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Biomedical subjects

D A Smith

Publications and source records attributed to D A Smith.

At least 145 records · Page 8Linked to original sources
PubMed1995

The lateralized processing of affect in emotionally labile extraverts and introverts: central and autonomic effects.

The purpose of the present study was to better understand both the lateralized hemispheric processing of emotion and the differential neural processing of arousal in extraverts and introverts. We preselected right-handed male and female extraverts and introverts who were high in emotional lability. Each subject was exposed to two positive and two negative emotional stimuli under each of three counterbalanced conditions, including affective, cognitive, and neutral, while EEG and electrodermal activity (EDA) were recorded. Results showed that introverts are more aroused and that extraversion interacts with gender to produce differentiated patterns of lateralized neural activity. In addition, affective conditions produced higher levels of arousal than did cognitive or neutral conditions, particularly in the left hemisphere and under negative as opposed to positive stimuli. Finally, the hemispherically differentiated processing of positive and negative stimuli was affected by the contextual conditions under which they were experienced.

Adolescent↗
PubMed1995

Subcutaneous injection of an analog of neuropeptide FF prevents naloxone-precipitated morphine abstinence syndrome.

There is evidence that neuropeptide FF (NPFF) has antiopiate activity and may play a role in opiate dependence and subsequent abstinence syndrome. A fragment of NPFF was modified at the C-terminal in an effort to convert it to an NPFF antagonist. It was also dansylated at the N-terminal in an effort to render it more lipophilic and increase its penetration of the blood-brain barrier. Third ventricle administration of the resulting compound, dansyl-PQRamide (0.75 microgram and 1 microgram), dose-dependently antagonized the quasi-morphine abstinence activity of NPFF (10 micrograms) in opiate-naive rats. Subcutaneous injection of dansyl-PQRamide (13 mg/kg) in chronically morphine-infused rats attenuated opiate dependence as indicated by prevention of naloxone-precipitated abstinence syndrome. Dansyl-PQRamide displaced radiolabelled ligand from NPFF receptors in a concentration-dependent manner with a Ki of 13 microM, and had a half-life over 300 times longer than NPFF under aminopeptidase digestion.

Animals↗
PubMed1995

Strain-dependent cross-bridge cycle for muscle.

The cross-bridge cycle for actin, S1 myosin, and nucleotides in solution is applied to the sliding filament model for fully activated striated muscle. The cycle has attached and rotated isomers of each actomyosin state. It is assumed that these forms have different zero-strain conformations with respect to the filament and that strain-free rate constants are the nominal solution values. Only one S1 unit of heavy meromyosin is considered. Transition-state theory is used to predict the strain dependences of S1 binding to actin, the force-generating transition to rotated states, and the release/binding of nucleotide and phosphate. We propose that ADP release and ATP binding are blocked by positive strain and phosphate release by negative strain. At large strains, rapid dissociation of S1 nucleotide from actin is expected when the compliant element of the cross-bridge is strained in either direction beyond its elastic limits. The dynamical behavior of this model of muscle contraction is discussed in general terms. Its computed steady-state properties are presented in an accompanying paper.

Actins↗
PubMed1995

Strain-dependent cross-bridge cycle for muscle. II. Steady-state behavior.

Quantitative predictions of steady-state muscle properties from the strain-dependent cross-bridge for muscle are presented. With a stiffness of 5.4 x 10(-4) N/m per head, a throw distance of 11 nm, and three allowed actin sites/head, isometric properties and their dependence on phosphate and nucleotide levels are well described if the tension-generating step occurs before phosphate release. At very low ATP levels, rigorlike states with negative strain are predicted. The rate-limiting step for cycling and ATP consumption is strain-blocked ADP release for isometric and slowly shortening muscle. Under rapid shortening, ATP hydrolysis on detached heads is the rate-limiting step, and the ratio of bound ATP to bound ADP.Pi increases by a factor of 7. At large positive strains, bound heads must be forcibly detached from actin to account for tension in rapid extension, but forced detachment in shortening has no effect without destroying isometric attached states. Strain-blocked phosphate release as proposed produces modest inhibition of the ATPase rate under rapid shortening, sufficient to give a maximum for one actin site per helix turn. Alternative cross-bridge models are discussed in the light of these predictions.

Actins↗
PubMed1995

An investigation of the interaction between halofantrine, CYP2D6 and CYP3A4: studies with human liver microsomes and heterologous enzyme expression systems.

1. We have assessed the interaction of the antimalarial halofantrine with cytochrome P450 (CYP) enzymes in vitro, with the use of microsomes from human liver and recombinant cell lines. 2. Rac-halofantrine was a potent inhibitor (IC50 = 1.06 microM, Ki = 4.3 microM) of the 1-hydroxylation of bufuralol, a marker for CYP2D6 activity. Of a group of structurally related antimalarials tested, only quinidine (IC50 = 0.04 microM) was more potent. 3. Microsomes prepared from recombinant CYP2D6 and CYP3A4 cell lines were shown to catalyse halofantrine N-debutylation. 4. The metabolism of halofantrine to its N-desbutyl metabolite by human liver microsomes showed no correlation with CYP2D6 genotypic or phenotypic status and there was no consistent inhibition by quinidine. 5. The rate of halofantrine metabolism showed a significant correlation with both CYP3A4 protein levels (r = 0.88, P = 0.01) and the rate of felodipine metabolism (r = 0.86, P = 0.013), a marker substrate for CYP3A4 activity. Inhibition studies showed that ketoconazole is a potent inhibitor of halofantrine metabolism (IC50 = 1.57 microM). 6. In conclusion, we have demonstrated that halofantrine is a potent inhibitor of CYP2D6 in vitro and can also be metabolised by the enzyme. However, in human liver microsomes it appears to be metabolised largely by CYP3A4.

Alkylation↗
PubMed1995

Cavitation of mesenteric lymph nodes: a rare complication of coeliac disease, associated with a poor outcome.

Five cases are presented, all of which showed peculiar cavitation of mesenteric lymph nodes. Clinically, three presented with abdominal symptoms, a mass or obstruction, warranting laparotomy. Two patients showed cavitating mesenteric lymph nodes at autopsy. Lymph nodes were enlarged with central, partly cystic degeneration; milky fluid exuded from the cut surface. In each case, investigation showed intestinal villous atrophy and splenic atrophy; coeliac disease was confirmed by response to gluten withdrawal. Three patients died, two from cachexia and the other from pneumonia; the other two are alive and well one year and six years after presentation. Review of the literature shows 12 previously reported cases, with a mortality of about 50%. The diagnosis is made by the histopathologist, alerting appropriate treatment. The pathogenesis is unknown.

Adult↗
PubMed1995

Comparison of the disposition of two novel combined thromboxane synthase inhibitors/thromboxane A2 receptor antagonists in the isolated perfused rat liver.

1. The pharmacokinetics of two combined thromboxane synthase inhibitor/thromboxane A2 receptor antagonists were investigated in an isolated perfused rat liver preparation. 2. The clearance of both UK 101613 (15.4 +/- 1.9 ml/min) and UK 102333 (14.9 +/- 1.6 ml/min) was limited by hepatic bloodflow. Both hepatic uptake and biliary excretion of UK 101613 appeared to be active processes. The apparent biliary clearance of UK 101613 (10.3 +/- 2.3 ml/min) was less than perfusate clearance, indicating accumulation within the hepatocytes. 3. The efficiency of the active hepatic uptake of UK 101613 and UK 102333 explains the rapid removal of these compounds from the systemic circulation. The processes of biliary and/or metabolic clearance of UK 101613 and UK 102333 appear to be subsequent to and independent of perfusate clearance. 4. Although the compounds are of similar structure and have a similar hepatic extraction (> 0.9), UK 101613 had an apparent biliary clearance approximately twice that of UK 102333. This is due to the formation of a metabolite of UK 102333 which reduces the amount of parent compound available for biliary excretion. 5. Inhibition of this latter metabolism by ketoconazole (10 microM) resulted in the two compounds having comparable apparent biliary clearances.

Animals↗
PubMed1994

Molecular genetical and phenotypical analysis of the gerM spore germination gene of Bacillus subtilis 168.

The gerM gene, encoding a single product of 22.5 kDa, has been identified by subcloning and sequencing of DNA recovered from adjacent to a Tn917 insertion. The gene product has a potential lipoprotein signal sequence, but otherwise has no homology to known sequences. Spores of the gerM mutant were more heat sensitive than wild-type, but their dipicolinic acid content was normal. The level of cortical peptidoglycan in mutant spores is also normal but release at germination of hexosamine-containing fragments, the breakdown products of cortex degradation, is less complete than wild-type. The sporulation, resistance and germination phenotypes of the gerM mutant would be consistent with the gene product having a role, either directly or indirectly, in peptidoglycan synthesis during sporulation.

Amino Acid Sequence↗
PubMed1994

Design, synthesis, and neurochemical evaluation of 2-amino-5-(alkoxycarbonyl)-3,4,5,6-tetrahydropyridines and 2-amino-5-(alkoxycarbonyl)-1,4,5,6-tetrahydropyrimidines as M1 muscarinic receptor agonists.

Four regioisomers of 2-amino-(methoxycarbonyl)-3,4,5,6-tetrahydropyridine (2a-5a) were synthesized as the racemates to evaluate the utility of exocyclic amidines in the development of novel agonists for M1 muscarinic receptors. Of the four regioisomers, only racemic 2-amino-5-(methoxycarbonyl)-3,4,5,6-tetrahydropyridine (4a; CDD-0075-A) displayed high affinity (IC50 = 10 +/- 3.0 microM) and activity at muscarinic receptors coupled to PI metabolism in the rat cortex (260 +/- 4.5% stimulation above basal levels at 100 microM). A series of 2-amino-5-(alkoxycarbonyl)-3,4,5,6-tetrahydropyridines then was synthesized for further evaluation as M1 agonists. Only the propargyl derivative (4d) retained substantial agonist activity (120 +/- 14% at 100 microM) in this series. On the basis of the activity of the 5-(alkoxycarbonyl)-1,4,5,6- tetrahydropyrimidines (1a and 1d) and the 2-amino-5-(alkoxycarbonyl)-3,4,5,6-tetrahydropyridines, the corresponding cyclic guanidine derivatives were synthesized and tested. 2-Amino-5-(methoxycarbonyl)-1,4,5,6-tetrahydropyrimidine (7a) displayed a modest affinity for muscarinic receptors in the CNS (22 +/- 5.3 microM) and an ability to stimulate PI turnover in rat cerebral cortex (81 +/- 16% at 100 microM). The propargyl derivative (7d) also had modest binding affinity (31 +/- 15 microM) and high activity (150 +/- 8.5% at 100 microM), as expected based on the activity of propargyl esters of 1,4,5,6-tetrahydropyrimidine and 2-amino-3,4,5,6-tetrahydropyridine. Computational chemical studies revealed five distinct minimum-energy conformations for 1a, (R)-4a, and 7a, and three for 1d, (R)-4d, and 7d, each with a unique orientation of the ester moiety. Each of the five conformations for 1a could be superimposed upon a unique conformer of (R)-4a and 7a, suggesting that the compounds interact with muscarinic receptors in a similar fashion. Taken together, the data indicate the general utility of amidine systems as suitable replacements for the ammonium group of acetylcholine in developing ligands with activity at M1 muscarinic receptors in the central nervous system. Such compounds might be useful in the treatment of patients with Alzheimer's disease.

Alzheimer Disease↗
PubMed1994

Theory and observation of spontaneous oscillatory contractions in skeletal myofibrils.

At low levels of activation, an isometrically-held myofibrillar preparation on the descending limb may exhibit persistent oscillations of period 1-6 s in tension and sarcomere lengths. We propose a sarcomeric theory of spontaneous oscillatory contraction, based on the phenomena of force creep and delayed length activation. The time delay leads to oscillations and controls their period. A computer model using these ideas simulates spontaneous oscillatory contraction for fixed-end fibres only if isometric tension capacity varies slightly along the fibre. The form of this inhomogeneity controls a diversity of spontaneous oscillatory contraction behaviour: the tension waveform can vary from large and sinusoidal to small-amplitude pulses or chaotic behaviour, and these variations are observed in slow-twitch soleus fibres from the same animal (rat). The model predicts that oscillatory and quiescent regions coexist in the fibre, with large-amplitude sawtooth waveforms in sarcomere length in the former as observed. It can also generate travelling-wave structures, similar to those found by the Tokyo group, in oscillating regions when there is a spatial gradient in isometric tension capacity. Phase discontinuities in sarcomere length occur near the oscillatory-quiescent boundary. Predictions for the Ca2+ concentrations and sarcomere lengths in which spontaneous oscillatory contraction occurs and for differences in the spontaneous oscillatory contraction frequencies of fast- and slow-twitch fibres compare well with experiment. Spontaneous oscillatory contraction is also predicted under isotonic conditions.

Animals↗
PubMed1994

Individual differences in dispositional expressiveness: development and validation of the Emotional Expressivity Scale.

Although emotional expressivity figures prominently in several theories of psychological and physical functioning, limitations of currently available measurement techniques impede precise and economical testing of these theories. The 17-item Emotional Expressivity Scale (EES) was designed as a self-report measure of the extent to which people outwardly display their emotions. Reliability studies showed the EES to be an internally consistent and stable individual-difference measure. Validational studies established initial convergent and discriminant validities, a moderate relationship between self-rated and other-rated expression, and correspondence between self-report and laboratory-measured expressiveness using both college student and community populations. The potential for the EES to promote and integrate findings across diverse areas of research is discussed.

Adolescent↗
PubMed1994

The gerB region of the Bacillus subtilis 168 chromosome encodes a homologue of the gerA spore germination operon.

Spores of gerB spore germination mutants of Bacillus subtilis 168 are defective in response to the germinative mixture of L-asparagine, glucose, fructose and potassium ions (AGFK), but are normal in the L-alanine (ALA) triggered germination response. A lambda clone of 15 kbp carrying the gerB region has been identified. Sequencing of the gerB region of the clone revealed a cluster of three ORFs encoding putative proteins of 53.3, 41.3 and 42.4 kDa (GerBA, GerBB and GerBC, respectively). The first two of these proteins have substantial hydrophobic regions and the third is a possible lipoprotein. At least two, and probably all three products are required for normal germination in AGFK. The three proteins form a set of homologues of the products of the gerA operon, mutations in which cause a defect in the ALA germination pathway, but cause no defect in AGFK. The GerB proteins show 42%, 31% and 35% identity at the amino-acid level to the corresponding GerA proteins, and the homologues occur in the same order in both operons.

Alleles↗
PubMed1994

Reliability of P50 auditory event-related potential indices of sensory gating.

We examined the reliability of three traditional P50 auditory event-related potential indices under paired-click conditions: (a) the conditioning response (C), (b) the testing response (T), and (c) the testing to conditioning suppression ratio (T/C). Three alternative indices, (a) the (C - T) difference, (b) the (C - T)/(C + T) adjusted difference, and (c) the (T - T') residualized difference, where T' is the regression of T on C, were also studied. The N100 wave was used as a generalizability check. Although C and T amplitudes were reliably measured by traditional means, the T/C suppression ratio was not. For psychometric reasons that are described, the reliability of the suppression ratio is undermined principally by the correlation between C and T. The C - T difference score is a promising alternative to the unreliable T/C suppression ratio. Theoretical consequences of changed metrics are discussed.

Acoustic Stimulation↗
PubMed1994

Importance of metabolic stability and hepatic distribution to the pharmacokinetic profile of amlodipine.

1. In an isolated perfused rat liver (IPRL) model, the extensive hepatic uptake and subsequent slow redistribution of amlodipine into the perfusate have been demonstrated. The apparent liver volume for amlodipine was 920 ml compared with 38ml for nitrendipine. 2. Metabolism is the major clearance mechanism of amlodipine and nitrendipine in animals and man. In the IPRL, the intrinsic (metabolic) clearance and first-pass extraction values for amlodipine are similar to those of nitrendipine. This is in contrast with in vitro metabolic stability data in rat liver microsomes which indicate about 40-fold greater metabolic stability for amlodipine. 3. The discrepancy between relative clearance rates for the two preparations may be explained by consideration of the hepatic volume of the two compounds, with the higher liver volume of amlodipine amplifying the whole organ clearance.

Amlodipine↗
PubMed1994

Risperidone: review of its pharmacology and therapeutic use in schizophrenia.

The discovery of antipsychotic medications has revolutionized the treatment of schizophrenia and other psychotic disorders. However, side effects such as extrapyramidal symptoms (EPS) and tardive dyskinesia have been limiting factors in treatment. The introduction of atypical drugs such as clozapine and risperidone has ushered in a new era. This article provides an overview of the pharmacology, efficacy, and techniques for the clinical use of risperidone, which has recently become available.

Antipsychotic Agents↗
PubMed1994

Devices for continence.

Ameliorating the acute and chronic forms of incontinence is usually possible. When the functional status of the patient prohibits toileting, then devices are often necessary. The practicing nurse must make decisions on what devices are appropriate and how to teach clients to use them. Often, knowing the device exists is a start in the nurse's ability to eliminate functional incontinence. This article focuses on devices that collect urine, inhibit incontinence, and aid staff and clients to use the toilet.

Female↗