descriptive model.

Keeping crew members in good health is a major factor in the success or failure of long-duration manned space missions. Among the many possible agents that can affect the crew's general well-being, stress is certainly one of the most critical because of its implications on human health and performance, both physical and mental. Nevertheless, very few studies have been performed on this fundamental issue and none of them has addressed it in its entirety, considering its diverse physical and psychological aspects. In this work, a descriptive model is proposed to expound the mechanism and sequence of events which mediate stress. A critical analysis of the information provided by past manned spaceflights and by dedicated research performed in analogous environments is presented, and an extrapolation of the available data on human stress in such extreme conditions is proposed. Both internal and external stressors have been identified, at physical and psychosocial levels, thus providing the basis for their early detection and preventive reduction. The possible negative consequences of stress that may lead to disease in crewmembers are described. Finally, the most effective instruments which may be of help in reducing space-related human stress and treating its negative consequences are suggested.

Adaptation, Psychological↗
PubMed1991

Metabolic disorder as early consequence of simian immunodeficiency virus infection in rhesus macaques.

To establish whether the high plasma glutamate and low acid-soluble thiol (mainly cysteine) concentrations previously found in patients with HIV-1 infection are a consequence of the infection or a risk factor for its development, a closely related animal model, rhesus and fascicularis macaques infected with simian immunodeficiency virus (SIVmac251), was studied. The 23 infected macaques had significantly lower mean plasma thiol and higher glutamate concentrations than 18 uninfected controls (p less than 0.001). The changes were apparent by 1 week after infection. Thus, abnormal plasma glutamate and thiol concentrations are, at least in this model, a direct and early consequence of the retroviral infection.

Amino Acids↗
PubMed1989

Population consequences of cadmium toxicity in soil microarthropods.

Chronic toxicity experiments were performed using the collembolan Orchesella cincta (L.) and the oribatid mite Platynothrus peltifer (Koch), which were exposed to various levels of cadmium in the food (green algae). Experimental results were combined with life-history information to obtain realistic estimates of the intrinsic rate of population increase and its sensitivity to Cd stress. Chronic LC50 values for dietary exposure to Cd were estimated as 1.60 mumol/g for O. cincta and 3.18 mumol/g for P. peltifer. No-observed-effect concentrations (NOECs) for growth and reproduction were 0.042 mumol/g for O. cincta and 0.026 mumol/g for P. peltifer. The main effects of Cd were, however, different in each species. In O. cincta, Cd affected primarily female growth, without a direct effect on reproduction; in P. peltifer, the effect was primarily on reproduction. Uptake of Cd was higher in P. peltifer than in O. cincta, and caused a loss of zinc in the former species. As a consequence of their differing physiological responses to Cd, mites and collembolans also reacted differently in their population growth rates. The capacity for population increase of mites appeared to be rather sensitive to Cd, while collembolans were able, to some extent, to maintain their capacity for increase, in spite of toxic effects at the individual level. These results may contribute to developing ecotoxicological theory for the population consequences of toxic action in species with diverging life histories. Soil microarthropods may be suitable test organisms for evaluating the risk of chemicals to the soil ecosystem.

Animals↗
PubMed1989

[Pathologic consequences of a severe influenza outbreak (swine virus A/H1N1) under natural conditions in the non-immune sow at the beginning of pregnancy].

Pathological consequences of a severe outbreak of swine influenza (H1N1 virus) in the non immune sow at the beginning of pregnancy, under natural conditions. A sudden acute outbreak of fever, depression, anorexia and coughing in a group of nulliparous sows from a herd that was currently under epidemiological investigation lead to build a particular disposal of observation. The clinical signs were daily recorded including rectal temperature. Blood was taken from the sows at the beginning of the troubles and 3 weeks later for the detection of Aujesky's disease, coronavirus TGE-like, Influenza viruses A/H1N1 and A/H3N2 and Mycoplasma hyopneumoniae. Viral detection was attempted from nasal swabs and aborted fetuses during the acute phase. The clinical study showed fever reaching near 41 degrees C on most of the pigs and lasting usually from 2 to 5 days. The diagnosis of Influenza (virus swine H1N1) was established both on serology (massive seroconversion) and on the detection of the virus from the nasal swabs and from an aborted fetus. The control of the lungs of sows "not in pig" and culled showed extended lesions of bronchopneumonia and Pasteurella multocida was found. The technical consequences of this severe outbreak of Influenza on reproduction were mainly important at the beginning of pregnancy. Over 13 sows inseminated less than 1 week before the outbreak, only 3 farrowed (respectively 5.5 and 12 piglets); 7 returned to oestrus and 3 "not a pig" at 21 days (echotomography) did not show signs of heat and were culled. Over 8 pregnant sows (1 month of pregnancy), 6 farrowed normal litters and total embryonic resorption occurred in 2 sows. Over 18 pregnant sows (more than 45 days gestation) one aborted.

Abortion, Veterinary↗
PubMed1995

Analogs of alkyllysophospholipids: chemistry, effects on the molecular level and their consequences for normal and malignant cells.

In the search for new approaches to cancer therapy, the first alkyllysophospholipid (ALP) analogs were designed and studied about two decades ago, either as potential immunomodulators or as antimetabolites of phospholipid metabolism. In the meantime, it has been demonstrated that they really act in this way. However, their special importance is based on the fact that, in addition, they interfere with key events of signal transduction, such as hormone (or cytokine)-receptor binding or processing, protein kinase C or phospholipase C function and phosphatidylinositol and calcium metabolism. There are no strict structural requirements for their activity. Differences in the cellular uptake or the state of cellular differentiation seem to be mainly responsible for higher or lower sensitivities of cells towards ALP analogs. Consequences of the molecular effects mentioned on the cellular level are cytostasis, induction of differentiation (while in contrast the effects of known inducers of differentiation such as 12-O-tetradecanoylphorbol-13-acetate are inhibited, probably as a consequence of protein kinase C inhibition) and loss of invasive properties. Already in sublytic concentrations, alterations in the membrane structure were observed, and lysis may begin at concentrations not much higher than those causing the other effects described. Few ALP analogs have already entered clinical studies or are in clinical use. ALP analogs are the only antineoplastic agents that do not act directly on the formation and function of the cellular replication machinery. Therefore, their effects are independent of the proliferative state of the target cells. Because of their interference with cellular regulatory events, including those failing in cancer cells, ALP analogs, beyond their clinical importance, are interesting model compounds for the development of new, more selective drugs for cancer therapy.

Antineoplastic Agents↗
PubMed1993

Free radical-lipid interactions and their pathological consequences.

In this review we have tried to present the current thinking on the consequences for lipids of their interactions with free radicals and the pathological implications. In particular, atherosclerosis and cancer have been addressed. In the case of the former, it is not clear whether the initial oxidative event is an enzymic or free radical-mediated process as yet. However, the importance of the antioxidants in controlling LDL oxidation, macrophage uptake of oxidatively modified LDL and progression of atheroma in animal models certainly suggests an important propagative role for free radical-mediated events. With regard to cancer, oxidative modification of cell lipids has potential consequences for tumour cell proliferation. Whilst lipid hydroperoxides can serve as an origin of prostaglandins with tumour inhibitor (or immunosuppressive) properties, they may also influence cellular growth regulatory proteins normally dependent on membrane lipid integrity. Alternatively, they may function as a source of aldehydic breakdown products capable of 'down-regulating' cell proliferation through covalent modification of regulatory proteins. Oils rich in n-3 polyunsaturated fatty acids have toxic effects towards tumour cells. This toxicity is not mediated by prostaglandins but rather through the capacity of such agents to elevate the levels of lipid peroxides. This may be enhanced by active oxygen species released constitutively from tumour cells.

Animals↗
PubMed1995

Synaptic plasticity in the hippocampal slice: functional consequences.

There are 3 known forms of synaptic plasticity at CNS synapses: long-term potentiation (LTP) mediated by NMDA receptor activation, LTP mediated by voltage-dependent calcium channel (VDCC) activation, and long-term depression (LTD) mediated by the NMDA receptor. All 3 forms of synaptic plasticity can be observed in hippocampal CAl cells, all are induced by afferent activation, all involve Ca2+ influx, and all activate Ca(2+)-dependent mechanisms. We consider the functional consequences of the presence of 3, sometime opposing, forms of synaptic plasticity at the same synapse. We suggest that the 2 forms of LTP have different consequences for the synapse. We postulate that the co-existence of potentiating and depressing capabilities influences the network processing capabilities of neural networks.

Animals↗