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Biomedical subjects

D C Rice

Publications and source records attributed to D C Rice.

At least 91 records · Page 5Linked to original sources
PubMed1986

Elimination of chronically consumed caffeine in the pregnant monkey (Macaca fascicularis).

Characterization of alterations in caffeine elimination during pregnancy is essential in assessing the potential exposure of the fetus to caffeine and its metabolites. Female monkeys (Macaca fascicularis) were exposed to caffeine in their drinking water 7 days/week before, during and after pregnancy. The low exposure (0.15 mg/ml) corresponded to a level sometimes consumed by pregnant women (10-15 mg/kg/day) whereas the high exposure (0.35 mg/ml) was above average human consumption (25-30 mg/kg/day). Blood samples and 24-hr urine samples were collected every 2 weeks throughout dosing. Caffeine and metabolite concentrations in serum and urine were determined by high-performance liquid chromatography. Before pregnancy, geometric mean serum caffeine concentrations were approximately 1.6 and 4.9 micrograms/ml and serum theophylline concentrations were 6.6 and 13.3 micrograms/ml for the low and high dose groups, respectively. During pregnancy, serum caffeine concentrations increased by approximately 100% for both dose groups and, after parturition, declined to prepregnancy concentrations. Serum theophylline concentrations were usually greater than serum caffeine concentrations and did not change during pregnancy. The amount of caffeine and theophylline excreted in the urine over 24 hr increased during pregnancy and returned to prepregnancy levels after parturition. The results of this study indicate that pregnancy decreased caffeine elimination, resulting in a significant increase in serum caffeine levels. The changes in caffeine elimination may be related to alterations in serum estrogen and progesterone levels.

Animals↗
PubMed1985

Low lead exposure from birth produces behavioral toxicity (DRL) in monkeys.

Cynomolgus monkeys (Macaca fascicularis) were dosed from birth with 100, 50, or 0 micrograms/kg/day of lead. This treatment resulted in blood lead concentrations of 25, 15, or 3 micrograms/dl, respectively, before withdrawal of infant formula at 200 days of age, and steady-state concentrations of 13, 11, or 3 micrograms/dl. At approximately 3 years of age, monkeys were tested on an intermittent schedule, differential reinforcement of low rate (DRL). This schedule required the monkey to withhold responding for a specific time in order to be reinforced. The performance of treated monkeys did not improve as rapidly as controls as measured by increase in reinforced responses and decrease in nonreinforced responses during initial sessions. In addition, treated monkeys exhibited greater between session variability during terminal sessions. These effects were dose related. The results of the present experiment in conjunction with those of previous experiments with this same group of monkeys suggest that blood lead concentrations presently found routinely in the human population may produce neurotoxicity.

Animals↗
PubMed1985

Acute trimethyltin intoxication in the monkey (Macaca fascicularis).

Adult cynomolgus monkeys were administered trimethyltin (TMT) iv in dosages ranging from 0.75 to 4.0 mg TMT/kg and observed for behavioral changes. Animals were subsequently killed for light and electron microscopic examination. TMT showed a dose-related toxicity, with high dose animals (4.0 and 3.0 mg/kg) dying within 24 hr, and low dose animals (0.75 mg/kg) surviving without morphological effects. Animals given 1.10 mg TMT/kg displayed a reproducible clinical course, characterized by tremor, hyperactivity, and ataxia which progressed to stupor and finally unconsciousness. By light microscopy, neuropathology was most pronounced in the CA-3 and CA-4 regions of Ammon's horn. Degenerating pyramidal neurons, micro- and astrogliosis, and neuronophagia were commonly observed. Mild degenerative changes were identified in amygdala, medulla, spinal cord, and Purkinje cells. The fascia dentata remained intact. Ultrastructurally, injured neurons contained accumulations of lysosomes and lysosome-like structures within perikarya and neurites. Demyelination or vascular damage was not observed. Data indicate the monkey to be highly sensitive to TMT, with morphological injury most severe in limbic structures.

Animals↗
PubMed1985

Chronic low-lead exposure from birth produces deficits in discrimination reversal in monkeys.

Cynomolgus monkeys (Macaca fascicularis) were dosed from birth with 100, 50, or 0 micrograms/kg/day of lead. This protocol resulted in blood lead concentrations of 25, 15, or 3 micrograms/dl, respectively, before withdrawal of infant formula at 200 days of age. Blood lead concentration declined thereafter over the next 100 to 150 days to steady-state levels of 13, 11, or 3 micrograms/dl. At approximately 3 years of age, monkeys were tested on a series of three discrimination reversal tasks: nonspatial form discrimination, nonspatial color discrimination with irrelevant form cues, and nonspatial form discrimination with irrelevant color cues. The higher dose group was impaired relative to controls over the entire experiment (all three tasks combined), the two form discrimination tasks combined, and the form discrimination with no irrelevant cues. Deficits were most marked over the first several reversals. The lower dose group was impaired on the color discrimination task and on the last several reversals of all tasks combined. In addition, the higher dose group was impaired relative to the lower dose group over the entire experiment.

Animals↗
PubMed1985

The fate of chronically consumed caffeine in the monkey (Macaca fascicularis).

The metabolic fate of chronically administered caffeine was examined in monkeys. Caffeine and equal parts of citric acid were added to the drinking water of four female monkeys (Macaca fascicularis). The concentration was gradually increased over a 10-week period to 0.35 mg/ml for three of the monkeys. A monkey that was lactating, but had no infant, was exposed to caffeine in the drinking water at a concentration of 0.30 mg/ml. At these doses, administered for up to 50 weeks, there were no overt signs of toxicity as indicated by food and fluid consumption, body weight, or general condition of the monkey. Mean plasma caffeine concentrations were 3.8, 5.7, and 5.9 micrograms/ml, while mean plasma theophylline concentrations were 11.8, 13.0, and 20.1 micrograms/ml, respectively for the monkeys receiving 0.35 mg/ml. Mean plasma caffeine and theophylline concentrations for the lactating monkey were 10.7 and 21.4 micrograms/ml, while mean milk concentrations were 10.5 and 17.6 micrograms/ml, respectively, indicating that caffeine and its major metabolite theophylline are readily excreted in milk. The high plasma theophylline levels indicate that caffeine metabolism in the monkeys differs from that in humans. Theophylline was the main urinary metabolite. In addition, large amounts of 1.3-dimethyluric acid were excreted in the urine but only traces of this metabolite were found in the plasma. After withdrawal of caffeine, plasma caffeine levels decreased to almost zero in the first 24 hr with a half-life of 5.5 hr, and plasma theophylline levels declined with a half-life of 12.7 hr.

Animals↗
PubMed1985

Effect of diet on blood lead concentration in the cynomolgus monkey.

Infant cynomolgus monkeys (Macaca fascicularis) were reared from birth in an infant primate nursery and dosed with lead acetate (2 mg Pb/kg body wt/day) from approximately 100 days of age. The monkeys were switched from an infant formula diet to a diet of primate chow and water at 460 days of age. Beginning at approximately 935 days of age, various diets were fed in the following order: infant formula plus a restricted amount of primate chow, infant formula only, infant formula plus cellulose fiber, infant formula plus phytic acid, cow's milk, and primate chow plus water. Blood lead content was determined throughout the experiment. At 360 days of treatment (approx. 460 days of age) the blood lead concentration was 90 micrograms/dl but decreased to 50 micrograms/dl within 30 days after the diet was changed to primate chow and water. When the monkeys were 935 days of age the introduction of the infant formula plus a restricted amount of primate chow had little effect on blood lead concentrations. However, when primate chow was removed from the diet so that the monkeys were fed infant formula only, there was a rapid increase in blood lead from approximately 40 to 220 micrograms/dl. The addition of cellulose fiber to the infant formula had no effect on blood lead concentrations, whereas the addition of phytic acid caused an abrupt decrease to approximately 85 micrograms/dl. Blood lead concentrations increased to approximately 190 micrograms/dl when cow's milk only was fed and decreased to approximately 55 micrograms/dl when the monkeys were returned to a diet of primate chow and water.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Ketoconazole therapy for endemic blastomycosis.

Amphotericin B is effective in therapy for blastomycosis but causes a number of serious adverse reactions. Because ketoconazole has in-vitro activity against Blastomyces dermatitidis, we administered this agent in a dosage of 400 mg/d to 46 patients with blastomycosis, with 43 patients receiving at least 1 month of therapy. Thirty-five patients had cure without relapse over a mean follow-up of 17 months. Six had a relapse of infection but 4 of these had been noncompliant with therapy. Two patients improved initially but ultimately had progression of disease despite maintenance of adequate serum levels. Adverse effects were common but not severe. Three patients with extensive infection died--2 had received only one dose of ketoconazole and 1 had received therapy for only 2 weeks. The cure rate in these patients suggests that ketoconazole may replace amphotericin B as the initial treatment of blastomycosis that is not overwhelming.

Adult↗
PubMed1984

Behavioral deficit (delayed matching to sample) in monkeys exposed from birth to low levels of lead.

Monkeys (Macaca fascicularis) were dosed po from birth with 500 micrograms/kg/day of lead as lead acetate. Blood levels peaked at an average of 55 micrograms/dl by 100 days of age, and dropped after 200 days of age to a steady-state level averaging 33 micrograms/dl. No overt signs of lead toxicity were observed. Between 3 and 3.5 years of age, monkeys were tested on both a nonspatial (color) and a spatial delayed matching to sample paradigm. For the nonspatial paradigm, the monkey was required to press a button that was lit with one of three colors a specified number of times, which turned the light off. After a specified delay period (varying from 0 seconds to several minutes), three test buttons were lit, one with each of the three colors. The monkey pressed the button corresponding to the color that had appeared on the sample button in order to receive a fruit juice reward. For the spatial matching to sample, one of the three test buttons was lit. The monkey responded on this button a specified number of times, which turned the light off. After a predetermined delay of variable duration, all three test buttons were lit and the monkey responded on the previously lit one in order to be reinforced. The treated monkeys were impaired relative to controls on both the spatial and nonspatial matching tasks, even though they learned the matching tasks as readily as controls and performed as well as 0 sec delay.

Animals↗
PubMed1982

Early chronic low-level methylmercury poisoning in monkeys impairs spatial vision.

Five monkeys were treated from birth with oral doses of mercury as methylmercury (50 micrograms per kilogram of body weight per day); concentrations in the blood peaked at 1.2 to 1.4 parts per million; and declined after weaning from infant formula to a steady level of 0.6 to 0.9 part per million. There were no overt signs of toxicity. When tested between 3 and 4 years of age under conditions of both high and low luminance, treated monkeys exhibited spatial vision that was impaired compared with that of control monkeys.

Animals↗
PubMed1979

Operant conditioning of infant monkeys (Macaca fascicularis) for toxicity testing.

A technique has been developed that allows infant monkeys to perform on an operant schedule as soon as they are able to self-feed. Behavior is shaped in small increments through a series of operants; sensory and motor systems as well as performance on schedules using intermittent reinforcement may be tested as early as 3-4 weeks of age. This is accomplished by exposing the infant to the operant situation almost continuously, and allowing the infant to feed only by operantly responding. Infants exposed to lead post-natally differed from controls in pattern of fixed ratio responding, "activity" as measured by pattern of responding over the course of the session, and on a two-choice form discrimination reversal learning set paradigm. This technique allows rapid accumulation of large amounts of data without experimenter intervention.

Animals↗
PubMedDate not supplied

Subclinical changes in luteal function in cynomolgus monkeys with moderate blood lead levels.

The objective of the present study was to investigate luteal function in cynomolgus monkeys (n = 32), aged 15-20 years with blood lead levels (BLLs) in the range of < 3.0 micrograms dl-1 (control, n = 20), 10-15 micrograms dl-1 (low, n = 7) and 25-30 micrograms dl-1 (moderate, n = 5). Sampling was performed daily beginning with day 10 of the menstrual cycle and concluding on the first day of the subsequent menstrual cycle. Circulating levels of oestradiol (E2), progesterone (P4) and 20 alpha-hydroxyprogesterone (20-OHP) were normalized to the day of the ovulatory E2 surge. The area under the concentration curve (AUC) for P4 was significantly lower in monkeys with moderate BLLs compared to the control group (P = 0.04). The number of days for which circulating levels of P4 were greater than 1.0 ng ml-1 were also significantly fewer (P = 0.03) in monkeys with moderate BLLs compared to controls. There was no statistical evidence of a lead effect on circulating levels of E2, 20-OHP or menstrual cycle characteristics. These data suggest that chronic lead exposure suppresses corpora luteal production of P4 in the monkey at circulating BLLs lower than previously reported and relevant to humans with occupational exposure to lead.

Algestone↗
PubMedDate not supplied

T cell activation and retargeting using staphylococcal enterotoxin B and bispecific antibody: an effective in vivo antitumor strategy.

The aim of this work was to test for cure and immunity in a micrometastatic tumor model using in vivo T cell activation with staphylococcal enterotoxin B (SEB) and retargeting with antitumor x anti-CD3 F(ab')2 bispecific antibodies (bsAb). All studies were performed in C3H/HeN mice using syngeneic tumor cell lines. For survival studies, mice were injected intravenously on day 0 with CL62 (a p97-transfected clone of the K1735 murine melanoma tumor). Day-3 treatments included saline (control), SEB (50 gamma g intraperitoneal) with or without bsAb (5 micrograms i.v.). Cured mice, surviving beyond 60 days, were rechallenged with subcutaneous CL62, K1735, or a nonmelanoma control, AG104. SEB activation studies were performed with pulmonary tumor-infiltrating lymphocytes isolated from 10-day established CL62 tumors. Maximal tumor-infiltrating lymphocyte cytotoxicity was demonstrated 24 h following SEB injection, therefore bsAb treatments were administered 24 h after SEB. When survival was examined at 60 days, there were significantly more survivors in the group receiving SEB plus bsAb (70%) compared to the group receiving SEB alone (30%), and the controls (0%) (P = 0.02 and P < 0.01, respectively). Mice cured of CL62 using SEB alone or with bsAb demonstrated equal immunity to CL62, however, mice treated with SEB plus bsAb were more often immune to the p97-parental cell line, K1735(P = 0.001). Ag104 consistently grew in all mice. Results of these studies demonstrate that SEB plus bsAb can be effective, not only in curing tumors but also in providing protective immunity against targeted and non-targeted tumor antigens.

Animals↗
PubMedDate not supplied

Long-term consequences of intraoperative spillage of bile and gallstones during laparoscopic cholecystectomy.

Laparoscopic cholecystectomy is associated with a higher incidence of iatrogenic perforation of the gallbladder than open cholecystectomy. The long-term consequences of spilled bile and gallstones are unknown. Data were collected prospectively from 1059 consecutive patients undergoing laparoscopic cholecystectomy over a 3-year period. Details of the operative procedures and postoperative course of patients in whom gallbladder perforation occurred were reviewed. Long-term follow-up (range 24 to 59 months) was available for 92% of patients. Intraoperative perforation of the gallbladder occurred in 306 patients (29%); it was more common in men and was associated with increasing age, body weight, and the presence of omental adhesions (each P < 0.001). There was no increased risk in patients with acute cholecystitis (P = 0.13). Postoperatively pyrexia was more common in patients with spillage of gallbladder contents (18% vs. 9%; P < 0.001). Of the patients with long-term follow-up, intra- abdominal abscess developed in 1 (0.6%) of 177 with spillage of only bile, and in 3 (2.9%) of 103 patients with spillage of both bile and gallstones, whereas no intra- abdominal abscesses occurred in the 697 patients in whom the gallbladder was removed intact ( P < 0.001). Intraperitoneal spillage of gallbladder contents during laparoscopic cholecystectomy is associated with an increased risk of intra-abdominal abscess. Attempts should be made to irrigate the operative field to evacuate spilled bile and to retrieve all gallstones spilled during the operative procedure.

Bile↗
PubMedDate not supplied

Reproductive endocrine effects of chronic lead exposure in the male cynomolgus monkey.

The reproductive endocrine effects of chronic lead exposure were investigated in 9 year old male (n = 16) cynomolgus monkeys, orally dosed with lead acetate (1500 micrograms/kg/day) according to the following dosing regimens: continuous exposure from birth onward (lifetime, n = 4), beginning at postnatal day 300 (post-infancy, n = 5) and postnatal days 0 to 400 (infancy, n = 4), or vehicle only (control, n = 3). Altered Sertoli cell function was shown by a significant (P = 0.0286) decrease in the inhibin/follicle stimulating hormone (INH/FSH) ratio in both the lifetime and post-infancy groups compared to the control group. Gonadotropin releasing hormone (GnRH) stimulated levels of luteinizing hormone (LH) were significantly (P = 0.0370) lower in the lifetime group compared to the control group as determined by comparisons of the area under the curve. These data suggest that chronic lead exposure exerts a subtle effect on the pituitary as well as on Sertoli cell function.

Animals↗
PubMedDate not supplied

Methodological approaches to primate behavioral toxicological testing.

The monkey may often be the best model with which to characterize low-level effects of neurotoxicants, including those produced by developmental exposure. The nervous system of the monkey is very similar to the human and, like humans, monkeys have a long period of gestation, infancy, and sexual immaturity during which the nervous system continues to develop. The sensory systems of monkeys are very similar to humans, and intellectual capabilities may be tested that are not possible using other common laboratory species. The effects of low-level developmental exposure to neurotoxicants have been studied in the cynomolgus monkey using operant conditioning techniques to detect subtle defects. Intermittent schedules, a standard tool in behavioral pharmacology, have proved sensitive indicators of toxicity produced by developmental lead exposure. Such intellectual functions as learning, memory, adaptability, and distractibility have been explored by techniques including discrimination reversal, matching to sample, and delayed alternation. Such techniques have revealed impairment produced by lead similar to that observed in lead-exposed children. Visual deficits produced by methylmercury have been revealed by psychophysical techniques, in the absence of any obvious signs of toxicity.

Animals↗
PubMedDate not supplied

Lifetime low-level lead exposure produces deficits in delayed alternation in adult monkeys.

Cynomolgus monkeys (Macaca fascicularis) were dosed continuously from birth onward with 100, 50, or 0 micrograms/kg/day of lead. This resulted in blood lead concentrations of 25, 15, or 3 micrograms/dl respectively before withdrawal of infant formula at 200 days of age. Blood lead concentrations declined thereafter over the next 100-150 days to steady-state concentrations of 13, 11, or 3 micrograms/dl. At seven to eight years of age, monkeys were tested on a delayed alternation task. The task required the monkey to alternate responses between two pushbuttons; each alternation was rewarded with a small amount of apple juice. After each monkey learned the task, a delay was instituted between trials. The initial delay was 100 msec, and was increased in steps to 15 sec by the end of the experiment. Treated monkeys were impaired in their ability to learn the alternation task, but were not different from controls at short delay values (1 and 3 sec). At longer delay values (5 and 15 sec), treated monkeys again exhibited impairment. At the 15 sec delay value, some individuals in both treated groups exhibited marked perseveration, responding on the same button in some instances for hours at a time. Treated monkeys were also more variable in their performance across sessions than were controls. The data are interpreted as indicative of spatial learning and short-term memory deficits in the lead-exposed monkeys.

Animals↗
PubMedDate not supplied

Automated behavioral procedures for infant monkeys.

A method is described for testing infant monkeys on a variety of operant tasks as soon as they can self-feed, typically within the first week of life. Each infant was housed during the 16-21-hour experimental session in a cage to which operant behavioral equipment was attached. Computer control of the experimental contingencies and data acquisition allowed a relatively large number of monkeys to be tested simultaneously, as well as detailed analysis of response parameters. Infant monkeys are capable of learning a number of tasks that assess learning and memory, including visual discrimination and reversal, simultaneous discrimination, and spatial and nonspatial matching to sample. Infant monkeys also perform like older animals on intermittent schedules of reinforcement. The long experimental sessions allowed determination of feeding pattern over the course of the night. Analyses of these variables have proved sensitive to the effects of developmental exposure to neurotoxicants such as lead and caffeine.

Animals↗