Serum concentrations of prostacyclin and thromboxane in children before, during, and after cardiopulmonary bypass.

Twenty-six consecutive pediatric patients undergoing reparative procedures necessitating cardiopulmonary bypass were prospectively studied to determine changes in serum levels of 6-keto-prostaglandin F1 alpha and thromboxane B2. Cardiac lesions included acyanotic lesions (five patients), obstructive lesions (10 patients), and right-to-left shunts (11 patients). There was a significant (p less than 0.05) increase in 6-keto-prostaglandin F1 alpha from preoperative levels measured at the time of arterial and venous cannula insertion. This concentration was maintained throughout cardiopulmonary bypass and remained significantly elevated (p less than 0.001) in the recovery room, but returned to preoperative levels by the morning after the operation. Preoperative levels of thromboxane B2 varied widely and were not significantly different from intraoperative levels. The postoperative levels of thromboxane B2, however, were significantly different (p less than 0.05) from the intraoperative levels. In the pediatric age group undergoing cardiopulmonary bypass, 6-keto-prostaglandin F1 alpha and thromboxane B2 change during bypass but do not significantly differ when preoperative levels are compared to postoperative values.

Blood and brain mercury levels after chronic gestational exposure to methylmercury in rats.

Female rats were exposed to 0, 0.5, or 6 ppm Hg (as methylmercuric chloride, 10 rats/group) in drinking water. For half the rats, exposure began 4 weeks before mating and for the others, exposure began 7 weeks before mating. All mating was done with an unexposed male. Maternal exposure continued to post-natal day (PN) 16. Blood and whole-brain mercury concentrations were determined in pups on PN 0 (birth) and PN 21 (weaning). Maternal water consumption was monitored daily during gestation and lactation. Maternal water consumption increased 2- to 3-fold through gestation for all groups. Mercury levels in blood and brain were unrelated to the duration of exposure before mating, although reproductive success appeared to be so related. Mercury levels in both media were closely related to consumption during gestation, but apparently maternal exposure during lactation did not result in exposure to the nursing pups. Brain mercury in offspring decreased between birth and weaning from 0.49 to 0.045 ppm in the low-dose rats and from 9.8 to 0.53 ppm in the high-dose rats. The brain increased in weight only about 5.5-fold during this time, indicating that there was minimal mercury exposure and some net loss from brain during this period. Brain:blood ratios averaged about 0.14 at birth and 0.24 at weaning, suggesting differential loss from neural and non-neural tissue. These ratios are higher than those reported in studies using less chronic exposure conditions or with adult rats. Brain concentrations of mercury in females in the low-dose group were about 10-15% higher than those seen in their male siblings. At the higher dose, the males had slightly higher levels of mercury in the brain than did their female siblings at birth. The relationship between brain concentration (in ppm) and cumulative mercury consumption, also expressed on a ppm basis (cumulative mercury consumed divided by maternal body weight at parturition), was not linear but was well described by a power-function relationship: Hg = A*(cum exposure)b where the exponent, b, was 1.12 and 1.17 for blood and brain, respectively, at birth. This exponent was indistinguishable from 1.0 for both media at weaning, indicating that the relationship between exposure and blood and brain levels became linear.

Effect of once weekly treatment with 3,4-methylenedioxymethamphetamine on schedule-controlled behavior in rats.

The present study examined the effects of 3,4-methylenedioxymethamphetamine (MDMA), before and after once a week dosing, on the behavior of rats responding under a fixed ratio 20 schedule of reinforcement. Acutely, cumulative doses of MDMA dose-dependently decreased responding when compared to a series of water injections. Rats were then separated into two groups, one of which received only weekly MDMA ('paired') while the other received an additional injection of water each week ('unpaired'). Weekly dosing with MDMA resulted in significantly increased responding at low doses in the paired group but not in the unpaired group. When water injections were readministered there was a significant increase in responding in both groups. During the weekly regimen, locomotor activity also increased significantly over time after both water and MDMA injections. In conclusion, it appears that even weekly dosing with a small amount of MDMA can have long-lasting effects that are manifested in both operant and spontaneous behavior and that may be mediated by a conditioning mechanism.

Behavioral and developmental effects of two 3,4-methylenedioxymethamphetamine (MDMA) derivatives.

The effects of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstacy') and two structurally related compounds, N-methyl-1-(3,4-methylenedioxyphenyl)-1-ethanamine (MDM1EA) and N-methyl-1-(3,4-methylenedioxyphenyl)-3-butanamine (HMDMA) were examined in two preparations: (i) a drug discrimination procedure in MDMA-trained rats and (ii) the chicken embryo, for determination of the direct effects of these compounds on the developing organism. The highest doses of MDM1EA and HMDMA partially substituted for MDMA, whereas higher (30-60 mg/kg) doses of HMDMA evoked clonic seizures in a separate group of rats. In chicken embryos MDMA had no effect on body, brain or liver weight, while the highest dose of MDM1EA decreased body weight and the 2 lowest doses of HMDMA increased body weight. All doses of HMDMA decreased liver weight (expressed as % body weight) when compared with contemporaneous water-treated controls. Taken together, the results of these experiments suggest that structurally related compounds share some stimulus properties with MDMA and may therefore share abuse liability. Furthermore, both MDMA-related compounds produced adverse effects on the developing organism, whereas MDMA did not.

Animal models of manganese's neurotoxicity.

Manganese's neurotoxicity continues to present a puzzling array of differences across individuals and across published reports in the profile of effects seen in humans and nonhuman species, but some of the sources of individual variability are becoming clear from studies of animals. The kinetics of manganese is a critical component of any assessment of risk associated with exposure. After inhalation, the uptake of manganese into and elimination from the central nervous system are slow and some manganese remains in the nervous system a year after inhalation. Comparison with other parenteral routes suggests that manganese depots in lung prolongs exposure even after environmental exposure has ended. Manganese's neurotoxicity is associated with its appearance in basal ganglia structures, especially the globus pallidus. Manganese also appears in the pituitary gland but the functional consequences of this are not well understood. Other critical components in characterizing manganese's neurotoxicity appear to be the behavioral endpoints used, the species studied, and the exposure rate. Over neurological signs and excitability are associated with high exposure rates and the appearance of manganese throughout basal ganglia and basal forebrain regions. More focused behavioral endpoints are required to detect the subtle signs associated with slow exposure rates low exposure levels, but when such designs are used the effect is unequivocal. At lower exposure levels, doses of 5 mg/kg and greater, deficits in a task in which a monkey executed a rowing type motion against a spring approximating its body weight were clearly related to manganese exposure while other traditional measures of response patterns under schedules of reinforcement remained intact. Excitability and other signs of emotionality have not been reported at low exposure rates. In rodents, manganese accumulation and alterations in the function or concentration of neurotransmitters have been reported. Investigations of behavioral effects in these species, which usually involved locomotor activity, have resulted in less consistent results. Manganese produces a constellation of neurotoxic signs whose appearance and detection are influenced by dose and exposure rate. Despite investigations of manganese's neurotoxicity in animals over a wide range of exposure levels, a NOAEL has not been identified.

Animal studies of methylmercury and PCBs: what do they tell us about expected effects in humans?

Methylmercury and polychlorinated biphenyls (PCBs) exemplify the important interactions that should take place between epidemiological and laboratory investigations of developmental neurotoxicants. Often found in the same source, perhaps with multiplicative interactions, it is difficult to isolate specific profiles of effects without advanced behavioral procedures and controlled exposures using laboratory animals. The present review focuses on the effects of developmental exposure to methylmercury or PCBs as expressed in adult animals. The PCBs are subdivided into two structural classes, nonortho-substituted ("coplanar" or "dioxin-like") PCBs and ortho-substituted ("noncoplanar") PCBs, a distinction supported by different behavioral profiles and neural mechanisms of action. Methylmercury's profile is dominated by sensory effects with a likely cortical site of action. Some of these effects may be amplified with aging. Methylmercury's effects on functions generally termed cognitive can be understood by distinguishing between those reflecting the acquisition of a response-consequence relationship from those reflecting memory or contextual influences over behavior. Methylmercury does not appear to impair memory or discriminations, but retards acquisition of a response-reinforcer relationship. Like methylmercury, non-ortho-substituted PCBs do not appear to degrade memory and contextual control. Ortho-substituted PCBs impair performance on certain spatially-based discrimination and memory tasks. Methylmercury and non-ortho-substituted PCBs disturb the temporal pattern seen in fixed-interval schedules, but apparently without a significant change in the pattern of interresponse times. The ortho-substituted PCBs disrupted this pattern, but did so by increasing the number of short interresponse times.

Quantification of motor function in toxicology.

Disturbances of movement and other motor functions can result from exposure to toxicants and drugs. Sometimes, as with acute exposure to ethanol or solvents, these effects disappear when exposure ends. Other times, as with manganese, haloperidol, or chronic ethanol, motor disturbances are irreversible and may even lie undetected until after exposure has ended. Motor disturbances can take on many guises, including tremor, difficulty in positioning, fatigue, or rigidity. Techniques for measuring these different endpoints in primates will be addressed. One preparation that enables the simultaneous monitoring of positioning, tremor, and operant behavior in nonhuman primates is described, and tactics for obtaining spectral estimates of tremor from a positioning task are outlined. The spectra obtained from this preparation are reliable and valid: they are stable over a period of a year, they correspond to spectra obtained from accelerometers, and are altered by acute administration of ethanol or oxotremorine. These two drugs had opposite effects on tremor but affected bar positioning in a similar manner.

Oral caffeine consumption by rats: the role of flavor history, concentration, concurrent food, and an adenosine agonist.

Some determinants of caffeine consumption by rats were examined using the two-bottle choice test. To describe the role of flavor history, groups of eight rats each received one of three fluids as their only source of fluid beginning at 29 days of age and continuing throughout the experiments. One group ("water") received tapwater, a second group ("caffeine") received 0.5 mg/ml caffeine in tapwater, and a third group ("quinine") received 0.01 mg/ml quinine in tapwater. Two-bottle choice tests began when rats were 40 days old. In the initial tests, caffeine rats drank more caffeinated water than water rats. Quinine rats were midway between these two groups. On a second block of tests, quinine and water rats' caffeine consumption increased so that the three groups were indistinguishable. When 0.5 mg/ml caffeine was available for 24 h, about one third of the total fluid consumption was of caffeinated water for all three groups. The presence of food greatly increased both caffeine and water consumption across a range of caffeine concentrations spanning 0.125-4.0 mg/ml. Increasing caffeine concentration generally increased consumption of plain water and decreased that of caffeinated water (but not total caffeine consumed) for water rats. Caffeine rats generally drank more caffeine than water rats, largely due to a tendency toward increased consumption of the 0.5-mg/ml concentration. Consumption of caffeinated water peaked at 0.5 mg/ml and showed graded decreases at higher and lower concentrations. Caffeine consumption showed dose-related increases with presession administration of l-phenylisopropyl adenosine. The serines of experiments characterize some of the determinants of caffeine consumption in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug effects on an effortful operant: pentobarbital and amphetamine.

The behavioral effects of amphetamine and pentobarbital depend upon the conditions maintaining behavior. For example, amphetamine usually decreases the rate of operant behavior maintained by fixed ratio schedules while pentobarbital either increases it or leaves it unaffected. However, when considerable exertion is required, as in situations that require endurance, amphetamine tends to enhance performance while barbiturates degrade it. These differences complicate predictions of the effects of these two drugs on effortful operants. The present experiment was designed to characterize effortful responding behaviorally and pharmacologically. Cebus monkeys were trained to operate a lever by flexing their arms and extending their legs; this response exerted a force approximating their body weight. This operant was maintained by a multiple fixed ratio fixed interval (Mult FR FI) schedule. The two schedules maintained dramatically different response patterns. The FR schedule maintained vigorous, high rate responding characterized by a narrow IRT distribution centered at 0.5 sec. The FI schedule maintained very low overall rates of responding characterized by a variable IRT distribution with a median of 1.5 to 2 sec. Despite very low rates of responding during the FI component, no consistent rate increases appeared after amphetamine, and 0.3 mg/kg eliminated responding altogether. Pentobarbital increased overall rate but also shifted the interresponse time (IRT) distribution toward longer IRTs. The increase in overall rate arose from an earlier onset of responding during the FI component and occurred simultaneously with response slowing. The present studies do not support suggestions of a generalized enhancement of effortful performance by amphetamine or a generalized degradation by pentobarbital.

Human sensitivity to reinforcement in operant choice: How much do consequences matter?

The results of many human operant conditioning experiments appear to show that humans are less sensitive than nonhumans to operant consequences, suggesting species discontinuities in basic behavioral processes. A reanalysis of 31l data sets from 25 studies employing variable-interval schedules of reinforcement designed to assess sensitivity to reinforcement corroborates the claim that human behavioral allocation among alternatives often deviates from predictions based on rates of experimentally programmed consequences. Close inspection of the studies in question, however, suggests that methodological issues contribute heavily to the differences noted so far between humans and nonhumans and that an explanation based upon species discontinuities is not tenable.

Aging unmasks adverse effects of gestational exposure to methylmercury in rats.

The consequences of developmental exposure to methylmercury on behavior in aged animals were investigated. Methylmercury exposure was arranged by placing 0, 0.5 or 6.4 ppm Hg in the drinking water of female rats at least 4 weeks before mating and continuing until post-natal (PN) day 16. Brain Hg concentrations in cohorts of low- and high-dose offspring were 0.5 and 9.1 ppm at birth and 0.04 and 0. 52 ppm at weaning (described in another report). Lever pressing of female offspring was maintained under a Multiple Differential Reinforcement of High Rate 9:4 Extinction schedule of food reinforcement (Mult DRH 9:4 EXT). Under the DRH 9:4 schedule, a food reinforcer was delivered when nine responses occurred within 4 s. Under the Extinction schedule, responding had no programmed consequences. No exposure-related differences in reinforcement rate under the DRH schedule or discrimination between the DRH and extinction components were apparent initially. At 950 days of age, the overall response rates of controls had shown a gradual decline over the previous 500 days to about 80% of their beginning levels, but, otherwise, most controls were healthy. A gradual decline in the reinforcement rate began to appear in low- and high-dose rats at about 500 and 800 days of age, respectively. Microanalyses of the nine-response burst maintained by the DRH schedule revealed that the lever-press duration increased, the inter-response time (IRT) was unaffected, and the time between response bursts increased. Overall, the nine-response burst remained intact as a coherent response unit. The increased time between response bursts caused the decline in reinforcement rate. All rats displayed these effects as they aged, but the mercury-exposed rats did so sooner.

Developmental exposure to methylmercury alters behavioral sensitivity to D-amphetamine and pentobarbital in adult rats.

Female rats were exposed to 0, 0.5, or 6.4 ppm methylmercury in their drinking water before mating, and throughout gestation and lactation. When the female offspring were 4-6 months old, they were trained to respond under a multiple differential reinforcement of high rate (DRH) 9:4-- Extinction schedule of reinforcement. No differences among exposure groups were apparent in steady-state behavior. Drug challenges were conducted with multiple doses of D-amphetamine, scopolamine, pentobarbital, haloperidol, and dizocilpine, drugs selected for their different pharmacological effects. The ED(50) values for amphetamine's reinforcement rate-reducing effects for the control, 0.5-, and 6.4-ppm groups were 3.1, 1.9, and 0.9 mg amphetamine/kg body weight, respectively, demonstrating an increased sensitivity to D-amphetamine in methylmercury-exposed rats. Rats in the 6.4-ppm group also demonstrated a relative insensitivity to pentobarbital. Further, these exposed rats exhibited an inverted U-shaped dose-effect curve under the pentobarbital dose-effect determination, while controls showed only a declining curve. Exposed rats did not respond differentially to haloperidol, scopolamine, or dizocilpine, suggesting specificity. The present data suggest an involvement of catecholaminergic and GABAergic activity in methylmercury's neurotoxicity.

In utero lead exposure in squirrel monkeys: motor effects seen with schedule-controlled behavior.

Timed-pregnant squirrel monkeys were exposed orally to lead during the last 1/2 to 2/3 of gestation such that maternal lead levels ranged from 21 to 70 micrograms/dl in blood. Offspring of these lead-exposed monkeys were compared to gender-matched, untreated controls (blood-lead levels from 4 to 9 micrograms/dl), born at about the same time. When the monkeys were 3 to 7 years old they were trained to pull a T-shaped bar against 1 kg spring through a displacement of 1 cm. This performance was examined during acquisition of different fixed-ratio (1, 5, and 20) and fixed-interval (120", 300", and 600") schedules of reinforcement and during steady state under the fixed-ratio 5 and fixed-interval 600". Monkeys exposed prenatally to lead showed an increased number of responses failing to meet the requirement of pulling against 1 kg spring through a 1 cm displacement when behavior was maintained by a fixed-ratio schedule, which engenders a vigorous, high-rate pattern of responding. This increased number of incomplete responses first appeared in the acquisition of a fixed-ratio 5 and fixed-ratio 20 schedules of reinforcement, remained after the fixed-ratio 5 schedule was allowed to reach steady state, and did not appear under the fixed-interval schedule. Neither body weight not response rate were affected by lead, but it was necessary to control for these variables using multiple regression to isolate lead's effect. The appearance of incomplete responses while the monkeys pulled vigorously against a 1 kg spring suggests that lead exposure during gestation produced subtle motor impairments years after exposure has ended. Deficits in the acquisition of behavior (learning) under Concurrent Random Interval schedules of reinforcement have also been reported with these monkeys. Together, these reports reveal prolonged deficits in learning and motor function resulting from in utero exposure to lead at maternal blood lead levels (21-70 micrograms/dl) that could result from exposure to ambient air in heavily polluted urban environments or in occupational settings meeting current World Health Organization standards.

Ethanol's effects on tremor and positioning in squirrel monkeys.

Ethanol ingestion markedly reduces tremor in patients with essential tremor. This clinical observation prompted the present experiments, which were designed to investigate ethanol's reduction of tremor in squirrel monkeys trained to execute a bar-holding task. A lever was attached to the hub of a rotary variable differential transformer (RVDT) and three squirrel monkeys were trained to position this lever within a 4.5 cm band for 8 seconds for a fruit juice reward. Behavior was maintained by a random ratio 2 schedule of reinforcement. Angular position of the lever was sampled for 5.12 seconds while the monkey held the bar, differentiated twice and analyzed to obtain a spectral description of tremor in units of acceleration 2/Hz. During control and vehicle sessions a spectral peak appeared at about 6-8 Hz and the magnitude of this peak varied from 25 to 150 milli-g2/Hz (where g is the acceleration due to gravity). A second peak appeared in two animals at greater than 15 Hz. For one animal this high-frequency peak was dominant during control sessions but the 6-8 Hz peak was dominant after intubation with water or ethanol. Ethanol produced consistent and dose-related decreases in the amplitude of the spectrum describing tremor but the location of the spectral peaks did not differ from vehicle sessions. The doses that altered tremor also produced an increase in the number of short-duration holds as well as other, less consistent, alterations in the form of the response. These data confirm and quantify ethanol's potency as a tremorolytic agent.

Interactions between ethanol and pantothenic acid on tremor and behavior in squirrel monkeys.

Ethanol consumption alters the levels and distribution of pantothenic acid and its metabolic products, an effect that can be counteracted by preloading with pantothenic acid. Ethanol also produces significant disturbances in motor function and has a potent tremorolytic activity when administered acutely. To investigate the interaction of pantothenic acid and ethanol, the two substances were administered alone and in combination to three squirrel monkeys trained to perform a response-initiated positioning task that enabled the detection of tremor. Tremor was evaluated using spectral analytical techniques. Ethanol at 1.0 gm/kg produced a tenfold reduction in tremor over control sessions while pantothenic acid alone had no effect on tremor. Pantothenic acid (200 mg/kg, IP or IV) administered before ethanol intubation completely counteracted the tremor-reducing action of ethanol in two monkeys and partially counteracted it in a third. The interaction between pantothenic acid and ethanol was limited to these motor effects; the rate-reducing effect of ethanol was unaffected by pantothenic acid.

Discriminative and participant-rated effects of methylphenidate in children diagnosed with attention deficit hyperactivity disorder (ADHD).

Despite the demonstrated beneficial effects of methylphenidate and d-amphetamine for the treatment of attention-deficit hyperactivity disorder (ADHD), the discriminative and subjective effects of these compounds in children are not well understood. This study was designed to characterize such effects in children diagnosed with ADHD. In a series of 3 experiments, 17 children were examined to determine whether methylphenidate (n = 12) and d-amphetamine (n = 5) could be reliably discriminated at doses typically used in clinical practice. Under some conditions (e.g., when they were instructed to attend to the drug effects or when a wide range of doses was used), children discriminated methylphenidate (5.0-30.0 mg) from placebo. Children tested under a range of doses of d-amphetamine (2.5-20.0 mg) were unable to discriminate this drug from placebo reliably. Neither methylphenidate nor d-amphetamine produced reliable participant-rated effects.

The effects of chlorpromazine and imipramine on rate and stimulus control of matching to sample.

Pigeons were trained to perform simultaneous, two-color matching to sample under a multiple fixed-ratio fixed-interval schedule of food presentation. The sequence terminating with a peck on the matching key (a "match") was treated as a unit, analogous to a single key peck in conventional schedules. Except for intermittent reinforcement of matches, no consequent stimulus distinguished matches from mismatches (sequences terminating with pecks on the nonmatching key). The pattern of matches during nondrug sessions resembled that of simpler operants maintained by similar schedules. Matches increased in rate toward the end of both components; mismatch rates increased more slowly. Imipramine increased the rate of mismatches, disrupted schedule patterning, and lowered accuracy in a dose-dependent fashion. Chlorpromazine lowered the overall rate of matches but affected schedule patterns and accuracy less than imipramine. The types of errors during drug sessions were not systematically related to the types of errors that appeared during nondrug sessions. Stimulus control was evaluated for each of the four possible color configurations and was found to be by the entire configuration of colors, not simply by the color of the sample.

Effects of self-generated rules on the development of schedule-controlled behavior.

College students responded under a multiple differential-reinforcement-of-low-rate 5-s fixed-ratio 8 schedule, with components alternating every 2 min. After 40 programmed minutes of acquisition and 12 min of maintenance, without notice, both schedules changed to extinction for 28 min. During acquisition, between alternations of the multiple schedule, some subjects were asked to develop rules describing the schedule contingencies. Other subjects were given these same rules between alternations, and a third group neither received nor were asked to develop rules. By the end of the acquisition phase, self-generated-rule subjects were more likely to show schedule-typical behavior than were subjects not asked to generate rules. The behavior of those given rules was similar to those asked to generate rules at the end of acquisition, but yoked-rule subjects acquired schedule-typical behavior at a quicker rate. By the end of extinction, during the period corresponding to the previous fixed-ratio interval, all no-rule subjects who had earned points during acquisition and maintenance were responding at a rate of less than 30 responses per minute. Only 3 of the 9 self-generated-rule subjects and 2 of the 5 yoked-rule subjects were similarly responding at this low rate. Results suggest that asking subjects to develop self-rules facilitates acquisition, but can retard extinction. Results also suggest that self-generated rules function similarly to external rules.

Unusual etiology of hyperkalemia in an immunocompromised patient.

Hyperkalemia was found in an immunocompromised patient undergoing emergency cystoscopy. The cause of the hyperkalemia was an intraperitoneal rupture of the bladder. This case report discusses conditions that predispose patients to bladder rupture and anesthetic management of hyperkalemia.

Commissioning and operational experiences for the 160ML/d Woodman Point Sequencing Batch Reactor--control of settleability and denitrification using bioselectors.

Achieving and maintaining good biomass settling characteristics is a critical process design objective for any activated sludge wastewater treatment plant (WWTP), whether intermittent or continuous technology. One way of ensuring good sludge settleability in intermittent WWTPs is the incorporation of bioselectors in the process. A bioselector is essentially a small discrete reactor volume designed primarily for carbon absorption, in which activated sludge organisms are exposed to a high substrate concentration for a relatively short time. It is normally very much smaller than an anoxic zone and the activated sludge recycle is only a fraction of that typically adopted in continuous plants. With proper conditioning, recycled biomass rapidly absorbs and stores soluble organic wastewater components before transfer to the main treatment basin. This absorption and storage mechanism, and careful management of aeration throughout the intermittent treatment cycle, plays a crucial role in many subsequent growth and treatment processes, including sludge floc formation, denitrification and biological phosphorus removal. This paper examines some design considerations, and reviews the benefits of bioselectors by reference to the commissioning and initial operation of the new 160ML/d Woodman Point Sequencing Batch Reactor in Perth, Western Australia. The applicability of bioselectors in continuous plants is discussed.