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Biomedical subjects

M Myers

Publications and source records attributed to M Myers.

At least 37 records · Page 2Linked to original sources
PubMed2000

BRG-1 is recruited to estrogen-responsive promoters and cooperates with factors involved in histone acetylation.

Several factors that mediate activation by nuclear receptors also modify the chemical and structural composition of chromatin. Prominent in this diverse group is the steroid receptor coactivator 1 (SRC-1) family, which interact with agonist-bound nuclear receptors, thereby coupling them to multifunctional transcriptional coregulators such as CREB-binding protein (CBP), p300, and PCAF, all of which have potent histone acetyltransferase activity. Additionally factors including the Brahma-related gene 1 (BRG-1) that are involved in the structural remodeling of chromatin also mediate hormone-dependent transcriptional activation by nuclear receptors. Here, we provide evidence that these two distinct mechanisms of coactivation may operate in a collaborative manner. We demonstrate that transcriptional activation by the estrogen receptor (ER) requires functional BRG-1 and that the coactivation of estrogen signaling by either SRC-1 or CBP is BRG-1 dependent. We find that in response to estrogen, ER recruits BRG-1, thereby targeting BRG-1 to the promoters of estrogen-responsive genes in a manner that occurs simultaneous to histone acetylation. Finally, we demonstrate that BRG-1-mediated coactivation of ER signaling is regulated by the state of histone acetylation within a cell. Inhibition of histone deacetylation by trichostatin A dramatically increases BRG-1-mediated coactivation of ER signaling, and this increase is reversed by overexpression of histone deacetylase 1. These studies support a critical role for BRG-1 in ER action in which estrogen stimulates an ER-BRG-1 association coupling BRG-1 to regions of chromatin at the sites of estrogen-responsive promoters and promotes the activity of other recruited factors that alter the acetylation state of chromatin.

Acetylation↗
PubMed2000

Management of negative symptoms among patients with schizophrenia attending multiple-family groups.

OBJECTIVE: Outcomes for negative symptoms over a one-year period were examined in two groups of patients, one receiving psychoeducational multiple-family group treatment and one receiving standard care. METHODS: A total of 63 outpatients, ages 18 to 45 years, with DSM-IV diagnoses of schizophrenic disorders were randomly assigned to standard care or multiple-family group psychoeducation treatment at a large mental health center in Spokane, Washington. Treatment assignment was stratified by whether patients were taking typical or atypical antipsychotic medications. Negative symptom status was monitored monthly for one year by raters blind to group assignment and measured as a composite of five symptoms using the Modified Scale for the Assessment of Negative Symptoms. RESULTS: When the analysis controlled for baseline negative symptoms, participants in the multiple-family group experienced significantly reduced negative symptoms compared with those receiving standard care. Taking atypical antipsychotic medication or having a diagnosis of substance abuse was not associated with the severity of negative symptoms. An additional analysis of the five individual negative symptoms indicated small but consistent group differences on all dimensions except inattention. Negative symptoms were significantly correlated with relapse to acute illness but not with outpatient or inpatient service use. CONCLUSIONS: The study demonstrated that a psychoeducational multiple-family group intervention was more effective than standard care in managing negative symptoms over a 12-month period. The results are particularly relevant because negative symptoms are associated with relapse, poor social and occupational functioning, cognitive impairment, and lower subjective quality of life.

Adolescent↗
PubMed1999

Differential effects of the adenosine A(1) receptor allosteric enhancer PD 81,723 on agonist binding to brain and adipocyte membranes.

The benzoylthiophene analog, PD 81,723, has been shown to allosterically enhance agonist binding and functional activation of the mammalian adenosine (ADO) A(1) receptor subtype by putatively maintaining the receptor in a high affinity state. The present studies were conducted to evaluate the ability of PD 81,723 to enhance the binding of [3H]cyclohexyladenosine ([3H]CHA) to A(1) receptors of neural (cerebral cortex) and non-neural (adipocyte) origin in three different species; rat, guinea pig and dog. PD 81, 723 (0.3-100 microM) produced a concentration-dependent enhancement of [3H]CHA binding to rat brain A(1) receptors. These effects were also species-dependent with larger enhancements (150-200% of control) observed in guinea pig and dog brain membranes as compared to the rat (120% of control). In contrast, PD 81,723 did not produce any enhancement of [3H]CHA binding to A(1) receptors in adipocyte membranes from any of the species examined. Additional binding studies were conducted using pharmacological manipulations that have previously been shown to enhance the allosteric effects of PD 81,723. In the presence of 1 mM GTP, the allosteric effects of PD 81,723 (15 microM) were increased in rat, guinea pig and dog brain membranes, however, in adipocyte membranes from each species, no significant alteration in agonist binding was observed. Similarly, the A(1) receptor selective antagonist 8-cyclopentyl-1, 3-dipropylxanthine (added to effectively reduce the intrinsic antagonist properties of PD 81,723) was found to enhance the allosteric effects of PD 81,723 (15 microM) in brain, but produce no alteration of agonist binding in adipocyte membranes from each species. Examination of the dissociation kinetics of [3H]CHA binding from rat brain and adipocyte membranes revealed that PD 81,723 (15 microM) differentially slowed agonist dissociation from brain, but not adipocyte, membranes. Taken together, the present data support the hypothesis that in tissues that are sensitive to PD 81,723, this benzyolthiophene functions to maintain the A(1) receptor in a high-affinity state and that the relative proportions of high-affinity A(1) receptors present in specific tissues may contribute, at least in part, to the apparent differential effects of PD 81,723 on agonist binding. The tissue specific modulation of A(1) receptor function by PD 81,723 also illustrates the possibility that the locus of allosteric modulation by PD 81,723 may be manifest via a specific, but indirect and tissue-dependent, interaction with the A(1) receptor.

Adenosine↗
PubMed1999

Restenosis following angioplasty in the swine coronary artery is inhibited by an orally active PDGF-receptor tyrosine kinase inhibitor, RPR101511A.

BACKGROUND: Platelet-derived growth factor (PDGF), a purported mediator of arterial response to injury, stimulates proliferation, chemotaxis, and matrix production by activation of its membrane receptor tyrosine kinase. Because these activities underlie restenosis, inhibition of the PDGF-receptor tyrosine kinase (PDGFr-TK) is postulated to decrease restenosis. METHODS AND RESULTS: RPR101511A is a novel compound which selectively and potently inhibits the cell-free and in situ PDGFr-TK and PDGFr-dependent proliferation and chemotaxis in vascular smooth muscle cells (VSMC). To evaluate the effect of RPR101511A (30 mg. kg-1. d-1 BID for 28 days following PTCA) on coronary restenosis, PTCA was performed in hypercholesterolemic minipigs whose left anterior descending (LAD) coronary artery had been injured by overdilation and denudation, yielding a previously existing lesion. Angiographically determined prePTCA minimal lumen diameters (MLD) were similar in vehicle and RPR101511A-treated pigs (1.98+/-0.09 versus 2.01+/-0.08 mm) and increased to the same extent in the 2 groups following successful PTCA (2.30+/-0.06 versus 2.52+/-0.13). At termination, there was an average 50% loss of gain in the vehicle-treated group but no loss of gain with RPR101511A (2.16+/-0. 05 versus 2.59+/-0.11, P<0.001). Morphometric analysis of the LAD showed that RPR101511A caused a significant decrease in total intimal/medial ratio (0.96+/-0.58 versus 0.67+/-0.09, P<0.05). CONCLUSIONS: RPR101511A, which acts by inhibition of the PDGFr-TK, completely prevented angiographic loss of gain following PTCA and significantly reduced histological intimal hyperplasia.

Administration, Oral↗
PubMed1999

Clinical impact of preoperative respiratory syncytial virus testing.

The purpose of this study was to determine if preoperative assessment (i.e., physical examination and history review) of pediatric patients can predict positive test results for respiratory syncytial virus (RSV) infection, surgery cancellations, and adverse anesthetic outcomes. Approximately 400 pediatric patients were identified for the study from infection control statistics and classified by RSV test result and surgery cancellation status into three groups for analyses. Researchers analyzed retrospective chart data of preoperative histories and physical findings using one way analysis of variance to compare age among the groups and Fisher's exact test to compare patient characteristics and signs and symptoms of illness. The results show that active RSV infection cannot be predicted by history and physical findings alone. In addition, patients who had a history of pulmonary disease and who were wheezing at the time of their examinations were more likely to have their surgeries cancelled, independent of positive test results for RSV infection.

Ambulatory Surgical Procedures↗
PubMed1999

Brief intervention for harm reduction with alcohol-positive older adolescents in a hospital emergency department.

This study evaluated the use of a brief motivational interview (MI) to reduce alcohol-related consequences and use among adolescents treated in an emergency room (ER) following an alcohol-related event. Patients aged 18 to 19 years (N = 94) were randomly assigned to receive either MI or standard care (SC). Assessment and intervention were conducted in the ER during or after the patient's treatment. Follow-up assessments showed that patients who received the MI had a significantly lower incidence of drinking and driving, traffic violations, alcohol-related injuries, and alcohol-related problems than patients who received SC. Both conditions showed reduced alcohol consumption. The harm-reduction focus of the MI was evident in that MI reduced negative outcomes related to drinking, beyond what was produced by the precipitating event plus SC alone.

Adolescent↗
PubMed1999

Antiviral effect and pharmacokinetic interaction between nevirapine and indinavir in persons infected with human immunodeficiency virus type 1.

Nevirapine and indinavir have the potential of affecting the pharmacokinetics of each other. In a prospective trial, 24 human immunodeficiency virus (HIV)-infected subjects on stable nucleoside or no therapy were treated with 800 mg of indinavir every 8 h. After 7 days, 200 mg of nevirapine a day was added for 14 days and then increased to 200 mg twice a day. At day 7 (before nevirapine), there was a sevenfold difference among the subjects in indinavir area under the curve (AUC), and there was a significant correlation between indinavir AUC (r2=0.378, P=.019), minimum plasma concentration (Cmin; r2=0.359, P=.023), maximum plasma concentration (Cmax; r2=0.340, P=.028), and plasma HIV RNA decline. Nevirapine significantly reduced median indinavir Cmin (47.5%) and AUC (27.4%) and, to a lesser extent, Cmax (11%). Plasma HIV RNA values were </=20 copies/mL in 10 of 17 (58.8%) subjects at 58 weeks or last visit. These data suggest that indinavir dosing should be dependent on drug exposure and not on cotherapy with nevirapine.

Adolescent↗
PubMed1999

Clinical study of tooth shade lightening from dentist-supervised, patient-applied treatment with two 10% carbamide peroxide gels.

PURPOSE: Prescribed, patient-applied tooth lightening agents, or nightguard vital bleaching, typically utilizes a 10% carbamide peroxide agent applied during nocturnal hours. The purpose of this randomized double-blind study was to compare the amount of tooth color change in two groups of subjects using dentist-supervised, patient-applied 10% carbamide peroxide gel. MATERIALS AND METHODS: One group used Opalescence (Ultradent Products Inc., South Jordan, Utah) and the other NiteWhite Excel (Discus Dental, Inc., Los Angeles, California). Evaluation of tooth color for the six maxillary anterior teeth was done using a Vita shade guide at baseline, 1, 2, and 4 weeks. Subjects were instructed to apply the gel nocturnally using a custom-made soft tray 8 hours per day for 2 weeks. The 16 tabs of the shade guide were ranked according to value from darkest to lightest. The number (1-16) that correlated to the shade tab selected as the match for each tooth was the outcome variable. A Kruskal-Wallis one way analysis of variance on ranks was used. RESULTS: The test revealed no statistically significant difference between Opalescence and NiteWhite Excel for lightening the teeth (p = .807). The color change was still significant after 2 weeks without further bleaching activity. The baseline evaluation of the maxillary incisors and canines for all subjects, regardless of group, demonstrated a significant shade difference, with the canines being darker. This difference was not seen after 2 weeks of active bleaching or at the 4-week evaluation. CLINICAL SIGNIFICANCE: In this study comparing bleaching products, patients using Opalescence and NiteWhite Excel experienced a significant change in the color of their teeth relative to baseline values after 2 weeks of active treatment.

Adult↗
PubMed1999

Agroterrorism. Agricultural infrastructure vulnerability.

The intentional contamination of animal feed to reduce the availability of animal-derived human food or to infect human populations is seldom mentioned, but animal feed could be an easy target for bioterrorists. The period of delay between the contamination of the animal feed and adulteration of the human food product provides an additional degree of uncertainty about the source of the contamination and minimizes the possibility of apprehending the terrorist. The less obvious and more natural the source of biological contamination, the greater the likelihood that the animal feed contamination will be mistaken as a natural phenomenon. However, the problems related to managing natural food contamination and intentional food contamination remain the same. Rapid testing and separation of contaminated feed are important steps, followed by the more specific identification of the contaminant to determine the source of adulteration and/or the possibility of decontamination. At this time identification of the bioagents is dependent on the availability of antibody-specific test systems. The rapid development of specific antibodies for the development of sensitive and specific test kits is the key to identifying contamination and dealing effectively with the disposal or decontamination of the animal feed and, ultimately, preventing the contamination of animal-derived human food products.

Agriculture↗
PubMed1999

Population pharmacokinetics of nevirapine, zidovudine, and didanosine in human immunodeficiency virus-infected patients. The National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators.

The population pharmacokinetics of nevirapine (NVP), zidovudine (ZDV), and didanosine (ddI) were evaluated in a total of 175 patients infected with human immunodeficiency virus randomized to receive either a double combination of ZDV plus ddI or a triple combination of NVP plus ZDV plus ddI as a substudy of the AIDS Clinical Trials Group Protocol 241. Levels (approximating 3.5 determinations/patient) of the three drugs in plasma were measured during 44 of a total 48 weeks of study treatment, and a set of potential covariates was available for nonlinear mixed-effect modeling analysis. A one-compartment model with zero-order input and first-order elimination was fitted to the NVP data. Individual oral clearance (CL) and volume of distribution (V) averaged 0.0533 liters/h/kg of body weight and 1.17 liters/kg, respectively. Gender was the only covariate which significantly correlated with the CL of NVP. ZDV and ddI data were described by a two-compartment model with zero-order input and first-order elimination. Individual mean oral CL, VSS (volume of distribution at steady state), and V of ZDV were 1.84 liters/h/kg and 6.68 and 2.67 liters/kg, respectively, with body weight and age as correlates of CL and body weight as a correlate of VSS. The average individual oral CL, VSS, and V of ddI were 1.64 liters/h/kg and 3.56 and 2.74 liters/kg, respectively, with body weight as a significant correlate of both CL and VSS. The relative bioavailability (F) of ZDV and ddI in the triple combination compared to that in the double combination was also evaluated. No significant effects of the combination regimens on the F of ddI were detected (FTRIPLE = 1.05 and FDOUBLE = 1 by definition), but the F of ZDV was markedly reduced by the triple combination, being only 67.7% of that of the double combination. Large (>50%) intraindividual variability was associated with both ZDV and ddI pharmacokinetics. Individual cumulative area under the plasma drug level-time curve of the three drugs was calculated for the entire study period as a measure of drug exposure based on the individual data and the final-model estimates of structural and statistical parameters.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Properties and sex-specific differences of GABAA receptors in neurons expressing gamma1 subunit mRNA in the preoptic area of the rat.

Gamma-aminobutyric acid type A (GABAA) receptors expressed within the medial preoptic area (mPOA) are known to play a critical role in regulating sexual and neuroendocrine functions. In the rat brain, high levels of expression of the gamma1 subunit mRNA of the GABAA receptor are restricted to a limited number of regions that mediate sexual behaviors, including the mPOA. The biophysical and pharmacological profiles of native gamma1-containing receptors in neurons are unknown. Here, we have characterized the properties of GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) and currents elicited by fast perfusion of GABA to isolated mPOA neurons of juvenile male and female rats. No significant sex-specific differences were evident in the mean peak amplitude, distribution of event amplitudes, kinetics of current decay, or the frequency of sIPSCs. The profile of modulation of sIPSCs by diazepam, beta-CCM and zolpidem, allosteric modulators that act at the benzodiazepine (BZ) site of the GABAA receptor, support the assertion that mPOA neurons of both sexes express functional gamma1-containing receptors. The ability of zolpidem to modulate both sIPSC amplitude and currents elicited by rapid perfusion of GABA to mPOA neurons differed significantly between the sexes. Zolpidem reversibly induced negative modulation of currents in mPOA neurons isolated from male rats, but had no effect in mPOA neurons from female rats. Concentration-response analysis of responses in neurons acutely isolated from male rats indicated an IC50 of 58 nM with maximal decreases of approximately 50% of control peak current amplitude. In situ hybridization analysis demonstrated that levels of the gamma1 subunit mRNA are significantly higher in mPOA neurons from male than female rats. No significant sex-specific differences were detected in the levels of alpha1, alpha2, or alpha5 mRNAs. These results suggest that native gamma1-containing receptors are expressed in primary neurons of the mPOA and that sex-specific differences in the expression of this subunit may contribute to sexual dimorphism in GABAA receptor modulation by compounds acting at the BZ site.

Animals↗
PubMed1998

Estimates of the virological benefit of antiretroviral therapy are both assay- and analysis-dependent.

OBJECTIVE: To assess the potential discrepancies in reported changes in plasma viral load (PVL) depending on how values below the detection limit of the assay are handled in the data analysis phase of a randomized controlled clinical trial. DESIGN: Data from a recently completed clinical trial comparing combinations of zidovudine, didanosine and nevirapine were analysed. In this trial, PVL was measured using an assay with a lower quantification limit of 400 HIV-1 RNA copies/ml initially. All PVL values less than 500 copies/ml were retested with a more sensitive assay with a lower quantification limit of 20 copies/ml. METHODS: Several summary measures for assessing change in PVL were calculated using three different methods to adjust for PVL values less than the quantification limit of the assay. The differences between these measures were evaluated. RESULTS: We found that the magnitude of the discrepancy between summary measures used to report changes in PVL depended on the proportion of subjects with PVL less than the quantification limit of the assay, how those observations were handled in the data analysis, and the relative difference between the quantification limits of the conventional and more sensitive assay. CONCLUSION: The lack of consensus in reporting of PVL data in the literature makes the interpretation of published trial results difficult. In the absence of agreement on the most appropriate summary measure of PVL data, we recommend that all summaries include information on the quantification limit of the assay used, the proportion of observations at or below the quantification limit and how these observations were handled in the data analysis.

Analysis of Variance↗
PubMed1998

Phase 2 studies of adenosine cardioplegia.

BACKGROUND: Laboratory evidence supports the use of adenosine-supplemented cardioplegia. An initial phase 1 dose-ranging clinical evaluation demonstrated that an adenosine concentration of 15 mumol/L could be safely administered with warm blood cardioplegia and suggested that phase 2 studies were warranted. METHODS AND RESULTS: Two separate double-blind, randomized, placebo-controlled trials were performed in patients undergoing primary, isolated, nonemergent coronary artery bypass graft surgery. Patients were randomized to receive adenosine 15 mumol/L versus placebo in the first study (n = 200) and adenosine 50 or 100 mumol/L versus placebo in the second study (n = 128). Adenosine was infused with both initial and final doses of warm antegrade blood cardioplegia. The data from the 2 trials were combined using the methods of Mantel and Haenszel, and the results of the meta-analysis are presented as the relative risk with their associated 95% confidence intervals (CI). The different study groups were comparable with respect to all preoperative clinical characteristics, angiographic findings, and intraoperative variables. In both trials 1 and 2, no differences were found between groups in the incidence of the individual primary or secondary outcomes. Similarly, when both studies were combined, there was no significant evidence of any consistent treatment benefit (primary: death: relative risk [RR] = 1.02, 95% CI = 0.06, 16.6; myocardial infarction by CK-MB: RR = 0.84, CI = 0.54, 1.31; low output syndrome: RR = 1.38, CI = 0.29, 6.42; any of the above: RR = 0.98, CI = 0.78, 1.25; secondary: Q-wave myocardial infarction: RR = 1.30, CI = 0.41, 4.13; myocardial infarction by troponin T: RR = 0.7, CI = 0.40, 1.21; inotrope requirement: RR = 0.9, CI = 0.46, 1.79; intra-aortic balloon pump requirement: RR = 0.6, CI = 0.07, 4.81; P > 0.20). CONCLUSIONS: Despite promising experimental data, adenosine supplementation of warm blood cardioplegia did not demonstrate any statistically significant benefit in patients undergoing elective coronary artery bypass graft surgery. Although sample sizes were relatively small, based on our interim analyses, it is unlikely that increased patient enrollment would reveal any substantive clinical differences between groups.

Adenosine↗
PubMed1998

Hormone-dependent regulation of GABAA receptor gamma subunit mRNAs in sexually dimorphic regions of the rat brain.

Transmission mediated by gamma-aminobutyric acid type A (GABAA) receptors expressed within the medial preoptic area (mPOA) and the ventromedial nucleus (VMN) of the hypothalamus is known to play critical, but contrasting, roles in regulating steroid-dependent sexual behaviours in rats. Previous studies have demonstrated a striking dichotomy in receptor composition between the two regions with regard to gamma, but not alpha or beta, subunit expression. To test if gonadal steroids regulate the expression of the gamma subunit genes within the mPOA and the VMN, in situ hybridization analysis for messenger RNAs encoding the gamma 1, gamma 2Short (gamma 2S) and gamma 2Long (gamma 2L) subunits was done in gonadectomized male and female rats and in gonadally intact females over the oestrous cycle. No significant differences in the expression of the gamma subunit mRNAs were observed in gonadectomized male versus female rats. Significant effects of gonadal state in female rats were observed for gamma 1 mRNA levels in the mPOA and gamma 2L levels in the VMN. These data demonstrate that gonadal hormones exert activational control of expression of GABAA receptor gamma subunit mRNAs and suggest that differences in receptor structure may contribute to the functional modulation of female sexual behaviours mediated by GABAergic transmission in these regions.

Animals↗