Biomedical subjects
Publications and source records attributed to J Stewart.
Mononuclear phagocyte functions are critically dependent on cell surface recognition events. This review describes a number of receptors that appear to recognize simple sugars and function in the clearance of foreign or effete material or in the stimulation of other cellular processes.
In rats previously trained to self-administer heroin intravenously, the application of morphine directly to the ventral tegmental area (VTA) has been shown to reinstate responding after a period of extinction, suggesting that the activation of mesolimbic dopamine neurons might underlie the priming effects of i.v. injections of opiates and stimulants found previously. In the present experiments rats were trained to self-administer heroin intravenously. Following extinction training, and after a period of at least 30 min of no responding, bilateral microinjections of either 0.5 microliter saline or 10 micrograms/0.5 microliter (+)-amphetamine sulfate were made into the N. accumbens. Amphetamine, but not saline reinstated self-administration behavior for about 1 h. In contrast, bilateral intra-accumbens injections of either 5 or 10 micrograms/0.5 microliter morphine sulfate to these same animals led to only infrequent responses late in the 90 min session. Both drugs increased locomotor activity measured in independent tests. Because the locomotor activity produced by intra-accumbens morphine occurs independent of the mesolimbic dopamine system, unlike that produced by VTA morphine and intra-accumbens amphetamine, and because it does not show sensitization, it is argued that the reinstatement effects of opiates and stimulants on self-administration behavior are mediated by the mesolimbic dopamine system, and may be related to the ability of opiates and stimulant drugs to cause sensitization within that system.
Chlorophyllin was studied for its antimutagenic activity against aflatoxin B1 in Salmonella typhimurium strain TA98 using the plate-incorporation test in the presence of S9 activation. Comparative antimutagenicity between chlorophyllin and certain commonly studied antimutagens (i.e., vitamins A, C, and E, retinoic acid, and beta-carotene) was also examined. A dose-related inhibition of aflatoxin B1 mutagenicity by chlorophyllin was observed, with the mutagenicity being abolished by 860 nmole chlorophyllin per plate. The inhibitory activity of chlorophyllin occurred only when cells were treated concurrently with chlorophyllin and aflatoxin B1. The antimutagenic potency of chlorophyllin was comparable to that of vitamin A and higher than that of retinoic acid and beta-carotene. Vitamins C and E had no effect on aflatoxin B1 mutagenicity under the conditions used. The results of toxicity tests and a reconstruction experiment showed that inhibition of the mutagenicity of aflatoxin B1 by chlorophyllin and the other active agents was due to antimutagenicity.
The effect of age and of prolonged caloric restriction on glucose tolerance and insulin responsiveness has been studied in male Fischer 344 rats. Beginning at 1 month of age dietary intake of an experimental group (R) was limited to 60% of that of the control group (AL) which was allowed to eat ad libitum. Studies were carried out at intervals up to 24 months of age. In AL rats the oral glucose tolerance curve showed progressively higher peak levels of plasma glucose with age, and a decrease in the plasma insulin concentration at the time of the glucose peak. The R group did not show the increase in peak value with age and the corresponding insulin concentration was lower than that of the AL group. These results are compatible with a delay in the first phase of insulin secretion in aging AL rats. Insulin-stimulated glucose disposal was assessed by the method of Reaven et al. [Diabetes, 32 (1983) 175], at ages 4, 12, 18 and 24 months; using infusions of 2 mU of insulin and 1 mg of glucose/min per kg, the steady-state plasma glucose level (SSPG) was slightly lower in R than in AL rats, while the steady-state plasma insulin level was reduced by 40-60%. In rats aged 18-24 months the hepatic glucose output, measured with [3-3H]glucose, was the same for AL and R rats in the basal state and was reduced to the same extent by insulin. In the presence of epinephrine and propranolol, infusion of glucose and insulin at various rates demonstrated that the plasma glucose clearance rate increased linearly with increasing SSPI, and at comparable SSPI levels was lower in R than in AL rats. The ability of insulin to stimulate glycogenesis from glucose was measured in primary hepatocyte cultures. Insulin increased glycogenesis 3-fold in cells from AL rats and 4-6-fold in cells from R rats. There was no effect of age. The increased insulin responsiveness of R rats was not due to an increase in insulin binding or to a decrease in insulin degradation (measured with intact cells or as cytosolic insulinase activity).(ABSTRACT TRUNCATED AT 400 WORDS)
In Study I measures of cortical thickness were taken in 90-day-old male and female Sprague-Dawley, Wistar, and Long-Evans rats that were born to pregnant females shipped to the laboratory in late pregnancy and that were either gonadectomized at birth or left intact. No evidence for hemispheric differences in cortical thickness was found in any of the groups. Gonadectomy resulted in increased cortical thickness in male Sprague-Dawley and Wistar rats and in small increases in thickness of the left hemisphere in Long-Evans rats, especially males. No effects of gonadectomy were found in females of any strain. The lack of the expected right-over-left difference in cortical thickness in intact males may have been due to prenatal stress caused by housing, handling, and shipping. In Study 2 measures of cortical thickness were taken in 90-day-old male and female Sprague-Dawley rats that were bred in our laboratory, but otherwise similarly treated at birth. In this second study, the expected right-over-left hemispheric difference in cortical thickness was found in intact male rats; none was found in gonadectomized males or in either of the female groups. The lack of asymmetry in gonadectomized males appeared to be due to an increase in thickness in the left hemisphere. Taken together these studies provide support for the idea that hormones of testicular origin suppress cortical enlargement in the perinatal period, particularly in the left hemisphere.
A concurrent prospective study was conducted in Rwanda to compare the immunogenicity and safety of live, attenuated measles vaccine in ill and well children. Five hundred and eighteen children aged 8 to 19 months were selected from children attending the acute care and immunization services of two clinics. Two hundred and sixty-seven ill children and 251 well children were enrolled and examined. Serological tests were performed on blood samples obtained before and 40 days after measles immunization. Among the 208 ill children and 215 well children who were seronegative at baseline and had unequivocal follow-up serological results, seroconversion rates were 81% and 80%, respectively. Side effects were modest and were equally frequent in the two study groups (15.4% among ill children versus 15.1% among well children). These results support a change in measles immunization policy in developing countries with respect to immunization of children with acute illnesses. Such a change would make a great contribution to decreasing the enormous burden of measles in the developing world through increased immunization coverage.
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With increasing use of computerized tomography and ultrasonography, asymptomatic lesions of the adrenal gland are frequently detected. One such tumor is the adrenal myelolipoma, composed of adipose and hemic elements histologically resembling bone marrow. This tumor can be diagnosed by its characteristic appearance on CT scan, and fine-needle biopsy guided by CT can be used to obtain a tissue diagnosis. Because patients with adrenal myelolipoma typically have recurrence of symptoms after resection, surgical intervention is not indicated unless an enlarging tumor impinges on surrounding structures.
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The effects of short term (1-month) and life-long 60% ad libitum food restriction on the adrenocortical response to restraint stress were compared in young and aged Fischer 344 rats. In rats restricted for 1 month (study 1), the adrenocortical response differed as a function of age. In 8-month-old animals, the initial steep rise in corticosterone in response to stress was of similar magnitude in ad libitum and restricted animals. In 23-month-old animals the corticosterone response was severely blunted in restricted animals. In life-long restricted animals (study 2), the corticosterone response to restraint stress was tested at 8, 16, and 24 months of age. The general pattern of response to stress in these animals was similar to that in study 1. The 16- and 24-month-old animals showed the same blunted response to stress found in the 23-month-old animals restricted for only 1 month, suggesting that the severe restriction per se and not life-long food restriction blunted the response to stress in aged animals. The similarity between the response to stress in study 1 and study 2 was evident even though animals were tested in one case before feeding when corticosterone levels were high, and in the other 4-5 h after feeding when corticosterone levels were lower. In study 3 it was found that in food-restricted young rats, the mean corticosterone level over a 24-h period was significantly elevated above that in ad libitum fed young rats. In aged rats, however, except before daily feeding, corticosterone levels of food-restricted rats remained significantly below those of ad libitum fed animals, whose levels were, in turn, significantly elevated compared to those of ad libitum fed young rats. These findings suggest that in aged animals severe food restriction reduces basal corticosterone levels, adrenal responsiveness to stress, and adrenal size and has the potential to protect against the consequences of high corticosterone levels in aging.
Several recent reports have demonstrated that opiate action in both the ventral tegmental area (VTA) and the nucleus accumbens (N.Acc.) produces an increase in locomotor activity. In the present experiments, the effect of repeated bilateral injections into these sites of either morphine or the mu opioid receptor agonist Tyr-D-Ala-Gly-NMe-Phe-Gly-ol (DAGO) was investigated. As previously reported with morphine and other opioids, repeated injections of either morphine or DAGO into the VTA produced a progressive enhancement or sensitization of their locomotor activating effects. On the other hand, although both substances injected into the N.Acc. elicited increased locomotion, repeated injections did not lead to sensitization. It has been suggested that the increased locomotor activity produced by opiate injection into the VTA is dopamine-dependent while that produced by intra-N.Acc. injections is not. The present findings provide neuroanatomical support for the view that sensitization to the locomotor activating effects of opiates and opioids brought about by repeated drug exposure involves the mesolimbic dopamine system.
The pattern of c-myc gene organization and expression has been examined in resected colonic tumors and in the adjacent normal colon from 15 patients undergoing radical surgery. DNA hybridization showed no evidence of gene amplification or rearrangement. Transcripts of the c-myc messenger ribonucleic acid (mRNA) were elevated up to 32-fold in 12 of 15 tumors. The gene product, p62c-myc, was detected by both immunoblotting and immunohistology using a monoclonal antibody raised against a synthetic peptide immunogen. There was close correlation between c-myc mRNA copy number and p62c-myc abundance. Three well differentiated tumors contained high levels of transcript and protein, whereas four poorly differentiated tumors had the lowest levels. The assay of oncogene products may provide new biologically relevant tumor markers for determining prognosis and guiding treatment.
In conjunction with industrial hygiene surveys, mutagenicity studies were performed for the airborne contaminants in three polyurethane manufacturing plants. Airborne particles were collected on glass-fiber filters with Hi-Vol pumps from different locations in each plant. Gases were collected in multiple-sorbent cartridges. The collected airborne particles and sorbent cartridges were extracted with organic solvents. Each extract was tested for mutagenic activity using Salmonella typhimurium TA98 and TA100. The results showed that airborne particles from all three plants are mutagenic to TA98 with or without S9 activation. The mutagenicity with S9, however, was two to four times higher than that without S9. None of the samples of gases collected on sorbent cartridges showed mutagenic activity.
The SOS umu-test has been used for the detection of DNA-damaging agents. In this system the plasmid pSK1002 carrying a fused gene umuC-lacZ was introduced into Salmonella typhimurium TA1535. The SOS function induced by genotoxic agents is detected by a colorimetric measurement of beta-galactosidase activity encoded by the lacZ gene, which is regulated by the Umu operon. This system was used with modifications to study the SOS function inducibility of volatile chemicals (propylene oxide, methyl bromide, and ethylene dibromide) and air pollutants (diesel emission, welding fumes, and cigarette smoke). Tester cells were exposed directly to the test material. The enzyme activity of the treated cells was measured according to the established procedure. Results of the study showed that all chemicals and pollutants tested induced SOS function in a dose-related manner. These results indicate that the SOS umu-test is potentially useful for the in situ detection of genotoxic agents in occupational settings.
The effect of confinement during conditioning on subsequent test levels of locomotor activity and conditioned place preference (CPP) was investigated by giving rats discrimination training with morphine and saline in the presence of different tactile floor cues in an open field. Groups of rats were trained under one of three levels of confinement (not confined, confined to 1/4, or confined to 1/16 of the open field) and tested for locomotor activity and CPP in the entire open field after receiving a saline injection. Confined rats subsequently spent less time on the morphine-paired floor cues (CS+) and were more active throughout the open field during the test than rats not confined during conditioning. Rats confined to the smallest area spent the least time on the CS+ and were the most active. It is suggested that confinement may preserve the novelty of the testing environment, which in turn may interfere with rats' usual responses to incentive drug-paired stimuli. These findings may have important implications for versions of the CPP technique in which training and testing environments differ considerably.
In order to investigate whether the ability of peripheral blood monocytes to bind bacteria is impaired in diabetes, we studied carbohydrate-binding ("lectin-like") receptors and the receptor for the Fc portion of immunoglobulin on monocytes from 25 male Type 1 (insulin-dependent) diabetic patients and 10 age-matched healthy control subjects. Peripheral blood monocytes from the diabetic patients expressed lower levels of "lectin-like" receptors compared to the control subjects, whereas the expression of the receptor for the Fc portion of immunoglobulin was similar in both populations. There was no correlation between the degree of "lectin-like" binding activity and plasma glucose concentration or glycaemic control. Recognition of unopsonized bacteria by the "lectin-like" receptor is impaired in Type 1 diabetes; this may affect the efficient elimination of potential pathogens.
A novel version of the conditioned place preference (CPP) technique was used in an attempt to determine whether tactile stimuli previously associated with morphine elicit approach and sustained contact. Empirical support for this view has been equivocal, prompting some to question the validity of the CPP technique. In the present study, rats received, during conditioning, morphine (10 mg/kg, IP) paired exclusively with an open field floor made of four quadrants of one texture (CS+) and saline with another floor made of four quadrants of a different texture (CS-). On the test for CPP, rats were given saline and placed in an open field containing either 1, 2, or 4 quadrants of the CS+ (with 3, 2, 0 quadrants of the CS-, respectively). These animals showed high absolute CPP scores on the test, spending, on average, as much as 83% and 75% of their time on the CS+ when two and one CS+ quadrants, respectively, were present. Concurrent measures of activity indicated that animals were most active when all four quadrants were CS+ and least active when zero or one CS+ quadrant was present. Thus, once an animal approached and made contact with the CS+ it tended to maintain contact with this stimulus and to reduce its approach to and contact with other stimuli. The differentiating features of this version of the CPP technique, as well as the relationship between morphine-induced conditioned locomotion and CPP, are discussed.
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