Biomedical subjects

M Davis

Publications and source records attributed to M Davis.

At least 109 records · Page 6Linked to original sources

PubMed2000

Enhancement of the acoustic startle response by dopamine agonists after 6-hydroxydopamine lesions of the substantia nigra pars compacta: corresponding changes in c-Fos expression in the caudate-putamen.

Rats with 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway show enhanced locomotor and stereotyped behaviors when challenged with direct and indirect dopamine (DA) agonists due to the development of postsynaptic supersensitivity. To determine if this phenomenon generalizes to other motor behaviors, we have used this rat model of Parkinson's disease to examine the effects of the direct dopamine D(1) receptor agonist SKF 82958 and the indirect DA agonist L-3,4-dihydroxyphenylalanine (L-DOPA) on the acoustic startle response. In addition, we used the expression of c-Fos protein as a marker of neuronal activity to assess any corresponding drug-induced changes in the caudate-putamen (CPu) after L-DOPA administration. Male Sprague-Dawley rats received bilateral injections of 6-OHDA into the substantia nigra pars compacta and 1 week later were tested for startle after systemic administration of SKF 82958 (0.05 mg/kg) or L-DOPA (1, 5, 10 mg/kg). SKF 82958 produced a marked enhancement of startle with a rapid onset in 6-OHDA-lesioned but not SHAM animals. L-DOPA produced a dose- and time-dependent enhancement of startle in 6-OHDA-lesioned rats that had no effect in SHAM animals even at the highest dose (10 mg/kg). Furthermore, L-DOPA produced a dramatic induction of c-Fos in the CPu in 6-OHDA-lesioned animals. Consistent with other literature, these data suggest that neurons in the CPu become supersensitive to the effects of DA agonists after 6-OHDA-induced denervation of the nigrostriatal pathway and that supersensitive dopamine D(1) receptors may mediate the enhancement of startle seen in the present study.

Acoustic Stimulation↗

PubMed2000

Processing of cdk5 activator p35 to its truncated form (p25) by calpain in acutely injured neuronal cells.

Recently, it was shown that conversion of cdk5 activator protein p35 to a C-terminal fragment p25 promotes a deregulation of cdk5 activity, which may contribute to neurodegeneration in Alzheimer's disease. In this study, we present evidence that calpain is a protease involved in the conversion of p35 to p25. To activate calpain, rat cerebellar granule neurons were treated with maitotoxin (MTX). A C-terminus-directed anti-p35 antibody detected that p35 conversion to p25 paralleled the formation of calpain-generated alpha-spectrin (alpha-fodrin) breakdown products (SBDP's) in a maitotoxin-dose-dependent manner. Two calpain inhibitors (MDl28170 and SJA6017) reduced p35 processing but were unchanged when exposed to the caspase inhibitor carbobenzoxy-Asp-CH(2)OC(=O)-2, 6-dichlorobenzene or the proteasome inhibitors (lactacystin and Z-Ile-Glu(OtBu)Ala-Leu-CHO). p35 protein was also degraded to p25 when rat brain lysate was subjected to in vitro digestion with purified mu- and m-calpains. Additionally, in a rat temporary middle cerebral artery occlusion model, p35 processing to p25 again paralleled SBDP formation in the ischemic core. Lastly, in malonate-injured rat brains, the ipsilateral side showed a striking correlation of SBDP formation with p35 to p25 conversion and tau phosphorylation (at Ser202 and Thr205) increase. These data suggest that calpain is a major neuronal protease capable of converting p35 to p25 and might play a pathological role of activating cdk5 and its phosphorylation of tau in Alzheimer's disease.

Animals↗

PubMed2000

GABA in the deep layers of the superior Colliculus/Mesencephalic reticular formation mediates the enhancement of startle by the dopamine D1 receptor agonist SKF 82958 in rats.

GABA transmission in the deep layers of the superior colliculus/deep mesencephalic reticular formation (deep SC/Me) mediates several motor responses, including those expressed after systemic administration of dopamine agonists. In the present study we examined the role of the deep SC/Me in the modulation of the acoustic startle reflex and its enhancement by the dopamine D(1) agonist SKF 82958. Rats were implanted with bilateral cannulas into the deep SC/Me or superficial layers of the SC (super SC) and 1 week later were infused with various compounds. The GABA(A) antagonist bicuculline (0, 5, and 10 ng) produced a dose- and time-dependent enhancement of startle after infusion into the deep SC/Me, but not the super SC. Infusion of the GABA(A) agonist muscimol (0.1 microg) into the deep SC/Me, but not the super SC, blocked the enhancement of startle by systemic SKF 82958 (1 mg/kg) but had no effect on baseline startle by itself. This effect was not produced by infusion of the D(1) antagonist SCH 23390(1 microg) or the glutamate antagonist NBQX (0.1 microg). Deposits of FluoroGold into the deep SC/Me, combined with immunohistochemistry for glutamic acid decarboxylase (GAD), confirmed a direct GABAergic input from the substantia nigra pars reticulata (SNr) to the deep SC/Me. These results suggest that GABA tone in the deep SC/Me modulates the expression of startle as well as the enhancement of startle by dopamine D(1) agonists. On the basis of these data and previous work, we have proposed a striatonigral-tectal-reticular neural pathway mediating the effects of dopamine D(1) agonists on startle.

Acoustic Stimulation↗

PubMed2000

A microdialysis study on the mechanism of action of gabapentin.

To gain insight into the mechanism of action of the anti-epileptic, gabapentin, the effects of gabapentin on the in vivo extracellular gamma-aminobutyric acid (GABA) levels in the rat substantia nigra reticulata were studied using microdialysis. In order to investigate possible interference with different GABA-ergic compartments in the substantia nigra reticulata, we studied the effects of gabapentin under basal, K(+)-, nipecotic acid- and glutamate-stimulated conditions. Intraperitoneally (i.p.) administered gabapentin, at a dose of 100 mg/kg, did not significantly affect extracellular GABA levels under any condition. Thus, our data do not support the involvement of nigral GABA release in the mechanism of action of the anti-epileptic gabapentin.

Acetates↗

PubMed2000

Is the hippocampus necessary for contextual fear conditioning?

The hippocampus is widely believed to be essential for learning about the context in which conditioning occurs. This view is based primarily on evidence that lesions of the dorsal hippocampus disrupt freezing to contextual cues after fear conditioning. However, lesions that disrupt freezing produce no effect on fear-potentiated startle, a second measure of contextual fear. Moreover, hippocampal lesions also do not disrupt the contextual 'blocking' phenomenon, which provides an indirect measure of contextual fear. In these paradigms, at least, it appears that hippocampal lesions disrupt the expression of freezing, rather than contextual fear itself. This interpretation is supported by the finding that rats showing preserved contextual blocking after hippocampal lesions show deficits not only in contextual freezing, but also in unconditioned freezing. These findings are consistent with a growing body of data from other conditioning paradigms that contextual learning is spared after lesions of the dorsal hippocampus. Nonetheless, there remain some reports of impaired contextual fear conditioning after hippocampal lesions that cannot be attributed easily to a disruption of freezing. Thus, it is concluded that the hippocampus may be involved in contextual learning under certain--as yet, unspecified--circumstances, but is not critical for contextual learning in general.

Animals↗

PubMed2000

Measuring the Cosmic Equation of State with Counts of Galaxies.

The classical dN/dz test allows one to determine fundamental cosmological parameters from the evolution of the cosmic volume element. This test is applied by measuring the redshift distribution of a tracer whose evolution in number density is known. In the past, ordinary galaxies have been used for this; however, in the absence of a complete theory of galaxy formation, that method is fraught with difficulties. In this Letter, we propose studying instead the evolution of the apparent numbers of dark matter halos as a function of their circular velocity, observable via the line widths or rotation speeds of visible galaxies. Upcoming redshift surveys will allow the line width distribution of galaxies to be determined at both z approximately 1 and the present day. In the course of studying this test, we have devised a rapid, improved semianalytic method for calculating the circular velocity distribution of dark halos based on the analytic mass function of Sheth, Mo, & Tormen and the formation time distribution of Lacey & Cole. We find that if selection effects are well controlled and minimal external constraints are applied, the planned DEEP Redshift Survey could allow us to measure the cosmic equation-of-state parameter w to +/-10% (as little as 3% if Omegam has been well determined from other observations). This type of test also has the potential to provide a constraint on any evolution of w, such as that predicted by "tracker" models.

Journal Article↗

PubMed2000

Improving dideoxynucleotide-triphosphate utilisation by the hyper-thermophilic DNA polymerase from the archaeon Pyrococcus furiosus.

Polymerases from the Pol-I family which are able to efficiently use ddNTPs have demonstrated a much improved performance when used to sequence DNA. A number of mutations have been made to the gene coding for the Pol-II family DNA polymerase from the archaeon Pyrococcus furiosus with the aim of improving ddNTP utilisation. 'Rational' alterations to amino acids likely to be near the dNTP binding site (based on sequence homologies and structural information) did not yield the desired level of selectivity for ddNTPs. However, alteration at four positions (Q472, A486, L490 and Y497) gave rise to variants which incorporated ddNTPs better than the wild type, allowing sequencing reactions to be carried out at lowered ddNTP:dNTP ratios. Wild-type Pfu-Pol required a ddNTP:dNTP ratio of 30:1; values of 5:1 (Q472H), 1:3 (L490W), 1:5 (A486Y) and 5:1 (Y497A) were found with the four mutants; A486Y representing a 150-fold improvement over the wild type. A486, L490 and Y497 are on analpha-helix that lines the dNTP binding groove, but the side chains of the three amino acids point away from this groove; Q472 is in a loop that connects this alpha-helix to a second long helix. None of the four amino acids can contact the dNTP directly. Therefore, the increased selectivity for ddNTPs is likely to arise from two factors: (i) small overall changes in conformation that subtly alter the nucleotide triphosphate binding site such that ddNTPs become favoured; (ii) interference with a conformational change that may be critical both for the polymerisation step and discrimination between different nucleotide triphosphates.

Amino Acid Sequence↗

PubMed2000

The amygdala.

Explore the source record for details and available documents.

Journal Article↗

PubMed2000

Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2beta-carbo-1'-fluoro-2-propoxy-3beta-(4-chlorophenyl)tr opanes. Ligands for the imaging of dopamine transporters by positron emission tomography.

2beta-(R)-Carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((R)-FIPCT, R-6) and 2beta-(S)-carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((S)-FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were synthesized in 5% radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2beta-carbo-R-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (R-12) and 2beta-carbo-S-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (S-12) followed by treatment with no carrier-added potassium[(18)F]fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [(3)H]WIN 35428 and [(3)H]citalopram, respectively, demonstrated the following order of DAT affinity (K(i) in nM): GBR 12909 (0.36) > CIT (0.48) > (S)-FIPCT (0.67) >> (R)-FIPCT (3.2). The affinity of (S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demonstrated that the brain uptake of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [(18)F](R)-FIPCT and [(18)F](S)-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [(18)F](R)-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with [(18)F](S)-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT for DAT indicate [(18)F](R)-FIPCT and [(18)F](S)-FIPCT are potential radioligands for mapping brain DAT in humans using PET.

Animals↗

PubMed2000

Evidence for a low-density universe from the relative velocities of galaxies

The motions of galaxies can be used to constrain the cosmological density parameter Omega and the clustering amplitude of matter on large scales. The mean relative velocity of galaxy pairs, estimated from the Mark III survey, indicates that Omega = 0.35(-0.25)(+0.35). If the clustering of galaxies is unbiased on large scales, Omega = 0. 35 +/- 0.15, so that an unbiased Einstein-de Sitter model (Omega = 1) is inconsistent with the data.

Journal Article↗

PubMed2000

Economic evaluation of Safer Choices: a school-based human immunodeficiency virus, other sexually transmitted diseases, and pregnancy prevention program.

OBJECTIVE: To evaluate the cost-effectiveness and cost benefit of Safer Choices, a school-based human immunodeficiency virus, other sexually transmitted diseases, and unintended pregnancy prevention intervention for high school students. METHODS: The baseline cost-effectiveness and cost benefit were derived in 4 steps: (1) estimation of intervention costs; (2) adaptation of the Bernoulli model to translate increases in condom use into cases of human immunodeficiency virus and other sexually transmitted diseases averted, and development of a model to translate increases in contraceptive use into cases of pregnancy averted; (3) translation of cases averted into medical costs and social costs averted; and (4) calculation of the net benefit of the program. Multivariable sensitivity analysis was performed to determine the robustness of the base-case results. RESULTS: Under base-case assumptions, at an intervention cost of $105,243, Safer Choices achieved a 15% increase in condom use and an 11% increase in contraceptive use within 1 year among 345 sexually active students. An estimated 0.12 cases of human immunodeficiency virus, 24.37 cases of chlamydia, 2.77 cases of gonorrhea, 5.86 cases of pelvic inflammatory disease, and 18.5 pregnancies were prevented. For every dollar invested in the program, $2.65 in total medical and social costs were saved. Results of most of the scenarios remained cost saving under a wide range of model variable estimates. CONCLUSIONS: The Safer Choices program is cost-effective and cost saving in most scenarios considered. School-based prevention programs of this type warrant careful consideration by policy makers and program planners. Program cost data should be routinely collected in evaluations of adolescent prevention programs.

Adolescent↗

PubMed2000

Bypass surgery for chronic lower limb ischaemia.

BACKGROUND: Surgical bypass of an occluded arterial segment is the mainstay of treatment for patients with critical limb ischaemia. As with many surgical interventions, however, it was introduced without formal evaluation. OBJECTIVES: The objective of this review was to determine the effects of bypass surgery in patients with chronic lower limb ischaemia. SEARCH STRATEGY: The reviewers searched the Cochrane Peripheral Vascular Diseases Group trials register, MEDLINE, EMBASE, reference lists of relevant articles, and contacted principal trial investigators. SELECTION CRITERIA: All randomised controlled trials of bypass surgery versus control, or versus any other form of treatment. DATA COLLECTION AND ANALYSIS: At least two reviewers extracted data and assessed trial quality independently. The reviewers contacted investigators to obtain information or data needed for the review that could not be found in published reports. Dichotomous data were analysed using the Peto odds ratio (OR), and continuous data with the weighted mean difference (fixed effect and random effects models). MAIN RESULTS: Eight trials were identified which appeared to meet the inclusion criteria, but two were subsequently excluded. The remaining six trials involved a total of just over 700 patients, two trials comparing bypass surgery with angioplasty (PTA), and one with each of thromboendarterectomy, thrombolysis, exercise, and spinal cord stimulation. Four trials included patients with a range of disease severity (intermittent claudication and critical limb ischaemia), one was restricted to claudicants only and another to only critical limb ischaemia. The type of bypass procedure performed in each trial was similar: vein grafts for distal reconstructions; synthetic prostheses for aorto-iliac or ilio-femoral bypasses. The outcome measures varied, but four of the six trials included mortality and operative failure. In general the quality of the trials was good, but none was blinded because of the nature of the intervention. There were no clear differences between bypass surgery and PTA. Mortality and amputation rates did not differ significantly, although primary patency was significantly higher in the bypass group after 12 months (Peto OR 1. 6, 95% CI 1.0, 2.6) but not after four years (p=0.14). Compared with thrombolysis, amputation rates were significantly lower in the bypass group (Peto OR 0.2, 95% CI 0.1, 0.6), but mortality rates did not differ. Compared with thromboendarterectomy, restoration of blood flow was significantly greater in the bypass patients (Peto OR 9.2, 95% CI 1.7, 50.6), but mortality and amputation rates did not differ. Bypass did not differ significantly from exercise or spinal cord stimulation. REVIEWER'S CONCLUSIONS: There is limited evidence for the effectiveness of bypass surgery and further large trials are required.

Angioplasty, Balloon↗

PubMed2000

The role of proteolytic enzymes in focal ischaemic brain damage.

Although various neuroprotective and fibrinolytic drugs are currently under evaluation in the acute stages of ischaemic stroke, their therapeutic potential is likely to be limited by unwanted side effects and a narrow time window of opportunity for intervention. Proteolytic enzymes are involved in the catabolism of peptide neurotransmitters and structural cellular proteins in normal brain and have been implicated in the pathogenesis of neurodegenerative disorders. We hypothesised that activation of these enzymes might also play a crucial role in effecting ischaemic neuronal injury, thereby providing a potential site for therapeutic intervention in human stroke. Focal cerebral ischaemia was induced by thermocoagulation of the left middle cerebral artery in aged (30 month) male Wistar rats who were pre-treated with saline or the competitive N-methyl-D-Aspartate antagonist D-CPP-ene, which has been shown to be neuroprotective in young animal models of stroke. Major protease activities were analysed in the left (ischaemic) and right (non-ischaemic) hemispheres, following tissue homogenisation. Data have been analysed using Mann-Whitney tests and are presented as means +/- standard errors. Enzyme activity decreased in ischaemic brain; for example, the mean activity of dipeptidyl aminopeptidase I was 23 +/- 3 and 43 +/- 6 nmol substrate/hour/ml brain extract in the left and right hemispheres respectively (n = 10, p < 0.05). Ischaemic neuronal injury is not effected by the early activation of proteolytic enzymes and protease inhibitors are therefore unlikely to be of benefit in human stroke.

Animals↗

PubMed2000

Synergistic enhancement of the acoustic startle reflex by dopamine D1 and 5-HT1A agonists and corresponding changes in c-Fos expression in the dorsal raphe of rats.

RATIONALE AND OBJECTIVES: Several studies have reported an increase in dopamine (DA)-stimulated behavioral responses after manipulations that reduce brain serotonin (5-hydroxytryptamine, 5-HT) levels. Because others have shown that systemic administration of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) reduces 5-HT levels throughout the brain, we tested the effects of 8-OH-DPAT on the enhancement of the acoustic startle reflex by the dopamine D1 receptor agonist SKF 82958. In addition, we used the expression of the c-Fos protein as a marker of neuronal activity to assess any corresponding drug-induced changes within the dorsal raphe (DR). METHODS AND RESULTS: Male Sprague-Dawley rats pretreated (10 min) with 8-OH-DPAT (0.5 mg/kg) showed a marked potentiation of the enhancement of startle by SKF 82958 (0.1 mg/kg). Furthermore, SKF 82958 produced a dramatic induction of c-Fos in the DR, an effect that was blocked by 8-OH-DPAT. Double-labeling immunohistochemistry for c-Fos and 5-HT showed that SKF 82958-induced expression of c-Fos, and its blockade by 8-OH-DPAT, occurred in a percentage of 5-HT-containing cells of the DR. CONCLUSIONS: These data suggest the possibility that inhibition of the DR by 8-OH-DPAT mediates the potentiation of startle by SKF 82958, perhaps through a reduction in 5-HT release in the striatum. Such an interpretation is consistent with the hypothesis of an inhibitory role of the 5-HT system on DA-mediated behaviors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2000

Development of a modified picture-sort food frequency questionnaire administered to low-income, overweight, African-American adolescent girls.

There is essentially no ideal method of dietary assessment. Physiologic methods (i.e., doubly labeled water) probably come closest, but high cost, participant burden, and limited information limit their use. Furthermore, most dietary assessment methods have been designed for and tested in white adults. Very few have been designed for and tested in African-American adolescents. This study examined validity and reliability of a modified picture-sort food frequency questionnaire (FFQ) administered to 22 low-income, overweight, African-American adolescent girls, aged 11 to 17 years. The FFQ was administered to subjects twice during a 2-week period, and evaluated using the mean values of three 24-hour recalls. The natural log-transformed energy-adjusted, deattenuated correlation coefficients between the second FFQ and the mean from 3 recalls exceeded 0.50 for most nutrients, ranging from 0.32 (protein) to 0.87 (saturated fat). The energy and nutrient values from the first FFQ were greater than those from the second FFQ. Most correlation coefficients for the test-retest reliability of the FFQ were not significant. We conclude that although larger samples are needed to generalize results, the picture-sort dietary assessment method appears to be promising and merits further research.

Adolescent↗

PubMed2000

Hemispheric specialization in spontaneous gesticulation in a patient with callosal disconnection.

This is an investigation of spontaneous gesticulation in a left-handed patient with a callosal disconnection syndrome due to infarction of the total length of the corpus callosum. After callosal infarction, the patient gesticulated predominantly unilaterally with the left hand despite left apraxia. Bilateral gesticulation occurred later on and was presumably achieved by an increase in ipsilateral proximal control. Movement analysis further indicated that the two hemispheres are specialized for certain gesture types. Gestures with emotional connotation and batons (emphasizing prosody) were generated predominantly in the right hemisphere whereas physiographics which picture the linguistic content concretely and deictics (pointing) were of left-hemispheric origin.

Apraxias↗

PubMed2000

Fear and anxiety: animal models and human cognitive psychophysiology.

The aim of this paper is to explicate what is special about emotional information processing, emphasizing the neural foundations that underlie the experience and expression of fear. A functional, anatomical model of defense behavior in animals is presented and applications are described in cognitive and physiological studies of human affect. It is proposed that unpleasant emotions depend on the activation of an evolutionarily primitive subcortical circuit, including the amygdala and the neural structures to which it projects. This motivational system mediates specific autonomic (e.g., heart rate change) and somatic reflexes (e.g., startle change) that originally promoted survival in dangerous conditions. These same response patterns are illustrated in humans, as they process objective, memorial, and media stimuli. Furthermore, it is shown how variations in the neural circuit and its outputs may separately characterize cue-specific fear (as in specific phobia) and more generalized anxiety. Finally, again emphasizing links between the animal and human data, we focus on special, attentional features of emotional processing: The automaticity of fear reactions, hyper-reactivity to minimal threat-cues, and evidence that the physiological responses in fear may be independent of slower, language-based appraisal processes.

Animals↗

PubMed2000

Trigeminal neuralgia: opportunities for research and treatment.

Trigeminal neuralgia was the focus of a recent workshop convened by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Dental and Craniofacial Research (NIDCR). The workshop brought together basic scientists, clinicians, epidemiologists, and patient advocates. New research directions for epidemiology, diagnosis and assessment, pain mechanisms, and treatment were identified. (The workshop was held in Rockville MD on September 14, 1999, with financial support from NINDS, NIDCR, the NIH Office of Rare Diseases, and the NIH Pain Research Consortium.)

Animals↗