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Biomedical subjects

J A Mitchell

Publications and source records attributed to J A Mitchell.

At least 91 records · Page 5Linked to original sources
PubMed1997

Sodium salicylate inhibits cyclo-oxygenase-2 activity independently of transcription factor (nuclear factor kappaB) activation: role of arachidonic acid.

Acetylsalicylic acid (aspirin) is the drug most commonly self-administered to reduce inflammation, swelling, and pain. The established mechanism of action of aspirin is inhibition of the enzyme cyclo-oxygenase (COX). Once taken, aspirin is rapidly deacetylated to form salicylic acid, which may account, at least in part, for the therapeutic actions of aspirin. However, where tested, salicylic acid has been found to be a relatively inactive inhibitor of COX activity in vitro, despite being an effective inhibitor of prostanoids formed at the site of inflammation in vivo. Recently, the identification of a cytokine-inducible isoform of COX, COX-2, has led to the suggestion that salicylate produces its anti-inflammatory actions by inhibiting COX-2 induction through actions on nuclear factor kappaB (NF-kappaB). We have used interleukin 1beta-induced COX-2 in human A549 cells to investigate the mechanism of action of salicylate on COX-2 activity. Sodium salicylate inhibited prostaglandin E2 release when added together with interleukin 1beta for 24 hr with an IC50 value of 5 microg/ml, an effect that was independent of NF-kappaB activation or COX-2 transcription or translation. Sodium salicylate acutely (30 min) also caused a concentration-dependent inhibition of COX-2 activity measured in the presence of 0, 1, or 10 microM exogenous arachidonic acid. In contrast, when exogenous arachidonic acid was increased to 30 microM, sodium salicylate was a very weak inhibitor of COX-2 activity with an IC50 of >100 microg/ml. Thus, sodium salicylate is an effective inhibitor of COX-2 activity at concentrations far below those required to inhibit NF-kappaB (20 mg/ml) activation and is easily displaced by arachidonic acid.

Arachidonic Acid↗
PubMed1997

Induction of cyclooxygenase-2 in human saphenous vein and internal mammary artery.

Within vessels, cyclooxygenase (COX) is expressed constitutively (COX-1) in endothelial cells where its production of prostacyclin is thought to contribute to the maintenance of vascular integrity. Recently, a novel isoform of COX, COX-2, has been described that is induced in animal arterial vessels after physical damage or exposure to proinflammatory cytokines. However, induction of COX-2 in human vessels has not been characterized. Moreover, the relative ability of arteries and veins to express COX-2 has not been addressed. Thus, we have compared the ability of segments of human saphenous vein and internal mammary artery, obtained from the same patient, to express COX-2 activity and mRNA after organ culture in the presence and absence of interleukin-1 beta. COX-2 metabolites, measured by radioimmunoassay, were released by both the internal mammary artery and saphenous vein in the following rank order: prostaglandin E2 > or = prostacyclin thromboxane A2. Inclusion of interleukin-1 beta in the culture medium increased the release of prostanoids by the saphenous vein but not by the internal mammary artery. However, the selective COX-2 inhibitor NS-398 significantly attenuated prostacyclin release from both tissues. Northern blot analysis showed no detectable COX-2 mRNA in freshly prepared saphenous vein or internal mammary artery. In contrast, after 48 hours in organ culture, low levels of COX-2 mRNA were detected in both internal mammary artery and saphenous vein, an effect that was greatly increased by interleukin-1 beta. These observations show that COX-2 is induced in human saphenous vein and internal mammary artery and suggest that this may occur in humans after coronary artery bypass graft surgery. The induction of COX-2 and subsequent release of prostacyclin may represent an endogenous defense mechanism against endothelial damage incurred during surgical preparation of these vessels for bypass.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Dual action of nitric oxide on airway plasma leakage.

In the rat, plasma leakage in various vascular beds, including the whole lung, occurs after administration of lipopolysaccharide (LPS). LPS-induced microvascular plasma leakage in many organs is associated with an enhanced formation of nitric oxide (NO) after the induction of nitric oxide synthase (iNOS). However, there is limited information concerning the relationship between NO and plasma leakage into the airways. LPS (10 mg/kg, intravenously) caused a significant leakage of Evans blue dye, a marker of microvascular permeability, at 240 min in the trachea which was inhibited by the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg, intravenously), or dexamethasone (1 mg/kg, intravenously). This effect was paralleled by an increase in calcium-independent iNOS activity, assessed by measuring the conversion of radiolabeled L-arginine to L-citrulline, in LPS-treated animals. In contrast, L-NAME significantly increased plasma leakage in the trachea of vehicle-treated rats and this effect was inhibited by indomethacin. These results suggest that under "physiological" conditions endogenous NO suppresses plasma leakage but when iNOS is expressed the increased production of NO enhances plasma leakage. These findings may implicate a role for NO in the maintenance of airway function and in the inflammatory process occurring in diseases such as asthma, where iNOS is known to be expressed.

Animals↗
PubMed1997

In vivo treatment with endotoxin increases rat pulmonary vascular contractility despite NOS induction.

Pulmonary hypertension is a feature of clinical and experimental acute lung injury. Nitric oxide (NO) synthesis is increased in hyporesponsive systemic and pulmonary conductance arteries after endotoxin (LPS) injection in the rat. We examined the effects of NO synthase (NOS) induction by LPS on vascular reactivity of the isolated perfused rat lung (IPL) using the selective inducible (iNOS) inhibitor aminoguanidine (AG). Baseline pulmonary artery pressures (Ppa) were higher in the LPS compared with the sham-treated rats and were further increased only in the LPS-treated group by AG. Increased NOS activity in whole lung and the vasopressor effect of AG suggested that iNOS was active in pulmonary resistance vessels after LPS treatment. Vasoconstriction to hypoxia, angiotensin II (AII), and prostaglandin F2 alpha (PGF2 alpha) was enhanced or unchanged in LPS-treated rats despite NOS induction. Hence, iNOS activity counterbalances increased pulmonary vascular contractility in this model.

Angiotensin II↗
PubMed1996

The orphan receptor COUP-TF binds to a third glucocorticoid accessory factor element within the phosphoenolpyruvate carboxykinase gene promoter.

The phosphoenolpyruvate carboxykinase (PEPCK) gene promoter contains a glucocorticoid response unit (GRU) that includes, as a linear array, two accessory factor binding sites (AF1 and AF2) and two glucocorticoid receptor binding sites. All of these elements are required for a complete glucocorticoid response. AF1 and AF2 also partially account for the response of the PEPCK gene to retinoic acid and insulin, respectively. A second retinoic acid response element was recently located just downstream of the GRU. In this study we show that mutation of the 3' half-site of this element results in a 60% reduction of the glucocorticoid response of PEPCK promoter-chloramphenicol acetyltransferase (CAT) fusion constructs in transient transfection assays, thus the half-site is now termed AF3. A variety of assays were used to show that chicken ovalbumin upstream promoter transcription factor (COUP-TF) binds specifically to AF3 and that upstream stimulatory factor (USF) binds to an E-box motif located 2 base pairs downstream of AF3. Mutations of AF3 that diminish binding of COUP-TF reduce the glucocorticoid response, but mutation of the USF binding site has no effect. The functional roles of AF1, AF2, and AF3 in the glucocorticoid response were explored using constructs that contained combinations of mutations in all three elements. All three elements are required for a maximal glucocorticoid response, and mutation of any two abolish the response.

Base Sequence↗
PubMed1996

Identification and charaterization of the second retinoic acid response element in the phosphoenolpyruvate carboxykinase gene promoter.

A previously characterized retinoic acid response element (RARE1) in the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter confers approximately 50% of the response of this gene to retinoic acid (RA). Transient transfection experiments were performed using constructs containing progressive 5' deletions of the PEPCK promoter to locate other elements that contribute to the RA response. A second RARE (RARE2) was located between -402 and -306. Methylation interference and mobility gel shift assays indicated that RAR/RXR bound specifically to a segment of DNA located between -337 and -321. This region contains consensus and degenerate half-sites for receptor binding separated by 5 bp. Mutations in either half-site selectively decreased the RA response and diminished RAR/RXR binding in mobility gel shift assays. When both RARE1 and RARE2 were mutated, 80% of the RA response was lost. Finally, RARE2 conferred a RA response in a heterologous promoter context. We conclude that RAR/RXR binds to RARE2, and that this DR5-type element is a major contributor to the response of the PEPCK gene to RA.

Animals↗
PubMed1996

The clinical value of computerized information services. A review of 98 randomized clinical trials.

OBJECTIVE: To review all randomized clinical trials addressing the efficacy of clinical information systems and to determine the clinical settings, types of interventions, and effects studied. DATA SOURCES: Extensive and systematic MEDLINE searches were conducted using a combination of medical subject headings (MeSH) and textword terms to collect trial reports. Manual searches of books and monographs as well as informal contacts were also used. STUDY SELECTION: The eligibility criteria were (1) randomized controlled clinical trial, (2) computerized information intervention in the study group, and (3) effect measured on the process or outcome of care. DATA EXTRACTION: Two research assistants independently abstracted from the selected reports the following structured information: trial sites, computerized interventions, effect variables, and outcomes. Three investigators evaluated the combined list of trial features for setting, intervention, and effect. The statistical analysis included an evaluation of agreement in developing classifications and an analysis of the ratio of positive trial outcomes. DATA SYNTHESIS: Most information services were tested in outpatient care (82%), particularly in primary care (66%). The information intervention targeted the provider in 64% of the trials. The effect was primarily measured for the process of care (76%). Provider prompt/reminder, computer-assisted treatment planner, interactive patient education/therapy, and patient prompt/reminder were significantly successful interventions (sign test, P < .05). CONCLUSIONS: Randomized clinical trials confirm that four generic information interventions are active ingredients of computer systems and can make a significant difference in family medicine (physician and patient reminders, treatment planner, and patient education). To manage care and improve quality, primary care computer systems should incorporate these effective information services.

Information Systems↗
PubMed1996

Effect of physician profiling on utilization. Meta-analysis of randomized clinical trials.

OBJECTIVES: An American Medical Association survey reported that more than half of physicians are subjects of either clinical or economic profiling. This multilevel meta-analysis was designed to assess the clinical effect of peer-comparison feedback intervention (profiles) in changing practice patterns. METHODS: Systematic computerized and manual searches were combined to retrieve articles on randomized controlled clinical trials testing profiling reports. Eligible studies were randomized, controlled clinical trials that tested peer-comparison feedback intervention and measured utilization of clinical procedures. To use all available information, data were abstracted and analyzed on three levels: (1) direction of effects, (2) p value fro the statistical comparison, and (3) odds ratio (OR). MAIN RESULTS: In the 12 eligible trials, 553 physicians were profiled. The test result was p < .05 for the vote-counting sign test of 12 studies (level 1) and p < .05 for the z-transformation test of 8 studies (level 2). There were 5 trials included in the OR analysis (level 3). The primary effect variable in two of the 5 trials had a nonsignificant OR. However, the overall OR calculated by the Mantel-Haenszel method was significant (1.091, confidence interval: 1.045 to 1.136). CONCLUSIONS: Profiling has a statistically significant, but minimal effect on the utilization of clinical procedures. The results of this study indicate a need for controlled clinical evaluations before subjecting large numbers of physicians to utilization management interventions.

Confidence Intervals↗
PubMed1996

Effects of alcohol on blastocyst implantation site blood flow in the rat.

The effect of alcohol on blood flow at sites of blastocyst implantation versus adjacent intersites was measured in conscious unrestrained rats on day 5 of pregnancy. Alcohol (0.75 ml of 100% ethanol diluted 1:2, v/v) was injected into the femoral vein (1 g/kg body wt); controls received an equivalent volume of vehicle (physiological saline). Implantation sites were rendered visible by intravenous injection of Evans Blue dye. Blood flow was measured at 15 min after alcohol injection by the 86Rb fractionation method. In controls, blood flow was significantly greater (P < 0.05) at implantation sites (0.77 +/- 0.04 ml/min/g) than at intersites (0.43 +/- 0.03 ml/min/g). Alcohol markedly increased (P < 0.05) perfusion at both sites (2.17 +/- 0.22 ml/min/g) and intersites (1.74 +/- 0.15 ml/min/g) vs respective controls. Blood alcohol levels exceeded 100 mg/dl at 10 min post-injection. Mean cardiac output and haematocrit values did not differ significantly between control and treated rats. The data indicate that alcohol enhances uterine vascular perfusion and that the vascular bed of implantation sites is susceptible to the haemodynamic effects of alcohol. Enhanced uterine blood flow may contribute to the alcohol-induced changes in embryo development, blastocyst implantation and endometrial decidualization observed in the rat.

Animals↗
PubMed1996

Endothelin-1-induced contraction of pulmonary arteries from endotoxemic rats is attenuated by the endothelin-A receptor antagonist, BQ123.

OBJECTIVE: Sepsis is characterized by systemic vasodilation and hyporesponsiveness to constrictor agents, at a time when the pulmonary circulation exhibits varying degrees of vasoconstriction. Plasma endothelin-1 concentrations are increased, but the role of this potent vasoconstrictor peptide in modulating the vascular response to sepsis is unknown. Therefore, we assessed the effect of endothelin-A receptor antagonism in the response of pulmonary arteries from rats treated with lipopolysaccharide to endothelin-1, and determined the vasomotor role of the endothelin-B receptors that are known to be located on rat pulmonary artery smooth muscle and endothelium. DESIGN: Prospective, controlled study. SETTING: Animal research laboratory. SUBJECTS: Male Wistar rats (275 to 300 g). INTERVENTIONS: Animals were injected with either lipopolysaccharide (20 mg/kg i.p.) or saline (1 mL i.p.) 4 hrs before being killed. The main pulmonary arteries were cut into 2-mm rings, and suspended in an organ bath. In the first set of experiments, half of the rings underwent a procedure that removed the endothelium, and the contractile response to cumulative doses of endothelin-1 (10(-11) to 10(-6) M) was measured. Half of the rings were pretreated with the endothelin-A receptor antagonist, BQ123 (10(-5) M or 10(-6) M), and the other half of the rings were treated with vehicle. In a separate group of experiments, the contractile response to cumulative concentrations of the selective endothelin-B agonist, sarafotoxin S6c (10(-11) to 10(-6) M), was measured in rings at baseline tension. Second, the possible dilator effect of endothelin-B receptor activation was tested by the administration of sarafotoxin S6c (10(-7) to 10(-6) M) to rings preconstricted by 10(-6) M of U46619, a thromboxane receptor agonist, either in the presence or absence of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine-methylester (10(-4) M). Acetylcholine-induced (10(-4) M), endothelium-dependent vasodilation was also measured. MEASUREMENTS AND MAIN RESULTS: BQ123 (10(-5) or 10(-6) M) caused consecutive rightward shifts in the endothelin-1 concentration-contraction curves for all ring types, including the intact rings from endotoxemic animals. Sarafotoxin S6c failed to induce any direct constriction in rings from sham-treated or lipopolysaccharide-treated rats. However, sarafotoxin S6c induced transient vasodilation at the initial dose in rings from sham-treated rats but not lipopolysaccharide-treated rats-an effect that was attenuated by N omega-nitro-L-arginine-methylester. Acetylcholine induced an N omega-nitro-L-arginine-methylester-sensitive vasodilation that was reduced in rings from endotoxin-treated rats. CONCLUSIONS: Endothelin-A receptor blockade is an effective means of attenuating endothelin-1-induced contraction of isolated pulmonary artery rings, even from rats rendered endotoxemic. Endothelin-B receptors on the pulmonary artery cause vasodilation via the release of nitric oxide, and have no constrictor component. The functional effects of endothelin-B receptors on tone are lost after lipopolysaccharide treatment. The endothelium is involved in both the constrictor and dilator effects of endothelin in rat pulmonary artery, confirming a pivotal role for endothelial cells in the vascular response to sepsis.

Animals↗
PubMed1996

Activation of vascular thrombin receptors mediates cardiac response to alpha-thrombin in isolated, perfused guinea pig heart.

alpha-Thrombin alters vascular tone via a cell surface receptor. We used isolated guinea pig hearts perfused with buffer at constant flow to assess the effects of thrombin-receptor activation on coronary perfusion pressure, left ventricular function, and electrocardiogram. alpha-Thrombin produced concentration-dependent (0.03-1 U/ml), transient decreases in perfusion pressure followed by sustained increases. Concurrently, alpha-thrombin markedly reduced ventricular function. SFLLRN, a peptide that directly activates thrombin receptors, had qualitatively similar effects, except that it was less potent (0.1-30 microM). FSLLRN, a structurally similar peptide that does not activate thrombin receptors, had no effect. alpha-Thrombin and SFLLRN also changed S-T segment level and T-wave morphology. Previous alpha-thrombin exposure markedly inhibited the response to a alpha-thrombin but only moderately attenuated the response to SFLLRN. However, previous SFLLRN exposure did not alter subsequent response to alpha-thrombin or SFLLRN. Pretreatment with hirudin (3 U/ml), an inhibitor of thrombin's proteolytic action, prevented alpha-thrombin but not SFLLRN responses. Cromakalim (0.5 microM), a coronary vasodilator, reversed the effects of alpha-thrombin and SFLLRN on ventricular function, suggesting that depression of ventricular function resulted, in part, from vasoconstriction-induced myocardial perfusion deficit. Our results show that alpha-thrombin at physiologically relevant concentrations, has marked effects on coronary vascular resistance and ventricular function in isolated guinea pig hearts that are mediated by the proteolytically activated thrombin receptor.

Animals↗
PubMed1996

Effectiveness of computer-assisted interactive videodisc instruction in teaching rheumatology to physical and occupational therapy students.

A computer-assisted interactive videodisc instructional program, HP-RHEUM was designed to teach clinical findings in arthritis to occupational and physical therapy students. Using the Rheumatology Image Library videodisc produced by the National Library of Medicine, HP-RHEUM consists of instructional modules which employ advance organizers, examples/nonexamples, summaries, and immediate feedback. To see if HP-RHEUM would be as effective as traditional classroom instruction, control data were collected in 1991 from 52 OT and PT students. Treatment data were collected from 61 students in 1992 when HP-RHEUM entirely replaced lectures. Identical pre- and post-tests consisted of 70 multiple choice questions, with 24 matched to slides. On the slide questions the HP-RHEUM group had significantly higher scores. Otherwise, there was no significant difference in performance between groups. HP-RHEUM provided an independent learning method and enhanced visual comprehension of rheumatologic disease concepts.

Analysis of Variance↗
PubMed1996

Beyond relevance--characteristics of key papers for clinicians: an exploratory study in an academic setting.

OBJECTIVE: The purpose of this study was to determine what factors beyond relevance influence a clinician's decision to choose to read one journal article over another in satisfying an information need. DESIGN: Seventeen health care providers were interviewed and then surveyed regarding the characteristics of key articles (those they would not want to miss). On a Likert scale, the clinicians graded forty-two characteristics for importance in the decision process. Relevance was assumed and not at issue. SETTING: The study took place in an academic health science center. SUBJECTS: The subjects were seventeen clinicians, all with patient care responsibilities. There were four internists, four surgeons, three family practitioners, three pediatricians, two psychiatrists, and one clinical psychologist. RESULTS: Factors beyond relevance that most often influenced the decision process pertained to methodological rigor, authors and their institutional affiliations, document types, and population studied. CONCLUSIONS: Among the clinicians surveyed, factors beyond topicality influenced judgments as to what constitutes an important article. The emphasis respondents gave to certain attributes is echoed in other published work and highlights the need for more intensive investigation of these non-subject indicators as search parameters. Improved searching capabilities might well lead to a significant reduction in the clinician's information overload.

Attitude of Health Personnel↗
PubMed1996

The Missouri planning grant for the education and training of health sciences librarians.

The planning grant at the School of Library and Informational Science (SLIS) at the University of Missouri has two aims: (a) developing a model curriculum for health sciences librarianship at the master's level and (b) developing materials that can be delivered by alternative instructional methods. To accomplish the first aim, the faculty will investigate the possibility of offering courses in other disciplines, such as health care administration, educational technology, adult education, and medical sociology. In addition, the SLIS faculty will investigate the development of new kinds of placement for the students' practicum experience. To reach the second aim, the SLIS faculty will investigate alternative means of delivering both graduate and continuing education. Three instructional modalities will be evaluated. Some material will be delivered via satellite broadcast, some material will be made available via the World Wide Web and some will be presented in an intensive seminar. The outcome of the planning grant will be two distinct plans. The first will be a plan for the curriculum in health sciences librarianship at the master's level. The second will be a plan for offering instruction through alternative methods, both for graduate education and for continuing education.

Computer Communication Networks↗
PubMed1996

Providing location-independent access to patient clinical narratives using Web browsers and a tiered server approach.

Health care today depends upon timely access to patient medical data and the latest medical knowledge. As we make the transition from a hospital-based organization to an integrated health care delivery system, patient care information must move throughout the organization quickly and efficiently over increasing distances. The emergence of widely-dispersed referral networks demands novel solutions to the problems of delivering patient care information to providers. We have developed a mechanism to provide location-independent access to clinical narrative reports using a multi-tiered server model and World Wide Web technologies for delivery. To successfully deploy such a system to sites separated by large distances, it is important to reduce complexity at the client site. Using a "thin client", such as a web browser, in our design facilitates deployment and support while reducing cost per user. This architecture allows the application to be updated without modification to the end-user software and eases maintenance over long distances.

Computer Communication Networks↗