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Biomedical subjects

M W Smith

Publications and source records attributed to M W Smith.

At least 73 records · Page 4Linked to original sources
PubMed1997

Synthesis and biological activities of (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and its metabolites.

The imidazoquinoline (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and oxidation to (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H) -one [(R)-6], intermediate metabolites, where N-demethylation to the imidazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)-5 has taken place, are also observed in these incubates. A cross-species study on the metabolism of (R)-3 in vitro has shown large variations in the extent of metabolism from species to species. Imidazoquinolinones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and also show good dopaminergic (D2) and serotonergic (5HT1A) activities in binding assays. It is probable that these metabolites account at least in part for the in vivo activity found for (R)-3. Efficient syntheses for compounds 3-6 as single enantiomers from quinoline are presented together with information on the biological activities and metabolic stabilities of these compounds.

Aminoquinolines↗
PubMed1997

Degradation of human adrenomedullin(1-52) by plasma membrane enzymes and identification of metabolites.

Very little is known about degradation or metabolism of adrenomedullin. To this end, we incubated adrenomedullin with ovine adrenal, kidney and lung plasma membrane preparations and showed the major degradation products were ADM(2-52) and ADM(8-52). Smaller amounts of ADM(26-52), (27-52), (28-52) and (33-52) were also produced. Degradation was inhibited by EDTA and 1,10 phenanthroline but not by phosphoramidon, leupeptin and pepstatin. The above data are consistent with initial hydrolysis adjacent to hydrophobic residues by a metalloprotease, generating ADM(8-52), (26-52) and (33-52), followed by an aminopeptidase action to produce ADM(2-52), (27-52) and (28-52). Improved understanding of the metabolism of ADM may have therapeutic implications, for example in the treatment of heart failure.

Adrenal Glands↗
PubMed1997

Psychological predictors of peptic ulcer incidence in the Alameda County Study.

It has often been suggested that mood and personality predispose to peptic ulcer, but little prospective evidence exists. We used longitudinal data from the Alameda County Study to seek associations of psychological characteristics with later ulcer development, taking into account the possible confounding or mediating, taking into account the possible confounding or mediating roles of nonpsychological factors. Among 4,595 Alameda County Study subjects ulcer-free in 1965, we studied five baseline psychological measures (depression, hostility, ego resiliency, social alienation or anomy, and personal uncertainty) with respect to reported ulcer in 1973-1974. All five measures had significant age-adjusted associations with incident ulcer [odds ratio (O.R.) 1.8-2.6]. After adjustment for smoking, drinking, skipping breakfast, lack of sleep, painful medical conditions, and liver disease, three measures remained significant: depression, anomy, and hostility. The age-adjusted O.R. of 2.8 [95% confidence interval (C.I.) 1.6, 4.8] for an upper versus a lower tertile index of independently predictive psychological factors fell to 2.1 with adjustment for health-related behaviors and medical conditions, and reached 1.7 (C.I. 1.0, 3.1) after addition of education to the model. We conclude that depression, maladjustment, and hostility are prospectively associated with peptic ulcer. These associations are partially accounted for by confounding or mediation by standard risk factors, and are to some extent related to socioeconomic status.

Adult↗
PubMed1997

Plant 21D7 protein, a nuclear antigen associated with cell division, is a component of the 26S proteasome.

Previously, we cloned a carrot (Daucus carota L.) cDNA encoding a 45-kD protein, 21D7, located in the nuclei of proliferating cells. The 21D7 protein is similar to the partial sequence of a regulatory subunit of the bovine 26S proteasome, p58 (G. DeMartino, C.R. Moomaw, O.P. Zagnitko, R.J. Proske, M. Chu-Ping, S.J. Afendis, J.C. Swaffield, C.A. Slaughter [1994] J Biol Chem 269: 20878-20884) and to the deduced sequence encoded by the Saccharomyces cerevisiae gene SUN2 (M. Kawamura, K. Kominami, J. Takeuchi, A. Toh-e [1996] Mol Gen Genet 251: [146-152]). In our work, the expression of plant 21D7 cDNA rescued the yeast sun2 mutant. Fractionation of carrot and spinach (Spinacia oleracea L.) crude extracts showed that the 21D7 protein sedimented with the active 26S proteasomes. The cessation of cell proliferation in carrot suspensions at the stationary phase caused 26S proteasome dissociation and, correspondingly, the 21D7 protein sedimented together with the free regulatory complexes of the 26s proteasomes. Large-scale purification of carrot 26s proteasomes resulted in co-isolation of the 21D7 protein. Polyacrylamide gel electrophoresis under nondenaturing conditions showed that the 21D7 protein had the same mobility as the 26S proteasome and that proteasome dissociation changed the mobility of the 21D7 protein accordingly. We conclude that the 21D7 protein is a subunit of the plant 26S proteasome and that it probably belongs to the proteasome regulatory complex.

Animals↗
PubMed1997

Luteinizing hormone release and reproductive traits in anestrous, estrus-cycling, and ovariectomized cattle after tyrosine supplementation.

The role of rumen-protected L-tyrosine as a nutritional signal altering LH release and other reproductive traits in cattle was studied. In Exp. 1, 28 suckled crossbred cows were assigned randomly to five treatments (0 or 40 g of tyrosine daily in feed for 3 d followed by a single i.v. injection of 200 micrograms of GnRH or 1 mg/kg of naloxone on d 26 +/- 1 postpartum; no tyrosine plus an injection of saline was the control). Peak LH after GnRH was greater (P < .001) in GnRH-treated cows regardless of tyrosine supplementation. Compared to cows receiving saline, days to first postpartum ovulation were reduced (P < .05) by naloxone, tyrosine, and GnRH. In Exp. 2, 47 suckled crossbred cows were assigned randomly to six treatments (0, 20, or 40 g of tyrosine daily for 3 d before GnRH or saline was injected i.m. on d 23 +/- 1 postpartum). Injection of GnRH increased (P < .001) LH. An interaction (P = .08) of tyrosine and GnRH tended to reduce days to first postpartum ovulation. In Exp. 3, tyrosine (40 g) administered once daily for 3 d to ovariectomized cows (six cows per treatment) had no effect on any characteristic of LH before or after estradiol-17 beta. In Exp. 4, suckled cows (n = 136) were allotted randomly to two treatments (0 or 30 g of tyrosine daily for 3 d before a PGF2 alpha-synchronized estrus). Tyrosine increased (P = .05) the percentage of cows in estrus after PGF2 alpha but reduced (P = .05) AI conception rate. These results fail to support the thesis that tyrosine alters LH release in cattle. Supplemental tyrosine increased expression of estrus in suckled cows after PGF2 alpha and tended to reduce intervals to first postpartum ovulation.

Analysis of Variance↗
PubMed1997

PNU-96415E, a potential antipsychotic agent with clozapine-like pharmacological properties.

The atypical antipsychotic drug clozapine interacts with multiple transmitter systems, among them the D4 subtype of dopamine receptors. PNU-96415E is chemically unrelated to clozapine and has its highest binding affinity for the D4 and 5-HT2A receptors. In comparison to clozapine, PNU-96415E is weaker in binding to D1, D2, alpha1 and muscarinic receptors. PNU-96415E inhibited exploratory locomotor activity in mice and rats, and antagonized d-amphetamine-induced locomotor stimulation in rats. It antagonized apomorphine-induced cage climbing, and blocked head and body twitch produced by 5-HTP in mice. Like clozapine, but unlike haloperidol, PNU-96415E did not antagonize stereotypic behaviors produced by a high dose of d-amphetamine or methylphenidate in rats and mice. PNU-96415E blocked conditioned avoidance in rats but produced no catalepsy, a pattern similar to clozapine but different from haloperidol. In rats trained to discriminate clozapine from saline injections, the stimulus effect generalized completely with PNU-96415E, but not haloperidol. This profile of pharmacological activities is consistent with that of an atypical antipsychotic and, as in the case with clozapine, the behavioral effects of PNU-96415E cannot be ascribed to a single receptor mechanism.

Animals↗
PubMed1997

Ethnic-affiliation estimation by use of population-specific DNA markers.

During the past 10 years, DNA analysis has revolutionized the determination of identity in a forensic context. Statements about the biological identity of two human DNA samples now can be made with complete confidence. Although DNA markers are very powerful for distinguishing among individuals, most offer little power to distinguish ethnicity or to support any statement about the physical characteristics of an individual. Through a search of the literature and of unpublished data on allele frequencies we have identified a panel of population-specific genetic markers that enable robust ethnic-affiliation estimation for major U.S. resident populations. In this report, we identify these loci and present their levels of allele-frequency differential between ethnically defined samples, and we demonstrate, using log-likelihood analysis, that this panel of markers provides significant statistical power for ethnic-affiliation estimation. In addition to their use in forensic ethnic-affiliation estimation, population-specific genetic markers are very useful in both population- and individual-level admixture estimation and in mapping genes by use of the linkage disequilibrium created when populations hybridize.

Alleles↗
PubMed1996

Pharmacology of U-91356A, an agonist for the dopamine D2 receptor subtype.

U-91356A [(R)-5,6-dihydro-5-(propylamino)4H-imidazo[4,5,1-ij]quinolin -2-(1H)-one, monohydrochloride], bound with highest affinity to the dopamine D2 receptor subtype, although it also bound with somewhat lower affinities to the dopamine D3 and D4, as well as the 5-HT1A receptor subtypes. In addition to depressing dopamine synthesis and turnover, injection of U-91356A increased striatal acetylcholine concentrations. U-91356A also depressed firing rates of dopamine neurons. In mice, this compound stimulated cage climbing and locomotor activity in reserpinized animals; it also antagonized D-amphetamine-stimulated locomotor activity. It produced contralateral turning in rats with unilateral lesions of the substantia nigra. These data are consistent with roles for the dopamine D2 receptor subtype as a dopamine autoreceptor and as a stimulatory, postsynaptic dopamine receptor.

Aminoquinolines↗
PubMed1996

5-HT1D receptor agonist properties of novel 2-[5-[[(trifluoromethyl)sulfonyl]oxy]indolyl]ethylamines and their use as synthetic intermediates.

2-[5-[[(trifluoromethyl)sulfonyl]oxy]-1H-indol-3-yl]ethylamine (18), its N,N-di-n-propyl (12), N,N-diethyl (13), and N,N-dimethyl (14) derivatives, and 4-[3-[2-(N,N-dimethylamino)ethyl]-1H-indol-3-yl]-N-(p-methoxybenzyl) acrylamide (GR46611, 19) were synthesized and tested for binding affinities to cloned 5-HT1A, 5-HT1D alpha, 5-HT1D beta, and D2 receptors. In addition, the intrinsic efficacy was measured as the reduction of forskolin-stimulated cAMP in cells transfected with 5-HT1D alpha and 5-HT1D beta receptors in vitro. The 5-substituted indolyethylamines investigated displayed agonist activity at the 5-HT1D receptors with varying degrees of preference for the 5-HT1D alpha vs the 5-HT1D beta receptors. The primary amine and N,N-dimethyl substitution seemed to be optimal for 5-HT1D alpha affinity. Furthermore, the N,N-diethyl (13) and N,N-dimethyl (14) derivatives showed a 10-25 times preference for the 5-HT1D alpha vs the 5-HT1D beta receptor. In addition, all of the novel compounds showed affinity for the 5-HT1A receptor in vitro (Ki values ranging from 18 to 40 nM). The most promising derivative 14 was virtually devoid of central 5-HT1A agonist activity in rats, as determined by in vivo biochemical assays. Paradoxically, 14, like 19, induced a hypothermic response and a decrease in 5-HIAA levels in the prefrontal cortex and hypothalamus in guinea pigs after systemic administration. Sumatriptan failed to produce either of these effects due to a poor brain penetration.

5-Hydroxytryptophan↗
PubMed1996

Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study.

The chemokine receptor 5 (CKR5) protein serves as a secondary receptor on CD4(+) T lymphocytes for certain strains of human immunodeficiency virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome 3p21, and a 32-base pair deletion allele (CKR5Delta32) was identified that is present at a frequency of approximately0.10 in the Caucasian population of the United States. An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 deletion homozygotes occurred exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion heterozygotes was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 gene. The CKR5Delta32 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a dominant phenotype of delaying progression to AIDS among infected individuals.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Inhibition of dopamine neuron firing by pramipexole, a dopamine D3 receptor-preferring agonist: comparison to other dopamine receptor agonists.

Pramipexole, an amino-benzathiazole [(S)-4,5,6,7-tetrahydro-N-6-propyl-2, 6-benzothiazolediamine dihydrochloride monohydrate] direct-acting dopamine receptor agonist effective in treating Parkinson's disease, bound selectively and with high affinity to dopamine D2-like receptors, with highest affinity at dopamine D3 receptors. Ergot dopamine receptor agonists (bromocriptine, lisuride, pergolide) bound to both dopamine and non-dopamine receptors. Although all agonists depressed dopamine neuron firing, only pramipexole and quinpirole completely silenced firing when administered in slowly-accumulating doses. High-dose pergolide, but not other ergots, completely suppressed firing when given by a prompt bolus i.v. injection, suggesting efficacy limitations may have involved receptor desensitization for pergolide, but not for bromocriptine and lisuride. We conclude that pramipexole differs from ergot dopamine receptor agonists currently used in the treatment of Parkinson's disease by virtue of its selectivity for dopamine receptors, its preferential affinity for the dopamine D3 receptor subtype, and its greater efficacy for stimulating dopamine receptors, as indicated in these electrophysiology assays.

Animals↗
PubMed1996

H-ras transfection of the rat kidney cell line NRK-52E results in increased induction of c-fos, c-jun and hsp70 following sulofenur treatment.

The effect of the antineoplastic drug sulofenur on the induction of the immediate-early genes (IEG) c-fos and c-jun and the stress gene hsp70 was compared in the rat kidney epithelial-like cell line NRK-52E and a derivative H-ras-transfected (H/1.2NRK-52E) cell line. Fold induction for each gene after sulofenur (500 microM) treatment was greater in H/1.2NRK-52E. The maximum increases for NRK-2E and H/1.2NRK-52E were as follows: c-fos, approximately 10-fold and approximately 18-fold; c-jun, approximately 2.5-fold and approximately 3.6-fold; hsp70, approximately 13-fold and approximately 30-fold. In cells loaded with EGTA/AM or treated in low or no Ca2+ HBSS, c-fos induction was reduced similarly in both cell types. However, inhibition of protein kinases with staurosporin and calphostin C reduced c-fos by 80% in NRK-52E but by only 10-20% in H/1.2NRK.52E. These results indicate that sulofenur-induced IEG elevation is Ca(2+)-dependent and that the requirement for protein kinase C activation is bypassed in H-ras-transfected cells.

Animals↗
PubMed1996

How economic demand influences access to medical care for rural Hispanic children.

OBJECTIVES: In a study of access to medical care, the authors analyzed the relationship between factors influencing demand, local unmet needs, and the availability of physicians in a rural California community. METHODS: The California Department of Health Services screened 1,697 (90%) of children aged 1 to 12 years in McFarland, CA. The relation of demand to unmet needs was examined using multiple logistic regression. Factors influencing demand for medical care were: ability to pay (income, health insurance) desire to purchase care (ethnicity, education, perceived need), and incidental costs (transportation, child care, etc). Questions from the Hispanic Health and Nutrition Survey were reconstrued to fit the demand model. Local need and demand for physicians was compared with state levels to assess whether sufficient physicians were available. RESULTS: Eighty-six percent of the children were of Mexican ancestry. Factors influencing demand were linked with specific unmet needs. Although unmet needs were high, demand was low; 46% of all families were below the poverty level. Although four primary care physicians were needed, only one could be supported in the private sector because of low demand. CONCLUSIONS: Advantages to the demand model are: (1) it shows why medical services are underused and lacking in low-income areas although need is high, (2) it permits an economic rationale for extra services for poor diverse populations, (3) it estimates the amount of resources lacking to assure adequate levels of care, (4) it shows why facilitated access is needed for certain groups.

California↗
PubMed1996

Detection of estrus by visual observation and radiotelemetry in peripubertal, estrus-synchronized beef heifers.

The effectiveness of two estrus-detection methods (visual observation and radiotelemetric, pressure-sensitive, rump-mounted devices) was compared in peripubertal, crossbred yearling beef heifers. Heifers (n = 50) were fitted with a pressure-sensitive device affixed to their rumps to which a battery-operated radio transmitter was connected. Activation of the sensor sent a radiotelemetric signal to a microcomputer via a fixed radio antenna. Heifer identification, date, time, and duration of standing events were recorded. Estrus was synchronized by feeding melengestrol acetate (MGA) for 14 d and then injecting PGF2 alpha 17 d after the last daily dose of MGA. Following the injection of PGF2 alpha, heifers were observed visually for signs of estrus at 0730 and 1630 (45 min each). Estrus was detected in 41 of 49 heifers (one lost the device) by visual observation and(or) the radiotelemetric device. Number of standing events during estrus, determined by the radiotelemetric device, averaged 50.1 +/- 6.4 per heifer, with the duration of estrus ranging from 2.6 to 26.2 h (average = 14 +/- .8 h). Visual observation failed to detect 11 of 41 heifers (37%) that were detected by the radiotelemetric device. Heifers with fewer standing events (19.3 vs 60.5; P < .001) and estrus of shorter duration (8.4 vs 15.6 h; P < .001) were those not identified by visual observation. Based on intervals between the first detected standing event of estrus and time of insemination, a wide window of fertility seems to exist in some heifers. Radiotelemetric devices were useful in identifying a greater (P < .05) proportion (100%) of heifers in estrus (increased efficiency) compared with visual observation (73%). However, accuracy of both methods was similar.

Animals↗