Search PubMed⌕ Search

Biomedical subjects

D A Smith

Publications and source records attributed to D A Smith.

At least 163 records · Page 9Linked to original sources
PubMed1994

Resistance induced by drug abbreviated Schistosoma mansoni infections: treatment with the drug Ro11-3128 leads to enhanced antigen presentation.

Treatment of mice with the benzodiazepine derivative Ro11-3128 1-2 days post-infection with Schistosoma mansoni leads to arrest of virtually all schistosomula at the skin stage, and results in the development of protective immunity to challenge infection. A characteristic feature of Ro11-3128 treatment in vitro is the formation of exudates and membranous blebs at the schistosomular surface; other drugs tested, such as Ro15-5458 and oxamniquine which are also effective against the skin stages but relatively ineffective in inducing protection, do not induce this reaction. Here, we have examined whether such in vitro treatment causes enhanced presentation of schistosomular antigens by host antigen-presenting cells (APC) using an in vitro assay with activated peritoneal adherent cells as APC and T cells from S. mansoni antigen-sensitized mice. We have shown that viable mechanically transformed schistosomula (MS) can be processed and presented with similar kinetics to soluble antigen. However, in vitro drug treatment leads to enhanced presentation of MS. Experiments in which membranous blebs and antigen released by Ro11-3128-treated parasites during in vitro culture were separated from the remaining intact schistosomula, demonstrated significant stimulatory activity in the soluble and particulate-released antigen fractions. Filtration, antigen transfer experiments and SDS-PAGE analysis of the released material further suggested that most of the activity resided in the particulate fraction. Thus, quantitative and qualitative changes to antigen presentation by Ro11-3128 treatment early after infection may underlie the immunoprotective efficacy of Ro11-3128-abbreviated infections.

Animals↗
PubMed1994

The biology of meningiomas.

Biochemical and molecular biological analyses of central nervous system tumors have progressed considerably in the last two decades. It may soon be possible to reclassify tumors according to biochemical or genetic criteria that relate directly to the tumor's individual biologic potential. Beyond informing a prognosis, these studies may also indicate strategies by which a tumor's biologic destiny can be altered or interrupted. With regard to meningiomas, this promise has not yet been fulfilled, although new agents such as mifepristone are achieving modest success. The greatest efforts thus far have been devoted to the study of sex steroid receptors. Historically, interest in this line of inquiry was enlivened by perceived parallels with hormone receptors identified in breast cancer tissue. Although investigative results have varied widely, a consensus has emerged that a majority of meningiomas harbor genuine PR and AR. These results are now confirmed by powerful molecular biologic techniques that interrogate for the presence of specific receptor mRNA. Whether these proteins represent functioning receptors remains highly controversial. Neither in vitro stimulation studies nor clinical experience has disclosed a consistent or convincing pattern of response to resolve this question. The possibility exists that the expression of these specific receptor proteins is but an epiphenomenon, the signature of the underlying neoplastic process, but functionally disconnected from its initiation or maintenance. The role that polypeptide growth factors and neurohumoral agents have in the biology of meningiomas is not yet clear but is an area of intense investigative effort. Attempts to elucidate the activity and interplay of these substances in in vitro cell culture assays have yielded inconsistent outcomes. These assays are extremely complex, and the results can be dramatically influenced by a host of recognized and unrecognized variables making interlaboratory comparisons difficult. A fundamental unknown is the fidelity of such cell culture assays in mirroring the in vivo biology of a given tumor. At least some of these difficulties are overcome in the direct molecular analysis of the tumor genome, which identifies specific genes and gene products in the primary specimen.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Division↗
PubMed1993

Effects of bivalent cations on adenosine sensitivity in the rat hippocampal slice.

Ligand binding studies have demonstrated that bivalent cations can alter interactions between purinergic agonists and adenosine receptors in brain membranes. In the present study, we have investigated whether a similar interaction can be demonstrated in terms of a functional response to adenosine, which is the inhibition of synaptic transmission in the CA1 region of the rat hippocampus mediated via presynaptic A1 receptors. Our data suggest that alterations in cation concentrations do not significantly affect the sensitivity of these adenosine receptors, as long as changes are made in such a way as to leave presynaptic Ca2+ entry unaffected. The experimental results do not support the conclusion that there is a specific effect of either Ca2+ or Mg2+ on adenosine receptor sensitivity, such as has been described for agonist interactions with adenosine A1 receptors. We conclude that the effects of bivalent cations observed in ligand binding studies probably reflect an effect at an intracellular site, either on the receptor itself, or perhaps on associated GTP binding proteins.

Adenosine↗
PubMed1993

Cocaine inhibits hippocampal long-term potentiation.

Long-term potentiation (LTP) is a form of synaptic plasticity that may underlie learning and memory. The experiments reported here demonstrate that cocaine blocks the induction of LTP at the excitatory synapses in the CA1 region of the hippocampus, but does not appear to do so by blocking NMDA receptors or channels. Once LTP had been established, however, cocaine had no effect on the potentiated response. Cocaine was also able to block LTP initiated by superfusing slices with 25 mM TEA. The ability to block LTP was shared by the local anesthetics lidocaine and procaine, but not by tetrodotoxin, suggesting that the blockade of sodium channels alone did not disrupt LTP. Biochemical experiments demonstrated that cocaine can inhibit phosphorylation of purified Synapsin I by Ca2+/calmodulin-dependent protein kinase II. This effect, presumably mediated by effects on calmodulin, is a previously unreported action of cocaine, and suggests that cocaine at high dose levels might disrupt types of learning that are mediated by an LTP-like mechanism.

Animals↗
PubMed1993

Repetitive elastance measurement as a means of recording pharmacological responses in vascular smooth muscles.

We describe a method of recording pharmacological responses in isolated arterial segments, based on the direct measurement of vascular wall elastance. The segment outflow is intermittently occluded, and the elastance determined from the subsequent pressure-flow relationship. Since the measurement cycle can be repeated 12 times per minute, rapid pharmacological responses can be studied. The method is capable of demonstrating a sigmoid dose-response relationship to noradrenaline added to the perfusate.

Adult↗
PubMed1993

Regional binding of 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP) to muscarinic receptors in rat brain and comparative analysis of minimum energy conformations.

The binding of the muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), which has been suggested as an M3-selective antagonist in peripheral tissues, was examined through quantitative autoradiographic techniques in brain. The ability of 4-DAMP to displace [3H](R)-quinuclindinyl benzilate (QNB) binding to rat brain sections was compared with the known distribution of M1 and M2 muscarinic receptor subtypes as measured previously with pirenzepine and AF-DX 116 (Messer et al., 1989a). 4-DAMP displayed a high affinity for [3H](R)-QNB binding sites in rat brain sections. Analysis of 4-DAMP binding to various brain regions revealed heterogeneous binding profiles, suggesting an interaction with multiple receptor sites. Quantification of the autoradiograms indicated that 4-DAMP bound with the highest affinity to muscarinic receptors in the midline thalamus (IC50 values < 30 nM), and had a slightly lower affinity for hippocampal receptors (IC50 values between 30 and 46 nM). 4-DAMP also displayed a lower affinity for cortical receptors with IC50 values between 30 and 50 nM. The binding profile of the putative M3 muscarinic antagonist did not exhibit a marked selectivity for any single region of brain. The data suggest that whereas 4-DAMP may be selective for M3 receptors in peripheral tissues, it has limited selectivity in the CNS. Minimum energy conformations for 4-DAMP were calculated using molecular mechanics calculations. 4-DAMP displayed two global minimum energy conformations, differing in the relative position of the piperidine ring with respect to the aromatic rings. The minimum energy conformations of 4-DAMP were compared with conformations generated for pirenzepine (Messer et al., 1989a). The lowest energy conformation of 4-DAMP was superimposable on the lowest energy conformation of pirenzepine (RMS = 0.297 A). It is suggested that the conformations available to 4-DAMP permit binding to several muscarinic receptors in the CNS.

Animals↗
PubMed1993

Use of a clinical MR scanner for imaging the rat brain.

Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy are established techniques that enable noninvasive anatomic and functional tissue characterization in vivo. These tools have been employed to probe experimental models of neoplasia, cerebrovascular disease, brain injury, and neurotransplantation in small animals. To date, these studies have been executed primarily on research-dedicated instruments of limited availability or resolution. Using relatively straightforward software and hardware modifications of a widely used clinical MRI unit, we were able to image numerous structures within the living rat brain including the neostriatum, hippocampus, periaqueductal gray, and the ventricular system. Illustrative applications of this imaging technique in two intracerebral infusion models involving rats are presented. Such adaptation of clinical MRI scanners has the potential to significantly expand the availability of high resolution in vivo imaging of small animals for a variety of experimental protocols.

Animals↗
PubMed1993

Flat affect in schizophrenia does not reflect diminished subjective experience of emotion.

Although accorded historical significance, affective features of schizophrenia have only begun to receive systematic empirical attention. Interestingly, both early psychopathology writers and more recent investigators have reported frequent discrepancies between schizophrenics' feelings and outward expressions of emotion. Using a more comprehensive assessment of emotion, the present study examines the relationship between emotional experience and expression in a sample of medication-free schizophrenics. Compared with their normal counterparts, schizophrenics were indeed much less facially expressive of both positive and negative emotions during emotion-eliciting films, yet they reported experiencing as much positive and negative emotion. Therefore, the blunted affect typical of some schizophrenics misrepresents their underlying emotional experience. Future research into an inhibition hypothesis is recommended.

Adult↗
PubMed1993

Expression and relationships of seven public idiotypes of DNA-binding autoantibodies on monoclonal antibodies and serum immunoglobulins.

Many studies have shown that DNA-reactive autoantibodies share cross-reactive public idiotypes that are defined, usually, by single anti-idiotype reagents. Because anti-idiotype antibodies or antisera will be limited in their ability to detect all the idiotopes of a particular antibody, their use will tend to underestimate the full extent of idiotype sharing between different antibodies. In order to define more comprehensively the extent of idiotype sharing in DNA autoantibodies, a panel of DNA-binding monoclonal autoantibodies from lupus mice was examined with a range of anti-idiotype antisera prepared in rabbits (five sera), guinea pigs (four sera) and a sheep. Each idiotype was detected on more antibodies than its original reference monoclonal antibody, and idiotopes of each were also present on serum immunoglobulins from lupus mice. Of 23 monoclonal antibodies 65% reacted with one or more of the anti-idiotype reagents. On these criteria, all the idiotypes were public; none was private in its expression. In about half the cases the idiotypes were located in or near the antigen-binding sites of the antibodies, but a direct relationship to specificity was not obvious except in the case of Id.228 present on antibodies with a relatively high affinity for single-stranded DNA. In other cases there was no obvious relationship between idiotype and specificity. Antibodies from the same mouse did not each express the same array of idiotopes.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1993

Haloperidol dosing requirements: the contribution of smoking and nonlinear pharmacokinetics.

Previous data suggest the possibility that haloperidol daily dosing requirements may be confounded by smoking and, at higher doses, capacity-limited metabolism. Forty hospitalized patients suffering from an acute exacerbation of schizophrenia were treated for 2 weeks with fixed oral doses of haloperidol ranging from 10 to 70 mg/day (0.13 to 0.95 mg/kg/day) that produced mean steady-state concentrations between 4.5 and 55.4 ng/ml. No significant differences between the smoking and nonsmoking groups were obvious for the factors of weight, age, sex, daily doses, steady-state clearance, and steady-state haloperidol concentrations in plasma at week 1, week 2, and their mean. The hypothesis that the relationship between haloperidol dose and steady-state haloperidol concentration in plasma was affected by patients' smoking status and metabolic capacity was tested by multiple linear regression analysis and initially rejected. The relationship of dose to haloperidol concentration was fitted as a linear function. To improve the curve fit, the haloperidol concentrations and doses were transformed to their natural logs and then the regression line was refitted. The multiple regression analysis was repeated with the data in their transformed state. It was found that, although smoking status and dose of the drug did not independently affect the average haloperidol concentration, together they interacted in such a way that individual haloperidol concentrations were dependent on the smoking status at specific doses. Thus, two haloperidol dosing equations were generated, one for smokers and one for nonsmokers.

Adult↗
PubMed1993

Establishing a continence service using AHCPR guidelines.

The Agency for Health Care Policy and Research (AHCPR) has recently released practice guidelines for the management of adult urinary incontinence. The guidelines are designed to enhance the quality, effectiveness and appropriateness of health care in the area of incontinence. The purpose of this article is to describe assessment and management strategies as used in a continence clinic that incorporate AHCPR guidelines. This continence clinic exists within an established gynecology practice, however, continence services can be provided in nursing homes and/or home care agencies.

Female↗
PubMed1992

Speculations on the substrate structure-activity relationship (SSAR) of cytochrome P450 enzymes.

This brief review attempts to define the SSAR of two families of cytochrome P450. With P4502D catalytic competence is achieved by tight ionic binding which gives the enzyme high regioselectivity. In contrast P4503A achieves catalytic competence by a flexible binding site relying on hydrophobic forces that allow chemically vulnerable sites to be the principal sites of metabolism. In general, the different binding mechanism should be reflected in the enzyme, such that substrates of P4502D should have lower Km values than substrates of P4503A. Thus, routes of metabolism catalysed by P4502D may be saturated at substrate concentrations lower than routes catalysed by P4503A. The apparent differences between P4502D and P4503A in terms of substrate specificity bring into question what relationships govern other families of cytochrome P450. Our analysis of data suggests that the other principal form involved, generally, in the metabolism of pharmaceuticals in humans is P4502C9 (possibly 2C8 and 2C10). The enzyme is responsible for the metabolism of phenytoin, tolbutamide, tienilic acid [4], naproxen, ibuprofen, diclofenac [38], the 7-hydroxylation of S-warfarin [39] and the 7-hydroxylation of delta 1-tetrahydrocannabinol [40]. These compounds all have areas of strong hydrogen bond [4] forming potential (Fig. 8), all distanced 5-10A from the site of metabolism. Moreover the carboxylic acid function of naproxen, ibuprofen and diclofenac (pKa 4.5) and the sulfonylurea of tolbutamide (pKa 5.4) render the compounds ionized at physiological pH. The ionised group is positioned 7-11A from the site of metabolism. It is likely, therefore, that hydrogen bonding and possibly ion-pair interactions play a major role in determining the SSAR of the P4502C isoenzymes. These interactions would suggest that the P4502C enzymes are analogous to P4502D rather than P4503A. In this regard it is noteworthy that P4502C9 is selectively and potently inhibited by sulfaphenazole (IC50 of 0.6 microM), a compound that is structurally related (Fig. 8) to the substrates in terms of potential hydrogen bonding regions [4, 41]. Simplistically we suggest that the SSAR of the various P450 enzymes ranges from the highly selective enzymes dealing with endogenous substrates, through the enzymes metabolising exogenous substrates with narrow substrate structure requirements such as P4502D to P4503A with its broad substrate structure range. It would seem logical that animals and humans would evolve such combinations of isoenzymes to deal with the vast array of exogenous xenobiotics.

Cytochrome P-450 Enzyme System↗
PubMed1992

Evidence of hypothalamic involvement in the mechanism of transplacental carcinogenesis by diethylstilbestrol.

Disruption of hypothalamic sex differentiation in the fetus is one hypothesis to explain female reproductive system anomalies and cancer arising from prenatal exposure to diethylstilbestrol (DES). To further test this hypothesis, breeding performance and behavior were monitored in a colony of mice exposed prenatally to DES, using a schedule previously shown to produce anomalies and cancer of the female reproductive system. Fertility decreased with age more rapidly in DES-exposed females than in control females. DES-exposed females were less accepting of the male than control females. These observations support the hypothesis of abnormal hypothalamic sex differentiation as a basic mechanism in DES transplacental carcinogenesis.

Animals↗
PubMed1992

An extracellular enzyme from Fusarium solani f. sp. phaseoli which catalyses hydration of the isoflavonoid phytoalexin, phaseollidin.

Among the antimicrobial phytoalexins produced by Phaseolus vulgaris (French bean) are the prenylated isoflavonoids kievitone and phaseollidin. Two enzyme activities, kievitone hydratase and phaseollidin hydratase, occur in culture filtrates of the bean pathogen, Fusarium solani f. sp. phaseoli, and catalyse similar hydration reactions on the dimethylallyl moieties of the phytoalexins. The enzymes nearly co-purified during hydroxyapatite chromatography followed by preparative native gel electrophoresis. Eluates from successive slices taken from the native gel were assayed for both activities. Although they were not completely separated in the native gel, the activity profiles indicated that the two activities were distinct. The Km of phaseollidin hydratase for phaseollidin was approximately 7 microM.

Catalysis↗
PubMed1992

Effects of habitual caffeine use and acute ingestion: testing a biobehavioral model.

A recently proposed model of the biobehavioral effects of caffeine suggests that acute ingestion impacts physiology and behavior differentially depending on the level of habitual usage of the drug. Acute ingestion and habitual usage are particularly expected to affect arousal and attentional processes. Subjects in the present study were preselected for high and low habitual caffeine use, given caffeine or a placebo, exposed to white noise or no white noise, and asked to perform on several tasks. Included were an arousal/habituation task (pure tones), reaction time, paired associates, anagrams, and vigilance. Electrodermal activity and performance were recorded. As predicted, virtually all effects were on the arousal/habituation and attentional (vigilance) tasks. Both acute ingestion and habitual use increased tonic EDA, and chronic use also reduced phasic responding, especially in the presence of a strong habituating stimulus. Both acute and habitual use also liberalized the vigilance response criterion, in that subjects risked more false alarms in order to attain more hits. In addition, habitual use increased sensitivity and reduced accuracy, and acute ingestion increased vigilance response time in the presence of white noise. Overall, the model was partially supported by these early results, though considerable further research is needed.

Adult↗