Biomedical subjects
A Young
Publications and source records attributed to A Young.
Chronic treatment with 1-aminocyclopropanecarboxylic acid desensitizes behavioral responses to compounds acting at the N-methyl-D-aspartate receptor complex.
Functional antagonists at the N-methyl-D-aspartate (NMDA) receptor complex produce anti-depressant-like actions in preclinical models. Thus, an injection of a glycine partial agonist (1-aminocyclopropanecarboxylic acid; ACPC), a competitive NMDA antagonist (2-amino-7-phosphonoheptanoic acid; AP-7) or a use-dependent cation channel blocker (MK-801) reduced immobility in the forced swim test (FST) with efficacies comparable to imipramine (Trullas and Skolnick 1990). Seven daily injections of ACPC (200-400 mg/kg) abolished the effects of both this compound (200-1200 mg/kg) and AP-7 (200-300 mg/kg) in the FST. The loss in effectiveness of ACPC required 7 days of treatment to become fully manifest, and was reversed by discontinuing treatment. Other agents active in the FST (e.g. MK-801, imipramine, and nifedipine) were unaffected by this regimen. Moreover, ACPC and AP-7 remained active in the FST following repeated injections of MK-801, AP-7, or imipramine. Chronic treatment with ACPC did not affect its actions in the elevated plus-maze, but significantly attenuated the convulsant and lethal effects of NMDA (125 mg/kg). Tissue levels of ACPC indicate the modified behavioral responses produced by chronic treatment are not attributable to pharmacokinetic factors. These findings suggest repeated administration of ACPC may effect an "uncoupling" of NMDA and glycine receptors, resulting in an apparent desensitization of the behavioral actions of substances acting at these sites.
Controlling and predicting monoclonal antibody production in hollow-fiber bioreactors.
A simple optimization strategy is described which enables monoclonal antibody (MCA) production in hollow-fiber bioreactors to be controlled and predicted. The MCA production rate is demonstrated to increase linearly with the uptake rates of glucose and glutamine and with the production rates of lactate and ammonia. The uptake and production rates of these metabolites can, in turn, be predicted from the pumping rates of basal medium to the bioreactor. We recommend a period of 2 weeks at the start of the cultivation when intensive assaying and monitoring should be carried out. After this period, the medium flow rate and MCA production rate may be predicted by linear extrapolation.
Objectives and outcome of running an early inflammatory arthritis clinic.
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Chlamydiazyme plus blocking assay to detect Chlamydia trachomatis in endocervical specimens.
Three methods to detect Chlamydia trachomatis in endocervical swab specimens collected from 502 women with genitourinary or abdominopelvic symptoms were evaluated: (1) a direct immunofluorescence assay, (2) an enzyme-linked immunoabsorbent assay, confirming positive samples with a blocking assay, and (3) conventional tissue cell culture. C. trachomatis was detected by at least one method in 72 specimens, of which 56 (11%) were determined to be true-positive results by repeated testing and by performing a confirmatory assay. The sensitivity, specificity, and positive and negative predictive values were 91%, 100%, 100%, and 99%, respectively, for culture and the enzyme-linked immunoabsorbent assay plus blocking assay and 74%, 98%, 83%, and 96%, respectively, for the direct immunofluorescence assay. In this population of women, using the enzyme-linked immunoabsorbent assay with the confirmatory assay is a rapid, reliable, and cost-effective alternative to culture for diagnosing infection with C. trachomatis.
Intestinal hypersecretion of the refed starved rat: a model for alimentary diarrhoea.
Fluid transport was gravimetrically measured in vivo in the duodenum, jejunum, and ileum of anaesthetised fed, 72 hour starved and 72 hour starved rats refed for up to five days after starvation. Basal unstimulated fluid transport was monitored by instilling 0.9% NaCl into the lumen and measuring the gain or loss in weight of the closed intestinal loop. Fluid was absorbed in all the areas of the intestine in the fed rats. Increasing basal fluid absorption was observed in the duodenum over the three days of starvation but in the jejunum there was no significant change. In the ileum, the pattern was very different, on day 1 the fluid was absorbed but on days 2 and 3 there was an increasing secretion of fluid. Refeeding the rats with their normal diet restored the basal absorption of fluid in the duodenum within 24 hours, had no effect in the jejunum but in the case of the ileum the hypersecretion of fluid observed in the day 3 starved rat was maintained on day 1 of refeeding, increased further on day 2, decreased on day 3 but returned to absorption on day 4. The normal absorption was restored to the ileum on day 5 of refeeding. Fluid secretion was induced in all the rat groups by bethanechol (ip 60 micrograms/kg bw) a stable cholinergic agonist, PGE2 (ip 10 micrograms/kg (bw) and E coli STa (luminally instilled, 500 ng/ml) a secretory enterotoxin. All the secretagogues gave enhanced secretion compared with the fed by day 2 of starvation which increased considerably on day 3. Refeeding returned their secretion back to the fed level in the duodenum within 24 hours, in the jejunum within 48 hours but in the ileum their induced secretion on day 2 of refeeding was greater than that of the day 2 of refeeding was greater than that of day 3 starved and took until day 4 to return to the fed levels for behanechol and PGE2 and until day 5 for E. coli STa. This behaviour of rat small intestine showing even greater hypersecretion in the refed state than the starved mimics the human condition of alimentary induced diarrhoea where incautious feeding of starved humans induces severe, often lethal diarrhoea. The refed starved rat appears to be a possible model for this condition.
Phospholipid peroxidation deacylation and remodeling in postischemic skeletal muscle.
Reperfusion of ischemic skeletal muscle is associated with white blood cell (WBC) sequestration and hydroperoxy-conjugated diene (HCF) formation, a marker of free radical-mediated phospholipid peroxidation. The purpose of this study was to define the kinetics of phospholipid fatty acyl peroxidation, deacylation, and remodeling in postischemic skeletal muscle during prolonged reperfusion in vivo, and to determine whether reperfusion with WBC and plasma-depleted blood would attenuate postischemic phospholipid peroxidation and myocyte necrosis. The isolated, paired, canine gracilis muscle model was used. After 5 h of ischemia, muscles underwent unaltered reperfusion or initial reperfusion with WBC-deficient blood cells resuspended in hydroxyethyl starch, followed by return to normal circulation (modified reperfusion). The concentration of native fatty acids and HCDs of linoleic acid extracted from muscle phospholipids was quantified by gas chromatography and positively identified by mass spectrometry. Ischemia and reperfusion resulted in phospholipid deacylation and a selective increase in phospholipid stearic acid content, but had no effect on total phospholipid phosphorus. Modified reperfusion decreased 1) early HCD formation (54%) and 2) postischemic skeletal muscle necrosis (49%). These data suggest that reperfusion results in phospholipid deacylation and remodeling, and that the initial oxidant stress during reperfusion may be a significant determinant of ultimate muscle necrosis.
Changes in normal glycosylation mechanisms in autoimmune rheumatic disease.
To investigate potential mechanisms controlling protein glycosylation we have studied the interrelationship between lymphocytic galactosyltransferase (GTase) activity and serum agalactosylated immunoglobulin G levels (G(0)) in healthy individuals and patients with rheumatoid arthritis and non-autoimmune arthritis. In RA there was reduced GTase activity and increased G(0). A positive linear correlation between B and T cell GTase was found in all individuals. The relationship between GTase and G(0) was found to be positive and linear in the control population and negative and linear in the RA population. Sulphasalazine therapy maintained normal levels of GTase and caused a reduction in G(0) in the RA population. IgG anti-GTase antibodies (abs) were significantly increased in the RA population, whereas IgM anti-GTase abs were significantly decreased in both the RA and the non-autoimmune arthritis groups. These data describe a defect in RA lymphocytic GTase, with associated abnormal G(0) changes, which is corrected by sulphasalazine. A possible regulatory mechanism controlling galactosylation in normal cells is suggested, in which there is parallel control of B and T cell GTase. IgM anti-GTase abs may be integrated into this normal regulatory process. This is disrupted in RA, where the positive feedback between GTase and G(0) is lost and there is an associated increase in IgG anti-GTase abs, which may result from isotype switching as IgM anti-GTase abs are reduced. We suggest that these mechanisms are of relevance to the pathogenesis of RA, and that their manipulation may form part of a novel therapeutic approach.
Hemispheric imbalance in schizophrenia.
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1-aminocyclopropanecarboxylates exhibit antidepressant and anxiolytic actions in animal models.
1-Aminocyclopropanecarboxylic acid (ACPC) is a high affinity ligand at strychnine-insensitive glycine receptors that exhibits partial agonist properties in both biochemical and electrophysiological measures. While ACPC was reported active in animal models commonly used to evaluate potential antidepressants (forced swim) and anxiolytics (plus-maze), the zwitterionic character of this compound could limit both penetration into the central nervous system and oral availability. The present experiments were designed to determine the duration of action of ACPC, its efficacy following oral administration, and to compare these effects with the more lipophilic ACPC methyl ester. Parenterally and orally administered ACPC were equipotent in reducing immobility in the forced swim test, an action manifested for at least 6 h. Both orally and parenterally administered ACPC methyl ester were approximately 3.3-fold more potent than ACPC in the forced swim test. In the elevated plus-maze, both ACPC and ACPC methyl ester were active for 1-2 h after parenteral administration. These findings suggest that 1-aminocyclopropanecarboxylates may constitute a novel class of antidepressant/anxiolytic agents.
Agalactosyl IgG: an aid to differential diagnosis in early synovitis.
Sixty consecutive patients presenting with early-onset synovitis were studied by measuring rheumatoid factor (RF) titers and the percentage of oligosaccharide chains attached to the C gamma 2 domain of IgG that lack galactose (GAL[0]). After 2 years of followup, 39 patients (65%) had developed rheumatoid arthritis (RA), and 21 had developed a variety of other inflammatory joint diseases. A combination of RF positivity and GAL(0) levels above the age-corrected mean gave a positive predictive value for a diagnosis of RA in 94% of these patients. These observations may well have clinical utility.
Phenotypic changes in T-cyt-transformed potato plants are consistent with enhanced sensitivity of specific cell types to normal regulation by root-derived cytokinin.
From over forty independently isolated potato lines transformed with wild-type and promoter-mutated T-cyt genes, a number of lines were selected for examination of phenotypic changes in growth and development for plants grown in soil in a controlled environment. The three lines chosen for most detailed examination showed a wide spectrum of phenotypic changes. In comparisons with control potato cv. Désirée, the plants of one line had a two- to three-fold increase in biomass production during early vegetative growth, advanced senescence and a shortened plant life-span. Another line showed abnormal cellulytic senescence. In two lines there were increases in tuber numbers and more skewed tuber size distributions which correlated with reduced shoot apical dominance and shortened dormancy of the stored tubers. None of the lines showed altered timing of onset of tuberization or flowering, although tuberization was consistently delayed when expressed as a function of increasing total plant weight. A hypothesis is proposed to explain the diverse phenotypes which postulates that (1) T-cyt transformation causes enhanced sensitivity to cytokinins in specific types of shoot cells which are already targets for regulation by normal root-derived cytokinins; (2) two distinct types of shoot target cells are present, one in shoot meristems and one in leaves; (3) the two types can acquire enhanced sensitivity, either separately or in combination depending on the particular T-cyt transformation event. The scope for using the transformed plants in subsequent physiological, biochemical and molecular studies, aimed at examining the molecular basis of the model or selected consequences of T-cyt transformation in altering regulation of potato plant growth and development, is discussed. The attention is drawn to the possible involvement at the subcellular level of sucrose phosphate synthase in mediating the phenotypic effects caused by T-cyt transformation.
Changes in IgG glycoform levels are associated with remission of arthritis during pregnancy.
It was found that the percentage of IgG-associated agalactosyl N-linked oligosaccharides (G0) falls during normal human pregnancy and rises to values higher than before conception following delivery (n = 10, 39-55 days after delivery). Serial bleeds from a normal pregnant woman showed a fall in the percentage G0 during gestation and a rapid rise post-partum. A similar study on a pregnant arthritic woman with a pathologically elevated percentage G0 also showed a fall in percentage G0 during pregnancy and a rapid rise post-partum. The changes in IgG glycosylation in the pregnant arthritic woman occurred simultaneously with the pregnancy-induced remission and post-partum recurrence of disease. A further seven pregnant women with rheumatoid arthritis were studied and analysis of their G0 values pre- and post-partum confirmed the result. In a further series of experiments using an animal model of rheumatoid arthritis, DBA/1 mice with collagen-induced arthritis were found to have elevated G0 levels compared with control mice. The percentage G0 was found to fall simultaneously with pregnancy-induced remission to the same value as non-arthritic pregnant mice. Post-partum recurrence of arthritis in these mice was also accompanied by a simultaneous and rapid rise in percentage G0. Pseudopregnancy did not result in a change in the percentage G0, confirming the effect of true pregnancy. Since the proportion of agalactosyl IgG is abnormally high in the serum of patients with rheumatoid arthritis these changes in IgG glycoform levels, or the factors which control them, may be related to the mechanisms underlying remission of arthritis in humans during pregnancy.
Visual processing of stimulus compounds in newborn infants.
An experiment is described in which newborn infants' processing of stimulus compounds was investigated. After familiarization to two alternately presented stimuli which differed in colour and orientation, the newborns showed significant preferences for a stimulus which had a novel colour/orientation combination: the novel stimulus was produced by recombining features of the stimuli used for familiarization. This finding argues against the view that infants initially process separate components, or parts, of visual stimuli and are only able to attend to the correlations between them after about 3 months of age. Rather, the ability to process and remember stimulus compounds is present at birth.
Cumulative dose-response curves for bethanechol-induced electrogenic secretion in rat jejunum in vitro: is tachyphylaxis a significant factor?
Electrogenic secretion was monitored as the short-circuit current (Isc) by an automatic voltage clamp across the isolated rat jejunum incubated in vitro. Responses to consecutive additions of bethanechol (1 mM) to the serosal surface showed tachyphylaxis. Addition of prostaglandin E2, however, after a single dose of 1 mM-bethanechol, induced an undiminished Isc response indicating that the tachyphylaxis was homologous. Dose-response curves for serosal applications of bethanechol obtained by serial-cumulative addition did not show tachyphylaxis when compared with those from a non-cumulative technique. The method of automatically recording the intestinal Isc with serial-cumulative addition of a serosal secretagogue gives dose-response curves free from tachyphylaxis.
Segmental heterogeneity of rat colonic electrogenic secretion in response to the bacterial enterotoxin Escherichia coli STa in vitro.
The effects of the bacterial toxin Escherichia coli STa on electrogenic secretion in proximal, mid and distal rat colon were examined in vitro using the short-circuit current (Isc) as an index of secretion. All areas showed toxin-elevated Isc which was reduced by bumetanide. The proximal colon was the most sensitive (lowest ED50) but displayed the lowest maximal increase in Isc, the mid colon had the largest maximal electrogenic response while the distal colon proved to be the least sensitive (highest ED50). Atropine (1 microM) and tetrodotoxin (1.25 microM) reduced the maximum Isc response to STa by up to 42%, indicating that the enteric nervous system may be partly involved in the response.
Reduction in IgG galactose in juvenile and adult onset rheumatoid arthritis measured by a lectin binding method and its relation to rheumatoid factor.
Glycosylation changes in patients with juvenile chronic and adult onset rheumatoid arthritis have been studied using a novel binding method. Both these major types of arthritis showed decreased galactosylation of serum IgG, which confirms earlier studies using a different, more complex chemical method. No significant correlation between serum IgG, IgM, and IgA rheumatoid factors and age corrected G(o) (percentage of oligosaccharide chains lacking galactose) was found. The possibility that the less glycosylated IgG is preferentially confined to circulating IgM/IgG immune complexes cannot be excluded, however.
Preventing abuse during pregnancy: a national educational model for health providers.
The National Preceptorship Program was funded by the March of Dimes and established at Texas Woman's University in Houston to prepare health care providers to assess pregnant women for abuse and to initiate primary intervention strategies. Essential content was identified and a diversity of learner-focused teaching methods and learning strategies were required for the 21-hour program. Combining didactic and experiential strategies proved to be effective. Thirty-nine health care providers from across the country participated in the program. Process evaluation of the classroom and field learning experiences were particularly positive. A 1-year follow-up product evaluation revealed that participants had presented 120 seminars on preventing battering, had instituted assessment for battering in their agencies, and were planning future seminars.