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Biomedical subjects

T D Warner

Publications and source records attributed to T D Warner.

At least 37 records · Page 2Linked to original sources
PubMed2001

Sodium salicylate inhibits prostaglandin formation without affecting the induction of cyclooxygenase-2 by bacterial lipopolysaccharide in vivo.

The mechanisms underlying the anti-inflammatory properties of salicylate are not well understood. In particular, while salicylate inhibits prostaglandin production in vivo it only weakly inhibits cyclooxygenase (COX)-1 or -2 activity in vitro. Thus, it has often been suggested that in vivo salicylate may inhibit the expression rather than the activity of COX, particularly COX-2. Using a model of acute COX-2 expression in the rat, we show that salicylate inhibits COX-2 activity in vivo without affecting COX-2 expression. In anesthetized rats LPS (6 mg kg(-1), i.p.) increased the expression of COX-2 as evidenced by increased circulating levels of 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha), a stable breakdown product of PGI(2)), greatly exaggerated formation of 6-keto-PGF(1alpha) following arachidonic acid (AA) challenge (3 mg kg(-1), i.v.), and increased expression of COX-2, but not COX-1, protein. Diclofenac (3 mg kg(-1), i.p.) or the COX-2 selective agent diisopropyl fluorophosphate (10 mg kg(-1), i.p.) decreased the LPS-induced increase in circulating 6-keto-PGF(1alpha) and the exaggerated 6-keto-PGF(1alpha) production following AA challenge. Sodium salicylate (20 or 120 mg kg(-1), i.p.) (administered either 1 h prior, or once per day for 3 days prior, to LPS injection) reduced only the LPS-induced increase in circulating 6-keto-PGF(1alpha), but not the exaggerated 6-keto-PGF(1alpha) production following AA challenge or the expression of COX-2. Thus, salicylate inhibits LPS-induced COX-2 activity in a manner that is overcome by provision of excess substrate and independent of effects on COX-2 expression. In conclusion, our results exclude mechanisms other than direct enzyme inhibition as responsible for the anti-COX effects of salicylate.

6-Ketoprostaglandin F1 alpha↗
PubMed2000

Effects of nitric oxide-modulating amino acids on coronary vessels: relevance to sepsis.

Excessive nitric oxide (NO) production in septic shock is thought to contribute to the associated profound hypotension. Here we show that despite induction of NO synthase (NOS) in the hearts of endotoxin-treated rats, coronary vascular responses to the contractile peptide endothelin-1, were not modified. This was not due to any change in the expression of endothelin receptors. However, when the substrate for NOS, L-arginine, was added to the perfusate, increases in coronary perfusion pressure stimulated by endothelin were reduced in hearts from endotoxin-treated animals compared to those from controls. In addition, L-glutamine, which blocks the generation of L-arginine from intracellular stores, enhanced the increase in perfusion pressure stimulated by endothelin-1. These data suggest that L-arginine becomes rate limiting for the production of NO in the coronary vessels during septic shock. Moreover, it suggests that vascular reactivity may be modulated positively or negatively by supplementation with the relevant amino acids.

Animals↗
PubMed2000

A controlled study of imagery rehearsal for chronic nightmares in sexual assault survivors with PTSD: a preliminary report.

Imagery-rehearsal therapy for chronic nightmares was assessed in a randomized, controlled study of sexual assault survivors with posttraumatic stress disorder (PTSD). Nightmares, sleep quality, and PTSD were assessed at baseline for 169 women, who were randomized into two groups: treatment (n = 87) and wait-list control (n = 82). Treatment consisted of two 3-hr sessions and one 1-hr session conducted over 5 weeks. Of 169 participants, 91 women (Treatment, n = 43, Control, n = 48) completed a 3-month follow-up and 78 did not. At follow-up, nightmare frequency and PTSD severity decreased and sleep quality improved in the treatment group with small to minimal changes in the control group. Treatment effects were moderate to high (Cohen's d ranged from 0.57 to 1.26). Notwithstanding the large dropout rate, imagery-rehearsal therapy is an effective treatment for chronic nightmares in sexual assault survivors with PTSD and is associated with improvement in sleep quality and decreases in PTSD severity.

Adult↗
PubMed2000

Sleep disorder, depression, and suicidality in female sexual assault survivors.

The role of sleep in psychiatric illness in general, and depression and suicidality in particular, is poorly understood and has not been well researched despite the pervasiveness of sleep complaints in these conditions. As an exploratory, hypothesis-generating study, female sexual assault survivors with posttraumatic stress disorder (n = 153) who had enrolled in a nightmare-treatment program were assessed for subjectively determined sleep breathing and sleep movement disorders. Diagnoses of potential disorders were based on clinical practice parameters and research algorithms from thefield of sleep disorders medicine. Potential sleep breathing and sleep movement disorders were present in 80% of the participants (n = 123) and included three subgroups: sleep-disordered breathing only (n = 23); sleep movement disorder only (n = 45); and both sleep disorders (n = 55). Based on the Hamilton Depression Rating Scale and Suicide subscale, participants with potential sleep disorders suffered greater depression (Cohen's d = .73-.96; p < .01) and greater suicidality (Cohen's d = .57-.78; p < .05) in comparison to participants without potential sleep disorders. The group with both sleep disorders suffered from the most severe depression and suicidality. A provisional hypothesis is formulated that describes how sleep disorders may exacerbate depression and suicidality through the effects of chronic sleep fragmentation.

Depression↗
PubMed2000

Bisphenol A diglycidyl ether (BADGE) is a PPARgamma agonist in an ECV304 cell line.

Peroxisome proliferator activated receptors (PPAR)s are nuclear transcription factors of the steroid receptor super-family. One member, PPARgamma, a critical transcription factor in adipogenesis, is expressed in ECV304 cells, and when activated participates in the induction of cell death by apoptosis. Here we describe a clone of ECV304 cells, ECV-ACO.Luc, which stably expresses a reporter gene for PPAR activation. ECV-ACO.Luc respond to the PPARgamma agonists, 15-deoxy-Delta(12,14) PGJ(2), and ciglitizone, by inducing luciferase expression. Furthermore, using ECV-ACO.Luc, we demonstrate that a newly described PPARgamma antagonist, bisphenol A diglycidyl ether (BADGE) has agonist activities. Similar to 15-deoxy-Delta(12,14) PGJ(2), BADGE induces PPARgamma activation, nuclear localization of the receptor, and induces cell death.

Benzhydryl Compounds↗
PubMed2000

Regulation of iNOS mRNA levels in endothelial cells by glutathione, a double-edged sword.

Both inducible nitric oxide synthase (iNOS) and glutathione are important mediators in various physiological and pathological conditions in humans. In human endothelial cells the intracellular glutathione levels were modulated by N-acetyl-L-cysteine (NAC), a precursor of glutathione and 1,3-bis(chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. BCNU significantly decreased reduced glutathione (GSH) but increased oxidized glutathione (GSSG) whereas NAC markedly elevated GSH with a relatively small increase in GSSG. Appropriate concentrations of GSH and GSSG increase the expression of iNOS gene. However, either GSH or GSSG at a too high concentration inhibits its expression, indicating that iNOS gene is fine tuned by the metabolites of glutathione cycle. The changes of iNOS mRNA steady state levels by the glutathione metabolites were associated with a similar alteration in its gene transcription and NF-kappaB activity. BCNU at high concentrations also shortens the half-life of iNOS mRNA, suggesting a role of GSSG in the stability of the iNOS gene. Thus, the change of glutathione levels in vitro can regulate iNOS mRNA steady state levels in a bi-phasic manner in human endothelial cells.

Acetylcysteine↗
PubMed2000

Caring for medical students as patients: access to services and care-seeking practices of 1,027 students at nine medical schools. Collaborative Research Group on Medical Student Healthcare.

PURPOSE: The personal health care of medical students is an important but neglected issue in medical education. Preliminary work suggests that medical student-patients experience special barriers to health care services and report problematic care-seeking practices that merit further inquiry. METHOD: A self-report questionnaire was piloted, revised, and distributed to students at nine medical schools in 1996-97. The survey included questions regarding access to health services, care-seeking practices, and demographic information. RESULTS: A total of 1,027 students participated (52% response rate). Ninety percent reported needing care for various health concerns. Fifty-seven percent did not seek care at times, in part due to training demands, and 48% had encountered difficulties in obtaining care. A majority had received treatment at their training institutions, and students commonly pursued informal or "curbside" care from medical colleagues. Almost all participants (96%) were insured. Differences in responses were associated with level of training, gender, and medical school. CONCLUSION: Medical schools shoulder the responsibility not only of educating but also of providing health services for their students. Students encounter barriers to care and engage in problematic care-seeking practices. Greater attention to issues surrounding medical student health may benefit students and their future patients.

Adult↗
PubMed2000

Do antidepressants selectively suppress spontaneous (unexpected) panic attacks? A replication.

The purpose of this study was to test the following interrelated hypotheses in a larger sample by attempting to replicate supportive results from a small therapeutic study: (1) the pathogenesis of panic disorder includes at least two identifiable components: a biological component represented by spontaneous (unexpected) panic attacks, and a cognitive component represented by situational attacks and especially by phobias; (2) these components respond differently to treatment; (3) many biological processes respond to an effective intervention in proportion to their deviance from "normal" prior to treatment ("Law of Initial Value"); and (4) the response of spontaneous panic attacks to an effective treatment conforms to that model. Previously, the authors reanalyzed an 8-week therapeutic study of panic disorder that included groups treated with placebo and with imipramine (225 mg daily). The criteria of response were spontaneous panic attacks (biological component), situational panic attacks (both components), and agoraphobia ratings (cognitive component). The analyses compared the regression lines for posttreatment status on pretreatment status in the imipramine and placebo groups. The effect of imipramine on spontaneous panic attacks fitted the hypothesized model: the pre-post slope in the placebo group was approximately 1 (45 degrees), whereas the slope in the imipramine group was approximately 0. There was no significant difference in pre-post slopes between the imipramine and placebo groups for situational panic attacks or agoraphobia ratings. For this report, the authors applied the same approach to another larger data set from a study using a similar design, but a different antidepressant. In this multicenter, double-blind study, patients with panic disorder were randomly assigned to receive 10 weeks of treatment with placebo (N = 78) or fluoxetine 10 mg (N = 84) or 20 mg (N = 81) daily. Spontaneous and situational panic attacks were registered in a daily diary, and agoraphobia was rated at each visit. Using baseline and endpoint data, fluoxetine had a statistically significant, dose-dependent, suppressive effect on spontaneous panic attacks, as measured by the pre-post slopes in the three treatment groups. The placebo group showed some response (slope = 0.69). There were no significant drug effects on situational panic attacks. On ratings of agoraphobia, the slopes in the placebo and the fluoxetine 20 mg groups did not differ, but the slope in the fluoxetine 10 mg group was significantly less than that in the placebo group, suggesting a therapeutic drug effect on agoraphobia only at the lower dose. These results are consistent with the stated hypotheses. They suggest that the therapeutic effects of antidepressants on panic disorder may be due primarily to the specific suppression of spontaneous panic attacks among patients with high baseline pathologic findings. Implications of these results for concepts of pathogenesis, clinical practice, and therapeutic research regarding panic disorder are discussed.

Agoraphobia↗
PubMed2000

Cyclic AMP regulates cytokine stimulation of endothelin-1 release in human vascular smooth muscle cells.

Exposure of human vascular smooth muscle cells (HVSMCs) to cytokines markedly elevates endothelin-1 (ET-1) mRNA expression and peptide production. Cyclic AMP is a key regulator of many physiological processes. The aim of this study was to determine whether an elevation of intracellular cAMP may affect cytokine-induced production of ET-1 in HVSMCs. Cicaprost, a prostacyclin analogue, forskolin, an activator of adenylate cyclase, and Ro-20-1724, a phosphodiesterase type IV inhibitor, inhibited cytokine-stimulated ET-1 release in a concentration-dependent manner. Ro-20-1724 also inhibited cytokine-induced upregulation of preproendothelin-1 mRNA expression in saphenous vein (SV) vascular smooth muscle cells (VSMCs). These findings demonstrate that ET-1 mRNA expression and peptide production is modulated by elevations in cAMP levels. Further studies are necessary to elucidate which other pathways may be involved in the regulation of cytokine-stimulated ET-1 release from HVSMCs.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed2000

Signal transduction pathways involved in cytokine stimulation of endothelin-1 release from human vascular smooth muscle cells.

Endothelin-1 (ET-1) mRNA expression and peptide production in human vascular smooth muscle cells (HVSMCs) are markedly increased by exposure to cytokines. As the transcription factor nuclear factor-kappaB (NF-kappaB) often mediates the effects of cytokines in target cells the aim of this study was to determine whether the production of ET-1 following exposure of HVSMCs to cytokines depends upon activation of NF-kappaB. BAY 11-7082, an inhibitor of cytokine-induced inhibitor protein (IkappaB) phosphorylation, inhibited cytokine-stimulated upregulation of preproendothelin-1 mRNA expression and ET-1 peptide production. In addition, immunoblotting showed that cytokine stimulation of ET-1 release in VSMCs involves nuclear translocation of NF-kappaB. In conclusion, NF-kappaB activation is involved in the stimulation by cytokines of ET-1 release from HVSMCs. As upregulated production of ET-1 within VSMCs may underlie the causative role of ET-1 in a number of disease states this finding indicates that NF-kappaB within HVSMCs could be central to a number of vascular pathologies.

Cells, Cultured↗
PubMed2000

The prostacyclin-mimetic cicaprost inhibits endogenous endothelin-1 release from human pulmonary artery smooth muscle cells.

There is increasing evidence supporting a role for endothelin-1 (ET-1) in human pulmonary hypertension. The aim of this study was to determine the relative roles of human pulmonary microvascular endothelial cells (HPMVE) and human pulmonary artery smooth muscle (HPASM) cells to produce ET-1 under inflammatory conditions and to investigate further possible control mechanisms of ET-1 production by HPASM. Although HPMVE cells produced more ET-1 than HPASM when cultured with fetal calf serum (FCS) alone and after treatment with cytokines; HPASM produced significant amounts of ET-1 after stimulation with cytokines. Cytokine-stimulated increase in ET-1 production by HPASM was inhibited by cicaprost, a prostacyclin analogue, and other agents that are known to increase intracellular cyclic AMP. Cicaprost also inhibited proliferation of HPASM in response to FCS lending support to the theory that part of the clinical benefit seen in long-term treatment with prostacyclin in pulmonary hypertension may be a result of inhibition of ET-1 production in these cells.

Cell Division↗
PubMed2000

Perspectives of patients with schizophrenia and psychiatrists regarding ethically important aspects of research participation.

OBJECTIVE: Significant controversy surrounds the ethics of psychiatric research. Nevertheless, few data have been gathered to improve our understanding of how individuals with serious mental illness and psychiatrists view ethically important aspects of biomedical research participation. METHOD: The authors assessed views of clinically diagnosed patients with schizophrenia from three sites by means of structured interviews and views of psychiatrists at two sites with written surveys regarding attitudes affecting motivation to participate in biomedical research, attitudes related to autonomy and influences on participation decisions, and attitudes toward the inclusion of vulnerable populations in research. The schizophrenia patients were asked to indicate their personal views; the psychiatrists were asked to provide their personal views and to predict schizophrenia patients' views. Responses were compared by using repeated measures multivariate analysis of variance. RESULTS: Sixty-three patients with schizophrenia and 73 psychiatry faculty and residents participated. Overall, responses to 23 rated attitudes revealed remarkably similar rank orders and several areas of agreement between patients and psychiatrists. Both groups strongly supported schizophrenia research and autonomous decision making by participants. They saw helping others and helping science as important reasons for protocol participation. Patients endorsed the feeling of hope associated with research involvement, a perspective underestimated by psychiatrists. Psychiatrists also underestimated the patients' acceptance of physician, investigator, and family influences on participation decisions. Psychiatrists agreed more strongly than patients that vulnerable populations should be included in research. CONCLUSIONS: This study helps to characterize previously neglected attitudes of psychiatric patients and clinicians toward ethically important aspects of biomedical research participation. Schizophrenia patients offered highly discerning views, and interesting similarities and differences emerged in comparing responses of patients and psychiatrists.

Adult↗
PubMed2000

Perceptions of the ethical acceptability of using medical examiner autopsies for research and education: a survey of forensic pathologists.

BACKGROUND: Forensic pathologists face difficult moral questions in their practices each day. Consistent ethical and legal guidelines for autopsy tissue use extending beyond usual clinical and legal imperatives have not been developed in this country. OBJECTIVE: To obtain the perceptions of medical examiners regarding the ethical acceptability of autopsy tissue use for research and education. METHOD: A written, self-report questionnaire was developed and piloted by a multidisciplinary team at the University of New Mexico, Albuquerque. All individuals who attended a platform presentation at the National Association of Medical Examiners Annual Meeting in September 1997 were invited to participate. RESULTS: Ninety-one individuals completed the survey (40% of all conference registrants and approximately 75% of presentation attendees). Sixty-three percent of respondents had encountered an ethical dilemma surrounding autopsy tissue use, and one third reported some professional ethics experience. Perspectives varied greatly concerning the ethical acceptability of using autopsy tissues to demonstrate or practice techniques (eg, intubation, brachial plexus dissection) and of fulfilling requests to supply varying kinds and quantities of tissues for research and education. Most respondents indicated that consent by family members was important in tissue use decisions. Respondents agreed on the importance of basic values in education and research, such as integrity, scientific or educational merit, and formal institutional approval of a project. Characteristics of the decedent did not influence decisions to release tissues, except when the individual had died from a mysterious or very rare illness. Attributes of medical examiners, with the exception of sex, also did not consistently predict responses. CONCLUSION: Significant diversity exists in beliefs among medical examiners regarding perceptions of the appropriate use of autopsy tissues for education and research. There is need for further inquiry and dialogue so that enduring policy solutions regarding human tissue use for education and research may be developed.

Attitude of Health Personnel↗
PubMed1999

Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis.

The beneficial actions of nonsteroid anti-inflammatory drugs (NSAID) can be associated with inhibition of cyclo-oxygenase (COX)-2 whereas their harmful side effects are associated with inhibition of COX-1. Here we report data from two related assay systems, the human whole blood assay and a modified human whole blood assay (using human A549 cells as a source of COX-2). This assay we refer to as the William Harvey Modified Assay. Our aim was to make meaningful comparisons of both classical NSAIDs and newer COX-2-selective compounds. These comparisons of the actions of >40 NSAIDs and novel COX-2-selective agents, including celecoxib, rofecoxib and diisopropyl fluorophosphate, demonstrate a distribution of compound selectivities toward COX-1 that aligns with the risk of serious gastrointestinal complications. In conclusion, this full in vitro analysis of COX-1/2 selectivities in human tissues clearly supports the theory that inhibition of COX-1 underlies the gastrointestinal toxicity of NSAIDs in man.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Expression of cyclooxygenase-2 in rat vascular smooth muscle cells is unrelated to nuclear factor-kappaB activation.

The promoter region of cyclooxygenase-2 (COX-2) gene contains binding sites for a number of important transcription factors including cyclic AMP response element, nuclear factor-IL6, nuclear factor-kappaB (NF-kappaB) and TGF-beta response element. Several reports have documented that the activation of NF-kappaB triggers the expression of COX-2 gene. In the present study, NF-kappaB was activated by TNF-alpha in rat aortic smooth muscle cells as demonstrated by electrophoretic mobility shift assay. The activity of NF-kappaB induced by TNF-alpha was blocked by calpain inhibitor I, a potent NF-kappaB inhibitor. However, the activation of NF-kappaB was not related to the expression of COX-2 induced by TNF-alpha since calpain inhibitor I blocked the activation of NF-kappaB but not the expression of COX-2 mRNA or protein. Mutation of rat COX-2 NF-kappaB-like sites in the promoter region did not significantly reduce the promoter activity. These results suggest that the transcriptional regulation of COX-2 expression by NF-kappaB depends upon the types of cells studied and that activation of this transcription factor alone does not play an important role in the expression of COX-2 in rat smooth muscle cells.

Animals↗
PubMed1999

Ex vivo assay to determine the cyclooxygenase selectivity of non-steroidal anti-inflammatory drugs.

1. In this study we describe experiments to establish ex vivo the selectivity of non-steroidal anti-inflammatory drugs (NSAIDs) given in vivo. 2. Anaesthetised (Inactin, 120 mg kg(-1)) male Wistar rats (220-250 g) received an i.v. dose of one of the following compounds (dose mg kg(-1)): aspirin (20), diclofenac (3), L-745,337 (30), nimesulide (15), salicylate (20), sulindac (10). Blood samples were taken before and up to 6 h after dosing and the plasma obtained from it was tested for its ability to inhibit prostanoid formation in IL-1beta-treated A549 cells (COX-2 system) and human washed platelets (COX-1 system). For control the same compounds were also added directly to the assay systems. 3. All drugs, except sodium salicylate, inhibited COX-1 and COX-2 when added directly to the test systems. Plasma from aspirin-treated rats was without effect on either COX-1 or COX-2, consistent with the rapid in vivo metabolism to salicylate. Conversely, plasma from sulindac-treated rats inhibited COX-1 and COX-2 with potencies according with in vivo metabolism to sulindac sulphide. Diclofenac was COX-1/2 non-selective when tested in vitro, but a slightly preferential inhibitor of COX-2 when tested ex vivo. Nimesulide was confirmed as preferential inhibitor of COX-2 both in vitro and ex vivo. L-745,337 was a selective COX-2 inhibitor when tested in vitro or ex vivo. 4. In conclusion, our experiments show clearly (a) NSAIDs inactivation, (b) activation of prodrugs, and (c) NSAIDs selectivity. Our assay provides useful information about the selectivity of NSAIDs that could be extended by the analysis of plasma samples taken from humans similarly treated with test drugs.

Analgesics↗