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Usefulness of the guppy, Poecilia reticulata, in carcinogenicity testing: special advantages and problems.

The guppy, Poecilia reticulata, native to fresh and brackish waters of northeastern South America and adjacent islands of the Caribbean, has been introduced throughout much of the tropical and subtropical world. It tolerates comparatively wide ranges of temperature, salinity, and crowding. This hardiness plus high fecundity, live birth, fast growth, and early maturation make it an excellent laboratory organism for disciplines ranging from behavioral studies to toxicity testing. In 4 published carcinogenicity studies, 8 of 11 known mammalian carcinogens produced neoplasms in the liver and occasionally at other sites. The guppy's overall popularity, however, has magnified problems concerning stock origin. The natural variability of this species has been increased by artificially selected breeding and by exotic natural selection pressures of foreign environments on introduced populations. The source of many guppy stocks today is ultimately the pet trade, and a good genetic history of such strains is not often available. Differences in stock origin may account for some differential responses of growth and sensitivity to environmental variables noted in the literature. The establishment of carefully maintained inbred strains for cancer research is the best solution to this problem.

Animals↗

Tolerance to the anxiolytic effects of the triazolobenzodiazepines triazolam and alprazolam, as measured by the ingestion of a hypertonic sodium chloride solution in rats.

Rats were adapted to a water-deprivation regimen that allowed daily 1-hr drinking sessions of a single fluid, either 1.5% NaCl solution or water. Oral, presession, acute doses of triazolam (0.05-1.6 mg/kg) or alprazolam (0.4-6.4 mg/kg) produced dose-related increases in session NaCl solution ingestion. The relative potencies found for these two drugs approximated their relative Ki values reported in the literature. The increased ingestion produced in this and other experiments by anxiolytic agents is presented as an alternative way of evaluating punishment attenuation, and hence anxiolytic activity. Chronic oral dosing (every 2nd day) with triazolam (0.2 mg/kg) or alprazolam (1.2 mg/kg) led, after several weeks, to partial, but surmountable, tolerance to the increased NaCl solution ingestion produced by these drugs, which was confirmed by a rightward shift in the dose-effect relations. During chronic dosing, no corresponding declines in the independently evaluated increases in water intake produced by these drugs occurred. Abrupt drug discontinuation produced a precipitous decrease in NaCl solution intake, with subsequent recovery. For triazolam, the initial discontinuation decrease in intake to below the original base line suggested the possible accrual of a mild physiological dependence under this moderate chronic dose regimen.

Alprazolam↗

[Entomological study on the malaria transmission in coastal and lagoon areas: the case of a village built on a brackish lake].

In a longitudinal study we have observed the fluctuation in density of two Anopheles populations responsible for malaria transmission in a village built on a brackish lake. The two A. gambiae complex species are A. melas and A. gambiae s.s. The former is the most abundant (88%). The brackish lake ecosystem gives to both species possibilities of adaptation. The salt water species of the A. gambiae complex, A. melas, was found to be tolerant to waters with very low salinity. On the other hand, A. gambiae s.s. was found to support relatively high salinity rates. Both specimens live together the whole year round but their frequencies vary with the inundation of the lake. During inundation the salt rate decreases and A. melas eventually disappears. Transmission is low, seasonal and short on the lake. It is perceptible between March and August. The inoculation rate (11 infected bites per man/year) is lower than what we have observed in other lagoon areas of Benin, or even in the city of Cotonou (33 infected bites per man/year). The low malaria transmission on the lake is probably due to the presence of an important population of A. melas with low infection rates and the widespread use of bed nets.

Adaptation, Physiological↗

Clinical pharmacokinetics of escalating i.v. doses of dexanabinol (HU-211), a neuroprotectant agent, in normal volunteers.

The pharmacokinetics of dexanabinol (HU-211), a synthetic, nonpsychotropic cannabinoid with neuroprotectant action, was evaluated in a phase I clinical trial. The compound was administered at doses of 48 mg, 100 mg, and 200 mg as short i.v. infusions in a Cremophor-ethanol vehicle diluted with saline. All administrations were well-tolerated and no compound-related side-effects were observed. Plasma concentrations of dexanabinol were quantitated using a GC/MS/MS technique which provided a limit of quantitation of 100 pg/ml. The elimination of dexanabinol was best fitted to a 3-compartment model with a rapid distribution half-life (< 5 min), an intermediate phase half-life of approximately 90 min, and a slow terminal elimination half-life (approximately 9 h). The pharmacokinetics were linear over the evaluated dose range. The plasma clearance of the drug was high (1,700 ml/min) and the volume of distribution approximately 15 l/kg. These data are similar to those reported for naturally occurring cannabinoids such as delta 9-tetrahydrocannabinol and cannabidiol.

Adult↗

Improved glucose tolerance by acute vanadate but not by selenate exposure in genetically obese rats (fa/fa).

OBJECTIVE: To describe the impact of acute vanadate and selenate exposure on glucose tolerance of obese Zucker rats (fa/fa). DESIGN: Intravenous glucose tolerance tests (2.4 mmol/kg, continuously from 0 to 30 min) were performed in conscious Zucker rats exposed to a bolus-continuous infusion of sodium vanadate (2.45 mumol/h) or sodium selenate (0.90 and 2.45 mumol/h) and were compared to intraindividual control experiments with saline infusion. RESULTS: Vanadate infusion improved glucose tolerance and decreased insulin release, as shown by total areas under the curves (0-120 min: Glucose, min.mmol/l: control, 983 +/- 59 vs vanadate, 915 +/- 54, P < 0.02; Insulin min.nmol/l: control, 117.5 +/- 19.9 vs vanadate, 88.5 +/- 26.2, P < 0.01). In contrast, infusion of selenate increased glucose induced insulin release during the first phase of the IVGTT (0-60 min, incremental area under the insulin curve: by 57% and 110% for low and high selenate infusion rate, respectively) and transiently improved glucose tolerance (0-60 min, decrease of incremental area under the glucose curve: 31% and 28%, respectively). That effect of selenate was lost with progression of the experiment during the second hour of the IVGTT, when plasma glucose continued to decline slowly in control experiments, but increased in selenate exposed rats without any adequate insulin secretory response to hyperglycemia. CONCLUSION: The results demonstrate improved glucose tolerance and decreased plasma insulin concentration during acute vanadate exposure. Only a transient insulinotropic effect with improved glucose tolerance is induced during acute selenate exposure, and is followed by progressive development of hyperglycemia indicating selenate toxicity.

Animals↗

Single-dose tolerance to morphine-induced analgesic and hypoactive effects in infant rats.

A single injection of morphine or isotonic saline was administered to rats at either 1, 5, 9, ro 13 days of age. At 26-29 days of age, animals were tested for pain responsivity and activity following either morphine (5 mg/kg) or saline. Animals which received morphine at 1 day of age displayed tolerance at 26 days of age, whereas animals which received morphine at either 5, 9, or 13 days of age failed to display tolerance. This age-dependent change in susceptibility to single-dose morphine tolerance may involve alterations in opiate receptor ontogeny.

Age Factors↗

Biotin supplementation improves glucose and insulin tolerances in genetically diabetic KK mice.

Because biotin treatment may lower blood glucose in insulin-dependent diabetes, we chose to study such an effect in non-insulin dependent diabetes. Twenty-six diabetic KK mice, moderately hyperglycemic and insulin resistant, were treated for 10 weeks: 9 animals with 2 mg of biotin/Kg, 8 with 4 mg of biotin/Kg, and 9 with saline (controls). Blood glucose levels, oral glucose tolerance, insulin response to oral glucose, and blood glucose decrease in response to insulin were quantitated. Compared to controls, biotin treatment lowered post-prandial glucose levels, and improved tolerance to glucose and insulin resistance. Serum immunoreactive insulin levels in biotin-treated mice were like the controls.

Animals↗

Pretreatment of seed with H2O2 improves salt tolerance of wheat seedlings by alleviation of oxidative damage and expression of stress proteins.

Increased salinity is a stringent problem to crop production while seed pretreatment can effectively induce salt tolerance in plants. Hydrogen peroxide (H(2)O(2)), a stress signal molecule, was evaluated as seed treatment to produce the metabolic changes, which could lead to improved salt tolerance in wheat. Soaking in 1, 40, 80 and 120 microM H(2)O(2) revealed a low penetration, reaching maximum at 5h (2.58+/-0.23 micro mol g(-1) fresh seeds at 120 microM) and declining thereafter to the level of water control by 8h. This revealed the activation of antioxidants and H(2)O(2) scavenging in seed after 5h. Seeds treated with 1-120 microM H(2)O(2) for 8h and germinated in saline (150 mM NaCl) medium curtailed the mean germination time (MGT) being even less than water controls. Level of H(2)O(2) in seedlings arising from H(2)O(2)-treated seeds grown under salinity was markedly lower than salinized controls, suggesting the operation of antioxidant system in them. These seedlings exhibited better photosynthetic capacity, particularly the stomatal conductance (gs), thus improving the leaf gas exchange due to stomatal component of photosynthesis. Moreover, H(2)O(2) treatment improved leaf water relations and maintained turgor. Although Na(+) and Cl(-) content increased due to salinity, H(2)O(2)-treated seedlings displayed greater tissue K(+), Ca(2+), NO(3)(-) PO(4)(3-) levels and improved K(+):Na(+) ratio. H(2)O(2) treatment enhanced the membrane properties, as revealed from greatly reduced relative membrane permeability (RMP) and less altered ion leakage pattern (comparable to water controls). Seedlings exhibited the expression of two heat-stable (stress) proteins with apparent molecular masses of 32 and 52 kDa. Results suggest that H(2)O(2) signals the activation of antioxidants in seed, which persists in the seedlings to offset the ion-induced oxidative damage. These changes led to the expression of stress proteins and improved physiological attributes, which supported the seedling growth under salinity.

Adaptation, Physiological↗

Lack of tolerance to ethanol-induced dopamine release in the rat ventral striatum.

The effect of ethanol challenge on the extracellular concentrations of dopamine, 3,4-dihydroxy-phenylacetic acid and homovanillic acid was studied in the ventral striatum of rats repeatedly treated with ethanol. Ethanol-treated animals (1 g/kg i.p. twice a day for 12 days) developed marked tolerance to the behavioral signs of ethanol intoxication when challenged with ethanol (2 g/kg i.p.). However, in ethanol-treated animals the increased output of dopamine and metabolites after ethanol challenge (1 or 2 g/kg i.p.) was not statistically different from that observed in saline-treated rats. These results indicate that tolerance does not develop to the ethanol-induced stimulation of dopamine release and support the hypothesis that activation of the mesolimbic dopamine system contributes to the reinforcing properties of ethanol.

3,4-Dihydroxyphenylacetic Acid↗

Ecological and toxicological effects of inorganic nitrogen pollution in aquatic ecosystems: A global assessment.

We provide a global assessment, with detailed multi-scale data, of the ecological and toxicological effects generated by inorganic nitrogen pollution in aquatic ecosystems. Our synthesis of the published scientific literature shows three major environmental problems: (1) it can increase the concentration of hydrogen ions in freshwater ecosystems without much acid-neutralizing capacity, resulting in acidification of those systems; (2) it can stimulate or enhance the development, maintenance and proliferation of primary producers, resulting in eutrophication of aquatic ecosystems; (3) it can reach toxic levels that impair the ability of aquatic animals to survive, grow and reproduce. Inorganic nitrogen pollution of ground and surface waters can also induce adverse effects on human health and economy. Because reductions in SO2 emissions have reduced the atmospheric deposition of H2SO4 across large portions of North America and Europe, while emissions of NOx have gone unchecked, HNO3 is now playing an increasing role in the acidification of freshwater ecosystems. This acidification process has caused several adverse effects on primary and secondary producers, with significant biotic impoverishments, particularly concerning invertebrates and fishes, in many atmospherically acidified lakes and streams. The cultural eutrophication of freshwater, estuarine, and coastal marine ecosystems can cause ecological and toxicological effects that are either directly or indirectly related to the proliferation of primary producers. Extensive kills of both invertebrates and fishes are probably the most dramatic manifestation of hypoxia (or anoxia) in eutrophic and hypereutrophic aquatic ecosystems with low water turnover rates. The decline in dissolved oxygen concentrations can also promote the formation of reduced compounds, such as hydrogen sulphide, resulting in higher adverse (toxic) effects on aquatic animals. Additionally, the occurrence of toxic algae can significantly contribute to the extensive kills of aquatic animals. Cyanobacteria, dinoflagellates and diatoms appear to be major responsible that may be stimulated by inorganic nitrogen pollution. Among the different inorganic nitrogenous compounds (NH4+, NH3, NO2-, HNO2NO3-) that aquatic animals can take up directly from the ambient water, unionized ammonia is the most toxic, while ammonium and nitrate ions are the least toxic. In general, seawater animals seem to be more tolerant to the toxicity of inorganic nitrogenous compounds than freshwater animals, probably because of the ameliorating effect of water salinity (sodium, chloride, calcium and other ions) on the tolerance of aquatic animals. Ingested nitrites and nitrates from polluted drinking waters can induce methemoglobinemia in humans, particularly in young infants, by blocking the oxygen-carrying capacity of hemoglobin. Ingested nitrites and nitrates also have a potential role in developing cancers of the digestive tract through their contribution to the formation of nitrosamines. In addition, some scientific evidences suggest that ingested nitrites and nitrates might result in mutagenicity, teratogenicity and birth defects, contribute to the risks of non-Hodgkin's lymphoma and bladder and ovarian cancers, play a role in the etiology of insulin-dependent diabetes mellitus and in the development of thyroid hypertrophy, or cause spontaneous abortions and respiratory tract infections. Indirect health hazards can occur as a consequence of algal toxins, causing nausea, vomiting, diarrhoea, pneumonia, gastroenteritis, hepatoenteritis, muscular cramps, and several poisoning syndromes (paralytic shellfish poisoning, neurotoxic shellfish poisoning, amnesic shellfish poisoning). Other indirect health hazards can also come from the potential relationship between inorganic nitrogen pollution and human infectious diseases (malaria, cholera). Human sickness and death, extensive kills of aquatic animals, and other negative effects, can have elevated costs on human economy, with the recreation and tourism industry suffering the most important economic impacts, at least locally. It is concluded that levels of total nitrogen lower than 0.5-1.0 mg TN/L could prevent aquatic ecosystems (excluding those ecosystems with naturally high N levels) from developing acidification and eutrophication, at least by inorganic nitrogen pollution. Those relatively low TN levels could also protect aquatic animals against the toxicity of inorganic nitrogenous compounds since, in the absence of eutrophication, surface waters usually present relatively high concentrations of dissolved oxygen, most inorganic reactive nitrogen being in the form of nitrate. Additionally, human health and economy would be safer from the adverse effects of inorganic nitrogen pollution.

Acid Rain↗

Endotoxemia and remote organ injury following intestinal reperfusion.

This study addresses the hypothesis that endotoxin (LPS) is an important proximal mediator of remote organ dysfunction following intestinal reperfusion. Sprague-Dawley rats underwent intestinal ischemia for 120 min followed by 60 min of reperfusion (IIR). Animals underwent pretreatment with polymyxin B (PMB, 200 micrograms, sc) or the induction of tolerance to LPS prior to assignment to the IIR or sham group. Controls received equal volumes of normal saline. Lung and intestinal injury was quantitated using an edema index. Bile flow was quantitated by measuring the volume of bile produced per 15 min. The intestinal edema index of IIR animals pretreated with PMB was nearly 50% less than that of saline-treated animals sustaining the same injury (P < 0.05). The induction of LPS tolerance reduced the edema index of IIR animals by 28% compared to the saline-treated IIR group (P < 0.05). Neither treatment reduced this parameter to that of sham-operated controls (P < 0.05). The lung edema index of animals pretreated with PMB was 50% of that of saline-treated IIR animals (P < 0.05). This remained significantly greater than that of sham-operated controls (P < 0.05). LPS tolerance did not affect the lung edema index of animals sustaining IIR. Bile flow rates following IIR were not significantly affected by PMB or LPS tolerance. These data do not support the hypothesis that LPS is an important proximal mediator of the remote organ injury associated with IIR. However, they do suggest that LPS may be one of many mediators responsible for this injury.

Animals↗

Cross-tolerance studies of serotonin receptors involved in behavioral effects of LSD in rats.

Like hallucinogenic 5-HT2 agonists, LSD (d-lysergic acid diethylamide) produces characteristic decreases in locomotor activity and investigatory behaviors of rats tested in a novel environment. Because LSD is an agonist at both 5-HT1A and 5-HT2 receptors, however, the respective influences of these different receptors in the behavioral effects of LSD remain unclear. In particular, the paucity of selective 5-HT1A antagonists has made it difficult to assess the specific contribution of 5-HT1A receptors to the effects of LSD. An alternative approach to the delineation of receptor-specific effects is the use of cross-tolerance regimens. In the present studies, rats were pretreated with saline, 8-hydroxy-2(di-n-propylamino)-tetralin (8-OH-DPAT) (0.5 mg/kg SC), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (1.0 mg/kg SC), or LSD (60 micrograms/kg SC), every 12 h for 5 or 8 days. Thirty-six hours later, rats were tested in a behavioral pattern monitor 10 min after injection of saline, 0.5 mg/kg 8-OH-DPAT, 1.0 mg/kg DOI, or 60 micrograms/kg LSD. As expected, tolerance to the decreases in locomotor activity produced by acute administrations of 8-OH-DPAT, DOI, or LSD occurred when rats were pretreated chronically with 8-OH-DPAT, DOI, or LSD, respectively. Furthermore, pretreatment with either 8-OH-DPAT or DOI produced cross-tolerance to LSD. These results support the hypothesis that the effects of LSD in this model reflect a combination of 5-HT1A and 5-HT2 effects and support the view that there is an interaction between 5-HT1A and 5-HT2 receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Scopolamine blocks play fighting behavior in juvenile rats.

Play fighting, social investigation, and locomotor activity of prepubescent male laboratory rats were observed 20 min following administration of scopolamine hydrobromide. Play fighting was inhibited by an intraperitoneal dosage of 0.3 mg/kg and was effectively blocked at all dosages greater than 0.5 mg/kg; activity and social investigatory behavior were increased by scopolamine. Play fighting inhibition following a threshold dosage of 0.3 mg/kg scopolamine was effective at 30 min; after 120 min, drug- and saline-treated groups failed to differ reliably. Behavioral tolerance to scopolamine was observed after five days of daily treatment with 0.5 mg/kg scopolamine; play fighting, following a 0.5 mg/kg dosage of scopolamine, did not differ from that of saline-treated controls. The results are discussed in terms of central and peripheral effects of scopolamine and the competing response hypothesis.

Aggression↗

Dissipation of contingent tolerance to the anticonvulsant effect of diazepam: effect of the criterion response.

The effect of convulsive stimulations on the dissipation of tolerance to the anticonvulsant effect of diazepam was investigated using the kindled-convulsion model. Amygdala-kindled rats were rendered tolerant to diazepam's anticonvulsant effect by 25 "bidaily" (one/48 h) diazepam injections (2.5 mg/kg), each followed 1 h later by a convulsive stimulation. They were then divided into nine groups for the tolerance-dissipation phase of the experiment. Of the nine groups, three received bidaily control handling for one trial, three trials, or seven trials; three received bidaily saline injections, each 1 h before a convulsive stimulation, for one, three, or seven trials; and three received bidaily diazepam injections, each 1 h after a convulsive stimulation, for one, three, or seven trials. Finally, each rat received a tolerance-retention test (i.e., a diazepam injection followed 1 h later by a convulsive stimulation) 48 h after its last tolerance-dissipation trial. The tolerance dissipated gradually but completely over the 4-, 8-, and 16-day test intervals in the rats that received a convulsive stimulation before each injection during the tolerance-dissipation phase, whether they were injected with saline or diazepam; in contrast, tolerance did not dissipate in the rats that received saline injections but no stimulations. Remarkably, the discontinuance of the bidaily diazepam injections, even for 16 days, was not sufficient to dissipate the tolerance that had developed to diazepam's anticonvulsant effect; nor was the continuation of the bidaily diazepam injections sufficient to keep tolerance from dissipating.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Drainage of the subretinal fluid and injection of saline solution into the vitreous body.

In a group of 250 cases operated upon for retinal detachment, drainage of the subretinal fluid was carried out in 96%. Since in 54 cases, i.e. 22%, a large quantity of subretinal fluid was evacuated, saline solution was injected into the vitreous. The following complications due to drainage were noted: intraocular haemorrhages (16%), incarceration of the retina (1%) and temporary iridocyclitis (2%). None of these complications prevented reattachment. In 54 cases in which injection of saline solution into the vitreous was carried out, we have noted: temporary occlusion of the central retinal artery (5 cases), temporary cloudiness in the vitreous body (2 cases) and traumatic cataract (1 case). The injection of saline solution into the vitreous was well tolerated. Although the complications due to drainage are rather numerous (intraocular infection and haemorrhages, incarceration of retina, secondary retinal hole, glial proliferation in the vitreous, dehiscence at the place of drainage), these complications rarely occur if the drainage is carried out in a proper manner. Despite the fact that drainage and injection of saline solution into the vitreous do not cause more severe complications, however, we consider that the method of avoiding drainage and internal tamponage, whenever it is possible, represents a fully justified trend.

Drainage↗

Dextromethorphan attenuates and reverses analgesic tolerance to morphine.

Tolerance to the antinociceptive (analgesic) effect of morphine, a mu-opioid agonist, was developed in male CD-1 mice as assessed by a shift to the right of the analgesic (tail-flick) dose-response curves and an increase in the ED50 values. Administration of dextromethorphan at 30 mg/kg s.c., but not saline, 30 min prior to an escalating 3 times per day (t.i.d.) morphine dosing schedule prevented a 5-fold increase in the morphine ED50 value observed on treatment day 4. Concurrent administration of dextromethorphan at 12 mg/kg/24 h by s.c. infusion prevented the 6-fold increase in the morphine ED50 value that was observed in control mice that received morphine at 30 mg/kg/24 h by s.c. infusion. Implantation of two 25 mg morphine pellets resulted in a 10-fold increase in the morphine ED50 value on treatment day 4. Administration of dextromethorphan at 30 mg/kg s.c. t.i.d., but not saline, resulted in a reversal of morphine tolerance with the almost complete return of the morphine ED50 value to the control (opioid naive) value. These results demonstrate that dextromethorphan, an NMDA receptor antagonist can modulate morphine (mu-receptor)-mediated tolerance.

Analgesics↗

Influence of amphotericin B on the ciliary beat frequency of nasal mucosa.

OBJECTIVE: A new therapeutic approach in eosinophilic fungal rhinosinusitis is topical application of antifungals such as amphotericin B. The tolerability of a recently applied concentration of this drug by human nasal mucosa was tested in vitro. METHODS: Ciliary beat frequency (CBF) was measured by a photometric technique, combining a light microscope, a photometer, a photograph-multiplier, and a computed analyzing unit. RESULTS: Treatment for 20 minutes with amphotericin B finally diluted in saline to 0.1 mg/mL caused no decrease in CBF. By contrast, both amphotericin B diluted in distilled water and distilled water without additives lowered CBF about 50%. This decrease was not reversible after reincubation for 20 minute in saline. CONCLUSIONS: The results confirm the good tolerability of topical amphotericin B in the nasal and paranasal cavity. Because of the negative effect of distilled water, final dilution in physiologic solvents should be considered.

Amphotericin B↗

Genetically modified cyanobacterium Nostoc muscorum overproducing proline in response to salinity and osmotic stresses.

In the parent Nostoc muscorum an active proline oxidase enzyme is required to assimilate exogenous proline as a fixed nitrogen source. Cyanobacterial mutants, resistant to growth inhibitory action of proline analogue L-azetidine-2-carboxylate (Ac-R), were deficient in proline oxidase activity, and were over-accumulators of proline. Proline over-accumulation, resulting either from mutational acquisition of the Ac-R phenotype, or from salinity-induced uptake of exogenous proline, confirmed enhanced salinity/osmotic tolerance in the mutant strain. The nitrogenase activity and photosynthetic O 2 evolution of the parent were sensitive to both salinity as well as osmotic stresses than of Ac-R mutant strain. In addition, the mutation to Ac-resistant phenotype showed no alteration in salinity inducible potassium transport system in the cyanobacterium.

Azetidinecarboxylic Acid↗